HK1236750B - Ex vivo organ care system - Google Patents

Description

Isolated organ care system

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application Serial No. 62/006,871, filed on June 2, 2014, entitled “EX VIVO ORGAN CARE SYSTEM,” and U.S. Provisional Application Serial No. 62/006,878, filed on June 2, 2014, entitled “EX VIVO ORGAN CARE SYSTEM,” the entire subject matter of which is incorporated herein by reference.

Technical Field

The present application generally relates to systems, methods and devices for ex vivo (outside the living body) organ care. More specifically, in various embodiments, the present invention relates to ex vivo organ care under physiological conditions or near physiological conditions.

Background Art

Current organ preservation techniques typically involve cryogenic storage of organs wrapped in ice along with a chemical perfusion solution. In the case of liver transplantation, when cryogenic techniques are used to preserve the liver ex vivo, tissue damage caused by ischemia may occur. The severity of these injuries increases with the length of time the organ is stored ex vivo. For example, continuing with the liver as an example, a liver can typically be stored ex vivo for approximately seven hours, after which it cannot be used for transplantation. This relatively short timeframe limits the number of recipients that can be reached from the donor site, thereby limiting the pool of recipients for a harvested liver. Even within this timeframe, the liver may still be significantly damaged. A significant issue is that there is no visual indication of damage. As a result, a suboptimal organ may be transplanted, leading to post-transplant dysfunction or other damage. Therefore, there is a desire to develop technologies that can extend the time organs, such as the liver, can be stored ex vivo in a healthy state and enable functional assessment. These technologies would reduce the risk of transplant failure and expand the pool of potential donors and recipients.

Summary of the Invention

The following summary is intended to be illustrative only and not limiting. Other implementations of the disclosed subject matter are possible.

Embodiments of the disclosed subject matter can provide technology related to portable isolated organ care, such as isolated liver organ care. In some embodiments, the liver care system can maintain the liver at or near normal physiological conditions. To do so, the system can circulate an oxygenated, nutrient-enriched perfusion fluid to the liver at or near physiological temperature, pressure, and flow rate. In some embodiments, the system uses a perfusion fluid based on a blood product to more accurately simulate normal physiological conditions. In other embodiments, the system uses a synthetic blood substitute solution, while in still other embodiments, the solution can include a blood product in combination with a blood substitute product.

Some embodiments of the disclosed subject matter relate to a method for utilizing lactate and liver enzyme measurements to assess: i) the overall perfusion status of an isolated liver, ii) the metabolic status of an isolated liver, and/or iii) the overall vascular patency of an isolated donor liver. This aspect of the disclosed subject matter is based on the ability of liver cells to produce lactate when the liver is deprived of oxygen and to metabolize/utilize lactate for energy when the liver is well perfused aerobically.

Some embodiments of the organ care system may include a module having a base frame and an organ chamber assembly mounted to the base frame and suitable for accommodating the liver during perfusion. The organ care system may include a fluid conduit having a first interface for connecting to the hepatic artery of the liver, a second interface for connecting to the portal vein, a third interface for connecting to the inferior vena cava, and a fourth interface for connecting to the bile duct. The organ care system may include a lactate sensor for sensing lactate in fluid provided to the liver and/or flowing out of the liver. The organ care system may also include sensors for measuring pressure and flow in the hepatic artery, portal vein, and/or inferior vena cava.

Some embodiments may be directed to a method for determining the perfusion state of a liver. For example, the method for assessing the perfusion state of a liver may include the following steps: placing a liver in a protective chamber of an organ care system; pumping a perfusion fluid into the liver; providing a flow of the perfusion fluid away from the liver; measuring a lactate value of the fluid directed away from the liver; measuring the amount of bile produced by the liver; and assessing the state of the liver using the measured lactate value, oxygen saturation level, and/or the amount and quality of bile produced.

Some embodiments may relate to a method for providing a physiological flow rate and physiological pressure to the hepatic artery and portal vein. In some embodiments, the flow originates from a single pump. In particular, the system may include a mechanism for a user to manually distribute a single source of perfusate to the hepatic artery and portal vein and to adapt the distribution to the physiological flow rate and physiological pressure. In other embodiments, the system automatically distributes a single source of perfusate flow to the hepatic artery and portal vein to produce a physiological pressure and physiological flow rate, for example, using an automated control algorithm.

Some embodiments of the organ care system can include a nutritional subsystem that infuses the perfusion fluid as it flows through the system and delivers a maintenance solution, which in some embodiments is stored in a reservoir. According to one feature, the maintenance solution includes nutrients. According to another feature, the maintenance solution includes therapeutic agents and/or additives (e.g., vasodilators, heparin, bile salts, etc.) that are delivered to support prolonged preservation to reduce ischemia and/or other reperfusion-related liver damage.

In some embodiments, the perfusion fluid includes blood removed from the donor during the liver harvesting process through exsanguination. Initially, blood from the donor is loaded into a reservoir, and the cannulation site in the organ chamber assembly is bypassed with a bypass conduit to allow the perfusion fluid to flow through the system in a normal manner in the absence of a liver, also known as a "priming tube." Before cannulating the harvested liver, the system can be primed by circulating blood from the exsanguinated donor through the system to warm, oxygenate, and/or filter the system. Nutrients, preservatives, and/or other therapeutic agents can also be provided during the priming process via the nutrition subsystem's syringe pump. During the priming process, various parameters can also be initialized and calibrated via the operator interface. Once properly primed and running, the pump flow can be reduced or interrupted, the bypass conduit can be removed from the organ chamber assembly, and the liver can be cannulated into the organ chamber assembly. Depending on the situation, the pump flow can be restored or increased.

In some embodiments, the system can include multiple compliance chambers. Compliance chambers are essentially small fluid accumulators in a conduit with flexible, elastic walls for simulating human vascular compliance. Thus, the compliance chambers can assist the system in more accurately simulating blood flow in the human body, for example, by filtering/reducing fluid pressure spikes caused by, for example, flow rate variations. In one configuration, the compliance chambers are located in the perfusate path leading to the portal vein and at the output of the perfusion fluid pump. According to one embodiment, the compliance chambers are positioned proximate to a clamp used to adjust pressure to achieve physiological hepatic artery and portal vein flow.

In some embodiments, the organ chamber assembly includes a pad or pouch assembly sized and shaped to fit within the bottom of the housing. Preferably, the pad assembly includes a pad formed of a material sufficiently resilient to cushion the organ from mechanical shock and impact during transport. According to one feature, where the organ chamber assembly is configured to receive a liver, the pad of the present invention includes a mechanism that allows the pad to conform to livers of varying sizes and shapes to limit the impact and vibration encountered by the liver during transport.

Some embodiments of the organ care system are divided into a multiple use module and a single use module. The single use module can be sized and shaped to interlock with a portable base frame of the multiple use module for electrical, mechanical, gas and fluid interoperability with the multiple use module. According to one embodiment, the multiple use module and the single use module can communicate with each other via an optical interface, which automatically performs optical alignment when the disposable single use module is installed in the portable multiple use module. According to another feature, the portable multiple use module can provide power to the disposable single use module via a spring loaded connection, which also automatically connects when the disposable single use module is installed in the portable multiple use module. According to one feature, the optical interface and the spring loaded connection can ensure that the connection between the single module and the multiple use module is not lost due to jostling during transportation over rough terrain, for example.

In some embodiments, a disposable single-use module includes multiple ports for sampling fluid from the perfusate path. The ports can be interlocked so that sampling fluid from a first port of the multiple ports simultaneously prevents sampling fluid from a second port of the multiple ports. This safety feature reduces the possibility of mixing fluid samples and inadvertently opening a port. In one embodiment, the single-use module includes ports for sampling from one or more of the hepatic artery, portal vein, and/or IVC interface.

Some embodiments of the disclosed subject matter relate to a method of providing treatment to a liver. An exemplary method may include: placing a liver in a protective chamber of a portable organ care system; pumping a perfusion fluid into the liver via the hepatic artery and portal vein; directing the perfusion fluid flow away from the liver via the vena cava; operating a flow control to alter the flow of the perfusion fluid so that the perfusion fluid is pumped into the liver via the hepatic artery and portal vein and flows away from the liver via the vena cava; and treating the liver therapeutically. Treatment may include, for example, treating the liver with one or more of immunosuppressive treatment, chemotherapy, gene therapy, and radiation therapy. Other treatments may include surgical applications including split transplantation and cancer resection.

In some embodiments, the disclosed subject matter can include a perfusion circuit for ex vivo perfusion of a liver, the perfusion circuit comprising: a single pump for providing a pulsatile flow of a perfusion fluid in the circuit; a gas exchanger; a divider configured to divide the flow of perfusion fluid into a first branch and a second branch; wherein the first branch is configured to provide a first portion of the perfusion fluid to a hepatic artery of the liver at a high pressure and a low flow rate, wherein the first branch is in fluid pressure communication with the pump; wherein the second branch is configured to provide a remaining portion of the perfusion fluid to a portal vein of the liver at a relatively low pressure and a higher flow rate, wherein the second branch is in fluid pressure communication with the pump; The second branch further includes a clamp positioned between the distributor and the liver for selectively controlling the flow of perfusion fluid to the portal vein; the second branch further includes a compliance chamber positioned between the distributor and the liver, the compliance chamber configured to reduce the pulsatile flow characteristics of the perfusion fluid from the pump to the portal vein; wherein the pump is configured to transmit fluid pressure to the liver through the first branch and the second branch; a drain configured to receive perfusion fluid from an uncannulated inferior vena cava of the liver; and a reservoir positioned completely below the liver and between the drain and the pump, the reservoir configured to receive perfusion fluid from the drain and store a certain amount of fluid. Other embodiments are possible.

In some embodiments, the disclosed subject matter may include: a solution pump comprising a stepper motor coupled to a threaded rod; a carriage coupled to the rod and configured to move along a linear axis as the rod rotates, the carriage configured to compress a plunger of a syringe when moved in a first direction and to retract the plunger of the syringe when moved in a second direction; a clamp configured to couple to the plunger; a connecting assembly comprising a port configured to couple to a tip of a syringe; a first one-way valve configured to allow fluid to flow into the syringe through the port when the syringe is retracted; a second one-way valve configured to allow fluid to flow out of the syringe through the port when the syringe is compressed; a pressure sensor coupled to the connecting assembly for determining a pressure of a fluid within the connecting assembly; a controller configured to control operation of the stepper motor; and a sensor configured to determine when the syringe is fully retracted. Other embodiments are possible.

In some embodiments, the disclosed subject matter may include a method comprising: rotating a rod to move a carriage connected to the rod along a linear axis of the rod; compressing a plunger of a syringe as the carriage moves in a first direction along the linear axis; delivering fluid from the syringe into a port of a connection assembly and through a first one-way valve while the plunger is compressed; retracting the plunger of the syringe as the carriage moves in a second direction along the linear axis; delivering fluid through a second one-way valve and through a port of the connection assembly to the syringe while the plunger is retracted; and sensing fluid pressure of the connection assembly and sensing a position of the plunger while the syringe is retracted. Other embodiments are possible.

In some embodiments, the disclosed subject matter may include an ex vivo perfusion fluid for machine perfusion of a donor liver, the ex vivo perfusion fluid comprising an energy-rich component, bile salts, electrolytes, and a buffering component. The fluid may include a blood product. The energy-rich component may be one or more compounds selected from the following: carbohydrates, pyruvate, flavin adenine dinucleotide (FAD), β-nicotinamide adenine dinucleotide (NAD), β-nicotinamide adenine dinucleotide phosphate (NADPH), phosphate derivatives of nucleosides, coenzymes, and their metabolites and precursors. The fluid may also include one or more components selected from the following: anticoagulants, lipids, cholesterol, fatty acids, oxygen, amino acids, hormones, vitamins, and steroids. The perfusion solution is substantially free of carbon dioxide. Other embodiments are possible.

These and other embodiments of the disclosed subject matter will be more fully understood after review of the following figures and detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following figures are intended to illustrate non-limiting examples of the disclosed subject matter.Other implementations are possible.

FIG1 is an exemplary diagram of the liver.

FIG2 is a photograph of an exemplary single-use module.

3A-3I illustrate different views of an exemplary organ care system and its components.

FIG4 illustrates an exemplary system that may be used within an embodiment of the organ care system.

FIG5 illustrates an exemplary system that may be used within an embodiment of the organ care system.

6A-6E illustrate exemplary pump configurations that may be used within embodiments of the organ care system.

7A-7Q illustrate exemplary solution infusion pumps that may be used within embodiments of the organ care system.

FIG8 illustrates an exemplary system that may be used within an embodiment of the organ care system.

FIG. 9 illustrates an exemplary system that may be used within an embodiment of the organ care system.

FIG. 10 illustrates an exemplary system that may be used within an embodiment of the organ care system.

FIG. 11 illustrates an exemplary system that may be used within an embodiment of the organ care system.

12A-12G illustrate exemplary graphical user interfaces that may be used within embodiments of the organ care system.

FIG. 12H illustrates an exemplary system that may be used within an embodiment of an organ care system.

13A-13R illustrate exemplary embodiments of a single-use module and components thereof that may be used in embodiments of an organ care system.

14A-14S illustrate exemplary embodiments of an organ chamber and components thereof that may be used in embodiments of an organ care system.

15A-15D illustrate exemplary embodiments of a support structure that may be used in embodiments of an organ care system.

16A-16J illustrate exemplary pads and components thereof and flexible material support surfaces that may be used in embodiments of the organ care system.

FIG. 17 illustrates an exemplary system that may be used within an embodiment of the organ care system.

18A-18G illustrate an exemplary heater assembly and components thereof that may be used within embodiments of an organ care system.

19A-19C illustrate exemplary sensor systems that may be used within embodiments of the organ care system.

20A-20C illustrate exemplary systems that may be used within embodiments of the organ care system.

21A-21K illustrate an exemplary hepatic artery cannula that may be used within embodiments of the organ care system.

22A-22G illustrate an exemplary portal vein cannula that may be used within embodiments of the organ care system.

23A-23N illustrate exemplary connectors that may be used within embodiments of an organ care system.

24A-24L illustrate exemplary connectors that may be used within embodiments of an organ care system.

25A-24D illustrate exemplary clamps that may be used within embodiments of the organ care system.

26-27 illustrate exemplary processes that may be used in embodiments of the organ care system.

FIG. 28 illustrates exemplary test results from an embodiment of an organ care system.

FIG. 29 illustrates an exemplary process that may be used in embodiments of an organ care system.

FIG. 30 illustrates an exemplary system that may be used within an embodiment of an organ care system.

FIG31 shows the hepatic artery flow (HAF) trends throughout 8 hours of storage on OCS.

FIG32 shows portal vein flow (PVF) trends throughout 8 hours of storage on OCS.

FIG33 shows a graphical depiction of hepatic artery pressure and portal vein pressure throughout 8 hours of OCS liver perfusion.

FIG34 is a graphical depiction of arterial lactate levels following 8 hours of OCS liver perfusion.

FIG35 is a graphical depiction of total bile production following 8 hours of OCS liver perfusion.

FIG36 is a graphical depiction of AST levels at 8 hours of OCS liver perfusion.

FIG37 is a graphical depiction of ACT levels at 8 hours of OCS liver perfusion.

FIG38 is a graphical depiction of colloid osmotic pressure over an 8-hour storage period on OCS.

FIG39 is a graphical depiction of carbonate levels following 8 hours of OCS liver perfusion.

FIG40 is a depiction of pH levels detected throughout 8 hours of storage on OCS.

Figure 41 shows images of tissue taken from samples in Phase I, Group A.

FIG42 depicts hepatic artery flow during 12 hours of OCS liver perfusion.

FIG43 depicts portal vein flow during 12 hours of OCS liver perfusion.

FIG44 depicts hepatic artery pressure and portal vein pressure during 12 hours of OCS liver perfusion.

FIG45 depicts arterial lactate during 12 hours of OCS liver perfusion.

FIG46 depicts bile production during 12 hours of OCS liver perfusion.

FIG47 depicts AST levels following 12 hours of OCS liver perfusion.

FIG48 depicts ACT levels in 12-hour OCS liver perfusion.

FIG49 depicts hepatic artery flow on a simulated transplant OCS liver preservation apparatus versus a simulated transplant control cold preservation apparatus.

FIG50 depicts portal vein flow on a simulated transplant OCS liver preservation apparatus versus a simulated transplant control cold preservation apparatus.

FIG. 51 depicts hepatic artery pressure and portal vein pressure in a simulated transplant OCS liver preservation apparatus and a simulated transplant control cold preservation apparatus.

FIG52 depicts arterial lactate in simulated transplants on an OCS liver preservation apparatus versus a simulated transplant on a control cold preservation apparatus.

FIG53 depicts bile production in a simulated transplant OCS liver preservation arm versus a simulated transplant control cold preservation arm.

Figure 54 depicts AST levels in simulated transplant OCS liver preservation arm versus simulated transplant control cold preservation arm.

Figure 55 depicts ACT levels in a simulated transplant OCS liver preservation arm versus a simulated transplant control cold preservation arm.

FIG56 depicts the colloid oncotic pressure of a simulated transplant OCS liver preservation device versus a simulated transplant controlled cold preservation device.

Figure 57 depicts bicarbonate levels in a simulated transplant OCS liver preservation arm versus a simulated transplant control cold preservation arm.

Figure 58 depicts pH levels of a simulated transplant OCS liver preservation apparatus versus a simulated transplant control cold preservation apparatus.

FIG59 shows histological examination of parenchymal and bile duct tissue.

FIG60 shows histological examination of parenchymal and bile duct tissues.

FIG61 is a diagram of the location of samples from pig liver.

FIG62 shows hepatic artery pressure (HAP) trends during 24 hours of perfusion on OCS.

FIG63 shows portal vein pressure in the OCS liver preservation apparatus versus the control cold preservation apparatus.

FIG. 64 shows hepatic artery flow in an OCS liver preservation apparatus versus a control cold preservation apparatus.

Figure 65 shows portal vein flow in the OCS liver preservation apparatus versus the control cold preservation apparatus.

Figure 66 depicts arterial lactate in the OCS liver preservation arm versus the control cold preservation arm.

Figure 67 shows AST levels in the OCS liver preservation arm versus the control cold preservation arm.

Figure 68 shows ALT levels in the OCS liver preservation arm versus the control cold preservation arm.

Figure 69 depicts GGT levels in OCS liver preservation arms versus control cold preservation arms.

Figure 70 depicts pH levels of an OCS liver preservation apparatus versus a control cold preservation apparatus.

Figure 71 depicts HCO3 levels in an OCS liver preservation apparatus versus a control cold preservation apparatus.

Figure 72 depicts bile production in the OCS liver preservation apparatus versus the control cold preservation apparatus. Figure 72 demonstrates that both apparatuses maintained bile production rates >10 ml/hr.

DETAILED DESCRIPTION

Although the following description uses section headings, these headings are included only for the convenience of the reader. The section headings are not intended to be limiting or to impose any limitations on the subject matter herein. For example, components described in one section of the specification may additionally or alternatively be included in other sections. The embodiments disclosed herein are exemplary only and fall within the scope of this disclosure, and the disclosed embodiments and various features may be interchangeable with each other.

I. Introduction

A. Overview

Embodiments of the disclosed subject matter can provide techniques for maintaining a liver ex vivo, such as during a transplant procedure. The system can maintain the liver in conditions that mimic those of the human body. For example, the system can supply a blood substitute to the ex vivo liver in a manner that simulates the blood flow provided by the body. More specifically, the system can provide a blood substitute flow with flow and pressure characteristics similar to those in the human body to the liver's hepatic artery and portal vein. In some embodiments, a pumping system employing a single pump can achieve the desired flow. The system can also heat the blood substitute to a temperature that simulates normal human body temperature and provide nutrients to the blood substitute to maintain the liver and promote normal bile production. By implementing these techniques, the duration of time a liver can be maintained outside the human body can be extended, making the geographical distance between donor and recipient less important than before. In addition, some embodiments disclosed herein for maintaining a liver ex vivo can also be used to assess the condition of a liver prior to transplantation. In some embodiments, the techniques described herein can also be used to treat a damaged and/or diseased liver ex vivo using therapies that would be harmful if administered in vivo. Other embodiments fall within the scope of the disclosed subject matter.

Although the disclosure herein focuses on embodiments intended to maintain or treat the liver, the disclosure is not limited thereto. For example, the techniques described herein may also be used or adapted for use with other organs such as the lungs, heart, intestines, pancreas, kidneys, spleen, bladder, gallbladder, stomach, skin, and brain.

II. Liver Compared to Other Organs

Although the liver is one of many organs in the human body, it may present challenges in ex vivo maintenance and transport that other organs, such as the heart and lungs, do not. Some exemplary differences and considerations are described below.

A. The liver uses two perfusate supply units

Importantly, the liver utilizes two distinct perfusate input pathways, compared to only one for other organs. The hepatic circulation is unique due to its dual vascular blood supply, each with different flow characteristics. Referring to FIG1 , which illustrates an exemplary conceptual diagram of a liver 100 , the liver utilizes two blood supplies, namely, the portal vein 10 and the hepatic artery 12 . In particular, the hepatic artery delivers blood to the liver with high pressure, pulsatile flow, but at a relatively low flow rate. Hepatic blood flow typically accounts for approximately one-third of the total hepatic blood flow. The portal vein delivers blood to the liver with low pressure and minimal pulsation at a higher flow rate. Portal venous flow typically accounts for approximately two-thirds of the total hepatic blood flow.

The liver's intended dual blood supply can present challenges when attempting to artificially supply physiological blood flow to the organ while it is in an ex vivo system. While these challenges may be difficult to address using a dual-pump design, they may be exacerbated when using a single-pump design. Some embodiments of the subject matter disclosed herein can address these challenges.

B. Auxiliary drainage of blood

In vivo, the liver is located beneath the diaphragm. Due to this positioning, venous drainage and hepatic blood flow via the inferior vena cava 14 are typically enhanced by diaphragmatic contraction caused by pressure exerted on the liver. As the diaphragm moves with the lungs as they draw in and expel air, the diaphragm's movement acts on the liver by applying pressure to the organ, pushing blood out of the tissue. It would be desirable to mimic this phenomenon in an isolated liver to help promote blood flow out of the liver and prevent blood accumulation in the organ.

C. Colloid osmotic pressure

In order to minimize edema formation in the isolated liver, the perfusate should have a high colloid osmotic pressure, for example, dextran, 25% albumin and/or fresh frozen plasma. In some embodiments, the colloid osmotic pressure of the circulating perfusate is maintained between 5 mmHg and 35 mmHg, more particularly between 15 mmHg and 25 mmHg. Non-limiting examples of possible colloid osmotic pressures are 15 mmHg, 16 mmHg, 17 mmHg, 18 mmHg, 19 mmHg, 20 mmHg, 21 mmHg, 22 mmHg, 23 mmHg, 24 mmHg and 25 mmHg, or any range bounded by the values indicated herein.

D. Metabolism and _CO2 levels

The liver is a metabolic hub in the body and is in a constant metabolic state. Most compounds absorbed by the intestine first pass through the liver, so it is possible to regulate the levels of many metabolites in the blood. For example, sugar is converted into fat and other energy storage (e.g., gluconeogenesis and glycolysis) leading to the production of CO _2. The liver consumes approximately 20% of the total body oxygen content. Therefore, the liver produces a higher level of CO ₂ than most other organs. In vivo, organs can self-regulate and remove excess carbon dioxide from the organs. However, for isolated organs, it is desirable to remove excess carbon dioxide from the organs to maintain physiological levels of oxygen and carbon dioxide, and therefore maintain pH levels. The system described in this application can be convenient for setting up a blood chemical balance suitable for isolated organ preservation.

E. Bile production

The liver is an organ that produces excreta. Excreta, bile, is usually produced and excreted by the organ in vivo. Bile is produced by hepatocytes in the liver. In vivo, the liver utilizes bile salts to produce bile, and bile salts are recycled back to the liver through the enterohepatic circulation system to be reused. Bile salts stimulate hepatocytes to produce more bile. In vitro, bile salts do not circulate back to the liver. Therefore, it is desirable to supplement the perfusate with bile salts to assist the organ to produce bile. In addition, in some cases, the bile produced by the liver can provide an indication (e.g., quantity, color, and consistency) of the suitability of the organ for transplantation.

F. Support the liver

The liver is the largest solid organ in the body, but it is fragile and vulnerable. In vivo, the liver is protected by the rib cage and other organs. Unlike many other organs, the liver does not include protective elements and is not defined by a rigid structure. Therefore, when the liver is removed from the body and maintained in vitro, it should be treated more delicately than other organs. For example, it is desirable to provide appropriate support for the liver, place the liver on a low-friction surface, and/or cover the organ with a wrapping to protect the organ from damage during transportation and when maintained in vitro.

G. Perfusion fluid

Given that the liver has a wide range of vital functions compared to other organs (e.g., detoxification, protein synthesis, glycogen storage, and production of biochemical substances required for digestion), the perfusate used in the organ care system described herein can be specifically designed to maintain the liver in a near-physiological state to maintain its normal function. For example, because the liver is in a constant state of metabolic energy consumption, the oxygen content in the perfusion fluid can be maintained at a level close to or exceeding physiological levels to meet its high demand as a metabolic sink. Similarly, the perfusion fluid can also be designed to include sufficient concentrations of high-energy components such as carbohydrates and electrolytes to provide the liver with an energy source to perform its functions.

The flow rate of the perfusion fluid can also be appropriately adjusted to ensure that oxygen and nutrients are delivered to the isolated liver at an appropriate rate. In addition, the carbon dioxide content in the perfusion fluid can be lower than the level in the physiological state, thereby further promoting the balance of the liver's biological reactions for metabolism and oxidation. In some embodiments, the perfusion fluid used herein contains a small amount of carbon dioxide or no carbon dioxide. In some embodiments, the perfusion fluid used herein also contains a sufficient amount of bile salts to maintain the liver's need to produce bile. Therefore, the perfusion fluid used in the organ care system described herein can be designed to maintain the normal cellular function of the liver to maintain the liver in a viable state.

III. Description of Exemplary System Components

A. Overall structure

FIG3 illustrates an exemplary organ care system 600 that can be used to protect an organ, such as a liver, while it is ex vivo, for example, during a transplant or medical procedure. Generally speaking, the organ care system 600 is configured to provide conditions to an ex vivo organ that simulate the conditions the organ experiences in vivo. For example, in the case of a liver, the organ care system 600 can provide perfusion flow to the organ in a manner that simulates blood flow (e.g., flow rate, pressure, and temperature) in the human body and provide similar environmental characteristics (e.g., temperature).

In some embodiments, the organ care system 600 can be divided into two parts: a disposable single-use portion (e.g., 634) and a non-disposable multiple-use portion (e.g., 650) (also referred to herein as a single-use module and a multiple-use module). As the names imply, the single-use portion can be replaced after the liver is delivered, and the multiple-use portion can be used again. Generally speaking, although not required, the single-use portion includes those parts of the system that are in direct contact with biological materials, while the multiple-use portion includes those parts that are not in contact with biological materials. In some embodiments, all components in the single-use portion are sterilized before use, while components in the multiple-use portion are not sterilized. Each of these two parts is described in detail below. This configuration allows the following operating method: after use, the entire single-use module 634 can be discarded and replaced with a new single-use module. This can allow the system 600 to be used again after a shorter turnaround time.

Typically, the single-use portion and the multiple-use portion can be configured to be removably connected to each other via a mechanical interface. Additionally, the single-use portion and the multiple-use portion can include mechanical, gas, optical, and/or electrical connectors to allow the two portions to interact with each other. In some embodiments, the connectors between the portions are designed to connect/disconnect to each other in a modular manner.

The disposable module 634 and the multiple-use module 650 can be constructed at least in part from durable yet lightweight materials such as polycarbonate plastic, carbon fiber epoxy composites, polycarbonate ABS plastic blends, glass-reinforced nylon, acetal, straight ABS, aluminum, and/or magnesium. In some embodiments, the entire system 600 weighs less than 100 pounds when including the multiple-use module, organ, battery, gas reservoir, and fillers, nutrients, preservatives, and perfusion fluids and less than about 50 pounds when excluding these items. In some embodiments, the single-use module 634 weighs less than 12 pounds when excluding any solutions. In some embodiments, the multiple-use module weighs less than 50 pounds when excluding all fluids, batteries, and gas supplies.

With the cover removed and the front panel open, an operator can easily access many of the components of the disposable module 634 and the multiple use module 650. For example, an operator can access various components of the single use module and the multiple use module and can remove a single use module from the multiple use module and/or install it to the multiple use module.

Although certain components are described herein as being located in either the single-use portion or the multiple-use portion of system 600, this is for exemplary purposes only. That is, components identified herein as being located in the single-use portion may also be located in the multiple-use portion, and vice versa.

B. Exemplary Multiple-Use Modules

3A-3I , the multiple use module may include several components including a housing, a cart, a battery, a gas supply, and at least a portion of an infusion pump, a control system, and a perfusion fluid pump.

1. Cart/housing

3A to 3I , an exemplary embodiment of an organ care system is shown as an organ care system 600, which may include a housing 602 and a cart 604. The cart 604 may include a platform and wheels for transporting the system 600 from one location to another. A latch 603 may secure the housing 602 to the cart 604. To further assist with portability, the system 600 may also include a handle hinge mounted to the left side of the housing 602, and two rigidly mounted handles 612a and 612b mounted on the left and right sides of the housing 602. The housing 602 may also include a removable top cover (not shown) and a front panel 615 hinged to a lower panel by hinges 616a and 616b. The cover may include a handle to assist in removal.

The system 600 may include an AC power cable 618 and a frame for securing the power cable, both of which may be located on the lower section of the left side of the housing 602. A power switch 622 may also be located on the lower section of the left side, which may enable an operator to restart the system software and electronics.

FIG3G shows a front perspective view of the multiple use module 650 with the single use module 634 removed. As shown, the multiple use module 650 can include the cart 604 and the housing 602, as well as all components mounted to/in the housing 602. The multiple use module 650 also includes a bracket assembly 638 for receiving the single use module 634 and locking the single use module 634 in place. An exemplary bracket assembly 638 is shown in FIG3H.

In some embodiments, the housing 602 can include a fluid-tight basin configured to collect any irrigation fluid and/or any other fluid that may inadvertently leak from the upper portion of the housing 602 and prevent any irrigation fluid and/or any other fluid from reaching the lower portion of the housing 602. Thus, in some embodiments, the basin can shield the electronic components of the system 600 from leaked fluid. In some embodiments, the basin 652 can be sized to accommodate the total amount of fluid used in the system 600 at any particular time.

The system 600 may also include an operator interface module 146 and a cradle 623 for holding the operator interface module 146. The operator interface module 146 may include a display 624 for displaying information to the operator. The operator interface module 146 may also include a rotatable and depressible knob 626 for selecting between a plurality of parameters and display screens. The knob 626 may also be used to set parameters for the automatic control of the system 600 and to provide manual control over the operation of the system 600. In some embodiments, the operator interface module 146 may include its own battery and may be removed from the cradle 623 and used in a wireless mode. While in the cradle 623, the power connection enables the operator interface module 146 to be charged. The operator interface module may also include control buttons for controlling the pump, silencing or disabling alarms, entering or exiting standby mode, and activating a perfusion clock, which initiates the display of data acquired during organ care.

5 , system 600 may also include a plurality of interconnected circuit boards to facilitate data transfer and power distribution to, from, and within system 600. For example, multiple-use module 650 may include a front-end interface circuit board 636 that is optically and electromechanically coupled to a front-end circuit board 637 of single-use module 650. System 600 may also include a battery interface board 711, a main board 718, and a power supply circuit board 720 located on multiple-use module 650. Main board 718 may be configured to make system 600 fault tolerant, such that if a fault occurs in the operation of a given circuit board, main board 718 may save one or more operating parameters (e.g., pumping parameters) in non-volatile memory. When system 600 is restarted, system 600 may subsequently recapture these parameters and continue to execute according to these parameters. Furthermore, system 600 may partition critical functions among multiple processors so that if one processor fails, the remaining critical functions can continue to be performed by the other processors.

2. Power system

Referring also to FIG4 , the multi-use portion of system 600 may include a power subsystem 148 configured to provide power to system 600. Power subsystem 148 may use replaceable batteries and/or an external power source to power system 600. In some embodiments, power subsystem 148 may be configured to switch between external power and the onboard battery without interrupting system operation. Power subsystem 148 may also be configured to automatically distribute externally supplied power between powering system 600, charging the battery, and charging the internal battery of operator interface module 146. The battery in the power system may serve as a primary power source and/or as a backup power source in the event that the external power source fails or becomes insufficient. Furthermore, power system 148 may be configured to be compatible with a variety of external power sources. For example, the power system may be configured to accept multiple input voltages (e.g., 100V to 230V), multiple frequencies (e.g., 50Hz to 60Hz), single-phase power, three-phase power, AC power, and/or DC power. Furthermore, in some embodiments, operator interface module 146 may have its own battery 368.

The housing 602 can include a battery well 628 configured to hold one or more batteries 352. In embodiments with more than one battery, the battery well 628 can also include a locking mechanism 632 configured to prevent more than one battery from being removed from the battery well 628 at any given time while the system 600 is operating. This feature can provide an additional level of fault tolerance to help ensure that power is always available. The system 600 can also include a tank well 630 that can be configured to receive one or more gas tanks.

5 , a cable 731 can deliver power (e.g., AC power 351) from the power supply 350 to the power supply circuit board 720 via connectors 744 and 730. The power supply 350 can convert the AC power to DC power and distribute the DC power as described above. The power supply circuit board 720 can couple the DC power 358 and data signals from connectors 726 and 728 to corresponding connectors 713 and 715 on the front-end interface circuit board 636 via corresponding cables 727 and 729. The cable 729 can carry the power and data signals to the front-end interface board 636. The cable 727 can carry power to the heater 110 via the front-end interface board 636. The connectors 713 and 715 can intermate with corresponding connectors 712 and 714 of the front-end circuit board 637 located on the single-use module 634 to provide power to the single-use module 634.

The power supply circuit board 720 can also provide DC power 358 and data signals from connectors 732 and 734 on the power supply circuit board 720 to corresponding connectors 736 and 738 on the main circuit board 718 via cables 733 and 735, respectively. Cable 737 can couple DC power 358 and data signals from connector 740 on the main circuit board 718 to the operator interface module 146 via connector 742 on the operator interface module bracket 623. The power supply circuit board 720 can also provide DC power 358 and data signals from connectors 745 and 747 to connectors 749 and 751 on the battery interface board 711 via cables 741 and 743. Cable 741 can carry the DC power signal and cable 743 can carry the data signal. The battery interface board 711 can distribute DC power and data to one or more batteries 352 (batteries 352a, 352b and 352c in Figure 5), and the one or more batteries 352 can contain electronic circuits that allow them to connect to corresponding chargers so that the controller 150 can monitor and control the charging and discharging of the one or more batteries 352.

3. Priming fluid pump

The system 600 may include a pump 106 configured to pump a perfusate through the organ care system. The perfusate is typically a blood product-based perfusion fluid that can simulate normal physiological conditions. In some embodiments, the perfusate can be a synthetic blood substitute solution and/or the perfusate can be a blood product combined with a blood substitute. In embodiments where the perfusate is a blood product-based perfusion fluid, the perfusate typically contains red blood cells (e.g., oxygen-carrying cells). The perfusate is described more fully below.

In some embodiments, the pump 106 may have a systolic phase and a diastolic phase. The amount of perfusate pumped by the pump 106 may be changed by changing one or more characteristics of the pump itself. For example, the number of strokes per minute and/or the stroke displacement may be changed to achieve desired flow rate and pressure characteristics. In some embodiments, the pump 106 may be configured to use a stroke rate of 1 st/min (reciprocating times/minute) to 150 st/min and a displacement of 0.1 inch to 1.5 inches. However, more particularly, a nominal stroke rate of 60 st/min±5 st/min and a displacement of 0.5 inches may be used. These values are exemplary only and values outside these ranges may also be used. By changing the characteristics of the pump 106, a flow rate between 0.0 L/min (liters/minute) and 10 L/min may be achieved.

In some embodiments, the perfusion fluid pump 106 is divided into two separable portions: a pump driver portion located in the multiple-use portion 650 and a pump interface assembly located in the single-use portion 634. This interface assembly of the single-use portion can shield the pump driver of the multiple-use portion from direct contact with blood biologicals.

Figures 6A-6D illustrate an exemplary embodiment of a pump 106. Figures 6A-6C illustrate various views of a pump interface assembly 300 according to an exemplary embodiment. Figure 6D illustrates a perspective view of an exemplary pump driver portion 107 of the perfusion fluid pump 106. Figure 6E illustrates the pump interface assembly 300 mated with the pump driver portion 107 of the perfusion fluid pump assembly 300 according to an exemplary embodiment.

The pump interface assembly 300 includes a housing 302 having an exterior side 304 and an interior side 306. The interface assembly 300 includes an inlet 308 and an outlet 310. The pump interface assembly 300 may also include an inner O-ring seal 312 and an outer O-ring seal 314, two deformable diaphragms 316 and 318, an annular support 320, and half-rings 319a and 319b that fit between the O-ring 314 and the support 320. The half-rings 319a and 319b may be made of foam, plastic, or other suitable materials.

An inner O-ring 312 can be fitted into an annular track along the periphery of the inner side 306. A first deformable diaphragm 316 can be mounted above the inner O-ring 312 in a fluid-tight interconnected manner with the inner side 306 of the housing 302, forming a chamber between the inner side of the first deformable diaphragm 316 and the inner side 306 of the housing 302. A second deformable diaphragm 318 can be mounted on top of the first deformable diaphragm 316 to provide fault tolerance in the event that the first deformable diaphragm 316 rips or tears. Illustratively, the deformable diaphragms 316 and 318 can be formed from a thin polyurethane film (approximately 0.002 inches thick). However, any suitable material of any suitable thickness can be used. Referring to Figures 6A and 6B, a bracket 320 can be mounted above the second deformable diaphragm 318 and rings 319a, 319b and secured to the housing 302 along the periphery of the inner side 306. Threaded fasteners 322a-322i can attach bracket 320 to housing 302 via corresponding threaded holes 324a-324i in bracket 320. An outer O-ring 314 can interfit into an annular groove in bracket 320 to provide a fluid-tight seal with pump assembly 106. Before O-ring 314 is inserted into the annular groove of bracket 320, half-rings 319a and 319b are typically placed in the groove. O-ring 314 can then be compressed and positioned within the annular groove in bracket 320. After being positioned within the annular groove, O-ring 314 can expand within the groove to secure itself and half-rings 319a and 319b in place.

The pump interface assembly 300 may also include heat stake posts 321a-321c protruding from its exterior side 304. The posts 321a-321c may receive thermal adhesive to heat stake the pump interface assembly 300 to the C-shaped bracket 656 of the single-use portion of the system 300.

As shown in FIG6C , fluid outlet 310 includes outlet housing 310a, outlet fitting 310b, flow regulating ball 310c, and outlet 310d. Ball 310c is sized to fit within outlet 310d but not through inner bore 326 of outlet 310. Fitting 310b is bonded to outlet 310d (e.g., with epoxy or another adhesive) to capture ball 310c between inner bore 326 and fitting 310b. Outlet housing 310a is bonded to fitting 310b in a similar manner.

In operation, the pump interface assembly 300 is configured and positioned to receive a pumping force from a pump driver 334 of the perfusion fluid pump assembly 106 and transmit the pumping force to the perfusion fluid 108, thereby circulating the perfusion fluid 108 to the organ chamber assembly 104. According to an exemplary embodiment, the perfusion fluid pump assembly 106 may include a pulsating pump having a driver 334 that may contact the diaphragm 318. The fluid inlet 308 may draw the perfusion fluid 108, for example, from the reservoir 160, and provide the fluid into a chamber formed between the inner diaphragm 316 and the interior 306 of the housing 302 in response to the pump driver moving in a direction away from the deformable diaphragms 316 and 318 and thereby deforming the diaphragms 316 and 318 in the same direction.

When the pump actuator moves away from the deformable diaphragms 316 and 318, the pressure head of the fluid 108 within the reservoir 160 causes the perfusion fluid 108 to flow from the reservoir 160 into the pump assembly 106. In this regard, the pump assembly 106, the inlet valve 191, and the reservoir 160 are oriented to gravity feed the perfusion fluid 108 into the pump assembly 106. Simultaneously, the flow regulating ball 310c is drawn into the orifice 326 to prevent the perfusion fluid 108 from also being drawn into the chamber through the outlet 310. It should be noted that in the illustrated embodiment, the outlet valve 310 and the inlet valve 191 are one-way valves, but in alternative embodiments, the valves 310 and/or 191 are two-way valves. In response to the pump driver 334 moving in a direction toward the deformable diaphragms 316 and 318, the flow regulating ball 310c moves toward the fitting 310b to open the inner aperture 326, which enables the outlet 310 to allow the perfusion fluid 108 to be discharged from the chamber formed between the inner side 306 of the housing 302 and the inner side of the deformable diaphragm 316. A separate one-way inlet valve 191, shown in FIG. 1 , between the reservoir 160 and the inlet 308 prevents any perfusion fluid from being discharged from the inlet 308 and flowing back into the reservoir 160.

In embodiments of system 600 that are separated into a single-use module 634 and a multiple-use module 650, pump assembly 107 can be rigidly mounted to multiple-use module 650, and pump interface assembly 300 can be rigidly mounted to the disposable single-use module 634. Pump assembly 106 and pump interface assembly 300 can have corresponding interlocking connectors that mate together to form a fluid-tight seal between the two assemblies 107 and 300.

More specifically, as shown in the perspective view of FIG6D , the perfusion fluid pump assembly 107 can include a pump driver housing 338 having a top surface 340 and a pump driver 334 housed within a cylinder 336 of the housing 338. The pump driver housing 338 can also include a docking port 342 including a slot 332 sized and shaped to mate with a flange 328 protruding from the pump interface assembly 300. The top surface 340 of the pump driver housing 338 can be mounted to a bracket 346 located on the non-disposable, multi-use module 650. The bracket 346 can include features 344a and 344b for abutting tapered protrusions 323a and 323b, respectively, of the pump interface assembly 300. The bracket 346 can also include a cutout 330 sized and shaped to align with the docking port 342 and slot 332 on the pump driver housing 338.

In operation, the seal between pump interface assembly 300 and fluid pump assembly 107 can be formed in two steps, as shown in Figures 6D and 6E. In the first step, flange 328 is positioned within docking port 342, and tapered protrusions 323a and 323b are positioned on the clockwise side of corresponding features 344a and 344b located on bracket 346, adjacent to corresponding features 344a and 344b. In the second step, as shown by arrows 345, 347, and 349, pump interface assembly 300 and fluid pump assembly 106 are rotated in opposite directions (e.g., rotating pump interface assembly 300 counterclockwise while holding pump assembly 106 stationary) to slide flange 328 into groove 332 of docking port 342. At the same time, the tapered protrusions 323a and 323b slide under the bracket features 344a and 344b, respectively, so that the inner surfaces of the bracket features 344a and 344b engage the tapered outer surfaces of the tapered protrusions 323a and 323b, pulling the inner side 306 of the pump interface assembly 300 toward the pump driver 334 and interlocking the flange 328 with the docking port 342, and interlocking the tapered protrusions 323a and 323b with the bracket features 344a and 344b to form a fluid tight seal between the two assemblies 300 and 106.

In some embodiments, the system 100 can be configured such that the flow characteristics (including pressure and flow rate) of the perfusion fluid provided to the hepatic artery and portal vein are directly controlled and controlled at the pressure generated by the pump 106 (e.g., the hepatic artery and portal vein can be in fluid pressure communication with the pump 106). This embodiment differs from embodiments in which a pump provides perfusion fluid to a reservoir (e.g., a reservoir located above the liver) and gravity then provides fluid pressure to the liver.

4. Solution infusion pump

The system 600 can include a solution pump 631 that can be configured to infuse one or more solutions into the perfusion module circuit. In some embodiments of the organ care system 600, the solution pump 631 can be an off-the-shelf pump such as the MedSystem III from CareFusion, Inc. of San Diego, California, and/or can be a solution pump as described below with reference to Figures 7A to 7P. The infusion solution provided by the solution pump 631 can be used, for example, to provide continuous management of the organ, such as inotropic support, blood glucose control, or pH control. Furthermore, although the solution pump 631 is generally considered to be part of the multiple-use module 650, components of the solution pump 631 can be single-use and replaced each time the system is used.

Solution pump 631 can be configured to deliver one or more solutions simultaneously (also referred to as having one or more channels). In some embodiments, solution pump 631 can deliver three solutions: a maintenance solution, bile salts, and a vasodilator such as epoprostenol sodium. Each of these solutions is described more fully below. Solution pump 631 can support a variety of infusion rates (e.g., from 1 ml/hr (milliliter/hour) to 200 ml/hr, although higher and lower rates are possible). The infusion rate can be adjusted in time increments (e.g., 1 ml/hour (milliliter/hour) increments, although higher and lower rates are possible), and changes in infusion rate typically take effect within five seconds, but this is not required. At infusion rates of 10 ml/hr and lower, the infusion volume can be accurate to within +/- 10% of the infusion rate setting, but this is not required. At infusion rates above 10 ml/hr, the infusion volume can be accurate to within +/- 5% of the infusion rate setting, but this is not required.

The solution pump can be configured to maintain any desired accuracy when the input pressure (relative to the static pressure of the solution pump line connector) is 0 to -50 mmHg on the solution side and 0 to +220 mmHg on the organ side. Preferably, the infusate should not have any flow discontinuity greater than three seconds. After the solution pump has been degassed, bubbles greater than 50 uL are usually not injected into the perfusion module. In some embodiments, the pipeline portion between the solution pump 631 and the organ can include a valve (e.g., a pinch valve) to further control the flow of solution to the organ. The solution pump 631 can provide status information such as infusion status and errors for each channel.

The solution pump 631 can be used with one or more disposable cartridges that provide the solution. For example, the tubing between the solution supply and the solution pump 631 can include a spike that connects to an IV bag (injection bag). In embodiments that include a disposable cartridge for supplying the solution, the cartridge should be able to operate for at least 24 hours.

The solution pump 631 can be configured to be controlled via one or more communication ports. For example, the solution pump 631 can be controlled via commands received via a serial port, a network (e.g., Ethernet, wireless), and/or cellular communication. Various aspects of the solution pump 631 can be controlled, such as the initial available amount of solution for each channel and the infusion status (e.g., infusion in progress or paused). The general status and/or alarm status of each channel can also be accessed via the communication port. The status of each channel can include indications such as the presence of a disposable cartridge, the availability of an initial amount, the infusion status, the infusion rate, the remaining time until empty, and the total amount infused. Furthermore, the solution pump 631 can be configured so that each channel has a fault mode infusion rate that can be written to/read from the communication port. In some embodiments, sensors located throughout the organ care system 600 can be connected (directly or indirectly via the controller 150) to facilitate automatic control of the solution pump 631 via the controller 150 using an open or closed feedback loop.

The solution pump 631 can be configured to indicate when a fault occurs. For example, when a fault or occlusion is detected, the solution pump 631 can illuminate a fault indicator associated with the faulty channel and/or send a notification via the communication port. The solution pump 631 can be configured to pause the infusion in the faulty channel and to resume the infusion after the fault or occlusion has been cleared. In embodiments where the infusion rate is set via the communication port, if the signal to/from the communication port is lost, the solution pump 631 can be configured to set the infusion rate to a preprogrammed fault mode infusion rate.

Solution pump 631 can include one or more fault detection algorithms/mechanisms. For example, if a hardware fault is detected, solution pump 631 can send an alarm that a hardware fault has occurred to the equipment connected to the communication port. If a blockage is detected on the solution side and/or organ side, solution pump 631 can send an alarm that a blockage has occurred to the device connected through the communication port. Solution pump 631 can be configured to perform self-tests, including power-on self-tests and background self-tests. The results of these self-tests can be indicated on the solution pump 631 itself and/or communicated through the communication port.

As noted above, the solution pump may be an off-the-shelf solution pump and/or a custom designed pump.With reference to Figures 7A-7P, an exemplary embodiment of a custom designed solution pump 631 is shown and described.

Some embodiments of the solution pump disclosed herein may use a syringe connected to a motor to control the delivery of an infusion solution. The syringe's capacity to hold fluid can be increased by increasing its diameter. This increased fluid capacity can reduce the number of times a syringe needs to be replaced with a new preloaded syringe. However, syringes with increased diameters can result in a loss of precision during solution delivery, as the amount of solution delivered increases when the plunger is depressed one unit as the diameter increases. Another exemplary embodiment of a solution pump uses a relatively small diameter syringe, which can allow for more precise solution delivery. However, the solution can be quickly depleted due to the syringe's low fluid capacity. Replacing a syringe with a new preloaded syringe can lead to issues such as the introduction of bubbles, interruption of solution delivery, user inconvenience, and feasibility challenges. Therefore, in some embodiments, a relatively small diameter syringe can be connected to an external fluid solution source and a perfusion circuit via a fluid line and a series of one-way valves. In these embodiments, when the syringe is depressed, the solution can flow through the one-way valve and into the perfusion circuit. When the syringe is retracted, the solution can flow from the external fluid source into the syringe through another one-way valve to refill the syringe with solution. Thus, some embodiments of the design can allow for fine control over solution delivery (eg, by using a smaller diameter syringe) while eliminating the need to replace the preloaded syringe with another preloaded syringe.

7A to 7P , an exemplary embodiment of a solution pump 9000 is shown. In this embodiment, the solution pump 9000 can use a removable/replaceable cassette 9020 to provide an infusion solution. FIG7C and FIG7D illustrate exploded views of the solution pump 9000 and the infusion cassette 9020, respectively. In this embodiment, the solution pump 9000 includes three channels, and therefore, the solution pump 9000 is configured to provide up to three different solutions. Other embodiments may include more or fewer channels.

Solution pump 9000 may be a syringe pump driven by stepper motors 9002a, 9002b, and 9002c. Stepper motors 9002 may rotate corresponding lead screws 9005. A carriage 9042, having a carriage cover 9004, is in communication with lead screws 9005 and can move back and forth along lead screws 9005. The interior of carriage 9042 may also be tapped with mating threads to facilitate movement along lead screw 9005 as lead screw 9005 rotates. Furthermore, carriage 9042 may also move along linear guides 9041, which facilitate back and forth movement along lead screw 9005. A pin 9003 may be attached to carriage cover 9004 and to a carrier 9036 configured to hold a syringe plunger 9017, enabling the plunger to be depressed and retracted as carriage 9042 moves back and forth along lead screw 9005. The pin 9003 may be threaded to facilitate attachment to the carrier 9036, but this is not required. In the embodiment shown in Figures 7E, 7F, 7G, and 7H, the carrier 9036 may be shaped to fit around and retain the plunger 9017. The carrier 9036 may be manufactured in two parts that may be press-fit together using protrusions 9045, fitted together by screws, and/or other fasteners to clamp the syringe plunger.

In some embodiments, the stepper motor 9002 can be configured to operate at different speeds depending on whether the syringe is extended or compressed. For example, when the syringe is compressed (e.g., during an infusion), the motor can move at a lower speed, such as four steps per second, while when the syringe is extended (e.g., during a refill), the motor can move at a higher speed, such as 16,000 steps per second. Other speeds are also possible. In addition, each stepper motor 9002 can include an optical encoder located on the motor shaft (or elsewhere) enclosed therein, which can be used to track the position and/or speed of the motor 9002. Therefore, the position of the syringe's plunger can be calculated.

7 C, stepper motors 9002a, 9002b, 9002c are positioned parallel to each other, but other configurations are also possible. Pin 9003 passes the groove 9008 in the top cover 9001 and can be attached to the carrier 9036 that is connected with the plunger 9017 of syringe 9016. The connection via pin 9003 and carrier 9036 between slide 9042 and plunger 9017 can be used for syringe being pressed down and retracted, and this can make syringe provide fluid or self refill fluid when being correctly connected. For example, when stepper motor 9002 rotates lead screw 9005 in clockwise mode, when pin 9003 is connected to carrier 9036, slide 9042 and slide cover 9004 and plunger 9017 can move along the direction that plunger 9017 is pressed down and releases fluid solution from syringe 9016. When the stepper motor rotates in a counterclockwise manner, the carriage 9042 can move in the opposite direction and can retract the plunger 9017, thereby refilling the syringe 9016 with fluid from a fluid source, such as an external IV bag.

The solution pump 9000 can include an optical switch 9007 that can be used to detect when the syringe is in a "home" position or other position. In some embodiments, the home position can be when the syringe is extended and filled with solution, but other home positions are also possible. The optical switch 9007 can be U-shaped and configured to transmit a light beam between the two upper portions of the U-shaped body (e.g., by having a transmitter on one side and a receiver on the other side). In some embodiments, when the carriage 9042 is in its home position, a light barrier 9006 on the carriage cover 9004 can interrupt the light beam from the optical switch 9007, thereby providing information about the syringe's position. The light barrier 9006 can be made of any material that interrupts the light beam, such as opaque plastic and/or metal. In some cases, the solution pump 9000 may lose track of the position of the carriage 9042 due to, for example, a failure. If this occurs, the carriage 9042 returns to the home position, allowing the syringe 9016 to be filled and the plunger 9017 to be extended. This can allow the pump 9000 to regain the position of the syringe without accidentally delivering any additional solution. In some embodiments of the solution pump 9000, an additional optical switch 9007 can be included to determine when the syringe is nearly empty or completely empty.

The solution pump 9000 may also include a pressure sensor 9009 to detect blockage of the delivery line 9010 or the output line 9011. When the pressure sensor 9009 detects a blockage by sensing a pressure exceeding or falling below a predetermined threshold, an alarm may be provided to indicate the presence of the blockage. The pressure sensor may be any commercially available sensor suitable for this purpose. In one embodiment, the sensor may be a MEMSCAP SP854 transducer having a hydraulic fluid and a diaphragm. The pressure sensor 9009 may extend through an opening 9012 in the top cover 9001.

The stepper motor 9002, linear guide 9041, and pressure sensor 9009 can be mounted to a structural plate 9013. A printed circuit board ("PCB") 9015 can be mounted to the opposite side of the structural plate 9013 and includes the electronics for operating the solution pump 9000. The plate 9013 can be made of aluminum or any other suitable material and can include flanges 9014 to provide increased rigidity. The plate can also include a series of mounting holes to provide connection points to the top and bottom covers.

The top cover 9001 can be joined to the bottom cover 9018 to enclose the solution pump 9000. The two parts can be joined along the edges and can be fastened with screws or another fastener. A mounting plate 9019 can be attached to the bottom cover 9018 (labeled 9015 in some figures) and attached, for example, to an inner wall of the system 600. The top cover 9001 can also include an opening 9025 for a connector cable that can connect to other places in the system 600, such as the controller 150.

The solution pump 9000 can engage an infusion cassette 9020 that houses a syringe 9016. In one embodiment, the top cover 9001 can include a lug 9023 having a pin. As shown in Figures 7A and 7B, a protrusion 9021 on the infusion cassette 9020 can engage the pin on the lug 9023 to provide a connection between the solution pump 9000 and the infusion cassette 9020. In addition, the solution pump 9000 can engage the infusion cassette 9020 via a circumferential groove on the pressure sensor 9009 that can receive a clamp release portion 9022 of the infusion cassette 9020.

Infusion cassette 9020 can include a delivery line 9010 having an IV bag spike 9024 at one end that can be connected to an IV bag or other external solution source. The other end of delivery line 9010 can be connected to a one-way check valve 9026, designed to allow fluid to flow only out of the IV bag and toward syringe 9016. One-way check valve 9026 can be connected to connector 9027. Output line 9011 can be connected to a second one-way check valve 9032, designed to allow fluid to flow only out of syringe 9016 and toward port 9034. One-way check valve 9032 can also be connected to connector 9027. Output line 9011 can include a filter 9033 that filters particles and air from the solution. Filter 9033 can be any filter with hydrophobic properties suitable for this purpose. The output line 9011 can also be coupled to a port 9034 that connects to the perfusion module. Port 9034 can include a Luer connector. The output line 9011 can also include a roller clamp 9035 that can close the output line 9011. During use, the roller clamp 9035 can remain open to allow fluid to pass through the output line 9011.

7I to 7K , connector 9027 can be, for example, a Y-shaped connector. Connector 9027 can include connectors 9043 and 9044. Connector 9043 can be connected to delivery line 9010, and connector 9044 can be connected to output line 9011. Connector 9027 can also include a vertical infusion line. This vertical infusion line can be connected to a connector mounting member. Connector 9027 can also include an alignment protrusion 9028.

7L to 7P , an exemplary connector mount 9029 is shown. Connector mount 9029 can include a connection port 9031 that can be coupled to connector 9027 and a syringe mount 9030 that can be coupled to syringe 9016. A pressure diaphragm (not shown) can be placed in connector mount 9029 to monitor the pressure of the fluid circuit between syringe 9016, delivery line 9010, and output line 9011 (e.g., using pressure sensor 9009). The pressure diaphragm can be attached to connector mount 9029 at a location opposite connection port 9031. Connector mount 9029 can also be used to removably attach cartridge 9020 to top cap 9001 using a snap-on connector. For example, wings 9055 can extend through openings in top cap 9037. By squeezing wings 9055 together, bottom portion 9056 can bend outward, thereby releasing bottom portion 9056 from, for example, a corresponding connector portion on pressure sensor 9009.

In one embodiment, the syringe 9016 can deliver fluid when the plunger 9017 is compressed by the stepper motor 9002 moving the carriage 9042 along the lead screw 9005. The fluid from the syringe can enter the vertical infusion line, pass through the one-way check valve 9032, enter the output line 9011, pass through the filter 9033, and join the perfusion fluid circulating in the system 600. Once the plunger 9017 is nearly or fully compressed so that there is little or no fluid being delivered from the syringe, the syringe can be retracted, allowing fluid to flow from the IV bag (not shown), through the delivery line 9010, through the one-way check valve 9026, into the vertical infusion line, and into the syringe 9016, thereby refilling the syringe.

Infusion box can comprise top cover 9037, and top cover 9037 can engage bottom cover 9038, thereby syringe 9016 is enclosed.Gasket 9039 can provide sealing around the groove 9008 in top cover 9001, to prevent fluid from entering solution pump 9000 through groove 9008.Gasket can be made of any suitable sealing material, and this sealing material comprises foam.Shipping lock 9040 can be remained on plunger 9017 and carrier in fully retracted position so that carriage 9042 can be engaged in initial position.One purpose of shipping lock 9040 can guarantee that hole 9092 in carrier 9036 is in correct position so that when user installs box 9020, drive pin 9003 is extended in hole 9092.Shipping lock 9040 can be removed before use.

As will be appreciated, the type and configuration of the syringe used in cartridge 9020 can affect how the system is controlled. For example, as the bore of the syringe increases, the plunger requires fewer strokes to deliver a fixed amount of solution. Furthermore, syringes can have different capacities, which can affect how often the syringe needs to be refilled. Therefore, it can be beneficial for solution pump 9000 to know the type of syringe installed in cartridge 9020. Therefore, in some embodiments, system 9000 includes a mechanism by which system 9000 can determine what type of syringe is included in cartridge 9020. For example, in embodiments where solution pump 9000 is configured to operate with two different types of syringes, the pump can include a magnet and a Hall effect sensor configured to determine which of the two syringe types is being used. For example, cartridge 9020 can include a magnet with a north pole and a south pole. The magnet can be oriented so that only one of the two poles interacts with the Hall effect sensor. When a first type of syringe is used, the N pole can be configured to interact with a Hall effect sensor, and similarly, when a second type of syringe is used, the S pole can be configured to interact with a Hall effect sensor. By determining which of the two poles interacts with the Hall effect sensor, the solution pump 9000 can determine which type of syringe is used in the cartridge 9020. The sensor configuration is merely exemplary, and other sensors can be used to determine which type of syringe is used in the cartridge 9020.

The solution pump 9000 can be controlled by one or more control systems. For example, the solution pump 9000 can be controlled by the controller 150 and/or can include an internal control system. Regardless of the location of the controller, the controller can be configured to know how many partial rotations or full rotations the stepper motor 9002 needs to provide the necessary amount of solution and/or refill the syringe. Thus, for example, the controller can know that the stepper motor needs 40 steps to provide 1 mL of solution. In some embodiments, the amount of solution provided by the solution pump 9000 can be manually controlled and/or can be automatically controlled by the controller 150.

The solution pump 631 can be configured to provide a solution flow rate varying between 0.5 mL/hr and 200 mL/hr, although other flow rates are possible.

Some embodiments of the solution pump 631 may include a priming cycle that can be used to prime the tubing of the pump 631 and eliminate air within the tubing of the pump 631. For example, a user can assemble a dry, complete tubing set and perform a priming cycle until the air is eliminated. For example, each priming cycle can use a special fast forward motion and a fast fill motion to advance 3 mL of air (or solution). In some embodiments, the priming cycle is under user control and/or can be performed automatically.

In some embodiments, when the motor 9002 is operated at a higher speed (e.g., during refilling and/or priming), the high speed cycle can include ramp-up and ramp-down periods into and out of high speed operation. These ramp-up and ramp-down periods can be used to overcome the rotational inertia of the motor 9002. This functionality can be implemented in firmware and/or by the controller controlling the pump 631 using, for example, a lookup table that has been calculated to adjust the pulse rate of the motor 9002 for constant acceleration and/or deceleration. The ramp-up and ramp-down periods can also be used during low speed operation.

In some embodiments, the solution pump 631 can be configured to compensate for the inherent recoil that may be caused when the direction of travel of the syringe is reversed. For example, the fluid flow may be particularly affected by the inherent recoil in the motor 9002 and the lead screw 9005. Errors caused by recoil can affect the recovery of the infusion flow after the refill cycle. In order to compensate for these possible errors, the firmware in the pump and/or controller can capture the pressure in the syringe chamber at the end of all infusion strokes. Subsequently, a rapid refill cycle can be performed and the firmware and/or controller can advance the plunger at a moderately fast rate until the pressure in the syringe chamber equals the pressure captured during the last infusion stroke. When this pressure is reached, all system recoils have generally been resolved and the pump can continue to infuse at a desired rate.

While stepper motors generally offer the highest torque for a given motor size and can be easily driven, they also consume a significant amount of power and can generate a significant amount of mechanical noise. Therefore, in some embodiments of the pump 631, the firmware and/or controller may include a dynamic torque function that can operate the motor 9002 at the minimum torque required at any given time. This can be achieved by using a digital-to-analog converter that controls the current limit of each stepper motor driver, which in turn controls the torque provided by the motor. Thus, the stepper motor torque can be adjusted to effectively provide the desired motion. When stationary, a lower current can be supplied to the motor to maintain its stationary position without slipping. At the beginning of each forward infusion stroke, the stepper motor can be operated at a predetermined minimum torque at the selected infusion rate. If the encoder indicates that the stepper is not moving as expected, the torque can be increased until proper movement is achieved. In this way, the forward infusion stroke can be performed with the minimum torque required to complete the job.

The solution pump 631 can also be configured to compensate for slippage between the actual position of the syringe plunger and the desired position. For example, when the firmware and/or controller determines that the syringe position (e.g., provided by an encoder) has slipped behind the desired position, the firmware and/or controller can double the rate until the syringe position catches up. This process of slippage, torque increase, and/or rate doubling can occur quickly enough to provide uninterrupted infusion at the selected rate.

FIG7Q shows an exemplary embodiment of a microcontroller structure that can be included in the solution pump 631, but this is not required and other configurations are possible. In this embodiment, the microcontroller structure includes a processor (e.g., a PIC 18F8722 processor) that receives input from, for example, the controller 150, a pressure input sensor, a motor current and diagnostic voltage sensor, a Hall effect magnetic sensor, an optical interrupter, and/or an encoder. The processor uses the information it receives to provide feedback to the controller 150 and/or to control a stepper motor driver to actuate the syringe in the corresponding channel.

5. Gas systems including variable delivery rate control

The multi-use module 650 may include an onboard gas supply, such as one or more conventional gas cylinders and/or an oxygen concentrator that can be fitted to the gas tank slot 630. The gas supply system may include: i) one or more regulators for reducing the pressure of gas provided by the one or more gas cylinders; ii) a pressure sensor configured to measure the pressure in the gas supply; and iii) a gas pressure gauge that provides a visual indication of the sufficiency of the gas supply. Each of these components may be manually controlled and/or may be connected to and automatically controlled by the controller 150. For example, the controller 150 may automatically regulate the gas flow into the gas exchanger 114. While the gas provided by the gas source may vary, in some embodiments, the gas supply may provide a gas composed of 85% _O₂ , 1% _CO₂ , and the balance _N₂ , with a blending accuracy of 0.030%. In some embodiments, the gas supply may contain between 50% and 95% _O₂ , with the balance being _N₂ and/or Ar. In some embodiments, the multiple gases can be supplied pre-mixed from a single cylinder or can be provided from multiple cylinders and mixed within the system 600. In some embodiments, the gases can be provided from a portable oxygen concentrator, such as the Oxus portable oxygen concentrators from Oxus, Inc. of Rochester Hills, Michigan, or the Freestyle series of portable oxygen concentrators available from AirSep, Inc. of Buffalo, New York.

In some embodiments, system 600 can support gas flow rates from 0 mL/min to 1000 mL/min and can have a set point resolution of 50 ml/min, wherein the air flow delivery accuracy is ± 20% within the range of 200 mL/min to 1000 mL/min. System 600 and gas supply part 172 can be configured to provide air flow when a circulation pump fails. The ranges listed above are exemplary and also can use values outside the values specifically identified. Finally, in some embodiments, system 600 and gas supply part 172 can be configured to provide an indication of the pressure in the gas supply part 172 by multiple interfaces (e.g., by a meter on the gas supply part 172 and/or the operator interface module 146).

6. Controller and User Interface

The system 600 may include a control system (e.g., controller 150) that controls the overall operation of the system 600 and the components used therein. Generally speaking, the control system may include an onboard computer system connected to one or more components in the system 600 and connected to one or more sensors, network connectors, and/or user inputs. The control system may utilize information obtained from sensors, network connectors, and/or user inputs to control the various components in the system 600. For example, the control system may be used to implement one or more open or closed feedback systems for the operation of the control system 600. The control system may be a common off-the-shelf computer and/or a specially designed computer system. It should be noted that although the system 600 is conceptually described with reference to a single controller, the control of the system 600 may be distributed among multiple controllers or processors. For example, any or all of the subsystems described may include a dedicated processor/controller. Alternatively, the dedicated processors/controllers of the various subsystems may communicate with and via a central controller/processor. For example, in some embodiments, a single controller located in the multiple use module 650 can control the entire system 600; in other embodiments, a single controller located in the single use module 634 can control the entire system 600; and in still other embodiments, the controller can be split between the single use module 634 and the multiple use module 650.

As another example, in some embodiments, the controller 150 may be located on the main circuit board 718 and may perform all control and processing required for the system 600. However, in other embodiments, the controller 150 may be distributed, with some processing functions located on the front end interface circuit board 636, some processing functions located on the power circuit board 720, and/or some processing functions located in the operator interface module 146. Appropriate cabling may be provided between the various circuit boards depending on whether and to what extent the controller 150 is distributed within the system 600.

8 depicts an exemplary block diagram of an illustrative control scheme for system 600. For example, system 600 may include controller 150 for controlling the operation of system 600. As shown, the controller 150 can be connected to several subsystems in an interoperable manner: an operator interface subsystem 146, which can help an operator monitor and control the system 600 and monitor the status of the organ; a data acquisition subsystem 147, which can include various sensors for obtaining data related to the organ and the system 600 and for transmitting this data to the controller 150; a power management subsystem 148, which is used to provide fault-tolerant power to the system 600; a heating subsystem 149, which is used to provide controlled energy to the heater 110 that heats the perfusion fluid 108; a data management subsystem 151, which is used to store and maintain data related to the operation of the system 600 and about the liver; and a pumping subsystem 153, which is used to control the pumping of the perfusion fluid 108 in the system 600.

An exemplary embodiment of the data acquisition subsystem 147 will now be described with reference to FIG9 . In this embodiment, the data acquisition subsystem 147 includes sensors for obtaining information about how the system 600 and the liver are functioning. The data acquisition subsystem 147 can provide this information to the controller 150 for processing. For example, the data acquisition subsystem 147 can be coupled to the following sensors: temperature sensors 120 , 122 , 124 ; pressure sensors 126 , 128 , 130 (which may be the pressure sensors 130 a , 130 b mentioned elsewhere herein); flow rate sensors 134 , 136 , 138 ; oxygenation/hematocrit/temperature sensor 140 ; Hall effect sensor 388 ; shaft encoder 390 ; battery sensors 362 a , 362 b , 362 c ; available external power sensor 354 ; operator interface module battery (UIM BATT.) sensor 370 ; and gas pressure sensor 132 . How system 600 uses information from data acquisition subsystem 147 will now be described with respect to heating subsystem 149 , power management subsystem 148 , pumping subsystem 153 , data management subsystem 151 , and operator interface subsystem 146 .

10 , an exemplary block diagram of a power management system 148 for providing fault-tolerant power to a system 600 is depicted. The system 600 can be powered by one of a plurality of power sources, such as an external power source (e.g., 60 Hz, 120 VAC in North America or 50 Hz, 230 VAC in Europe) or by any one of one or more batteries 352. Although the remainder of this specification refers to an AC power source as an external power source, it should be understood that a DC power source may also be used. The controller 150 can receive data from an available AC line voltage sensor 354 that can indicate whether the AC voltage 351 is available and/or sufficient for use by the system 600.

In response to the controller 150 detecting that external power is unavailable, the controller 150 can send a signal to the power switching circuitry 356 to provide system power from the one or more batteries 352. The controller 150 can determine which of the one or more batteries 352 is most fully charged via the battery charge sensor 362 and then switch that battery for operation via the switching network 356. As power is switched from one power source to another, the system can be designed to prevent interruptions in the operation of the system 600.

Alternatively, in response to the controller 150 detecting that suitable external power is available, the controller 150 can determine whether to use the external power source to provide system power and to power the user interface module 146, to charge one or more batteries 352, and/or to charge the internal battery of the user interface module 146, which may also have its own internal charger and charge controller. To use available external power (e.g., AC power 141), the controller 150 can signal the external power to be drawn into the power management system 148 via the switching system 164. In the case where the external power source is AC, the power management system 148 can also receive the external AC and convert it to DC to provide power to the system 600. The power management system 148 can be universal and can handle any line frequency or line voltage commonly used worldwide. According to the illustrative embodiment, in response to a low battery indication from one or more battery sensors 362, the controller 150 can also direct power to the appropriate battery via the switching network 364 and the charging circuit 366. In response to the controller 150 receiving a low battery signal from the sensor 370 (which can monitor the battery in the user interface module 146), the controller 150 can also or alternatively direct the charging voltage 367 to the user interface battery 368. In some embodiments, the power management subsystem 148 can select a battery to power the system 600 using an algorithm that best provides battery life, including selecting the battery based on the least charge as a priority and other factors such as the least number of charge cycles. If the battery currently powering the system 600 is removed by the user, the power management subsystem 148 can automatically switch to the next battery according to the algorithm to continue powering the system 600.

11 , an exemplary embodiment of the heating subsystem 149 is shown. The heating subsystem 149 can control the temperature of the perfusion fluid 108 within the system 600 using, for example, a dual feedback loop approach. In a first loop 251 (perfusion fluid temperature loop), the perfusion fluid temperature thermistor sensor 124 provides two (fault-tolerant) signals 125 and 127 to the controller 150. Signals 125 and 127 generally indicate the temperature of the perfusion fluid 108 as it exits the heater assembly 110. The controller 150 can regulate drive signals 285 and 287 to drivers 247 and 249, respectively. Drivers 247 and 249 can convert the corresponding digital level signals 285 and 287 from the controller 150 into heater drive signals 281 and 283, respectively, having sufficient current levels to drive the first and second heaters 246 and 248 to heat the perfusion fluid 108 to a desired temperature range. In response to the controller 150 detecting that the perfusion fluid temperatures 125 and 127 are below the desired temperature range, the controller 150 may set the drive signals 281 and 283, respectively, to the first heater 246 and the second heater 248, to sufficient levels to continue heating the perfusion fluid 108. Conversely, in response to the controller 150 detecting that the perfusion fluid temperatures 125 and 127 are above the desired temperature range, the controller 150 may reduce the drive signals 281 and 283, respectively, to the first heater 246 and the second heater 248. In response to detecting that the temperature of the perfusion fluid 108 is within the desired temperature range, the controller 150 may maintain the drive signals 281 and 283 at a constant level or a substantially constant level. The temperature control system may be controlled to heat the perfusate to a temperature range between 0°C and 50°C, more particularly between 32°C and 42°C, and even more particularly between 32°C and 37°C. These ranges are merely exemplary, and the temperature control system may be controlled to heat the perfusate to any temperature range within 0°C and 50°C. The desired temperature may be user selectable and/or automatically controlled by the controller 150. As used herein and in the claims, "normal temperature" is defined as a temperature between 34°C and 37°C.

In some embodiments, the controller 150 can change the drive signals 281 and 283 that control the first and second heaters in substantially the same manner. However, this is not required. For example, each heater 246 and 248 can respond differently to a specific current or voltage level drive signal. In this case, the controller 150 can drive each heater 246 and 248 at slightly different levels to achieve the same temperature from each heater. In some embodiments, the heaters 246 and 248 can each have an associated calibration factor, which the controller 150 stores and utilizes when determining the specific drive signal level provided to a specific heater to achieve a specific temperature result. In certain configurations, the controller 150 can set one of the thermistors in the dual sensor 124 as the default thermistor and use the temperature reading from the default thermistor if the thermistor gives two different temperature readings. In some embodiments, if the temperature reading is within a predefined range, the controller 150 can use the higher of the two readings. Drivers 247 and 249 may apply heater drive signals 281 and 283 to corresponding drive leads 282 a and 282 b on heater assembly 110 .

In the second loop 253 (heater temperature loop), the heater temperature sensors 120 and 122 can provide signals 121 and 123 to the controller 150, respectively, indicating the temperature of the heaters 246 and 248. According to the illustrated embodiment, an upper temperature limit can be established for the heaters 246 and 248 (e.g., by default, operator selection, or automatically determined by the controller 150), and the temperature of the heaters 246 and 248 is not allowed to increase above the upper temperature limit. As the temperature of the heaters 246 and 248 increases and approaches the upper temperature limit, the sensors 121 and 123 can indicate this to the controller 150, which can then reduce the drive signals 281 and 283 to the heaters 246 and 248 to reduce or stop power to the heaters 246 and 248. Thus, when a low temperature signal 125 or 127 from the perfusion fluid temperature sensor 124 causes the controller 150 to increase the power supplied to the heaters 246 and 248, the heater temperature sensors 120 and 122 ensure that the heaters 246 and 248 are not driven to such an extent that their respective heater plates 250 and 252 become hot enough to damage the perfusion fluid 108.

In some embodiments, controller 150 can be configured to maintain the perfusion fluid temperature between 0°C and 50°C. In some embodiments, the perfusate is maintained within a temperature range of 32°C to 42°C, or in more specific embodiments, within a range of 35°C to 37°C. In some embodiments, the controller can be configured to limit the temperature of heater plates 250 and 252 to 38°C, 39°C, 40°C, 41°C, or 42°C. All ranges and numbers identified herein are exemplary, and values outside these ranges may also be used. Finally, when the term "substantially" is used in the claims with respect to a particular temperature value or range, this means that the temperature is within the operating temperature swing of the heater/control system being used. For example, if the desired temperature is "substantially 32°C" and a heater/control system that maintains the temperature within ±5% of the desired value is used in the controlled product, then any temperature within ±5% of 32°C is "substantially 32°C."

As can be seen, if desired, second circuit 253 can be configured to take precedence over first circuit 251, so that temperature readings from temperature sensors 120 and 122 indicating that heaters 246 and 248 are approaching their maximum allowable temperature overcome any low-temperature signals from perfusion fluid temperature sensor 124. In this regard, subsystem 149 can ensure that the temperature of heater plates 250 and 252 does not rise above the maximum allowable temperature, even if the temperature of perfusion fluid 108 has not reached the desired temperature value. This priority feature can be particularly important in fault scenarios. For example, if both perfusion fluid temperature sensors 124 fail, second circuit 253 can prevent overheating and damage to perfusion fluid 108 by switching control exclusively to heater temperature sensors 120 and 122 and lowering the temperature setpoint to a fixed value. In some embodiments, controller 150 can account for two time constants for the delays associated with temperature measurements from heaters 246 and 248 and perfusion fluid 108 to optimize the dynamic response of temperature control.

In some embodiments, the user can be provided with the option to disable the blood warming feature of the system 600. In this way, the system can more effectively support cooling of the liver during the post-preservation freezing process. In some embodiments, the heater assembly 110 (or a separate device such as a gas exchanger with an integrated cooling interface) can be used as a chiller to cool the temperature of the perfusion fluid.

Turning now to the operator interface subsystem 146, Figures 12A through 12G illustrate various exemplary display screens of the operator interface subsystem 146. The display screens enable the operator to receive information from and provide commands to the system 600. Figure 12A depicts an exemplary top-level "Home" screen 400. Through screen 400, the operator can generally access most, if not all, of the data available from the data acquisition subsystem 147 and can generally provide any desired commands to the controller 150. For example, the user can monitor and adjust the pumping subsystem 153 through screen 400. As described in more detail with reference to Figures 12B through 12G, screen 400 can also allow the operator to access more detailed display screens to obtain information, provide commands, and set operator-selectable parameters.

In this exemplary embodiment, screen 400 includes various sections that each display different pieces of information and/or accept different inputs. However, screen 400 is merely exemplary and the information displayed by screen 400 can be customized by the user (e.g., using dialog box 590 described below in FIG. 12F ). The values displayed on screen 400 can be updated at regular intervals, such as once per second. In this specific example, screen 400 includes the following sections:

• A portion 402 showing the hepatic artery flow rate. This value may be an indication of the flow rate at the flow sensor 138b.

• A portion 404 showing the portal vein flow rate. This value may be an indication of the flow rate at the flow sensor 138a.

• A portion 406 showing the oxygen saturation (SvO ₂ ) of the perfusion fluid as it leaves the liver as measured by, for example, sensor 140 .

• A portion 408 showing the hematocrit (HCT) level of the perfusion fluid as it leaves the liver as measured by, for example, sensor 140 .

A portion 410 showing the desired and measured temperatures of the perfusate. In this embodiment, the larger top number represents the measured temperature, while the smaller numbers listed below represent the set point for the desired perfusate temperature. The temperature can be measured from one or more locations, such as at the output of heater assembly 110, using temperature sensors 120 and 122, and in some embodiments, sensor 140.

A portion 412 showing the flow rate measured by the flow sensor 136 .

A portion 414 displays the systolic/diastolic pressure in the hepatic artery. The numbers in parentheses below the systolic/diastolic pressure are the arithmetic mean values of the pressure waveform. The systolic/diastolic/mean pressure in the hepatic artery can be determined by the pressure sensor 130a.

A portion 416 showing the waveform of the hepatic artery pressure over time.

A portion 418 showing the systolic and diastolic pressures in the portal vein. The numbers in parentheses below the systolic and diastolic pressures are the arithmetic mean of the two. The systolic and diastolic pressures in the portal vein can be determined by the pressure sensor 130b.

• Section 420 showing the waveform of portal vein pressure over time.

• Section 422 showing hepatic artery pressure averaged over time (eg, two minutes).

• A portion 424 showing the hepatic artery flow rate averaged over time (eg, two minutes).

A portion 426 of a graphical representation of the values from portions 422 and 424 over time. In this embodiment, the graph represents a ₃ ^1/2 hour time window. In some embodiments, portion 426 can be controlled by the user to display different time periods.

A portion 428 displays an icon indicating that the irrigation pump is running.

• A portion 429 (not shown in this example) may show an organ type indicator that indicates which organ is being perfused and which operating mode is being used. For example, "M" may be used to indicate that the system 600 is in maintenance mode.

A portion 430 that displays the status of a storage medium (eg, an SD card) included in the system 600 .

• A section showing the flow rate from the onboard gas supply 432. This section may also show the amount of time remaining before the onboard gas supply runs out.

A section 434 that displays the status of the power system. In this embodiment, system 600 includes three batteries, each with a corresponding status indicator that displays the battery's charge level. This section also indicates whether system 600 is connected to an external power source (by displaying a plug icon). In some embodiments, this section may also include a numerical indication of the amount of time the battery will operate system 600 in the current operating mode.

• A section 436 that displays the status and remaining charge of a battery included in the operator interface module 146. This section may also include an indication of the amount of time remaining that the battery in the operator interface module 146 can support the operator interface module 146 in a wireless mode of operation.

A section 438 that displays the network connection and/or cellular connection status. This section may also identify whether the operator interface module 146 is operating in a wireless 464 manner, as well as a graphical representation 463 of the strength of the wireless connection between the operator interface module 146 and the rest of the system 600.

• Additional sections may be displayed to show when one or more alarms and/or portions of the system 600 have been disabled by the user.

As seen in Figures 12A to 12G, some sections may also include an alarm range indicator (e.g., indicator 440) that indicates where the current value falls within the allowable range. Each section may also include an alarm indicator (not shown) that indicates that the corresponding value is outside the range indicated by the corresponding range indicator. The range indicator for each corresponding value may be associated with an alarm value set in dialog box 512 or independently set by the user. Screen 400 may be implemented on a touch screen interface. In sections that accept user input, the user may use knob 626 to touch a particular section to change the value in the particular section.

12B, 12C, and 12D, the user may choose to enter a configuration menu 484. In some embodiments of the system, the configuration menu 484 may be limited to a portion of the screen so that the user can continue to monitor the information displayed on the screen. The user may use the configuration menu to program desired operating parameters for the system 600. In this embodiment of the configuration menu 484, the menu has three tabs 484a, 484b, and 484c ("Liver," "System," and "Action").

In tab 484a, a liver tab is shown. In this tab, the user can enter the alert dialog box 512 (described below with reference to FIG. 12E ), select the data shown in the middle graphic box, select the data shown in the bottom graphic box, set the desired gas flow rate, and set the desired temperature. Changes made in tab 484a can be reflected in screen 400.

In tab 484b, the system tab is shown. In this tab, the user can adjust one or more display features of system 600. For example, the user can select which units are used to display various measurements (e.g., Pascals versus mmHg), restore factory defaults, save new default settings, and restore saved default settings. A service technician can also enable a wireless connection from a service notebook to system 600 from this tab. Changes made in tab 484b can be reflected in screen 400.

In tab 484c, an Actions tab is shown. Within this menu, the user can display the status of the machine, display a summary of all alarms, adjust the scale of displayed measurements, and/or interact with the data stored by system 600. For example, in some embodiments, the user can remove a sample of the perfusion fluid and perform an external test on it. The user can then manually enter the values obtained from the external test into the data stream maintained by system 600. In this manner, system 600 can include all data related to the transplanted organ, regardless of whether the data was generated externally by system 600.

Referring to FIG12E , an alarm dialog box 512 displays parameters associated with the operation of system 600. In this embodiment, alarms are displayed for hepatic artery flow (HAF), portal vein pressure (PVP), hepatic artery pressure (HAP), inferior vena cava pressure (IVCP), perfusion fluid temperature (Temp), oxygen saturation (SvO ₂ ), and hematocrit (HCT). Dialog box 512 may include more or fewer parameters. Row 514 indicates the upper alarm limit (e.g., a value above which an alarm will be triggered), and row 516 indicates the lower alarm limit (e.g., a value below which an alarm will be triggered). The user can also enable/disable individual alarms by selecting the associated alarm icon in row 518. The icons in row 518 may indicate whether an individual alarm is enabled or disabled (e.g., the alarm for IVCP is disabled in FIG12E ). Alarm limits may be predetermined, user-settable, and/or determined in real time by controller 150. In some embodiments, system 600 may be configured to automatically switch between multiple sets of alarm limits for a given flow mode when changing flow modes. Changes made in dialog box 512 may be reflected in screen 400 .

12F shows an exemplary user interface (dialog box 590) in which the user can select what is displayed in various portions of screen 400. For example, in 12F, the user can select to display real-time waveforms of hepatic artery pressure, portal vein pressure, or IVC pressure, or to display trend graphs of those or other measured parameters in a portion of screen 400. Other waveforms may also be calculated and displayed by controller 150.

12G illustrates an exemplary user interface (dialog box 592) in which a user can adjust parameters of the pumping subsystem 153. In this example, the user can adjust the pump flow rate and turn the pump on/off.

The data management subsystem 151 can receive data and system information from various other subsystems and store the data and system information. When the operator needs it, the data and other information can be downloaded to a portable memory device and organized in a database. The stored data and information can be accessed by the operator and displayed through the operator interface subsystem 146. The data management system 151 can be configured to store information in one or more places. For example, the data management subsystem 151 can be configured to store data in a memory inside the system 600 (e.g., a hard drive, a flash drive, an SD card, a compact flash card, RAM, ROM, a CD, a DVD) and/or in a memory outside the system (e.g., a remote storage memory or cloud storage).

In embodiments using external storage, the data management subsystem 151 (or another portion of the controller 150) can communicate with the external storage via various communication connections, such as point-to-point network connections, intranets, and the Internet. For example, the data management subsystem 151 can communicate with remote storage media or the "cloud" (e.g., data servers and storage devices on shared and/or private networks) via a WiFi network (e.g., 802.11), a cellular connection (e.g., LTE), Bluetooth (e.g., 802.15), an infrared connection, a satellite-based connection, and/or a hardwired network connection (e.g., Ethernet). In some embodiments, the data management subsystem can be configured to automatically detect the best network connection for communicating with the remote storage device and/or the cloud. For example, the data management subsystem can be configured to default to a known WiFi network and automatically switch to a cellular network when no known WiFi network is available. Remote and cloud-based embodiments are discussed more fully below.

12H , the pumping subsystem 153 will now be described in greater detail. The controller 150 can operate the pumping subsystem 153 by sending a drive signal 339 to the brushless three-phase pump motor 360 using Hall sensor feedback. The drive signal 339 can rotate the pump motor shaft 337, thereby extending and retracting the pump screw 341 and the pump driver 334. According to the illustrative embodiment, the drive signal 339 is controlled to change the direction and speed of rotation of the motor shaft 337 to cyclically extend and retract the pump driver 334. This cyclical motion can pump the perfusion fluid through the system 600.

To commutate the motor winding current, the controller 150 can receive a first signal 387 from a Hall sensor 388 integrally positioned within the pump motor shaft 337, indicating the position of the pump motor shaft 337. The controller 150 can receive a second, higher-resolution signal 389 from a shaft encoder sensor 390, indicating the precise rotational position of the pump screw 341. The controller 150 can use the current motor commutation phase 387 and the current rotational position 389 to calculate the appropriate drive signal 339 (both magnitude and polarity) to cause the necessary rotational change in the motor shaft 337, and thus the appropriate positional change in the pump screw 341, to achieve the desired pumping action. The controller 150 can change the pumping rate (i.e., how often the pumping cycle repeats) by varying the magnitude of the drive signal 339, and can change the pumping stroke (e.g., how far the pump driver 334 moves during a cycle) by varying the rotational direction. In general, the cyclic pumping rate regulates the pulsatile rate at which perfusion fluid 108 is provided to the liver, while (for a given rate) the pumping stroke regulates the amount of perfusion fluid provided to the liver.

Both the rate and the stroke volume affect the flow rate of the perfusion fluid 108 to the liver and indirectly affect the pressure of the perfusion fluid 108. As described herein, the system 600 can include three flow rate sensors 134, 136, and 138 and three pressure sensors 126, 128, and 130. Sensors 134, 136, and 138 can provide corresponding flow rate signals 135, 137, and 139 to the controller 150. Similarly, sensors 126, 128, and 130 can provide corresponding pressure signals 129, 131, and 133 to the controller 150. The controller 150 can use all of these signals as feedback to ensure that the commands provided by the controller 150 to the perfusion pump 106 have the desired effect on the system 600. In some cases, the controller 150 can generate various alarms in response to signals indicating that a particular flow rate or fluid pressure is outside an acceptable range. In addition, the use of multiple sensors enables the controller 150 to distinguish between mechanical problems with the system 600 (e.g., a catheter obstruction) and biological problems with the liver.

Although the use of three pressure sensors is disclosed above, this is not required. In many embodiments described herein, only two pressure sensors are used (e.g., pressure sensors 130a, 130b). In such cases, the input to the third pressure sensor can be omitted. However, in some embodiments of the systems disclosed herein, a third pressure sensor can be used to measure the pressure of the perfusion fluid flowing from the inferior vena cava (or elsewhere in the system 100). In such cases, the controller 150 can process the pressure signals from the sensors as described above.

The pumping system 153 can be configured to control the position of the pump driver 334 at each moment of the pumping cycle to allow for fine adjustment of the pumping rate and volume distribution. This enables the pumping system 153 to deliver perfusion fluid 108 to the liver in any desired pulsatile pattern. According to one illustrative embodiment, the rotational position of the shaft 337 can be sensed by the shaft encoder 390 and adjusted by the controller 150 in at least about 100 increments per revolution. In another illustrative embodiment, the rotational position of the shaft 337 can be sensed by the shaft encoder 390 and adjusted by the controller 150 in at least about 1000 increments per revolution. According to another illustrative embodiment, the rotational position of the shaft 337 can be sensed by the shaft encoder 390 and adjusted by the controller 150 in at least about 2000 increments per revolution. The position of the pump screw 341, and therefore the position of the pump driver 334, can be initially calibrated to a reference position of the pump screw 341.

As described above, system 600 can be manually controlled using controller 150. However, some or all of the control of the system can be automated and performed by controller 150. For example, controller 150 can be configured to automatically control the perfusion fluid flow (e.g., pressure and flow rate) of pump 106, solution pump 631, pump 106, gas exchanger 114, heater 110, and/or flow fixture 190. Control of system 600 can be accomplished with minimal user intervention or even without user intervention. For example, controller 150 can be programmed with one or more predetermined programs and/or can use information from various sensors in system 600 to implement open and/or closed feedback loops. For example, if the controller determines that the oxygen level of the perfusion fluid exiting the IVC is too low or the _CO2 level is too high, controller 150 can adjust the gas supply to gas exchanger 114 accordingly. As another example, controller 150 can control the infusion of one or more solutions based on sensor 140 and/or any other sensor in system 600. As another example, if the controller senses that the liver is producing too much CO ₂ , the controller can lower the temperature of the liver to 35° C. (assuming it was previously maintained at a higher temperature) to reduce the metabolic rate and, therefore, the CO ₂ production rate or O ₂ consumption. As yet another example, the controller 150 can adjust the flow of gas to the gas exchanger 114 based on measurements from one or more sensors in the system 600 .

In some embodiments, the controller 150 can be configured to control various aspects of the system 600 based on the lactate level in the perfusion fluid. In one embodiment, multiple perfusion fluid lactate values can be obtained over time. For example, the user can remove a perfusion fluid sample and use an external blood gas analyzer to determine the lactate value, and/or the system 600 can use an onboard lactate sensor (e.g., a lactate sensor located in the measurement drain 2804). The lactate value can be measured in the IVC or elsewhere and can be repeatedly obtained at predetermined time intervals (e.g., every 30 minutes). The controller 150 can analyze the trend of the lactate value over time. If the lactate level tends to decrease or remains relatively flat, this can indicate that the liver is being properly perfused. If the lactate level tends to increase, this can indicate inadequate perfusion, which can cause the controller 150 to increase pump flow, adjust the infusion rate of vasodilators, and/or change the gas flow to the gas exchanger 114.

Automating the control process can provide many benefits, including providing finer control over the system's parameters, which can lead to a healthier liver and/or reduce the burden on the user.

In some implementations, system 600 may include a global positioning device that tracks the geographic location of the system.

C. Exemplary Single-Use Modules

Turning now to the single-use module, an exemplary embodiment of which is described herein as single-use module 634, but other embodiments are possible. As noted above, this portion of system 600 typically includes at least all components of system 600 that come into contact with biological materials, such as perfusate, as well as various peripheral components, flow conduits, sensors, and supporting electronics used in conjunction with these components. After system 600 is used to transport an organ, the single-use module can be removed from system 600 and discarded. A new (and sterile) single-use module can be installed in system 600 to transport a new organ. In some embodiments, module 634 does not include a processor, but instead relies on controller 150, which can be distributed between front-end interface circuit board 636, power supply circuit board 720, operator interface module 146, and main circuit board 718 for control. However, in some embodiments, the single-use module can include its own controller/processor (e.g., located on front-end circuit board 637).

13A to 13H , an exemplary single-use module 634 is shown. 13M to 13R show another exemplary single-use module 634 having an alternatively shaped organ chamber 104. However, it should be noted that certain components have been omitted in some of the views to improve clarity of the drawings (e.g., some of the tube connectors, ports, and/or clamps have been omitted).

The single-use module 634 may include a base frame 635 having an upper section 750a and a lower section 750b. The upper section 750a may include a platform 752 for supporting various components. The lower section 750b may support the platform 752 and may include structure for pivotally connecting to the multiple-use module 650.

The lower base section 750b may include a C-shaped mount 656 for rigidly mounting the perfusion fluid pump interface assembly 300, and a protrusion 662 for sliding into and snap-fitting into a slot 660. In some embodiments, the lower base section 750b may also provide a structure for mounting portions of the perfusion circuit, including the gas exchanger 114, the heater assembly 110, the reservoir 160, and the perfusion flow compliance chambers 184 and 186. In some embodiments, the lower base section 750b may also accommodate various sensors, such as the sensor 140, the flow rate sensors 136, 138a, 138b, and the pressure sensors 130a and 130b, via appropriate mounting hardware. The lower base section 750b may also be mounted with the front-end circuit board 637. This embodiment is merely exemplary and the components listed above as part of the base frame lower section 750b (eg, pressure sensors 130a, 130b) may be located elsewhere, such as in the upper section 750a.

The upper base section 750a can include a platform 752. The platform 752 can include handles 753a and 753b formed therein to assist in mounting and removing the single-use module 634 from the multiple-use module 650, although the handles can be located elsewhere in the single-use module 634. The platform 752 can include one or more apertures (e.g., 717) to allow tubing and/or other components to pass through the platform 752. The platform 752 can also include one or more integrally formed supports (e.g., 716) to hold components, such as fluid injection ports and/or sampling ports, described more fully below, in place on top of the platform 752. The upper base section 750a can also include a flow clamp 190, described more fully below, for regulating the flow of perfusion fluid to the portal vein. The organ chamber assembly 104 can be configured to be mounted to the platform 752 via one or more supports 719. 13I , the organ chamber assembly 104 can be mounted so that its left and right sides (relative to the primary drain) are angled approximately 15° relative to the platform 752. Doing so can facilitate drainage of perfusion fluid from the organ chamber assembly 104, particularly under transient conditions that may be encountered during transport (e.g., aircraft takeoff and landing).

1. Organ chamber

The system 600 may include an organ chamber configured to hold an isolated organ. The design of the organ chamber may vary depending on the type of organ. For example, the design of the organ chamber may vary depending on whether it is used to transport a liver, a heart, and/or a lung. Although the following description focuses on an organ chamber 104 configured to transport a liver, this embodiment is merely exemplary and other configurations are possible. For example, other configurations of the organ chamber 104 may also be used to transport a liver.

a) Shape/emission structure

14A to 14H , an exemplary embodiment of an organ chamber 104 is shown in various views. In this embodiment, the organ chamber 104 includes a base 2802, a front member 2816, a removable cover 2820, and a support surface 2810 (the support surface 2810 is described in detail with reference to FIG. 15A to FIG. 15D ). In some embodiments, the organ chamber 104 may also include a cushion 4500 for supporting the liver. The bottom of the organ chamber 104 may be configured to have a quasi-funnel shape, wherein the sides of the funnel are angled approximately 15° relative to the platform 752, as more clearly shown in FIG. 13I .

In general, the base member 2802 can include: one or more drains (e.g., 2804, 2806); one or more ports (e.g., 2830) for inserting tubes, connectors, and/or instruments into the organ chamber 104 when the lid (e.g., 2820) is closed; one or more hinged portions (e.g., 2832); and one or more mounting brackets (e.g., 2834). In some embodiments, as shown in FIG. 14I , the mounting brackets 2834 are molded. In some embodiments, the base member 2802 is configured to fit over and support a support surface 2810 on which a liver is typically positioned. The organ chamber 104 and the support surface 2810 can be made of any suitable polymer plastic, such as polycarbonate.

The base 2802 of the chamber 2204 can be shaped and positioned within the system 600 to facilitate drainage of perfusion media from the liver 101. The organ chamber 104 can have two drains: a measurement drain 2804 and a main drain 2806, which can receive overflow from the measurement drain. The measurement drain 2804 can drain perfusate at a rate of approximately 0.5 L/min, significantly less than the rate of perfusion fluid 250 flowing through the liver 101, which is between 1 L/min and 3 L/min. The measurement drain 2804 can lead to the sensor 140, which can measure _SaO2 , hematocrit, and/or temperature, and then to the reservoir 160. The main drain 2806 can lead directly to the debubbler/filter 161 without passing through the sensor 140. In some embodiments, the sensor 140 cannot obtain accurate measurements unless the perfusion fluid 108 is substantially free of bubbles. To achieve a bubble-free perfusate column, the base 2802 is shaped to collect the perfusion fluid 108 draining from the liver 101 into a pool located above the measurement drain 2804. The perfusate pool generally allows bubbles to dissipate before the perfusate enters the drain 2804. The pool above the drain 2804 can be facilitated by an optional wall 2808 that can partially block the flow of perfusate from the measurement drain 2804 to the main drain 2806 until the perfusate pool is large enough to ensure that bubbles dissipate from the flow. The main drain 2806 can be lower than the measurement drain 2804 so that once the perfusate overflows the recess surrounding the drain 2804, the perfusate flows around and/or over the wall 2808 to be discharged from the main drain 2806.

In alternative embodiments of the dual drain system, other systems are used to collect the perfusion fluid into a reservoir that feeds the measurement drain. In some embodiments, the flow from the liver is directed to a container, such as a smaller cup 2838, which feeds the measurement drain. Cup 2838 is filled with perfusion fluid, and excess blood overflows the cup and is directed to the main drain and, from there, to the reservoir. In this embodiment, cup 2838 performs a similar function to wall 2808 in the above-described embodiment by forming a smaller reservoir of perfusion fluid from which bubbles can dissipate before flowing into the measurement drain on their way to the oxygen sensor. In another embodiment of the measurement drain, a tapered recess can be formed around measurement drain 2804 at the bottom of base 2802, performing the same function as the cup described above.

The top of the organ chamber 104 can be covered with a sealable cover comprising a front member 2816, a removable cover 2820, an inner cover (not shown) with a sterile drape, and a seal 2818. The removable cover 2820 can be hingedly and removably coupled to the base member 2802 via a hinge 2832. The seal 2818 can seal the front member 2816 and/or the base 2802 to the cover 2820 to form a fluid-tight and/or airtight seal. The seal 2818 can be made of, for example, rubber and/or foam. In some embodiments, the front member 2816 and the cover 2820 are sufficiently rigid to protect the liver 101 from indirect or direct physical contact.

The various views shown in Figures 14I through 14S illustrate an alternative embodiment of an organ chamber. In this embodiment, the base 2802 of the organ chamber 104 has a different shape. Figures 14I through 14K illustrate top views, Figures 14L through 14O illustrate side views, Figures 14P through 14R illustrate bottom views, and Figure 14S illustrates an exploded view of the alternative embodiment. The organ chamber 104 includes a base 2802, an organ support surface 2810, and a removable cover 2820.

For example, the top of the organ chamber can be covered with a single sealable lid 2820. The removable lid can be connected to the organ chamber base member in an articulated and detachable manner via a hinged portion 2832. The lid is fastened to the base by a series of latches 2836 or other mechanisms. The seal 2818 of the lid can be made of rubber and/or foam, and the seal 2818 can seal the lid to the base to create a fluid-tight or airtight seal. The combination of the lid and the base is sufficiently rigid to protect the liver from direct or indirect physical contact. The organ chamber contains holes (e.g., 2830) for connection of catheters to cannulated blood vessels (including HA, PV, and bile duct). The organ chamber includes a structure 2840 positioned above the measurement and drainage device 2804, which holds the end of the IVC in place during transport of the organ. The structure guides the perfusate leaving the IVC cannula to the measurement and drainage device.

In an alternative embodiment (not shown), the organ chamber 104 may include a dual-lid system comprising an inner lid and an outer lid. More specifically, in one embodiment, the organ chamber assembly may include a shell, an outer lid, and an intermediate lid. The shell may include a bottom and one or more walls for accommodating the organ. The intermediate lid may cover the opening of the shell to substantially enclose the organ within the shell and may include a frame and a flexible diaphragm suspended within the frame. The flexible diaphragm may be transparent, opaque, translucent, or substantially transparent. In some embodiments, the flexible diaphragm includes sufficient diaphragm material to contact the organ contained within the chamber. This feature allows a medical operator to indirectly touch/examine the organ through the diaphragm while still maintaining the sterility of the system and the organ. For example, the area of the diaphragm in the intermediate lid may be 100% to 300% larger than the area defined by the intermediate lid frame, or have an area that is 100% to 300% larger than the two-dimensional area occupied by the liver. In some embodiments, the flexible diaphragm can be selected so that an operator can perform ultrasound of the liver through the diaphragm while maintaining the sterility and/or environment of the chamber.

In some embodiments, the middle cover can be hinged to the housing. The middle cover can also include a latch for fastening the sealed middle cover to the opening above the organ chamber. The outer cover can be hinged and latched or removable in a similar manner. In some configurations, a gasket is provided to form a fluid-tight and/or airtight seal between the middle cover frame and one or more organ chamber walls, and/or to form a fluid-tight and/or airtight seal between the periphery of the outer cover and the framework of the middle cover. In this way, the environment around the liver 101 can be kept, and no matter whether the outer cover is opened.

Covering the organ chamber 104 can be used to minimize gas exchange between the perfusion fluid 108 and the ambient air, which can help ensure that the oxygen probe measures the desired oxygen value (e.g., the value corresponding to the perfusate leaving the liver 101) and can help maintain sterility. The closure of the organ chamber 2204 can also be used to reduce heat loss from the liver. Since the surface area of the liver is large, heat loss can be considerable. When the system 600 is placed in a relatively low temperature environment (e.g., a vehicle, or outdoors when the system 600 is moved in and out of the vehicle), heat loss can be an important issue during liver transportation. In addition, before transplantation, the system 600 can be temporarily placed in a hospital holding area or operating room, both of which typically have temperatures within the range of 15°C to 22°C. At such ambient temperatures, it is important to reduce heat loss from the organ chamber 2204 to allow the heater 230 to maintain the desired perfusate temperature and liver temperature. Sealing the liver 101 in the organ chamber 2204 can also help maintain temperature uniformity in the liver 101.

Referring also to Figures 15A-15D, an exemplary embodiment of a support surface 2810 configured to support liver 101 is shown. This embodiment includes a drainage channel 2812, a drain 2814, and an orifice 2815. Drain channel 2812 is configured to direct perfusate from liver 101 and direct it toward drain 2814. In some embodiments, when support surface 2810 is mounted in base 2802, drain 2814 is located above and/or adjacent to measurement drain 2804, thereby ensuring that a large amount of perfusate 108 is drained from support surface 2810 to measurement drain 2804. Orifice 2815 is configured to provide a supplemental area for draining perfusate from support surface 2810. Furthermore, support surface 2810 can be configured for use with pad 4500 (described below). Support surface 2810 can also include an orifice 2813, which can be used to secure pad 4500 using, for example, screws or rivets. In some embodiments, when the support surface 2810 is installed in the organ chamber 104, the support surface 2810 is installed so that it is positioned at an angle of approximately 5 degrees relative to horizontal, although other angles (eg, 0 to 60 degrees) may be used.

16F to 16J, in an alternative embodiment, support surface 4700 is a flexible material that supports and cushions organs, and support surface 2810 is omitted. The material is a composition that provides a compliant, smooth surface on which sensitive liver tissue can be placed. The surface can be perforated in the following manner: the number, arrangement, and diameter of the perforations can allow drainage from the liver while providing an anti-damage surface for liver tissue. In this or other embodiments, support 4700 is a layer of material comprising a top layer 4706 and a bottom layer 4708 of a flexible material 4706, and an inner layer of a frame 4702 that is a ductile metal substrate (e.g., aluminum). In some embodiments, top layer 4706 and bottom layer 4708 can be made of polyurethane foam and/or porous silicone foam.

The assembly is supported by the organ chamber base 2802, suspending the support surface 4700 at an appropriate height above the bottom of the organ chamber base 2802 to provide displacement under the weight of the organ. The frame 4702 of the support surface 4700 can be held in place relative to the organ chamber base 2802 by using fasteners 4704, such as molded pins, rivets, screws, or other hardware, inserted through openings 4610 in the frame 4702.

In some embodiments, the malleable metal frame 4702 extends into the protrusion 4712. The protrusion 4712 may also be enclosed by a top layer 4706 and a bottom layer 4708. The protrusion 4712 can be formed to surround the liver to stabilize its position in the x, y, and z axes. The user can selectively support the liver by bending the protrusion 4712 to simulate how the liver is supported in the human body. In some embodiments, multiple portions of the frame 4702 may be tapered and terminate in a rounded shape, as shown in FIG16G . The tapered portions of the frame 4702 can: i) allow the protrusion 4712 to be more easily rolled and reduce or even eliminate the possibility of wrinkling; and ii) reduce the weight of the support surface 4700. The rounded portion can provide a surface that is easy for the user to grip. The tapered shape of this portion of the frame 4702 can be specifically selected so that the frame 4702 follows a natural arc when rolled, rather than folding or bending. The protrusion 4712 can have any desired shape to surround the liver. In use, the liver is placed on the top layer 4706 of the support surface 4700, allowing the support surface 4700 to be pressed down. The protrusions 4712 can then be formed into a position around the liver.

b) Liver stabilization

In some embodiments, the liver can be stabilized during transport by one or more systems designed to support the liver and keep it in place without damaging the liver by applying undue pressure to the liver. For example, in some embodiments, the system 600 can use a soft liver-stabilizing pad (e.g., 4500) to support the liver together with a wrap/tarp (e.g., 4600). In some embodiments, the stabilization system can allow some movement of the liver up to predetermined limits (e.g., the system can allow the liver to move up to 2 inches in any direction). In some embodiments, the surface on which the liver is placed can have a low friction surface, which also helps to reduce damage to the liver. The side of the pad that contacts the support surface 2810 can have a high friction surface to help keep the pad in place.

The pad can be designed to form a cradle that selectively and controllably supports the liver 101 without applying undue pressure to the liver 101. That is, the liver 101 rests only on the support surface 2810 and not on other surfaces, which could cause physical damage to the portion of the liver that rests thereon during transport. For example, the pad can be formed of a material that is sufficiently resilient to reduce mechanical vibration and shock to the liver during transport.

An exemplary embodiment of a liver stabilization pad and wrap is shown as pad 4500 in Figures 16A to 16E and as wrap 4600 in Figure 16D. Pad 4500 can include two layers: a top layer 4502 and a bottom layer 4504. In some embodiments, top layer 4502 can be made of polyurethane foam, and bottom layer 4504 can be made of porous silicone foam. In this embodiment, top layer 4502 can be 6 mm thick, and bottom layer 4504 can be 3/16 inch thick, but other thicknesses and materials can be used. Top layer 4502 and bottom layer 4504 can be bonded to each other using an adhesive such as MOMENTIVE Silicone RTV 118 silicone. The shape of pad 4500 can be optimized for the liver (e.g., as shown in Figure 16A). For example, the shape of pad 4500 can include curved corners and one or more finger-like portions (e.g., 4506, 4508, 4510, 4512, 4514, and 4516). The pad 4500 may also include one or more holes 4520 through which the pad 4500 may be fastened to the support surface 2810 using, for example, rivets and/or screws. In some embodiments, the pad 4500 may be approximately 16 by 12 inches, although other sizes are possible.

Sandwiched between the top layer 4502 and the bottom layer 4504 may be a deformable metal base 4518. Deformable base 4518 may be constructed from a rigid yet flexible material such as metal, although other materials may be used. In some embodiments, deformable base 4518 is aluminum 1100-0 with a thickness of 0.04 inches. Base 4518 may be configured to allow for easy manipulation by the user, yet resist changes in positioning due to vibration or impact of the liver. Deformable base 4518 may include fingers 4522, 4524, 4526, 4528, 4530, 4532 corresponding to fingers 4506, 4508, 4510, 4512, 4514, 4516, respectively. A user may selectively support the liver by bending the various fingers in pad 4500 in a manner that simulates how the liver is supported in the human body. An exemplary embodiment of pad 4500 with the fingers in a curled position is shown in FIG. 16D. In some embodiments, each finger in the deformable base 4518 can be tapered (e.g., as shown by 4534) and terminate in a rounded shape. The tapered fingers in the base 4518 can: i) allow the fingers to curl more easily and reduce or even eliminate the likelihood of the fingers buckling when bent; and ii) reduce the weight of the pad 4500. The rounded portion can provide a surface that is easy for the user to grip. The tapered shape of the fingers can be specifically selected to facilitate rolling the pad's fingers to follow a natural arc rather than folding or bending.

16F to 16J , in an alternative embodiment, the stabilizer can include three layers. The top layer 4706 and the bottom layer 4708 can be made of porous silicone foam. Each foam layer can be 3/16 inch thick, but other thicknesses and materials can be used. The inner layer is a frame 4702 of a deformable metal base made in the form of a narrow frame. The frame 4702 can be constructed of a rigid but flexible material (e.g., metal), but other materials can be used. In some embodiments, the frame 4702 is aluminum 1100-0 with a thickness of 0.04 inches. The frame 4702 can be constructed so that it is easily manipulated by the user, but resists changes in positioning due to vibration or impact of the liver.

The top layer 4706 and bottom layer 4708 can be bonded to each other and to the frame 4702 using an adhesive such as MOMENTIVE Silicone RTV 118 silicone. The top layer 4706 and bottom layer 4708 cover the area within the frame 4702, thereby forming a conformable support surface 4700 on which the liver rests for transport. The shape of the support surface 4700 can be optimized for the liver. For example, the shape of the support surface 4700 can include curved corners and one or more protrusions 4712 to limit movement of the liver during transport. In some embodiments, a wrap 4600 can be placed over the liver to hold it in place and maintain moisture during transport. For example, as shown in FIG16D , one side of the wrap 4600 (e.g., the right side in FIG16D ) can be attached to the pad, and the remainder of the wrap can be placed over the liver. In other embodiments, the wrap can be secured on multiple edges or all edges. The wrap 4600 can also be used in conjunction with a flexible support surface 4700. In some embodiments, the wrapper can perform one or more functions such as securing the liver during transplantation, helping to maintain sterility, and retaining moisture in the liver by acting as a vapor barrier. The wrapper can be made of a polyurethane sheet and can be opaque or transparent to facilitate visual inspection of the liver. The dimensions of the wrapper 4600 can vary. For example, the wrapper 4600 can have a length between 0.5 inches and 24 inches and a width between 0.5 inches and 24 inches.

2. General Description of the Perfusion Circuit

As mentioned above, the liver has two blood supply sources: the hepatic artery and the portal vein, which provide approximately one-third and two-thirds of the liver's blood supply, respectively. Generally, when comparing the blood supply provided by the hepatic artery and the portal vein, the blood supply provided by the hepatic artery has a higher pressure but a lower flow rate, while the blood supply provided by the portal vein has a lower pressure but a higher flow rate. Furthermore, the hepatic artery generally provides a pulsatile blood flow to the liver, while the portal vein does not.

The system 600 can be configured to deliver perfusion solution to the liver using a single pump in a manner that simulates the human body (e.g., appropriate pressure, volume, and pulsatile flow). For example, in normal flow mode, the system 600 can circulate perfusion fluid to the liver in the same manner as blood circulates in the human body. More specifically, the perfusion fluid enters the liver through the hepatic artery and portal vein and exits the liver via the IVC. In normal flow mode, the system 100 pumps perfusion fluid to the liver 102 at a near-physiological rate of between approximately 1 L/min and 3 L/min, but in some embodiments, this range can be 1.1 L/min to 1.75 L/min (although the system can also be configured to provide flow rates outside this range, e.g., 0 L/min to 10 L/min). Each of the aforementioned numbers is the total flow rate per minute provided to the hepatic artery and portal vein.

With reference to Figure 17, an exemplary embodiment of a perfusion kit 100 is shown. Perfusion kit 100 can include a reservoir 160, a one-way valve 191, a pump 106, a one-way valve 310, compliance chambers 184 and 186, a gas exchanger 114, a heater 110, a flow meter 136 and 138a and 138b, a distributor 105, a flow fixture 190, pressure sensors 130a and 130b, an organ chamber 104, a sensor 140, a defoamer/filter 161, and the pipe/interface connecting them. The liver can also be connected to a bag 187 for collecting the bile produced therefrom. In some embodiments, perfusion kit 100 is fully contained in a single-use module 634, but this is not required. In some embodiments, the inferior vena cava (IVC) is cannulated so that the flow from the IVC can be directed to a catheter that can measure IVC pressure, flow rate, and oxygen saturation. In other embodiments, the IVC is not cannulated, and the perfusate flows freely from the IVC into the organ chamber 104 (and ultimately into a drain in the organ chamber 104).

In one embodiment, the perfusion fluid flows from the reservoir 160 to the valve 191 and then to the pump 106. After the pump 106, the perfusion fluid can flow to the one-way valve 310 and then to the compliance chamber 184. After the compliance chamber 184, the perfusion fluid can flow to the gas exchanger 114 and continue to the heater 110. After the heater 110, the perfusion fluid can flow to the flow meter 136, which is configured to measure the flow rate at this portion of the perfusion circuit. After the flow meter 136, the perfusion fluid flows to the distributor 105, which can divide the perfusion fluid flow into branches 313 and 315. In some embodiments, the distributor 105 can split the perfusion fluid flow between the hepatic artery and the portal vein in a ratio of between 1:2 and 1:3. Branch 313 ultimately provides the portal vein of the liver, while branch 315 ultimately provides the hepatic artery of the liver. Branch 313 may include a flow meter 138a and a compliance chamber 186, which provides perfusion fluid to a flow clamp 190. The perfusion fluid may flow to the pressure sensor 130a through the flow clamp 190 before being provided to the liver's portal vein. Branch 315 may include a flow meter 138b, which provides the perfusion fluid to the pressure gauge 130b before being provided to the liver's hepatic artery. After the perfusion fluid leaves the liver, some of the perfusion fluid is collected by a measurement drain 2804, while the remainder is collected by a main drain 2806. The perfusion fluid collected by the measurement drain 2804 may be provided to the sensor 140. The perfusion fluid leaving the sensor 140 may be provided to the defoamer/filter 161. The perfusion fluid collected by the drain 2806 may be provided directly to the defoamer/filter 161. The perfusion fluid leaving the defoamer/filter 161 may be provided to the reservoir 160. Additionally, bile produced by the liver may be collected in bag 187 .

In some embodiments, the system 100 is operated with at least 1.6 L of perfusion fluid (or other fluid) in the system.

3. Storage

The disposable module 634 can include a perfusate reservoir 160 mounted below the organ chamber 104. The reservoir 160 can be configured to store and filter the perfusate 108 as it circulates through the perfusion set 100. The reservoir 160 can include one or more one-way valves (not shown) that prevent the perfusate from flowing in the wrong direction. In some embodiments, the reservoir 160 has a minimum capacity of 2 L, but smaller capacities can be used. In some embodiments, the reservoir 160 can include a filter (shown separately as a defoamer/filter 161 in FIG. 17 ) designed to capture particles in the perfusate 108. In some embodiments, the filter is configured to capture particles larger than 20 microns in the perfusate 108. In some embodiments, the reservoir 160 includes a defoamer (shown separately as a defoamer/filter 161 in FIG. 17 ) that reduces and/or eliminates foam generated by the perfusate 108. In some embodiments, the reservoir 160 can be made of a transparent material and can include level markings so that a user can estimate the amount of perfusion fluid in the reservoir 160. In some embodiments, the reservoir 160 can be configured to allow a minimum of 4.5 L per minute of fluid inlet from the organ chamber 104, although other flow rates are possible. In some embodiments, the reservoir 160 includes an outlet to atmosphere that includes a sterile barrier (not shown).

The reservoir 160 can be positioned at various locations within the system 600. For example, the reservoir 160 can be located above the liver, completely below the liver, partially below the liver, near the liver, etc. One potential benefit of some embodiments described herein is that the reservoir can be located below the liver, as gravity-induced pressure head of the perfusion fluid is not required.

4. Valve

In some embodiments, valves 191 and 310 are one-way valves configured to ensure that perfusion fluid in system 100 flows in the proper direction through system 100. Exemplary embodiments of valves 191 and 310 are described above with respect to pump 106.

5. Priming fluid pump

Exemplary embodiments of the pump 106 are described more fully above with reference to Figures 6A to 6E. As described above, in some embodiments, the pump is assembled between the multiple use module 650 and the single use module 634. For example, the single use module 634 may include a pump interface assembly, while the multiple use module 650 includes a pump driver portion.

6. Comply with the chamber

Although pump 106 provides a generally pulsatile output, the characteristics of this flow are generally adapted to match the flow typically provided to the liver by the human body. For example, the portal vein does not typically provide a pulsatile blood flow to the liver while it is in vivo. Therefore, in some embodiments, to provide a non-pulsatile flow of perfusion fluid to the liver's portal vein, one or more compliance chambers can be used to mitigate the pulsatile flow generated by pump 106. In some embodiments, compliance chambers are essentially small coaxial fluid accumulators with flexible, elastic walls that mimic the compliance of human blood vessels. Compliance chambers can assist system 600 by more accurately simulating blood flow in the human body, for example by filtering/reducing fluid pressure spikes caused by, for example, the flow profile from pump 106. In the embodiment of system 600 described herein, two compliance chambers are used: compliance chambers 184 and 186. Various characteristics of the compliance chambers can be varied to achieve desired results. For example, the combination of i) the pressure-volume relationship and ii) the total volume of the compliance chambers can influence the performance of the compliance chambers. Preferably, the characteristics of each compliance chamber are selected to achieve the desired effect.

In some embodiments, compliance chamber 184 is located between valve 310 and gas exchanger 114 and operates to partially smooth the pulsatile output of pump 106. For example, compliance chamber 184 can be configured so that the flow of perfusion fluid ultimately provided to the hepatic artery of the liver simulates fluid flow in the human body. In some embodiments, compliance chamber 184 can be omitted if the output of pump 106 produces a perfusion flow to the hepatic artery that closely simulates that of the human body.

In some embodiments, compliance chamber 186 is located between distributor 105 and flow clamp 190. Compliance chamber 186 can be operated to significantly reduce or even eliminate the pulsatile nature of the perfusion fluid flow ultimately provided to the portal vein. Furthermore, although compliance chamber 186 is located before flow clamp 190 in branch 313, this is not required. For example, flow clamp 190 can be located before compliance chamber 186. However, in this embodiment, it is desirable to adjust the parameters of compliance chamber 186.

7. Gas exchanger

The system 600 may also include a gas exchanger 114 (also referred to herein as an oxygenator) configured to, for example, remove _CO2 from the perfusion fluid and add _O2 . The gas exchanger 114 may receive input gas from an external or onboard source (e.g., a gas supply 172 or an oxygen concentrator) via a gas regulator and/or a gas flow chamber, which may be a pulse-width modulated solenoid valve that controls the gas flow, or any other gas control device that allows for precise control of the gas flow rate. In some embodiments, the gas exchanger 114 is a standard diaphragm oxygenator such as an interventional lung assist diaphragm ventilator from NOVALUNG or a component of the Quadrox series from Maquet of Wayne, New Jersey. In an illustrative embodiment, the gas may be a mixture of oxygen, carbon dioxide, and nitrogen. An exemplary gas mixture is: 80% _O2 , 0.1% _CO2 , and the balance _N2 , with a mixing accuracy of 0.030%. In some embodiments, the output of sensor 140 can be used by controller 150 to control the operation of the gas exchanger, regulator, and/or gas flow chamber.

In some embodiments, under standard conditions, at a blood flow rate of 500 mLpm, the oxygenator 114 can have an oxygen delivery rate of 27.5 mLpm/LPM. Under standard conditions, at a blood flow rate of 500 mLpm, the oxygenator 114 can also have a carbon dioxide delivery rate of 20 mLpm. Standard conditions can include, for example, gas = 100% O ₂ , blood temperature = 37.0 ± 0.5° C., hemoglobin = 12 ± 1 mg%, SvO ₂ = 65 ± 5%, pCO ₂ = 45 ± 5 mmHg, and a gas to blood ratio of 1:1. The above values are exemplary only and are not limiting. Delivery rates higher and/or lower than the rates identified above may be used.

8. Heater/Cooler

The perfusion set 100 can include one or more heaters configured to maintain the temperature of the perfusion fluid 108 at a desired level. By heating the perfusion fluid and flowing the heated fluid through the liver, the liver itself can also be warmed. Although the heater can warm the perfusion fluid to a wide temperature range (e.g., 0°C to 50°C), the heater typically warms the perfusion fluid to a temperature of 30°C to 37°C. In more specific embodiments, the heater can be configured to heat the perfusion fluid to a temperature of 34°C to 37°C, 35°C to 37°C, or any other range within 0°C to 50°C. In some embodiments, the range described herein can also be extended to 42°C.

18A to 18G , an exemplary embodiment of a heater assembly 110 is shown. FIG. 18A to FIG. 18F depict various views of the perfusion fluid heater assembly 110. The heater assembly 110 may include a housing 234 having an inlet 110a and an outlet 110b. As shown in the longitudinal and transverse cross-sectional views, the heater assembly 110 may include a flow channel 240 extending between the inlet 110a and the outlet 110b. The heater assembly 110 can be conceptualized as having a symmetrical upper half 236 and lower half 238. Therefore, FIG. 18F shows only an exploded view of the upper half.

A flow channel 240 can be formed between a first flow channel plate 242 and a second flow channel plate 244. An inlet 110a allows perfusion fluid to flow into the flow channel 240, and an outlet 110b allows perfusion fluid to flow out of the heater 110. The first flow channel plate 242 and the second flow channel plate 244 can have substantially bioinert perfusion fluid 108 contact surfaces for providing direct contact with the perfusion fluid flowing through the channel 240. The fluid contact surfaces can be formed by a treatment or coating on the plates or can be the plate surfaces themselves. The heater assembly 110 can include a first electric heater 246 and a second electric heater 248, respectively. The first heater 246 can be positioned adjacent to and thermally coupled to a first heater plate 250. The first heater plate 250, in turn, can be thermally coupled to the first flow channel plate 242. Similarly, the second heater 248 can be positioned adjacent to and thermally coupled to a second heater plate 252. A second heater plate 252 can be thermally coupled to the second flow channel plate 244. According to an illustrative embodiment, the first and second heater plates 250, 252 can be formed from a material, such as aluminum, that relatively evenly conducts and distributes heat from the first and second electric heaters 246, 248, respectively. The uniform thermal distribution of the heater plates 250 and 252 enables the flow channel plates to be formed from bio-inert materials, such as titanium, thereby reducing concerns regarding their thermal distribution characteristics. The heater assembly 110 can also include O-rings 254 and 256 for fluidically sealing the respective flow channel plates 242 and 244 to the housing 234 to form the flow channel 240. In some embodiments, the functions of the heater plate and the flow channel plate are combined in a single plate.

The heater assembly 110 may also include first assembly brackets 258 and 260. Assembly bracket 258 may be mounted on the top side 236 of the heater assembly 110 above the periphery of the electric heater 246 to sandwich the heater 246, heater plate 250, and flow channel plate 242 between assembly bracket 258 and the housing 234. Bolts 262a to 262j may be fitted through corresponding through-holes in bracket 258, the electric heater 246, the heater plate 250, and the flow channel plate 242 and screwed into corresponding nuts 264a to 264j to attach all of these components to the housing 234. Assembly bracket 260 may be mounted on the bottom side 238 of the heater assembly 110 in a similar manner to attach the heater 248, the heater plate 252, and the flow channel plate 244 to the housing 234. Resilient pads 268 may be interfitted within the periphery of bracket 258. Similarly, resilient pads 270 may be interfitted within the periphery of bracket 260. Bracket 272 can be assembled over pad 268. Bolts 278a to 278f can interfit through holes 276a to 276f in bracket 272 and thread into nuts 280a to 280f, respectively, to press resilient pad 268 against heater 246, thereby providing more efficient heat transfer to heater plate 250. Resilient pad 270 can be pressed against heater 248 in a similar manner by bracket 274.

The illustrative heater assembly 110 may include temperature sensors 120 and 122 and a dual sensor 124. The dual sensor 124, which may actually include a dual thermistor sensor for providing fault tolerance, may measure the temperature of the perfusion fluid 108 exiting the heater assembly 110 and may provide these temperatures to the controller 150. As described in further detail with respect to the heating subsystem 149, the signals from the sensors 120, 122, and 124 may be used in a feedback loop to control the drive signals to the first heater 246 and/or the second heater 248, thereby controlling the temperature of the heaters 256 and 248. In addition, to ensure that the heater plates 250 and 252, and therefore the blood-contacting surfaces 242 and 244 of the heater plates 250 and 252, do not reach a temperature that could harm the perfusion fluid, the illustrative heater assembly 110 may also include temperature sensors/leads 120 and 122 for monitoring the temperatures of the heaters 246 and 248, respectively, and providing these temperatures to the controller 150. In practice, the sensors attached to the sensors/leads 120 and 122 may be based on RTDs (resistance temperature devices). The signals from the sensors attached to the sensors/leads 120 and 122 may be used in a feedback loop to further control the drive signals to the first heater 246 and/or the second heater 248, thereby limiting the maximum temperature of the heater plates 250 and 252. As a fault protection, there may be a sensor for each of the heaters 246 and 248 so that in the event of a failure of one sensor, the system can continue to operate using the temperature of the other sensor.

Heater 246 of heater assembly 110 can receive drive signals 281a and 281b (collectively, 281) from controller 150 on corresponding drive leads 282a. Similarly, heater 248 receives drive signals 283a and 283b (collectively, 283) from controller 150 on drive leads 282b. Drive signals 281 and 283 control the current to the corresponding heaters 246 and 248, and therefore control the amount of heat generated by the corresponding heaters 246 and 248. More specifically, as shown in FIG18G , drive leads 282a include a pair of high and low leads that connect two sides of a resistive element 286 of heater 246. The greater the current supplied through resistive element 286, the hotter resistive element 286 becomes. Heater 248 operates in the same manner as drive leads 282b. According to the illustrative embodiment, element 286 has a resistance of approximately 5 ohms. However, in other illustrative embodiments, the element may have a resistance between about 3 ohms and about 10 ohms. Heaters 246 and 248 may be individually controlled by processor 150 .

The housing components of the heater assembly 110 can be formed from molded plastic, such as polycarbonate, and can weigh less than about 1 pound. More specifically, the housing 234 and brackets 258, 260, 272, and 274 can all be formed from molded plastic, such as polycarbonate. According to another feature, the heater assembly can be a single-use, disposable assembly.

In operation, the illustrative heater assembly 110 can use a power of about 1 watt to about 200 watts and can be sized and shaped to transition the perfusion fluid 108 flowing through the channel 240 at a rate of about 300 ml/min to about 5 L/min from a temperature of less than about 30° C. to a temperature of at least 37° C. in less than about 30 minutes, less than 25 minutes, less than about 20 minutes, less than about 15 minutes, or even less than about 10 minutes without substantially causing hemolysis of cells or denaturing proteins or otherwise damaging any blood product portion of the perfusion fluid.

The heater assembly 110 can include housing components, such as the housing 234 and brackets 258, 260, 272, and 274, formed from polycarbonate and weighing less than about 5 lb. In some embodiments, the heater assembly can weigh less than 4 pounds. In an illustrative embodiment, the heater assembly 110 can have a length 288 of about 6.6 inches, excluding the inlet 110a and the outlet 110b, and a width 290 of about 2.7 inches. The heater assembly 110 can have a height 292 of about 2.6 inches. The flow channel 240 of the heater assembly 110 can have a nominal width 296 of about 1.5 inches, a nominal length 294 of about 3.5 inches, and a nominal height 298 of about 0.070 inches. The height 298 and width 296 can be selected to provide uniform heating of the perfusion fluid 108 as it passes through the channel 240. The height 298 and width 296 may also be selected to provide a cross-sectional area within the channel 240 that is approximately equal to the interior cross-sectional area of a fluid conduit that carries the perfusion fluid 108 to and/or away from the heater assembly 110. In one embodiment, the height 298 and width 296 are selected to provide a cross-sectional area within the channel 240 that is approximately equal to the interior cross-sectional area of the inlet fluid conduit 792 and/or substantially equal to the interior cross-sectional area of the outlet fluid conduit 794.

Protrusions 257a - 257d and 259a - 259d may be included in the heater assembly 110 and may be used to receive a heat-activated adhesive for bonding the heater assembly to the multi-use unit 650 .

In addition to the heater 110 , the system 100 may further include an additional heater (not shown) (eg, a resistive heater) placed within the organ chamber 110 to provide heat.

9. Pressure/flow probe

In some embodiments, the system 600 may include pressure sensors 130a, 130b and flow sensors 138a, 138b. The probes and/or sensors may be obtained from standard commercial sources. For example, the flow rate sensors 136, 138a, and 138b may be ultrasonic flow sensors, such as those available from Transonic Systems Inc. of Ithaca, New York. The fluid pressure probes 130a, 130b may be conventional strain gauge pressure sensors or G.E. thermometers available from MSI. Alternatively, a pre-calibrated pressure transducer chip may be embedded in the organ chamber connector and connected to the controller 150. In some embodiments, the sensors may be configured to measure average, instantaneous, and/or peak flow/pressure values. In embodiments where an average value is calculated, the system may be configured to calculate the average pressure using a continuous average of sampled values. The sensors may also be configured to provide systolic and diastolic measurements. Although these sensors are shown as separate devices in FIG. 17 , in some embodiments, a single device may be used to measure both pressure and flow. In some embodiments, the sensor can be configured to measure pressure between 0 mmHg and 225 mmHg with an accuracy of ±(7% + 10 mmHg) per transducer. In some embodiments, the flow sensor can be configured to measure flow rates between 0 L/min and 10 L/min with an accuracy of ±12% + 0.140 L/min. In some embodiments, the pressure sensor and flow sensor can be configured to sample pressure/flow within the cannula tip, within the blood vessel, or in a tube located before the cannula.

Although there is a single sensor 130b and a single sensor 130a, these sensors may include more than one pressure sensor. For example, in some embodiments, sensor 130a may include two pressure sensors for redundancy. In such embodiments, when both sensors are functioning, controller 150 may average their outputs to determine the actual pressure. In embodiments where one of the two pressure sensors in sensor 130a fails, the controller may ignore the failed sensor.

As described more fully below with respect to Figures 23A to 23K, a pressure sensor can be included in the housing 3010 of the connector 3000 (and similarly on the connector 3050).

10. Flow Control

System 600 can be configured to provide a perfusate flow rate at flow sensor 136 (e.g., before dispenser 105) that varies from 0 to 10 L/min. In some embodiments, the system can be configured to provide a flow rate at flow sensor 136 of 0.6 L/min to 4 L/min, or even more specifically, a flow rate at flow sensor 136 of 1.1 L/min to 1.75 L/min. These ranges are exemplary only, and the flow rate at sensor 136 can be provided within any range that falls within 0 L/min to 10 L/min. System 600 can be configured to provide a perfusate flow rate to the hepatic artery of the liver that varies from 0 L/min to 10 L/min, more specifically, from 0.25 L/min to 1 L/min (e.g., as measured by flow sensor 130b). These ranges are exemplary only, and the flow rate at the hepatic artery can be provided within any range that falls within 0 L/min to 10 L/min. System 600 can be configured to provide a perfusate flow rate to the portal vein of the liver that varies from 0 L/min to 10 L/min, more particularly, from 0.75 L/min to 2 L/min (e.g., as measured by flow sensor 130a). These ranges are exemplary only, and the flow rate at the portal vein can be provided within any range that falls within 0 L/min to 10 L/min.

In some embodiments, system 100 can generate a perfusate flow rate of 0.3 L/min to 3.5 L/min through the perfusion module with at least 1.8 liters of perfusion fluid in the perfusion module. In some embodiments, the pressure provided to the hepatic artery through branch 315 can be between 25 mmHg and 150 mmHg, and more particularly between 50 mmHg and 120 mmHg, and the pressure provided to the portal vein through branch 313 can be between 1 mmHg and 25 mmHg, and more particularly between 5 mmHg and 15 mmHg. These ranges are exemplary only and corresponding pressures can be provided within any range within 5 mmHg to 150 mmHg.

11. Perfusion sensor

Sensor 140 can sense one or more characteristics of the perfusion fluid flowing from the liver by measuring the amount of light absorbed or reflected by the perfusion fluid 108 when applied at multiple wavelengths. For example, sensor 140 can be an _O2 saturation, hematocrit, and/or temperature sensor. Figures 19A-19C illustrate an exemplary embodiment of sensor 140. Sensor 140 can include a coaxial tube 812 of test-tube-shaped cross-section connected to catheter 798. Tube 812 can have at least one optically transparent window through which an infrared sensor can provide infrared light. An exemplary embodiment of sensor 140 can be a BLOP4 and/or BLOP4Plus probe from DATAMED SRL. Test tube 812 can be a single-piece molded component having connectors 801a and 801b. Connectors 801a and 801b can be configured to abut connection receiving portions 803a and 803b of catheter ends 798a and 798b, respectively. This interconnection between the tube 812 and the conduit ends 798a and 798b can be configured to provide a substantially constant cross-sectional flow area within the conduit 798 and the tube 812. Thus, this configuration can reduce, and in some embodiments, substantially eliminate, discontinuities at the interfaces 814a and 814b between the tube 812 and the conduit 798. Reducing/eliminating discontinuities can enable the blood-based perfusion fluid 108 to flow through the tube while reducing lysis of red blood cells and reducing turbulence, which can enable more accurate readings of perfusion fluid oxygen levels. This can also reduce damage to the perfusion fluid 108 by the system 600, which can ultimately reduce damage to the organ being transplanted.

The tube 812 can be formed from a light-transmitting material, such as any suitable light-transmitting glass or polymer. As shown in FIG19A , the sensor 140 can also include an optical transceiver 816 for directing light waves at the perfusion fluid 108 passing through the tube 812 and for measuring light transmission and/or light reflection to determine the amount of oxygen in the perfusion fluid 108. In some embodiments, the light emitter can be located on one side of the tube 812 and the detector for measuring light transmission through the perfusion fluid 108 can be located on the opposite side of the tube 812. FIG19C shows a top cross-sectional view of the tube 812 and the transceiver 816. The transceiver 816 can be fitted around the tube 812 such that the transceiver's interior flat surfaces 811 and 813 mate with the tube's flat surfaces 821 and 823, respectively, and the transceiver's interior convex surface 815 mates with the convex surface 819 of the tube 812. In operation, when UV light is transmitted from transceiver 816, the UV light travels from planar surface 811 through fluid 108 within cuvette 812 and is received by planar surface 813. Planar surface 813 may be configured with a detector for measuring light transmission through fluid 108.

In some embodiments, the sensor 140 can be configured to measure _SvO2 within a range of 0 to 99%, although in some embodiments, this can be limited to 50% to 99%. To the extent that the sensor 140 also measures hematocrit, the measurement range can be 0 to 99%, but in some embodiments, this can be limited to 15% to 50%. In some embodiments, the accuracy of the measurements made by the sensor 140 can be ±5 units, and the measurement can occur at least once every 10 seconds. In embodiments of the sensor 140 that also measures temperature, the measurement range can be from 0°C to 50°C.

In some embodiments, the system 600 can also include one or more lactate sensors (not shown) configured to measure lactate in the perfusion fluid. For example, the lactate sensor can be placed between the measurement drain 2804 and the defoamer/filter 161, in branch 315, and/or in branch 313. In this configuration, the system 600 can be configured to measure the lactate value of the perfusion fluid before and/or after processing by the liver. In some embodiments, the lactate sensor can be a coaxial lactate analyzer probe. In some embodiments, the lactate sensor can also be located outside the system 600 and use a sample of the perfusion fluid drawn from the sampling port.

In some embodiments, system 600 may also include one or more sensors (e.g., sensor 140 and/or other sensors such as disposable blood gas analysis probes) to measure pH, HCO ₃ , pO ₂ , pCO ₂ , glucose, sodium, potassium, and/or lactate. Exemplary sensors that can be used to measure the aforementioned values include off-the-shelf probes manufactured by Sphere Medical of Cambridge, England. As described above, the sensor can be coupled to measurement drain 2804. Alternatively, tubing can be used to transport perfusion fluid to/from the sensor. Some embodiments of the sensor utilize a calibration fluid before and/or after performing measurements. In embodiments utilizing such a sensor, the system may include a valve that can be used to control the flow of the calibration fluid to the sensor. In some embodiments, the valve can be manually actuated and/or automatically actuated by controller 150. In some embodiments of the sensor, no calibration fluid is utilized, which can allow for continuous sampling of the perfusion fluid.

In addition to using the aforementioned sensors in a feedback loop to control the system 600, some or all of the aforementioned sensors may also be used to determine the viability of a liver for transplantation.

In some embodiments, external blood analyzer sensors can also be used. In these embodiments, blood samples can be drawn from ports in branches 313, 315 (the ports are described more fully below). Blood samples can be provided for analysis using standard hospital equipment (e.g., a radiometer) or by a point-of-care blood gas analysis device (e.g., the I-STAT1 from Abbott Laboratories or the Epoc from Alere).

12. Sampling/infusion port

The system 600 can include one or more ports that can be used to sample the perfusion fluid and/or infuse fluid into the perfusion fluid. In some embodiments, the port can be configured to work with a standard syringe and/or can be configured with a controllable valve. In some embodiments, the port can be a Luer port. Essentially, the system 100 can include an infusion/sampling port at any location therein, and the following examples are not limiting.

17 , system 100 may include ports 4301, 4302, 4303, 4304, 4305, 4306, 4307, and 4308. Port 4301 may be used to provide a bolus infusion and/or flush to the hepatic artery (e.g., a post-storage flush). Port 4302 may be used to provide a bolus infusion and/or flush to the portal vein (e.g., a post-storage flush). Ports 4303, 4304, and 4305 may be coupled to corresponding channels of solution pump 631 and may provide infusion to the portal vein (in the case of 4303 and 4304) and to the hepatic artery (in the case of 4305). Ports 4306 and 4307 may be used to obtain samples of perfusion fluid flowing into the hepatic artery and portal vein, respectively. Port 4308 may be used to sample perfusion fluid in the IVC (or hepatic vein, depending on how the liver is harvested). In some embodiments, each port may include a valve operated by the user to obtain fluid from the port.

The port configuration shown in Figure 17 is exemplary and more or fewer ports can be used. In addition, the port can be located at other locations such as between the pump 106 and the distributor 105, between the organ chamber and the bile bag 187, in the bile bag 187, between the main drain 2806 and the defoamer/filter 161.

The single-use module 634 may also include a tube 774 for loading priming solution and drawn blood from a donor or a blood product from a blood bank into the reservoir 160. The priming tube 774 may be provided directly into the reservoir 160 and/or may be positioned so that one end thereof empties directly above the drain 2806 in the organ chamber 104. The single-use module 634 may also include a non-vented cap for replacing a vented cap on a selected fluid port used, for example, when flowing sterile gas through the single-use module 634.

In some embodiments, the system 100 may also include a vent and/or air purge port to remove air from the hepatic artery interface, the portal vein interface, or elsewhere in the system 100 .

In some embodiments, an additional infusion port can be included for the user to provide imaging contrast media to the perfusion fluid, thereby enhancing imaging of the liver. For example, ultrasound contrast media can be infused to perform contrast-enhanced ultrasound.

13. Organ Assistance

Although perfusion fluid can naturally drain from the liver due to the application of pressure to the hepatic artery and portal vein, system 600 can also include additional features that help perfusion fluid drain from the liver in a manner that mimics the human body. That is, in the human body, the diaphragm typically applies pressure to the liver when a person breathes. This pressure can help drain blood from the human liver. System 600 may include one or more systems designed to simulate the pressure applied to the liver by the diaphragm. Exemplary embodiments include contact and non-contact embodiments. In some embodiments, the amount of pressure applied to the liver can be less than the pressure in the liver's portal vein and/or hepatic artery. A simplified diagram of an exemplary embodiment of an organ assist system is shown in Figure 30.

One embodiment of a non-contact pressure system is a system that varies the air pressure in the organ chamber 104 to simulate the pressure exerted by the diaphragm on the liver. In this embodiment, the organ chamber 104 can be configured to provide a substantially airtight environment so that the air pressure within the organ chamber 104 can be maintained in an elevated (or depressed) state compared to the external atmosphere. When the air pressure in the organ chamber 104 increases, the air pressure can apply a pressure to the liver that simulates the pressure exerted by the diaphragm, thereby increasing the rate at which the liver expel perfusion fluid. In some embodiments, the air pressure can be varied in a manner that simulates a human respiratory rate (e.g., 12 to 15 breaths per minute) or other rates (e.g., 0.5 to 50 breaths per minute). The air pressure in the organ chamber 104 can be varied by various methods, including, for example, a dedicated air pump (not shown) and/or an onboard gas supply 172. In some embodiments, the air pressure within the organ chamber 104 can be controlled by a controller 150. In these embodiments, the controller may also be coupled with an air pressure sensor that measures the pressure within the organ chamber 104 used as part of a feedback control loop.

One embodiment of a contact pressure system is a system that uses a wrap and/or bladder to apply pressure to the liver. For example, a wrap can be placed over a portion or all of the liver within the organ chamber 104. The edges of the wrap can then be mechanically tightened to apply pressure to the portion of the liver covered by the wrap. In this example, one or more small motors attached to various points around the circumference of the wrap can be used to tighten the edges of the wrap. In another example of a contact pressure system, a removable bladder (not shown) can be used. In this embodiment, an inflatable bladder can be placed between the liver and the top surface (or some other portion) of the organ chamber 104. A pump can then be used to inflate/deflate the bladder. As the bladder inflates, it can press against the top surface (or other portion) of the organ chamber 104, thereby applying pressure to the liver contained therein. As with the non-contact system described above, pressure acting on the liver can be periodically applied to simulate the natural pressure provided by the diaphragm. In some embodiments, the pressure applied to the liver can be varied to simulate a human breathing rate (e.g., 12 to 15 breaths per minute) or other rates (e.g., 0.5 to 50 breaths per minute). Whether pressure is applied to the liver using a wrap or a bladder, the pressure can be controlled by the controller 150. In some embodiments, one or more sensors that measure the pressure applied to the liver can be included in the organ chamber 104 as part of a feedback control loop. Other methods of providing contact pressure to the liver are also possible.

14. Intubation

Operationally, in one embodiment, a liver can be obtained from a donor and connected to the system 600 by a cannulation method. For example, the interface 162 can be cannulated to the vascular tissue of the hepatic artery via a catheter located in the organ chamber assembly. The interface 166 can be cannulated to the vascular tissue of the portal vein via a catheter located in the organ chamber assembly. The liver releases perfusate through the inferior vena cava (IVC). In some embodiments, the IVC can be cannulated (not shown) via an interface 170 so that the fluid can be directed to a catheter that can measure IVC pressure, flow, and oxygen saturation. In another embodiment, the IVC can be cannulated to guide the flow within the organ chamber via an interface 170. In another embodiment, the IVC is not cannulated, and the organ chamber provides a device to guide the flow of perfusate so that it can be efficiently collected in a reservoir.

Each of ports 162, 166, and 170 can be cannulated to the liver by pulling vascular tissue over the end of the port and then tying or otherwise securing the tissue to the port. The vascular tissue is preferably a short segment of blood vessel that remains connected to the liver after the liver is resected and removed from the donor. In some embodiments, the short segment of blood vessel can be 0.25 inches to 5 inches, but other lengths are possible.

21A-21D , an exemplary embodiment of a hepatic artery cannula 2600 is shown. Cannula 2600 is generally tubular in shape and includes a first portion 2604 configured to be inserted into a tube used in system 100 and including a first orifice 2612. First portion 2604 may also include a ring 2602, which may be used to help frictionally secure first portion 2604 within the tube of system 100. Cannula 2600 may also include a second portion 2608, which may have a smaller diameter than first portion 2604 and be formed with a second orifice 2614. Second portion 2608 may also include a channel portion 2610 recessed from the surface of second portion 2608. In some embodiments, when a user ties the hepatic artery to second portion 2608, the user may place sutures in channel portion 2610 to help secure the hepatic artery. Between the first and second portions may be a collar 2606. The outer diameter of the collar can have a slightly larger diameter than the first portion 2604 to prevent the tube of the system 100 from extending over the second portion 2608 during insertion. Observing the cross-section shown in FIG21D , the inner diameter of the cannula 2600 can vary, with tapers 2616 between each inner diameter. The cannula 2600 can be formed in a variety of sizes, lengths, inner diameters, and outer diameters. In some embodiments of the system 600, it is advantageous for the first portion 2604 to have a relatively large inner diameter and the second portion 2608 to have a much smaller inner diameter to offset pressure and flow variations caused by the cannula 2600.

21H-21K , in an alternative embodiment, the cannula 2600 has a beveled cutting end 2618 .

The outer diameter of the first portion 2604 can be configured to be press-fitted into a silicone or polyurethane tube. Thus, while the outer diameter of the first portion 2604 can vary, an exemplary range of possible diameters is 0.280 inches to 0.380 inches. The outer diameter of the second portion 2608 can range between 4 and 50 Fr, more particularly between 12 and 20 Fr. In addition, the cannula 2600 can be made of various biocompatible materials such as stainless steel, titanium, and/or plastic (the size of the cannula 2600 can be adapted to enable the use of different materials).

In addition, 10% to 20% of the population has a genetic variant in which the liver includes an accessory hepatic artery. For these cases, the hepatic artery cannula can be a double-ended (e.g., Y-shaped) cannula. An exemplary embodiment of a Y-shaped hepatic artery cannula 2642 is shown in Figures 21E to 21G, where the same reference numerals are used to represent corresponding features in cannula 2600. The bifurcated design of the hepatic artery cannula 2642 can allow the system 100 to treat two vessels as one input for hepatic artery flow without changing the configuration of the system 100 and/or the controller 150.

In an alternative embodiment, when the liver includes an accessory hepatic artery, two hepatic artery cannulas 2600 may be attached to the Y-shaped tubing segment at one end and connected to the organ chamber at the other end.

22A-22D , an exemplary embodiment of a portal vein cannula 2650 is shown. Cannula 2650 is generally tubular in shape and includes a first portion 2654 configured to be inserted into a tube used in system 100 and including a first orifice 2660. First portion 2654 may also include a ring 2652, which may be used to help frictionally secure first portion 2654 within the tube of system 100. Cannula 2650 may also include a second portion 2656, which may have a larger diameter than first portion 2654 and be formed with a second orifice 2662. Second portion 2656 may also include a channel portion 2658 recessed from a surface of second portion 2656. In some embodiments, when a user ties the portal vein to second portion 5626, the user may place a suture in channel portion 2658 to help secure the portal vein. 22D, the inner diameter of the cannula 2600 can vary, with tapers 2664 between each inner diameter. The cannula 2650 can be formed in a variety of sizes, lengths, inner diameters, and outer diameters. In some embodiments of the system 600, it may be advantageous for the first portion 2654 to have a relatively large inner diameter and the second portion 2656 to have an even larger inner diameter to offset pressure and flow variations caused by the cannula 2650.

22E to 22G , in an alternative embodiment, the cannula 2650 has a collar 2666 between the first and second portions. The outer diameter of the collar can have a slightly larger diameter than the first portion 2654 to prevent the tube of the system 100 from extending over the second portion 2656 during insertion. The cannula 2650 can also have a beveled cut end 2668.

The outer diameter of the first portion 2654 can be configured to be press-fit within a silicone or polyurethane tube. Thus, while the outer diameter of the first portion 2654 can vary, an exemplary range of possible diameters is 0.410 inches to 0.510 inches. The outer diameter of the second portion 2656 can range between 25 and 75 Fr, more particularly between 40 and 48 Fr. In addition, the cannula 2650 can be made of various biocompatible materials such as stainless steel, titanium, and/or plastic (the size of the cannula 2600 can be adapted to enable the use of different materials).

23A to 23N , an exemplary hepatic artery connector 3000 is shown. The connector 3000 can be part of a branch 315 of the hepatic artery leading to the liver. For example, the connector 3000 can be inserted into and secured to the wall of the organ chamber 104. The connector 3000 can include a first portion 3006 and define an opening 3008, the first portion 3006 including a circumferential channel portion 3007. In some embodiments, the outer diameter of the first portion 3006 is sized to connect to a 1/4 inch tube, but other diameters are possible. In some embodiments, the tube connected to the first portion 3006 can be coupled using friction and/or a conventional cable tie (or other similar fastener) can be tied around the channel portion 3007 to connect the tube thereto. The connector 3000 can also include a second portion 3002 defining an opening 3003. In some embodiments, the outer diameter of the second portion 3002 can be configured to couple to ¼ inch tubing using a pressure/friction connection, although other sizes are possible. In some embodiments, the perfusion fluid flows from opening 3008 to opening 3003 .

The connector 3000 can include an interface configured to mate with an opening in the wall of the organ chamber 104. For example, the connector 3000 can include a ridge 3003 sized to fit within a corresponding opening in the wall of the organ chamber 104. The back stop 3004 can be larger than the opening to prevent the connector from being inserted too far and can also provide a surface to which an adhesive can be applied to adhere the connector 3000 to the organ chamber 104. In some embodiments, the ridge 3003 can include a protrusion 3011 configured to rotationally align the connector 3000 within the organ chamber 104. For example, in some embodiments, the protrusion 3011 and the corresponding opening in the organ chamber 104 can be configured to allow the connector 3000 to rotate about the longitudinal axis of the second portion 3003. In some embodiments, this rotation can be optimized to prevent air bubbles.

The connector 3010 may also include a housing 3010 configured to accommodate a pressure sensor 130b. In this embodiment, two pressure sensors comprise the pressure sensor 130b. In such an embodiment, the pressure sensor may be mounted in an opening 3009, which provides direct access to the fluid within the connector 3000. Additionally, some embodiments of the connector 3000 may include a vent 3005, which may be connected to a valve that can be opened to expel air bubbles trapped within the connector 3000. During operation, the user can attach one end of the tubing to the second portion 3002 and the other end of the tubing to the hepatic artery cannula 2600 (which can be connected to the hepatic artery). In some embodiments, the user can place the liver into the organ chamber 104, connect the cannula 2600 to one end of the tubing, and then use sutures to connect the end of the tubing to the hepatic artery. Next, since livers can vary in size, the user can trim the tubing to the appropriate length and attach it to the second portion 3003.

24A to 23L , an exemplary portal vein connector 3050 is shown. In some embodiments, portal vein connector 3050 is configured and functions in the same manner as connector 3000, except that the first and second portions can be coupled to 3/8-inch or 1/2-inch tubing instead of 1/4-inch tubing, although portal vein connector 3050 can also be configured for use with tubing of other sizes. Furthermore, as should be apparent from the name, portal vein connector 3050 can be configured to couple branch 313 to the portal vein of the liver.

While some dimensions are provided above, these dimensions are exemplary only, and each of the aforementioned components can be sized as needed to achieve the desired fluid characteristics. For example, in some embodiments, it may be beneficial to use a cannula of the largest diameter to avoid introducing undesirable pressure or flow variations. Furthermore, in practice, the diameter of the cannula can be selected by the surgeon to use the largest cannula that will physically fit within the vessel.

This article notes that some consider the "Fr" scale to end at "34." Therefore, in the range of determining an Fr size greater than 34 (or an Fr number that does not exist in the conventional Fr scale), the size can be calculated in mm by dividing the determined Fr number by 3.

15. Mobile fixture

25A-25B , an exemplary embodiment of a flow clamp 190 is shown. The flow clamp 190 can be used to control the flow rate and/or pressure of perfusion fluid flowing into the hepatic portal vein. The flow clamp 190 can include a cover 4001, a knob 4002, a pivot 4003, a pin 4004, a screw 4005, a support 4006, a slider 4007, a shaft 4008, and a body 4009. The slider 4007 can include a groove 4010 and a locking portion 4012 and can be configured to move up and down within the body 4009. In some embodiments, a tube carrying the perfusion fluid is placed within the body 4009, beneath the slider 4007. Figures 25C-25D illustrate a flow clamp 190 having molded components.

The flow clamp 190 can be configured to allow the user to quickly engage and disengage the clamp 190 while still having precise control over the amount of clamping force applied. In this embodiment, the cover 4001, knob 4002, pivot 4003, pin 4004, screw 4005, and support 4006 comprise a switch unit 4011. The pivot 4003 of the switch unit 4011 can rotate about a longitudinal axis formed by shaft 4008 (which can be formed by two separate screws). In this manner, when the switch unit 4011 is engaged (e.g., screw 4005 is vertical), as shown in FIG25A , the support 4006 forces the slider 4007 downward within the body 4009 (if perfusion fluid is present, the slider 4007 can depress the tube carrying the perfusion fluid and confine the fluid in the tube). The distance the slider is forced downward is a function of the extent to which the screw 4005 is extended relative to the pivot 4003. When the switch unit 4011 is disengaged, the switch unit 4011 pivots sideways so that the screw is no longer vertical and does not restrict the movement of the slider 4007. As the switch unit 4011 pivots, the support member can slide along the groove 4010. In some embodiments, the switch unit 4011 can be "locked" in place when the support member 4006 becomes seated in the locking portion 4012. The user can adjust the amount of flow restriction applied by the flow clamp 190 by rotating the knob 4002 to extend/retract the screw 4005 when the flow clamp 190 is engaged. In some embodiments, the pitch of the screw can be 4 threads to 40 threads, but other pitches can be used to adjust the precision of the flow clamp 190.

16. Filling

In some embodiments, the perfusion fluid includes concentrated red blood cells, also known as "banked blood." Alternatively, the perfusion fluid includes blood removed from the donor during the blood draw process during liver harvesting. Initially, blood is loaded into a reservoir 160 and the cannulation point in the organ chamber assembly is connected to a bypass conduit—also known as a "filling line"—to allow perfusion fluid to flow through the system in a normal manner even without the liver. Before cannulating the harvested liver, the system can be primed by circulating withdrawn donor blood through the system to warm, oxygenate, and/or filter the blood. Nutrients, preservatives, and/or other therapeutic agents can also be provided during priming via the infusion pump of the nutrition subsystem. Various parameters can also be initialized and calibrated during priming through the operator interface. Once properly primed and operational, the circulating pump flow can be reduced or stopped, the bypass conduit removed from the organ chamber assembly, and the liver can be cannulated into the organ chamber assembly. Pump flow can then be restored or increased as appropriate. The priming process is described more fully below.

17. IVC cannulation

In some embodiments, the inferior vena cava (IVC) may be cannulated, but this is not required. In these embodiments, additional pressure and/or flow sensors may be used to determine the pressure and/or flow of the perfusion fluid flowing from the liver. In some embodiments, the cannulated IVC may be directly coupled to sensor 140 and/or a reservoir. In other embodiments, the IVC may be cannulated to direct the discharge of the perfusion fluid (e.g., to allow it to drain freely). For example, the uncannulated end of the short tube connected to the IVC may be held in place by a clamp so that the perfusion fluid drains directly over the measurement drain 2804. In other embodiments, the IVC is not cannulated and the perfusion fluid can drain freely from the IVC. In other embodiments, the IVC may be partially ligated.

In embodiments where the IVC is cannulated and connected to a tube, it is desirable to keep the length of the tube as short as possible to achieve the desired result. That is, because physiological IVC pressure is low, even a relatively narrow tube length can result in an increase in IVC pressure. In embodiments of system 600 that include applying pressure to the liver (e.g., pressurizing chamber 104 as described above) to facilitate drainage, the liver may be able to tolerate a longer cannula/tube.

18. Biliary cannulation

In some embodiments of system 600, an off-the-shelf and/or custom-made cannula can be used to cannulate the bile duct of the liver. For example, a 14Fr bile duct cannula can be used. In addition, a bile bag 187 can be configured to collect bile produced by the liver. In some embodiments, bag 187 is transparent so that the user can observe the color of the bile with the naked eye. In some embodiments, bag 187 can collect up to 0.5L of bile, but other amounts are possible. In some embodiments, bag 187 can include a scale indicating how much bile has been collected. Although system 600 is described as including a soft shell (e.g., bag 187) for collecting bile, a hard shell container can also be used. Some embodiments of system 600 can include a sensor (e.g., capacitive, ultrasonic, and/or flow accumulation) for measuring the amount of bile collected. Subsequently, this information can be displayed to the user and/or sent to the cloud.

19. Blood collection/filter

Some embodiments of the system 600 using whole blood from a donor may include a leukocyte filter (not shown). In these embodiments, the leukocyte filter can be used when priming the system to filter blood received from the donor's body via a blood collection line connected to the donor's artery and/or vein. In some embodiments, the leukocyte filter can be configured to filter at least 1500 mL of blood in 6 minutes or less (although other rates are possible). In some embodiments, the leukocyte filter can be configured to remove 30% or more of all leukocytes in up to 1500 mL of whole blood.

20. Final flush application kit

Sometimes during surgery, it is desirable to remove all perfusion solution from the liver vasculature without disconnecting the liver from the system 100 (e.g., before the liver is implanted in a recipient). Therefore, embodiments of the system 600 can be used with a final flush administration kit. The kit can include a bag (or other container) for collecting a certain amount of liquid (e.g., flush solution and/or perfusate) so that when the flush solution is administered to the liver (e.g., via ports 4301, 4302), the system 100 is not exposed to an additional amount of fluid. Therefore, in some embodiments, the system 100 can include a drain line (not shown) that can be used to drain fluid from the reservoir 160 and/or elsewhere in the system 100 so that the liver does not need to be disconnected from the system 100 before additional fluid is added. In some embodiments, the system can also be configured to operate in a bypass mode, wherein one or more valves are used to temporarily isolate the liver from the system 100. For example, in this embodiment, a valve can be used before ports 4301, 4302 to stop the flow of fluid within the system 100. An additional drain port may then be included between drains 2804, 2806 and the valve. In this embodiment, a flush solution (or any other solution) may be provided through ports 4301, 4302 and drained from the additional drain port without circulating the flush solution through the rest of the system 100. In some embodiments, the drain line may hold at least 3 L of liquid, but this is not required.

D. Interface between single/multiple use modules

As shown in FIG3G and described in further detail below, the multiple-use module 650 can include a front-end interface circuit board 636 for interfacing with a front-end circuit board (shown as 637 in FIG13J ) of the disposable module 634. As described more fully below, power and drive signal connections between the multiple-use module 650 and the disposable module 634 can be made via corresponding electromechanical connectors 640 and 647 located on the front-end interface circuit board 636 and the front-end circuit board 637, respectively. By way of example, the front-end circuit board 637 can receive power for the disposable module 634 from the front-end interface circuit board 636 via the electromechanical connectors 640 and 647. The front-end circuit board 637 can also receive drive signals for various components (e.g., the heater assembly 110, the flow fixture 190, and the oxygenator 114) from the controller 150 via the front-end interface circuit board 636 and the electromechanical connectors 640 and 647. The front end circuit board 637 and the front end interface circuit board 636 can exchange control and data signals (e.g., between the controller 150 and the single use module 634) via optical connectors (shown as 648 in FIG. 20B ). As described in more detail below, the connection configuration employed between the front end circuit board 637 and the front end interface circuit board 636 can ensure that the critical power and data interconnections between the single use module 634 and the multiple use module 650, respectively, continue to operate even during transport over rough terrain, such as might be experienced during organ transport.

Turning now to the installation of the single-use module 634 within the multiple-use module 650, FIG3H illustrates a detailed view of the bracket assembly 638 described above, which is located on the multiple-use module 650 and is used to receive and lock the single-use module 634 in place. FIG3F illustrates a side perspective view of the single-use module 634 being mounted on the bracket assembly 638 and installed within the multiple-use module 650, and FIG3C illustrates a side view of the single-use module 634 installed within the multiple-use module 650. The bracket assembly 638 includes two mounting brackets 642a and 642b, which can be mounted to the inside of the rear panel of the housing 602 via mounting holes 644a to 644d and 646a to 646d, respectively. A crossbar 641 extends between the mounting brackets 642a and 642b and is rotatably attached to the mounting brackets 642a and 642b. Locking arms 643 and 645 are spaced apart along crossbar 641 and extend radially from crossbar 641. Each of locking arms 643 and 645 includes a respective downwardly extending locking protrusion 643a and 645b. Rod 639 is attached to crossbar 641 and extends radially upward from crossbar 641. Actuation of rod 639 in the direction of arrow 651 rotates locking arms 643 and 645 toward rear portion 606b of housing 602. Actuation of rod 639 in the direction of arrow 653 rotates locking arms 643 and 645 toward the front of housing 602.

As described above with respect to FIG6E , the infusion pump interface assembly 300 includes four protruding heat stakes 321 a to 321 d. During assembly, the protrusions 321 a to 321 d are aligned with and heat staked through corresponding apertures (e.g., 657 a, 657 b in FIG13B ) to rigidly mount the outer side 304 of the pump interface assembly 300 to the C-shaped bracket 656 of the single use module base 635.

During installation, in a first step, the single use module 634 is lowered into the multiple use module 650 while tilting the single use module 634 forward (as shown in FIG3F ). This process causes the protrusion 662 to slide into the groove 660. As shown in FIG6E , this process also causes the flange 328 of the pump interface assembly 300 to be positioned within the docking port 342 of the perfusion pump assembly 106 and the tapered protrusions 323 a and 323 b of the pump interface assembly 300 to be positioned clockwise of a corresponding one of the features 344 a and 344 b of the pump assembly bracket 346. In a second step, the single-use module 634 is rotated backward until the locking arm bracket of the single-use module base 635 engages the protrusions 643 and 645 of the spring-loaded locking arm 638, thereby forcing the protrusions 643 and 645 to rotate upward until the locking protrusions 643a and 645a are clear of the height of the locking arm bracket, at which point the spring rotates the locking arm 638 downward, allowing the locking protrusions 643a and 645a to releasably lock with the locking arm bracket of the disposable module base 635. This movement causes the curved surface 668 of the single-use module protrusion 662 of Figure 13B to rotate and engage the flat side 670 of the basin slot 660 of Figure 20B. The lever 639 can be used to rotate the locking arm 638 upward to release the single-use module 635.

6E , this motion also rotates the pump interface assembly 300 counterclockwise relative to the pump assembly 106 to slide the flange 328 into the slot 332 of the docking port 342 and simultaneously slide the tapered protrusions 323 a and 323 b under the corresponding bracket features 344 a and 344 b. As the tapered protrusions 323 a and 323 b slide under the corresponding bracket features 344 a and 344 b, the inner surfaces of the bracket features 344 a and 344 b engage the tapered outer surfaces of the tapered protrusions 323 a and 323 b to pull the inner side 306 of the pump interface assembly 300 toward the pump driver 334, forming a fluid-tight seal between the pump interface assembly 300 and the pump assembly 106. The rod 639 can be locked in place to securely hold the disposable module 634 within the multiple use module 650.

Interlocking the single-use module 374 into the multiple-use module 650 allows for both electrical and optical interconnections between the front-end interface circuit board 636 on the multiple-use module 650 and the front-end circuit board 637 on the single-use module 634. The electrical and optical connections enable the multiple-use module 650 to provide power to, control, and collect information from the single-use module 634. FIG20A is an exemplary conceptual diagram illustrating various optical couplers and electromechanical connectors on the front-end circuit board 637 of the disposable, single-use module 634 for communicating with corresponding optical couplers and electromechanical connectors on the front-end interface circuit board 636 of the multiple-use module 650. Because this correspondence is one-to-one, the various optical couplers and electromechanical connectors will be described only with reference to the front-end circuit board 637, rather than also describing the front-end circuit board 650.

According to an exemplary embodiment, the front-end circuit board 637 receives signals from the front-end interface circuit board 636 via an optocoupler and electromechanical connectors. For example, the front-end circuit board 637 receives power 358 from the front-end interface circuit board 636 via electromechanical connectors 712 and 714. The front-end circuit board 637 applies this power to components of the single-use module 634, such as the various sensors and transducers of the single-use module 634. Optionally, the front-end circuit board 637 converts the power to an appropriate level before distributing it. The front-end interface circuit board 636 can also provide heater drive signals 281a and 281b to the applicable connector 282a on the heater 246 of Figure 6E via electromechanical connectors 704 and 706. Similarly, electromechanical connectors 708 and 710 can couple heater drive signals 283a and 283b to the applicable connector 282b of the heater 248.

According to an exemplary embodiment, the front-end circuit board 637 can receive signals from temperature sensors, pressure sensors, fluid flow rate sensors, and oxygenation/hematocrit sensors, amplify the signals, convert the signals to digital format, and provide the signals to the front-end interface circuit board 636 via electrical and/or optical couplers. For example, the front-end circuit board 637 can provide the temperature signal 121 from the sensor 120 on the heater board 250 to the front-end interface circuit board 636 via the optical coupler 676. Similarly, the front-end circuit board 637 can provide the temperature signal 123 from the sensor 122 on the heater board 252 to the front-end interface circuit board 636 via the optical coupler 678. The front-end circuit board 637 can also provide the perfusion fluid temperature signals 125 and 127 from the thermistor sensor 124 to the front-end interface circuit board 636 via respective optical couplers 680 and 682. The perfusion fluid pressure signals 129, 131, and 133 can be provided from the respective pressure sensors 126, 128, and 130 to the front-end interface circuit board 636 via respective optical couplers 688, 690, and 692. The front-end circuit board 637 can also provide perfusion fluid flow rate signals 135, 137, and 139 from the corresponding flow rate sensors 134, 136, and 138 to the front-end interface circuit board 636 via corresponding optical couplers 694, 696, and 698. Furthermore, the front-end circuit board 637 can provide the oxygen saturation signal 141 and the hematocrit signal 145 from the sensor 140 to the front-end interface circuit board 636 via corresponding optical couplers 700 and 702. In another embodiment, the front-end circuit receives signals from an integrated blood gas analysis probe. In another embodiment, the front-end board transmits control signals to the fluid path restrictor to facilitate real-time control of the allocation of perfusate flow between the portal vein and hepatic artery catheters. The controller 150 can utilize the signals provided to the front-end interface circuit board 636, as well as other signals, to transmit data and otherwise control the operation of the system 600.

Although a front end circuit board 637 is described with the aforementioned couplers, more or fewer couplers may be used based on the number of connections required.

In some exemplary embodiments, one or more of the aforementioned sensors can be wired directly to the main system board 718 for processing and analysis, thereby bypassing the front-end interface board 636 and the front-end board 637 altogether. Such an embodiment is desirable when the user prefers to reuse one or more sensors before processing. In one such example, the flow rate sensors 134, 136, and 138 and the oxygen and hematocrit sensor 140 are electrically coupled directly to the system board 718 via the electrical coupler 611 shown in FIG. 23C , thereby bypassing any connection to the circuit boards 636 and 637.

FIG20B illustrates the operation of an exemplary electromechanical connector pair of the type used for electrical interconnection between circuit boards 636 and 637. FIG20C illustrates the operation of an optocoupler pair of the type used for optical coupling interconnection between circuit boards 636 and 637. One advantage of using both electrical connectors and optocouplers is that they ensure connection integrity even when system 600 is transported over rough terrain, such as along tarmac roads at an airport, in an airplane under inclement weather conditions, or in an ambulance over rough roads. The power to front end board 637 is isolated in the DC power supply located on front end interface board 636.

As shown in FIG20B , an electromechanical connector, such as connector 704, includes a portion, such as portion 703, located on the front interface circuit board 636 and a portion, such as portion 705, located on the front circuit board 637. Portion 703 includes an enlarged head 703a mounted on a substantially straight and rigid stem 703b. Head 703 includes an outwardly facing, substantially flat surface 708. Portion 705 includes a substantially straight and rigid pin 705, which includes a spring-loaded end 705b and an end 705a for contacting surface 708. Pin 705 can be moved axially in and out, as indicated by directional arrow 721, while maintaining electrical contact with surface 708 of enlarged head 703a. This feature enables single-use module 634 to maintain electrical contact with multiple-use module 650 even when subjected to mechanical disturbances associated with transportation over rough terrain. An advantage of flat surface 708 is that it allows for easy cleaning of the interior surface of multiple-use module 650. According to the illustrative embodiment, the system 600 employs a connector for electrical interconnection between the multiple use module 650 and the disposable single use module 634. An exemplary connector is part number 101342 manufactured by Interconnect Devices. However, any suitable connector may be used.

Optocouplers such as optocouplers 684 and 687 of front-end circuit board 637 are used and include corresponding counterparts such as optocouplers 683 and 685 of front-end interface circuit board 636. The optical transmitter and optical receiver portions of the optocouplers may be located on circuit boards 636 or 637.

When using electromechanical connectors, the allowable tolerances in the optical alignment between the optical transmitter and the corresponding optical receiver allow the circuit boards 636 and 637 to maintain optical communication even during transportation over rough terrain. According to the illustrative embodiment, the system 100 uses optical couplers manufactured by Osram with part numbers 5FH485P and/or 5FH203PFA. However, any suitable coupler may be used.

Couplers and connectors facilitate data transfer within system 600. Front-end interface circuit board 636 and front-end board 637 transmit data related to system 600 in a paced manner. As shown in FIG20C , circuit board 636 sends a clock signal to front-end board 637 that is synchronized with the clock on controller 150. Front-end circuit board 637 receives this clock signal and uses it to synchronize system data (such as temperature, pressure, or other required information) with the clock cycle of controller 150. This data is digitized by a processor on front-end circuit board 637 based on a preset sequence of clock signals and data types and addresses of data sources (i.e., the type and location of the sensor providing the data). Front-end interface circuit board 636 receives data from front-end board 637 and sends this data set to main board 618 for evaluation, display, and system control by controller 150. Additional optocouplers can be added between the multiple-use and single-use modules to transmit control data from the multiple-use module to the single-use module. This data may include heater control signals or clamp/flow restrictor controls.

IV. Description of Exemplary System Operation

A. Overview

As described below, the system 600 can be configured to operate in a variety of modes, such as a perfusion circuit filling mode, an organ stabilization mode, a maintenance mode, a freezing mode, and a self-test mode/diagnostic mode. During each mode, the system (with respect to the controller 150) can be configured to operate in a different manner. For example, as described more fully below, during different operating modes, characteristics such as perfusion fluid flow rate, perfusion fluid pressure, perfusion fluid temperature, etc. can vary.

In addition, some embodiments of the system 600 may include a self-test mode that can perform diagnostics. For example, the system 600 can automatically test the circuits and sensors in the single-use module and the multiple-use module before the organ is equipped on the system. The system 600 can also check to ensure that the single-use module is properly installed in the multiple-use module (e.g., all connections are secure and functional). In the event of a malfunction, the system can notify the user and prohibit further operation of the system until the problem is resolved.

B. Temperature monitoring and control

Generally, the temperature of an organ housed in the system 600 is controlled by the heated or cooled perfusion fluid circulating therein. Thus, the perfusion fluid itself can be used to control the temperature of the organ without the need for a dedicated heater/cooler within the organ chamber 104.

In some embodiments of the system 600, the controller 150 can be configured to receive signals from one or more temperature sensors (e.g., temperature sensors 120, 122, 124). Although these sensors are depicted as being located at or near the heater 110, this is not required. For example, temperature sensors that measure the temperature of the perfusion fluid can be located throughout the system 100, such as in the branches 313, 315, in the measurement drain 2804, in the drain 2806, and/or in the reservoir 160. Additional temperature sensors can also be included to measure other temperature aspects of the system 600. For example, the system 600 can include an ambient air temperature sensor that measures the ambient temperature surrounding the system 600, a temperature sensor that measures the ambient temperature within the organ chamber 104, and/or a sensor that measures the temperature of the surface and/or internal portion of an organ housed in the organ chamber 104.

The controller 150 can use information from various temperature sensors in the system 600 to control the temperature of the environment and/or the temperature of the perfusion fluid in the system 600. For example, in some embodiments, the controller 150 can maintain the perfusion fluid exiting the heater at a desired temperature. In some embodiments, the controller 150 can determine the temperature difference between the perfusion fluid flowing into the organ and the perfusion fluid flowing out of the organ. If the temperature difference is large, the controller 150 can indirectly determine the organ temperature and adjust the temperature of the perfusion fluid flowing into the organ to achieve the desired organ temperature. In addition, in some embodiments, the organ chamber 104 can include a heater/cooler, such as a resistive heater or a thermoelectric cooler, to heat/cool the environment within the organ chamber 104. The heater/cooler can be controlled by the controller 150.

While much of the disclosure herein focuses on warming an organ to a desired temperature, this is not intended to be limiting. In some embodiments, the system 600 can include a cooling unit (not shown) in addition to and/or in place of the heater 110. In these embodiments, the cooling unit can be used to cool the perfusion fluid and ultimately the organ itself. This is useful, for example, during post-preservation freezing procedures used with the heart, lungs, kidneys, and/or liver. In some embodiments, the cooling unit can include a gas exchanger with an integrated water-cooling feature, but other configurations are also possible.

C. Blood flow monitoring and control

Many organs in the human body (e.g., kidneys, lungs) receive a blood supply with a single set of pressure and flow characteristics. To the extent these organs are maintained ex vivo in an organ care system, perfusion fluid can be provided to the organ using a single pump and a single supply line. However, the liver differs from other organs in that it has two blood supplies, each with different pressure and flow characteristics. As described above, the liver receives approximately one-third of its blood supply from the hepatic artery and approximately two-thirds from the portal vein. The hepatic artery provides pulsatile blood flow at a relatively high pressure but a low flow rate. In contrast, the portal vein provides a largely non-pulsatile blood flow at a relatively low pressure but a high flow rate. Due to these different flow characteristics, providing perfusion fluid to an ex vivo liver can be challenging when using a single pump. Therefore, some embodiments of the organ care system 600 include a system configured to provide dual perfusion fluid streams in a manner that mimics the human body. Specifically, branch 315 of the system 100 can provide perfusion fluid to the hepatic artery in a pulsatile, high-pressure, low-flow manner. Branch 313 of system 100 can provide perfusion fluid to the portal vein in a non-pulsatile, low-pressure, high-flow manner.

As described above, pump 106 can provide a perfusion fluid flow at a predetermined flow rate, which can be split at distributor 105. In some embodiments, the fluid flow can be split between the hepatic artery and portal vein at a ratio of 1:2 to 1:3. In some embodiments, the distributor is configured so that branch 313 uses 3/8-inch tubing and branch 315 uses 1/4-inch tubing. In some embodiments, a portal vein clamp can be used to help achieve this split ratio and/or can be used to restrict the flow generated in the portal vein branch of the circuit (e.g., branch 313) to generate higher-pressure flow in the hepatic artery branch of the circuit (e.g., branch 315) and lower-pressure flow in the parallel portal vein branch of the circuit. In some embodiments, the user can manually adjust the portal vein clamp (e.g., flow clamp 190) to achieve an acceptable liver pressure within the range and adjust the pump flow rate to provide an acceptable hepatic artery flow rate. The combination of these two adjustments (portal vein clamp and pump flow rate) results in an acceptable hepatic artery flow and pressure and, correspondingly, an acceptable portal vein pressure and flow rate.

In some embodiments, the portal vein clamp can be implemented as a mechanism controlled by the system, such as an electromechanically controlled clamp or a pneumatically controlled clamp. The system can adjust the pump flow and the portal vein clamp in response to the values of pressure and flow measured on the hepatic artery branch and the portal vein branch to achieve pressure and flow within an acceptable range for these pathways. For example, in an embodiment using an automated portal vein clamp, if the controller 150 detects that the flow in the hepatic artery branch 315 is too low, the controller 150 can increase the flow rate provided by the pump 106. Similarly, if the controller detects that the pressure in the hepatic artery branch 315 is too low, the controller 150 can cause the portal vein clamp to close slightly to increase the pressure in the hepatic artery branch 315.

In some embodiments, the controller 150 can monitor the level of the perfusion fluid in the system 600. If the amount of perfusion fluid falls below a recommended level, the controller 150 can alert the user to this fact, allowing the user to take recommended actions, such as adjusting the pump flow rate and/or adding additional perfusion fluid to the system. Additionally, if the level falls below a critical level, the controller 150 can automatically reduce the pump flow rate to a reduced level or minimum level while alerting the user.

D. Gas monitoring and control

In some embodiments, system 600 can be configured to automatically control the pressure within the system by varying the flow rate of pump 106 and/or by controlling the infusion of a vasodilator. For example, one of the infusates provided by solution pump 631 can be or contain a vasodilator. When a vasodilator is administered, the perfusion fluid pressure for a given flow rate within system 100 can decrease (due to dilation of the vasculature in the liver). Thus, for example, decreasing the infusion rate of the vasodilator can result in an increase in the perfusate pressure. An optimal balance can be achieved at the minimum amount of vasodilator that results in adequate liver perfusion.

System 600 can be configured to control the gas content of the perfusion fluid in a manner that simulates the human body. Thus, in some embodiments, system 600 includes a gas exchanger (e.g., gas exchanger 114) configured to provide _O2 and/or other desired gases to the perfusion fluid. In principle, the gas exchanger operates by facilitating the flow of high-concentration gases to areas of low gas concentration. In this way, _O2 in the maintenance gas (e.g., the gas provided to the gas exchanger) can diffuse into the _O2 -depleted perfusion fluid, and relatively high levels of _CO2 in the perfusion fluid can diffuse into the maintenance gas before it exits the gas exchanger. The maintenance gas provided to the gas exchanger can include a suitable mixture of _O2 , _N2 , and _CO2 , wherein the _O2 concentration is higher and the _CO2 concentration is lower than that of the perfusion solution leaving a metabolically active liver. In some cases, the gas includes only _O2 and _N2 .

Some embodiments of the system 600 include an oxygenation sensor (e.g., sensor 140) that can be used to provide information about the oxygenation of the perfusion fluid. If the oxygenation level is too low, the rate at which gas is supplied to the gas exchanger can be increased to increase the oxygen level in the perfusion fluid. Similarly, if the level is too high, the rate at which gas is supplied to the gas exchanger can be decreased. Control of the supply of gas to the gas exchanger can be performed manually by a user (e.g., via an operator interface module 146) and/or automatically. In automated embodiments, the controller 150 can automatically increase or decrease the flow of gas from the onboard gas supply to the gas exchanger to achieve a desired change in oxygenation level.

However, the liver presents additional challenges in providing adequate perfusion fluid gas content. Due to its inherent metabolism, the liver produces _CO2, which replaces the _O2 contained in the perfusate. In some embodiments, measuring _O2 levels alone is insufficient to determine the amount of _CO2 present in the perfusion fluid. Therefore, in some embodiments, the system 600 can be configured to monitor the _CO2 level in the perfusion fluid alone to ensure that _CO2 remains within an acceptable range. In these embodiments, a gas exchanger can also be used to reduce or even eliminate _CO2 from the perfusion fluid as it passes through the gas exchanger.

To determine the carbon dioxide level in the perfusate, some embodiments of system 600 include a blood sample port so that the user can draw a blood sample to assess the carbon dioxide level in the perfusate via a third-party blood gas analyzer. Based on this analysis, the user can allocate the gas flow rate to the gas exchanger to achieve an acceptable carbon dioxide level in the perfusate. For example, carbon dioxide above an acceptable level may require a higher gas flow rate to the gas exchanger to reduce the resulting carbon dioxide level. However, it may be advantageous to keep the gas flow rate to the gas exchanger as low as possible to maximize the life of the onboard gas supply—an important factor in extended delivery situations.

Some embodiments of system 600 may include a blood gas analysis system (not shown). In these embodiments, the blood gas analysis system can be configured to sample the perfusion fluid flowing within system 100. For example, the blood gas analysis system can be configured to collect samples of the perfusion fluid at one or more locations in system 100, such as in branches 313, 315, in measurement drain 2804, and/or in main drain 2806. By measuring the concentration of oxygen and/or carbon dioxide in the perfusate, controller 150 can automatically increase or decrease (as appropriate) the gas flow to the gas exchanger to achieve the desired gas level in the perfusion fluid.

E. Solution delivery and control

As described above, some embodiments of the system 600 may include a solution pump configured to provide one or more solutions. In some specific embodiments, the runtime perfusion solution includes three solutions. The first solution may include one or more energy-rich components (e.g., one or more carbohydrates); and/or one or more amino acids; and/or one or more electrolytes; and/or one or more buffers (e.g., bicarbonate). In some specific embodiments, the first solution may include TPN (Clinimix E), a buffer (e.g., sodium bicarbonate and phosphate), heparin, and insulin. The second solution may include one or more vasodilators. In some specific embodiments, the vasodilator used is The third solution may include a bile acid or salt (e.g., taurocholic acid sodium salt). In some embodiments, the three solutions are kept separate from each other and administered separately (e.g., using three channels of the solution pump 631). In other embodiments, the three solutions, optionally all aqueous solutions, may be mixed together to form the runtime perfusion solution. In certain embodiments, a sufficient amount of heparin may be provided (e.g., an amount sufficient to maintain an activated clotting time (ACT) of about or greater than 400 seconds). V. Solution

Exemplary solutions that may be used in the organ care system 600 according to one or more embodiments are now described. Different solutions may be used at different times during the preservation/processing process.

A. Donor flushing

If the organ being harvested is an abdominal organ, the surgeon performing the harvesting may perform a donor flush, either in vivo or ex vivo, to remove donor blood and/or other substances from the organ. The flushing agent used during the donor flush may be an intracellular solution or an extracellular solution, such as University of Wisconsin solution, modified University of Wisconsin solution, or histidine-tryptophan-ketoglutarate (HTK) solution.

B. Initial flushing solution

In some embodiments, after the donor flush (whether the donor flush is performed in vivo or in vitro), and before the donor is placed in the storage chamber of the organ care system 600, an initial flush solution can be used to flush the liver in vivo or in vitro to remove residual blood and any solution used in the donor flush. This flush solution is referred to as the initial flush solution in this article, which is optionally a sterile solution. In some embodiments, the main components of the initial flush solution can include a buffered isotonic electrolyte solution such as Plasmalyte and an anti-inflammatory drug such as SoluMedrol. In some embodiments, the initial flush can be used to remove the fluid used during the donor flush. In some embodiments, the main components of the initial flush solution can include electrolytes and buffers. Non-limiting examples of electrolytes include various salts of sodium, potassium, calcium, magnesium, chloride, hydrogen phosphate, and bicarbonate. A suitable combination of electrolytes at a suitable concentration will help maintain the physiological osmotic pressure of the intracellular and extracellular environments in the liver. Non-limiting examples of buffers include bicarbonate ions. The buffer in the initial flush solution can be used to maintain the pH within the liver organ at or near physiological conditions, such as approximately 7.3 to 7.6, 7.4 to 7.6, or 7.4 to 7.5. Preferably, after the liver is initially flushed and cooled according to more than one embodiment described herein, the harvested liver can be placed in the organ care system 600 according to one or more embodiments.

C. Filling solution and additives

In some embodiments, before the liver is placed in the organ care system 600, the organ care system 600 can be filled with a filling solution. The filling solution can be sterile and can be used to assess the physical integrity of the system and/or help remove air from the system. The composition of the filling solution can be similar or identical to the composition of the perfusion solution during operation, which is described in more detail below. The filling solution can include certain additives to make the system compatible with liver preservation. For example, the liver regularly produces coagulation factors that promote blood clotting. To prevent blood (e.g., donor blood used as part of the perfusion fluid for preserving the liver on the organ care system 600) from clotting during preservation, an anticoagulant can be added as an additive to the filling solution. Non-limiting examples of anticoagulants include heparin. Heparin can be administered throughout the preservation period to maintain an ACT (activated clotting time) of ≥400 seconds, but other ACT values can be used. Depending on the liver being preserved, the amount of heparin required to achieve the desired ACT can vary. In some embodiments, heparin can be provided continuously or at intervals such as at 0 hours, 3 hours, and 6 hours after being equipped on the system 600. In certain embodiments, the organ care system 600 can be primed with a blood product (e.g., donor blood) or a synthetic blood product before the liver is placed in the organ care system 600. In certain embodiments, the system 600 can be primed with a filling solution and/or blood or a synthetic blood product. The system 600 can be filled with a mixture of a filling solution and blood or a synthetic blood product, or with a filling solution and blood or a synthetic blood product sequentially. In some embodiments, the organ care system 600 is filled with a perfusion fluid described herein (e.g., a perfusion fluid for preserving an organ). Alternatively or in addition, any of the following, bound to protein or dextran, can also be used: donor blood, red blood cells (RBCs), or RBCs supplemented with fresh frozen plasma.

Table 1 lists components that may be used in exemplary priming solutions.

Table 1. Composition of exemplary priming solutions

An exemplary priming solution may be added to the organ care system 600 via a priming step 5024, as more fully described with reference to FIG. 29 (described more fully below).

D. Run-time perfusion solution

While the harvested liver is being stored in the organ care system 600 (e.g., during transport), a perfusion fluid or perfusate can be used to perfuse the liver and maintain liver function at or near physiological conditions. In certain embodiments, the perfusion fluid includes a runtime perfusion solution (also referred to as a maintenance solution) and/or a blood product, such as donor blood, compatible blood from another individual, or synthetic blood. The perfusion fluid can be periodically/continuously infused by, for example, a solution pump 631 to provide nutrients that can maintain the liver during storage. In some embodiments, the runtime perfusion solution and/or the blood product are sterile.

The composition of the runtime perfusion solution and the priming solution will now be described in more detail. According to certain embodiments, the runtime perfusion solution having specific solutes and concentrations is selected and proportioned to enable the organ to function under physiological or near-physiological conditions. For example, these conditions include maintaining organ function at or near physiological temperature and/or preserving the liver in a state that allows normal cellular metabolism, such as protein synthesis, glucose storage, lipid metabolism, and bile production. In some embodiments, the priming solution and the runtime solution can be selected to be similar or even identical to each other.

In certain embodiments, the runtime perfusion solution is formed by combining components of a composition with a fluid, by diluting a more concentrated solution, or by concentrating a more dilute solution. In exemplary embodiments, suitable runtime perfusion solutions include an energy source and/or one or more stimulants to assist the organ in continuing its normal physiological function before and during transplantation, and/or one or more amino acids selected and proportioned to allow the organ to continue its cellular metabolism during perfusion. The runtime perfusion solution can include any of the therapeutic agents described in more detail below. Cellular metabolism includes, for example, protein synthesis that occurs while the perfusion is in effect. Some exemplary solutions are water-based, while other exemplary solutions are anhydrous, such as organic solvent-based, ionic liquid-based, or fatty acid-based.

During operation, the perfusion solution may include one or more energy-rich components to assist the liver in achieving its normal physiological functions. These components may include energy-rich materials that can be metabolized, and/or components of these materials that allow organs such as the liver to synthesize energy sources during perfusion. Exemplary sources of energy-rich molecules include, for example, one or more carbohydrates. Examples of carbohydrates include monosaccharides, disaccharides, oligosaccharides, polysaccharides, or combinations thereof, or precursors or metabolites thereof. Although not intended to be limiting, examples of monosaccharides suitable for solution include: octose; heptose; hexoses such as fructose, allose, altrose, glucose, mannose, gulose, idose, galactose, and talose; pentoses such as ribose, arabinose, xylose, and lyxose; tetroses such as erythrose and threose; and trioses such as glyceraldehyde. Although not intended to be limiting, examples of disaccharides suitable for use in the solution include (+)-maltose (4-O-(α-D-glucopyranosyl)-α-D-glucopyranose), (+)-cellobiose (4-O-(β-D-glucopyranosyl)-D-glucopyranose), (+)-lactose (4-O-(β-D-galactopyranosyl)-β-D-glucopyranose), and sucrose (2-O-(α-D-glucopyranosyl)-β-D-fructofuranoside). Although not intended to be limiting, examples of polysaccharides suitable for use in the solution include cellulose, starch, amylose, amylopectin, sulfomucopolysaccharides (such as dermatan sulfate, chondroitin sulfate, sulodexide, mesoglycan, heparan sulfate, idosanes, heparin, and heparinoids), dextrin, and glycogen. In some embodiments, monosaccharides, disaccharides, and polysaccharides of both aldoses and ketoses, or combinations thereof, are used. One or more isomers can be employed in the perfusion solutions described herein during operation, including enantiomers, diastereomers, and/or tautomers of monosaccharides, disaccharides, and/or polysaccharides, including those described and not described herein. In certain embodiments, one or more monosaccharides, disaccharides, and/or polysaccharides may have been chemically modified, for example, by derivatization and/or protection (with protecting groups) of one or more functional groups. In certain embodiments, carbohydrates such as dextrose or other forms of glucose are preferred.

Other possible energy sources include: coenzyme A; pyruvate; flavin adenine dinucleotide (FAD); thiamine pyrophosphate chloride (co-carboxylase); β-nicotinamide adenine dinucleotide (NAD); β-nicotinamide adenine dinucleotide phosphate (NADPH) and phosphate derivatives of nucleosides, i.e., nucleotides, including mono-, di-, and triphosphates (e.g., UTP, GTP, GDF, and UDP); coenzymes; or other biomolecules with similar cellular metabolic functions; and/or metabolites or precursors thereof. For example, phosphate derivatives of adenosine, guanosine, thymidine (5-Me-uridine), cytidine, and uridine, as well as other natural and chemically modified nucleosides, are contemplated.

In certain embodiments, one or more carbohydrates can be provided together with a phosphate source such as nucleotides. Carbohydrates can help organs produce ATP or other energy sources during perfusion. The phosphate source can be provided directly by ATP, ADP, AMP or other sources. In other illustrative embodiments, phosphoric acid is provided by phosphates such as glycerophosphate, sodium phosphate or other phosphate ions. Phosphoric acid can include any form in any ionic state, including protonated forms and forms with one or more counter ions. The energy source used can depend on the type of organ being perfused (for example, adenosine can be omitted when perfusing the liver).

One of the important functions of the liver is the production of bile. In some embodiments, the runtime perfusion solution includes one or more compounds that support bile production by the liver. Non-limiting examples of these compounds include cholesterol, primary bile acids, secondary bile acids, glycine, taurine, and bile acids (bile salts) to encourage the liver to produce bile in vitro, all of which can be used by the liver to produce bile. In some specific embodiments, the bile salt is sodium taurocholate.

Because the liver serves as the metabolic powerhouse of the body, it generally requires a constant source of energy and oxygen. Therefore, in addition to maintaining an appropriate concentration of energy-generating compounds in the perfusion fluid, the organ care system 600 described herein can also be configured to provide a constant supply of oxygen to the preserved liver. In some embodiments, oxygen is provided by diffusing a stream of oxygen through the perfusion fluid (e.g., in the gas exchanger 114) or a blood product to dissolve or saturate the liquid medium with oxygen—for example, by binding oxygen to hemoglobin in the blood product. In certain embodiments, the perfusion fluid supplied to the liver contains _O2 with a _PaO2 ≥ 200 mmHg (arterial perfusate). In certain embodiments, the perfusion fluid supplied to the liver contains carbon dioxide with a _PaCO2 ≤ 40 mmHg, thereby promoting and maintaining the liver's oxidative metabolic function. In certain embodiments, the perfusion fluid contains carbon dioxide with a PaCO2 ≤ ₃₀ mmHg, thereby maintaining the pH in the liver to maintain the liver's biological function.

The perfusion solution during operation as described herein may include one or more amino acids, preferably multiple amino acids, to support protein synthesis by organ cells. Suitable amino acids include, for example, any naturally occurring amino acid. The amino acids may be in various enantiomeric or diastereomeric forms. For example, the solution may be a D- or L-amino acid or a combination thereof, i.e., a solution that is enantioenriched in more D- or L-isomers or a racemic solution. Suitable amino acids may also be non-naturally occurring or modified amino acids, such as citrulline, ornithine, homocysteine, homoserine, β-amino acids such as β-alanine, aminocaproic acid, or a combination thereof.

Certain exemplary runtime perfusion solutions include some, but not all, naturally occurring amino acids. In some embodiments, the runtime perfusion solution includes essential amino acids. For example, the runtime perfusion solution can be prepared with one or more, or all, of the following amino acids: glycine, alanine, arginine, aspartic acid, glutamic acid, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and lysine acetate.

In certain embodiments, the runtime perfusion solution does not include non-essential and/or semi-essential amino acids. For example, in some embodiments, asparagine, glutamine, and/or cysteine are not included. In other embodiments, the solution contains one or more non-essential and/or semi-essential amino acids. Thus, in some embodiments, asparagine, glutamine, and/or cysteine are included.

The runtime perfusion solution may also contain electrolytes, particularly calcium ions, for promoting enzyme reactions and/or maintaining osmotic pressure within the liver. Other electrolytes may be used, such as sodium, potassium, chloride, sulfate, magnesium, and other inorganic and organic charged species or combinations thereof. It should be noted that any component provided below may be provided, as valence and stability permit, in ionic form, in protonated or unprotonated form, in salt or free base form, or as an ionic or covalent substituent in combination with other components described below that hydrolyze in aqueous solution and make the component available in aqueous solution, as appropriate and suitable.

In certain embodiments, the runtime perfusion solution contains a buffer component. For example, suitable buffer systems include 2-morpholinoethanesulfonic acid monohydrate (MES), cacodylic acid, H ₂ CO ₃ /NaHCO ₃ ( _pKa1 ), citric acid ( _pKa3 ), bis(2-hydroxyethyl)-imino-tris-(hydroxymethyl)-methane (Bis-Tris), N-carbamoylmethyliminoacetic acid (ADA), 3-bis[tris(hydroxymethyl)methylamino]propane (Bis-Tris propane) ( _pKa1 ), piperazine-1,4-bis(2-ethanesulfonic acid) (PIPES), N-(2-acetamido)-2-aminoethanesulfonic acid (ACES), imidazole, N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 3-(N-morpholino)propanesulfonic acid (MOPS), NaH ₂ PO ₄ /Na ₂ HPO ₄ ( _pKa2 ), N-tris(hydroxyethyl)methyl-2-aminoethanesulfonic acid (TES), N-(2-hydroxyethyl)-piperazine-N'-2-ethanesulfonic acid (HEPES), N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid) (HEPPSO), triethanolamine, N-[tris(hydroxyethyl)methyl]-glycine (Tricine), tris(hydroxymethylaminoethane) (Tris), glycineamide, N,N-bis(2-hydroxyethyl)glycine (Bicine), glycylglycine ( _pKa2 ), N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), or a combination thereof. In some embodiments, the solution contains sodium bicarbonate, potassium phosphate, or TRIS buffer.

The runtime perfusion solution may include other components to help maintain the liver during perfusion and protect the liver from ischemia, reperfusion injury, and other adverse effects. In certain exemplary embodiments, these components may include hormones (e.g., insulin), vitamins (e.g., multivitamins for adults, such as multivitamin MVI-Adult), and/or steroids (e.g., dexamethasone and SoluMedrol).

In another aspect, blood products can be provided with the runtime perfusion solution to support the liver during storage. Exemplary suitable blood products may include whole blood and/or one or more components thereof, such as serum, plasma, albumin, and red blood cells. In embodiments using whole blood, the blood may be passed through a leukocyte- and platelet-depleting filter to reduce pyrogens, antibodies, and/or other substances that may cause inflammation in the organ. Thus, in some embodiments, the perfusion fluid is whole blood that has been at least partially depleted of leukocytes and/or whole blood that has been at least partially depleted of platelets.

The perfusion fluid and the runtime perfusion solution containing the blood product can be provided at a physiological temperature and maintained approximately throughout the perfusion and recirculation. As used herein, "physiological temperature" refers to a temperature of about 25°C to about 37°C, such as about 30°C to about 37°C, such as about 34°C to about 37°C.

Other components or additives can be added to the perfusion solution during operation, and these components or additives include, for example, adenosine, magnesium, phosphate, calcium and/or its source. In some embodiments, additional components are provided to help the liver perform its metabolism during perfusion. These components include, for example, the form of adenosine, which can be used for ATP synthesis, for maintaining endothelial function and/or for reducing ischemia and/or reperfusion injury. Components can also include other nucleosides, such as guanosine, thymidine (5-Me-uridine), cytidine, uridine and other natural nucleosides and chemically modified nucleosides-including their nucleotides. According to some embodiments, a magnesium ion source is provided with a phosphate source, and in certain embodiments, a magnesium ion source is provided with adenosine to further enhance the ATP synthesis performed in the cells of the perfused liver. Various amino acids can also be added to support protein synthesis by hepatocytes. Applicable amino acids can include, for example, any naturally occurring amino acids and those mentioned above.

In some embodiments, the runtime perfusion solution also includes one or more vasodilators (e.g., vasodilators that can be used to increase or decrease vascular tone, thereby increasing or decreasing pressure within a blood vessel). In some specific embodiments, the vasodilator used is , but other vasodilators may also be used.

Table 2 lists components that can be used in a runtime perfusion solution for preserving a liver as described herein. The runtime perfusion solution can include one or more of the components described in Table 2.

Table 2. Composition of exemplary compositions for runtime perfusion solutions

Table 3 lists the components that can be used in the perfusion solution during an exemplary operation. The amounts provided in Table 3 describe preferred amounts relative to the other components in the table and can be proportionally provided to provide sufficient amounts of the composition. In some embodiments, the amounts listed in Table 3 can vary by approximately ±10% and still be used in the solutions described herein.

Table 3. Components of exemplary runtime perfusion solutions

In an exemplary embodiment of a runtime perfusion solution, the components in Table 3 can be combined in the relative amounts listed in Table 3 per approximately 1 L of aqueous fluid to form a runtime perfusion solution. In some embodiments, the amount of aqueous fluid in the runtime perfusion solution can vary by ± about 10%. The pH of the runtime perfusion solution can be adjusted to about 7.0 to about 8.0, for example, about 7.3 to about 7.6. The runtime perfusion solution can be sterilized, for example, by autoclaving, to increase purity.

Table 4 lists another exemplary runtime perfusion solution, which includes a tissue culture medium having the components shown in Table 4 in combination with an aqueous fluid, which can be used in the perfusion fluids described herein. The amounts of the components listed in Table 4 are relative to each other and to the amount of aqueous solution used. In some embodiments, approximately 500 mL of aqueous fluid is used. In some embodiments, the amount of aqueous solution can vary by ± about 10%. The amount of aqueous solution and the amounts of the components can be proportioned as appropriate for the application. In this embodiment, the pH of the runtime perfusion solution can be adjusted to about 7.0 to about 8.0, for example, about 7.3 to about 7.6.

Table 4. Composition of another exemplary runtime perfusion solution (approximately 500 mL of aqueous solution)

Because amino acids are the building blocks of proteins, the unique properties of each amino acid impart certain important properties to proteins, such as the ability to provide structure and catalyze biochemical reactions. The selection and concentration of amino acids provided in the runtime perfusion solution can, in addition to providing protein structure, also support normal physiological functions, such as sugar metabolism to provide or store energy, regulation of protein metabolism, mineral transport, nucleic acid (DNA and RNA) synthesis, blood glucose regulation, and support of electrical activity. Furthermore, the concentration of specific amino acids present in the runtime perfusion solution can be used to predictably stabilize the pH of the runtime perfusion solution.

In some embodiments, to prevent blood used as part of the perfusion fluid for preserving a liver on the organ care system 600 from clotting during preservation, an anticoagulant can be added as an additive to the runtime perfusion solution. Non-limiting examples of anticoagulants include heparin. In some embodiments, sufficient heparin can be included to prevent clotting for 500 to 600 seconds, although other times are possible.

In certain embodiments, the runtime perfusion solution comprises a plurality of amino acids. In certain embodiments, the runtime perfusion solution includes electrolytes, such as calcium and magnesium.

In one embodiment, the runtime perfusion solution includes one or more amino acids and one or more carbohydrates, such as glucose or dextrose. The runtime perfusion solution may also have additives, such as those described herein, that are administered at the time of use just prior to infusion into the liver perfusion system. For example, additional additives that may be included in the solution or added by the user at the time of use include hormones and steroids, such as dexamethasone and insulin, and vitamins such as adult multivitamins, such as adult multivitamins for infusion (e.g., MVI-Adult). Additional small and large biomolecules may also be included in the runtime perfusion solution or added by the user at the time of use, including therapeutic agents and/or components typically associated with blood or plasma, such as albumin.

In some embodiments, the therapeutic agent can be added before or during perfusion of the liver.The therapeutic agent can also be added directly to the system before or during perfusion of the organ, independent of the runtime perfusion solution.

With further reference to Table 3 or Table 4, some of the components used in the exemplary runtime perfusion solution are molecules, such as small organic molecules or large biomolecules, that are inactivated by sterilization, for example, by decomposition or denaturation. Therefore, these components can be prepared separately from the remaining components of the runtime perfusion solution. Separate preparation involves individually purifying each component using known techniques. The remaining components of the runtime perfusion solution are sterilized, for example, by autoclaving, and then combined with the biological component.

Table 5 lists certain biological components that can be purified separately after sterilization according to this two-step process and added to the solutions described herein (runtime perfusion solution and/or filling solution). These additional or supplementary components can be added to the runtime perfusion solution, filling solution or its combination individually, in various combinations, together as a composition, or as a combined solution. For example, in certain embodiments, the insulin and MVI-Adult listed in Table 5 are added to the runtime perfusion solution. In another embodiment, succinate sodium and sodium bicarbonate listed in Table 5 are added to the filling solution. The additional components can also be combined in one or more combinations or all combined together and placed in solution before being added to the runtime perfusion solution and/or filling solution. In some embodiments, the additional components are added directly to the perfusion fluid. The amounts of the components listed in Table 5 are relative to each other, and/or relative to the amounts of the components listed in one or more of Tables 1 to 4 and the amount of the aqueous solution used to prepare the runtime perfusion solution and/or the filling solution, and the ratio can be appropriately determined for the amount of the required solution.

Table 5. Exemplary biological components added to the solution prior to use

In one embodiment, a composition for use in an on-the-fly perfusion solution is provided, the composition comprising one or more carbohydrates, one or more organ stimulants, and a plurality of amino acids. The composition may also include other substances, such as those used in the solutions described herein.

In another embodiment, a system for perfusing a liver is provided, comprising a liver and a substantially cell-free composition comprising one or more carbohydrates, one or more organ stimulants, and a plurality of amino acids. The substantially cell-free composition can include a system that is substantially free of cellular material, particularly a system that is not derived from cells. For example, the substantially cell-free composition can include compositions and solutions prepared from a non-cellular source.

In another aspect, the runtime perfusion solution and/or priming solution can be provided as a kit comprising one or more organ maintenance solutions. An exemplary runtime perfusion solution can include the components identified above in the one or more fluid solutions for use in the liver perfusion fluid. In certain embodiments, the runtime perfusion solution can include multiple solutions that provide the runtime perfusion solution in various combinations. Alternatively, the kit can include dry components that can be regenerated in a fluid to form one or more runtime perfusion solutions or priming solutions. The kit can also include components from the runtime perfusion solution or priming solution in one or more concentrated solutions that, upon dilution, provide a preservation solution, nutrient solution, and/or supplement solution as described herein. The kit can also include a priming solution.

In certain embodiments, the kit is provided in a single package, wherein the kit includes one or more solutions (or components required to prepare one or more solutions by mixing with an appropriate fluid) and instructions for sterilization, flow and temperature control during perfusion and use, and other information necessary or appropriate for using the kit for organ perfusion. In certain embodiments, the kit is provided with only a single runtime perfusion solution (or a set of dry components for use in a solution when mixed with an appropriate fluid), along with a set of instructions and other information or materials necessary or useful for operating the runtime perfusion solution or priming solution.

In some embodiments, the runtime perfusion solution is a single solution. In other embodiments, the runtime perfusion solution may include a main runtime perfusion solution and one or more nutrient supplement solutions. The nutrient supplement solution may contain any compound or biological component suitable for runtime perfusion as described above. For example, the nutrient supplement solution may contain one or more of the components listed above in Tables 1 to 5. In addition, Table 6 lists the components used in exemplary nutrient supplement solutions. In some embodiments, the nutrient solution also contains sodium glycerophosphate. The amounts of the components in Table 6 are relative to the amount of aqueous solvent used in the solution (approximately 500 mL) and the ratio can be adjusted appropriately. In some embodiments, the amount of aqueous solvent varies by ± approximately 10%. In these embodiments, when a main runtime solution and one or more nutrient solutions are used, these solutions can be connected to the circulatory system of the organ care system 600 and controlled separately. Therefore, when one or more components in the nutrient solution need to be adjusted, the operator can re-prepare that specific nutrient solution with different concentrations of these components, or adjust the flow rate and/or pressure of only that nutrient solution without affecting the flow rate and/or pressure of the main runtime perfusion solution and the other nutrient solutions.

Table 6. Components of an exemplary nutrient solution (approximately 500 mL)

Components quantity Specification dextrose 40g. ±about 10%.

In one embodiment, the runtime perfusion solution and the priming solution have the same composition as described in any one of Tables 1 to 6 or a combination thereof.

In some embodiments, the perfusion fluid includes 1200 ml to 1500 ml of pRBCs, 400 ml of 25% albumin, 700 ml of Promali, antibiotics (Gram-positive and Gram-negative) of 1 g of cefazolin (or equivalent antibiotic) and 100 mg of ciprofloxacin (or equivalent antibiotic), 500 mg of methylprednisolone sodium (or equivalent anti-inflammatory drug), 50 mmol of Hco3, multivitamins, and 10,000 units of heparin administered at 3 hours and 6 hours PT (prothrombin time).

In certain specific embodiments, the perfusion fluid comprises blood from a liver donor, or concentrated red blood cells (RBCs), or concentrated RBCs with fresh frozen plasma, and a runtime perfusion solution containing one or more components selected from the group consisting of human albumin or dextran. In certain specific embodiments, the perfusion fluid comprises blood from a liver donor, or concentrated RBCs, or concentrated RBCs with fresh frozen plasma, and a runtime perfusion solution containing one or more components selected from the group consisting of human albumin, dextran, and one or more electrolytes.

E. Final rinse solution

After determining the appropriate recipient for liver transplantation and before the liver is removed from the organ care system 600, the liver organ will undergo another flushing process performed by a flushing solution. This flushing solution has a function similar to the initial flushing solution, which will remove residual blood in the liver and stabilize the liver. This flushing solution is referred to herein as the final flushing solution. In some embodiments, the final flushing solution has a composition similar to or identical to the above-mentioned initial flushing solution. The main components of the final flushing solution may include electrolytes (e.g., thiamin) and buffers as described herein. In certain embodiments, one or more commercially available preservation solutions used in low-temperature organ transplantation are used as the final flushing solution. After the liver is finally flushed and cooled according to one or more embodiments described herein, the liver can be removed from the organ care system 600 for transplantation into the recipient.

VI. Methods

An exemplary method for using the organ care system 600 disclosed herein will now be described in greater detail. FIG. 29 is a flow chart 5000 depicting an exemplary and non-limiting method for harvesting a donor liver and cannulating it into the organ care system 600 described herein. The process 5000 shown in FIG. 29 is exemplary only and may be modified. For example, the stages described herein may be altered, changed, rearranged, and/or omitted.

A. Organ collection

As shown in Figure 29, the process of obtaining and preparing a liver for cannulation and transport can begin by providing a suitable liver donor (stage 5004). The system 600 can be brought to the donor site, whereupon the process of receiving and preparing the donor liver for cannulation and preservation can continue down paths 5006 and 5008. Path 5006 primarily involves preparing the donor liver for preservation, while path 5008 primarily involves preparing the system to receive and preserve the liver, and then transporting the liver to the recipient site via the organ care system 600.

As shown in FIG29 , the first path 5006 can include draining the donor's blood (stage 5010), explanting the liver (stage 5014), flushing the liver with an initial flushing solution (stage 5016), and preparing and cooling the liver for the system (stage 5018). In particular, in the phlebotomy stage 5010, the donor's blood can be partially and/or completely removed and set aside so that it can be used as a blood product in the perfusion fluid that perfuses the liver during storage on the system. This stage can be performed by inserting a catheter into the donor's arterial or venous vascular system to allow the donor's blood to flow out of the donor and be collected in a blood collection bag. The donor's blood is allowed to flow until the required amount of blood, typically 1.0 liter to 2.5 liters, is collected, and the catheter is then removed. The blood extracted by phlebotomy is then optionally filtered and added to the system's fluid reservoir to prepare for use with the system. Alternatively, a device with a filter integrated with a cannula and a blood collection bag can be used to remove blood from the donor and filter out white blood cells and platelets in a single step. An example of such a filter is a Pall BC2B filter. Alternatively, a blood product can be used in place of the donor's blood in the perfusion fluid (not shown in FIG. 29 ).

After the donor's blood is drained, the donor liver can be harvested (stage 5014). Any standard liver harvesting method known in the art can be used. During liver harvesting, the liver vessels, including the hepatic artery, portal vein, inferior vena cava (IVC), and bile duct, are appropriately prepared and cut, leaving sufficient vessel length for cannulation (e.g., standard practice applicable to human or animal transplantation). In certain embodiments, the gallbladder is removed during liver harvesting, and care is taken to protect the common bile duct intact during liver preservation to maintain a stable bile fluid flow. After the liver is removed in a hospital setting, the liver is typically flushed (e.g., donor flush) or placed in a saline solution. In stage 5016, the harvested liver can then be flushed with an initial flushing solution to remove any residual blood and/or donor flushing solution, thereby improving the stability of the liver. An exemplary composition of the initial flushing solution is described in detail above.

After the liver is harvested and before it is placed on the organ care system 600, the liver can be cooled (stage 5018) to weaken or stop its metabolic function, thereby avoiding damage to the liver that may occur during transportation or placement of the liver in the organ care system 600. In some embodiments, the liver is cooled to a temperature within any range of about 4°C to 10°C, 5°C to 9°C, 5°C to 8°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C or 10°C, or defined by the values described herein. The liver can be cooled by ice or refrigeration. Other temperature ranges below 4°C and above 10°C are also possible. Alternatively, the initial flush solution can be cooled first, and then the initial flush solution can be used to flush the liver to cool the liver. Therefore, in these alternative embodiments, stages 5016 and 5018 can be performed simultaneously. Once the liver is prepared and cooled to the appropriate temperature, the liver can be ready to be placed on the liver care system 600.

Continuing with FIG. 29 , during the preparation of the liver via path 5006 , the system can be prepared via the stages of path 5008 so that the system is primed and ready to receive the liver for cannulation and preservation while the liver is prepared and cooled. By rapidly transferring the liver from the donor to the system and subsequently perfusing the liver with the perfusion fluid, the medical operator can minimize the amount of time the liver is deprived of oxygen and other nutrients, thereby reducing ischemia and other adverse effects that occur during current organ care techniques. In certain embodiments, the amount of time between perfusing the liver with the initial flush solution and beginning to flow the perfusion fluid through the liver via the organ care system 600 is less than about 15 minutes. In other illustrative embodiments, the time between is less than about ½ hour, less than about 1 hour, less than about 2 hours, or even less than about 3 hours. Similarly, the time between transplanting the liver into the organ care system 600 and the liver reaching a near-physiological temperature (e.g., about 34° C. to about 37° C.) occurs within a brief period of time, reducing ischemia within the liver tissue. In some illustrative embodiments, the time period is less than about 5 minutes, while in other applications, the time period may be less than about 1/2 hour, less than about 1 hour, less than about 2 hours, or even less than about 3 hours. In other words, when the cooled liver is first placed into the organ care system 600, the temperature of the liver is gradually increased to the desired temperature over a predetermined amount of time, thereby reducing any potential damage that could be caused by a sudden temperature change.

As shown in FIG29 , the system can be prepared in a series of stages in path 5008, including preparing a single-use module (stage 5022), priming the system with a priming solution (stage 5024), filtering blood from a donor and adding it to the system, for example, at a reservoir of the system (stage 5012), optionally priming the system with blood and/or perfusion fluid, and connecting the liver to the system (stage 5020). In particular, step 5022 of preparing the single-use module includes assembling a disposable single-use module as described herein (e.g., single-use module 634). After the single-use module is assembled or provided in appropriate components, the single-use module is then inserted into and connected to a multiple-use module (e.g., multiple-use module 650) using the methods described herein.

Specifically, in stage 5024, the liver care system 600 can first be filled with a filling solution, the composition of which is described more comprehensively above. In some embodiments, to assist in filling, the system can be provided with an organ bypass catheter that is installed in the organ chamber assembly. For example, in some specific embodiments, the bypass catheter includes three sections that are attached to the hepatic artery cannulation interface, the portal vein cannulation interface, and the inferior vena cava (IVC) cannulation interface (if present). With the bypass catheter attached/cannulated to the liver chamber assembly, the operator can cause the system to circulate the perfusion fluid through all paths used during actual operation. This allows the system to be thoroughly tested and filled before the liver is cannulated in place.

In stage 5012, blood from the donor can be filtered and added to the system, such as reservoir 160. The filtration process can help reduce the inflammatory process by completely or partially removing white blood cells and platelets. In addition, the donor blood can be used to optionally prime the system as described above and/or mixed with one or more priming solutions or runtime perfusion solutions to further prime the system as described above. In addition, the blood and runtime perfusion solution can be mixed together to form a perfusion fluid that is subsequently used to infuse and preserve the liver. In stage 5026, the system can be primed with blood and/or perfusion fluid by activating a pump and pumping the blood and/or perfusion fluid through the system using a bypass conduit in an appropriate location (as described above). As the perfusion fluid circulates through the system in the priming stage 5026, the perfusion fluid can optionally be heated to a desired temperature (e.g., normothermic temperature) as it passes through the system's heater assembly. Thus, prior to cannulating the harvested liver, the system can be primed by circulating a priming solution, drained donor blood, and/or a mixture of the two (e.g., a perfusion fluid) through the system to warm, oxygenate, and/or filter them. Nutrients, preservatives, and/or other therapeutic agents can also be provided during priming by adding these components to the priming solution. Various parameters can also be initialized and calibrated during priming via the operator interface during priming. Once properly primed and running, the pump flow can be reduced or circulation can be interrupted, the bypass catheter can be removed from the organ chamber assembly, and the liver can then be cannulated into the organ chamber assembly.

1. Intubation

In stage 5020, the liver can be cannulated and placed on the organ care system 600 while the liver is cooled as described above. During liver preservation, perfusion fluid can flow into the liver through the hepatic artery and portal vein and flow out from the liver through the inferior vena cava (IVC). Therefore, the hepatic artery, inferior vena cava (IVC) and portal vein can be cannulated accordingly and connected to the relevant flow paths of the liver care system 600 to ensure appropriate perfusion (as described above) by the liver. In some embodiments, the IVC is not cannulated but freely discharged. The bile duct can also be cannulated and connected to a reservoir (e.g., bile bag 187) in order to collect the bile produced by the liver.

The system 600 described herein can be designed to be compatible with the human liver artery anatomy. In most patients, the hepatic artery is the only major artery of the liver, and therefore the organ care system 600 can be a single-port cannula to be connected to the hepatic artery. However, in some cases (i.e., about 10% to 20% of the patient population with genetic differences), the liver donor also has an accessory hepatic artery in addition to the main hepatic artery. Therefore, in some embodiments, the liver care system 600 provides a dual-port cannula configuration (e.g., cannula 2642) so that both the main hepatic artery and the accessory hepatic artery can be cannulated and connected to the same perfusion fluid flow path. In some specific embodiments, the dual-port cannula is Y-shaped. Any other suitable shape or design for the dual-port cannula is envisioned.

In some embodiments, the cannula can be designed to be straight to reduce unnecessary pressure drops along the cannula flow path. In other embodiments, the cannula can be designed to be curved or angled as required by the shape, size, or geometry of other components of the organ care system 600. In some specific embodiments, the cannula is designed to have an appropriate shape, such as straight, angled, or a combination thereof, so that the total flow pressure within the cannula is maintained at a desired level to simulate physiological conditions.

2. Equipment

The liver can then be mounted on the organ care system 600 (stage 5020), more specifically in the organ chamber 104. Care should be taken to avoid excessive movement of the liver during mounting to reduce damage to the liver. As described in more detail above, the liver chamber can be specifically designed to hold the liver in a stable position that reduces its movement.

B. Storage/Transportation

1. Controlled early perfusion and rewarming

In certain embodiments, once the liver is mounted on the organ care system 600 by appropriately cannulating the blood vessels, the liver undergoes an early perfusion and/or rewarming process to restore the liver to normal body temperature (34° C. to 37° C.) (stage 5021). In some embodiments, the organ chamber can house a heating circuit to gradually warm the previously cooled liver to normal body temperature over a predetermined amount of time. In other embodiments, the initial perfusion fluid (for early perfusion) can be heated to near or at normal body temperature (e.g., 34° C. to 37° C.) while the liver is being perfused and warmed. As described herein, the liver stored on the organ care system 600 can be maintained under conditions close to a physiological state, including normal body temperature, to maintain normal biological function of the liver.

After the liver is mounted on the system and warmed to normal body temperature, a pump within the organ care system 600 (e.g., pump 106) can be adjusted to pump perfusion fluid through the liver, for example, into the hepatic artery and portal vein. Perfusion fluid exiting the IVC (or hepatic vein, depending on how the liver was harvested) can be collected and subjected to various treatments, including reoxygenation and carbon dioxide removal. Various nutrients can be added to the spent perfusion fluid to increase nutrient concentration to a value required for recirculation.

In some embodiments, during perfusion of a liver on the organ care system 600, the inflow pressures within the hepatic artery and portal vein are carefully controlled to ensure proper delivery of nutrients to the liver to maintain liver function. In some embodiments, the flow pressure within the hepatic artery can be, for example, 50 mmHg to 120 mmHg, and the flow pressure in the portal vein can be 5 mmHg to 15 mmHg, although pressures outside of these ranges are possible, such as 1 mmHg, 2 mmHg, 20 mmHg, 25 mmHg, 30 mmHg, 35 mmHg, 40 mmHg, 45 mmHg, 50 mmHg, 60 mmHg, 70 mmHg, 80 mmHg, 90 mmHg, 100 mmHg, 110 mmHg, 120 mmHg, or any range of pressures bounded by the values noted herein. In some embodiments, the flow rate in the hepatic artery and the flow rate in the portal vein can be maintained at about or greater than 0.25 L/min to 1.0 L/min and 0.75 L/min to 2.0 L/min, respectively, or within any range bounded by any of the values noted herein. In some embodiments, the flow rate in the hepatic artery and the flow rate in the portal vein can be maintained at about 0.25 L/min, 0.30 L/min, 0.35 L/min, 0.40 L/min, 0.45 L/min, 0.50 L/min, 0.55 L/min, 0.60 L/min, 0.65 L/min, 0.70 L/min, 0.75 L/min, 0.80 L/min, 0.85 L/min, 0.90 L/min, 0.96 L/min, 0.97 L/min, 0.98 L/min, 0.99 L/min, 0.10 L/min, 0.11 L/min, 0.12 L/min, 0.13 L/min, 0.14 L/min, 0.15 L/min, 0.16 L/min, 0.17 L/min, 0.18 L/min, 0.19 L/min, 0.20 L/min, 0.21 L/min, 0.22 L/min, 0.23 L/min, 0.24 L/min, 0.25 L/min, 0.2 95 L/min, 1.00 L/min, 1.10 L/min, 1.20 L/min, 1.30 L/min, 1.40 L/min, 1.50 L/min, 1.60 L/min, 1.70 L/min, 1.80 L/min, 1.90 L/min, 2.1 L/min, 2.2 L/min, 2.3 L/min, 2.4 L/min, 2.5 L/min, or a rate within any range bounded by the values noted herein.

In some embodiments, fluid flow, such as flow rate and/or flow pressure, within the organ care system 600 and the hepatic artery and portal vein can be controlled chemically and/or mechanically. Mechanical or chemical control of flow can be accomplished automatically or manually.

2. Manual control/automatic control

First, the mechanical control of fluid flow within the organ care system 600 and the hepatic artery and portal vein is described. In some embodiments, the flow pressure or flow rate within the flow path of the organ care system 600 can be measured by a pressure sensor or rate sensor built into the flow path or elsewhere in the system. Similarly, the pressure sensor or rate sensor can be located in the cannula of the hepatic artery and/or portal vein, or in the connector that connects the cannula to these blood vessels. The pressure sensor or rate sensor can provide the operator with readings about the flow within the flow path and/or within the hepatic artery and/or portal vein. Any other pressure monitoring methods or techniques known in the art are contemplated. If the pressure reading or rate reading deviates from the expected value, the operator can manually adjust the flow pump to increase or decrease the pumping pressure, thereby increasing or decreasing the flow rate of the perfusion fluid. Alternatively, the organ care system 600 can include a flow control module that has programmable desired values for flow rate and/or flow pressure, and that automatically adjusts the pumping pressure of the perfusion fluid, thereby also adjusting the flow rate, when the flow pressure and/or flow rate deviate from the desired values. Manual control and/or automatic control are described more fully above.

3. Chemical control

In other embodiments, pressure and/or fluid flow within the organ care system 600 and the hepatic artery and portal vein can be chemically controlled. In certain specific embodiments, pressure can be controlled or increased by administering one or more vasodilators (e.g., vasodilators that can be used to increase or decrease vascular tone, thereby increasing or decreasing pressure within the vessels). Vasodilation refers to the widening of blood vessels caused by the relaxation of smooth muscle cells within the vessel walls. When blood vessels dilate, the flow rate of the perfusate increases due to the decrease in vascular resistance. Any vasodilator known in the art can be used to dilate the hepatic artery and/or portal vein to increase fluid flow rate therein. In certain specific embodiments, the vasodilator used is specifically designed to increase fluid flow rate, as indicated by low flow pressure or flow rate and/or by any of the liver viability assessment techniques described in more detail below. When fluid flow is insufficient, an operator can manually add a vasodilator to the system's flow module or to the perfusion fluid to increase fluid flow rate. Alternatively, the organ care system 600 can include a flow control module that automatically adds more than one vasodilator to the flow path or perfusion fluid to increase flow rate. The amount of vasodilator provided can be, for example, between 1 μg/hour and 100 μg/hour, more specifically between 1 μg/hour and 5 μg/hour. These ranges are exemplary only, and any range falling within the range of 0 μg/hour to 100 μg/hour can be used.

Some of the aforementioned embodiments may be adapted for use with a liver being stored in system 600. For example, in this embodiment, an algorithm may be used to allow closed-loop control of hepatic artery pressure (HAP). The algorithm used may be a proportional-integral-derivative controller (PID controller). The PID controller may calculate how far the HAP is from a desired set point and attempt to minimize the error by increasing or decreasing the flow rate of a vasodilator (e.g., ).

Therefore, in some embodiments, the controller 150 (or other parts of the system) can determine the error (e.g., how far the HAP is from the user set point) and adjust the vasodilator flow rate to attempt to bring the error to zero. In embodiments where the algorithm runs once per second, the adjustments will be very small. Small, frequent adjustments can help stabilize control by ensuring that any noise in the system does not cause significant changes in the vasodilator flow rate. The algorithm can attempt to bring the HAP to the user set point. This means that when the HAP is above the set point, the algorithm can increase the vasodilator solution flow rate until the HAP reaches the user set point. If the HAP is below the user set point, the algorithm can decrease the vasodilator solution flow rate until the HAP reaches the user set point.

In some embodiments, the PID control algorithm does not reduce the vasodilator flow rate until the vasodilator flow rate has fallen below the set point. This may result in a drop below the target pressure. To help compensate for this, some embodiments may use a virtual set point that is +3 mmHg (or other value) above the user set point. This may be user-definable or hard-programmed. When the HAP is 7 mmHg above the user set point, the software may enable the virtual set point and attempt to adjust the HAP to +3 mmHg above the user set point. This may allow for some drop below the virtual set point. Once the HAP has stabilized at the virtual set point, the software may then adjust the HAP to the user set point. This approach may help "catch" the HAP as it is decreasing without causing a significant drop.

Referring to Figure 28, the aforementioned graphical representation of ascending aortic pressure in the cardiac system is shown. In Figure 28, the aforementioned exemplary graph 9500 is shown. The image shows the AOP (e.g., 9505) dropping to a virtual set point (9510), below the virtual set point, and then slowly dropping to the user set point (50 mmHg).

Because some embodiments use medication to control HAP, it may be beneficial to ensure that the system does not overload the liver with vasodilators when medication is not needed. To achieve this, the system can analyze how far the HAP is from the set point, and when the HAP is above the set point, the system (e.g., solution pump 631) can add vasodilators at a standard rate. If the HAP is below the set point, the system 600 can reduce the flow rate by a factor of four compared to when the system 600 adds vasodilators. This can help keep the system just above the HAP set point in the "active management" zone (e.g., approximately +0.5 mmHg to +1 mmHg), and may help minimize drops while quickly reducing the vasodilator rate.

Although the previous description focused on the liver, the same technique can be adapted for use with the heart by substituting AOP for HAP.

4. Evaluation

During stages 5028 and 5030, the operator can assess liver function to determine liver viability at the time of transplantation (viability after the present or possible viability in the future). Illustratively, step 5028 involves assessing liver function by utilizing any assessment technique described in more detail below. For example, the operator can monitor the fluid flow, pressure, and temperature of the system while intubating the liver. The operator can also monitor one or more liver function biomarkers to assess liver status. During assessment step 5030, based on the data and other information obtained during testing 5028, the operator can determine whether and how to adjust system characteristics (e.g., fluid flow, pressure, nutrient concentration, oxygen concentration, and temperature) and whether to provide additional treatment modes to the liver (e.g., surgical procedures, drug therapy described in more detail below). The operator can make any such adjustments in step 5032, and then steps 5028 and 5030 can be repeated to retest and reassess the liver and system. In some embodiments, the operator may also elect to perform a surgical, therapeutic, or other procedure (described in greater detail below) on the liver during the regulating step 5032 (or at other times). For example, the operator may assess liver function, such as by performing ultrasound or other imaging tests on the liver, measuring arterial and venous blood gas levels, and performing other assessment tests.

Thus, after or while the liver is preserved on the system, the operator can perform surgery on the liver or provide therapeutic or other treatments, such as immunosuppressive therapy, chemotherapy, genetic testing and therapy, or radiation therapy. Because the system allows the liver to be perfused at near physiological temperatures, fluid flow rates, and oxygen saturation levels, the liver can be maintained for extended periods of time (e.g., periods of at least 3 days or longer, greater than at least 1 week, at least 3 weeks, or a month or longer) to allow for repeated evaluation and treatment.

In some embodiments, the system allows a medical operator to assess the compatibility of the liver with the intended recipient to identify a suitable recipient (step 5034). For example, the operator can perform a human leukocyte antigen (HLA) matching test on the liver while the liver is intubated into the system. These tests may take 12 hours or longer and are performed to ensure the compatibility of the liver with the intended recipient. Preserving the liver using the system described herein can allow the preservation time to exceed the time required to complete the HLA matching, thereby potentially improving the post-transplantation effect. In the HLA matching test example, the liver can be tested for HLA while the preservation solution is pumped into the liver. Any other matching test known in the art is contemplated.

According to an illustrative embodiment, the testing 5028, evaluation 5030, and adjustment 5032 stages can be performed while the system is operating in normal flow mode. In normal flow mode, the operator can test the function of the liver under normal or near-normal physiological blood flow conditions. Based on the evaluation 5030, if necessary, the system settings can be adjusted in step 5032 to change flow, heating, and/or other characteristics to stabilize the liver in preparation for transport to a recipient site in stage 5036. In step 5036, the system can be transported to the recipient site with the preserved liver.

C. Transplantation Preparation

1. Final Flush/Cooling of the Liver

In certain embodiments, the liver can be flushed with a final flush solution to, for example, remove any residual blood and/or runtime perfusion solution before being removed from the system 600 and/or transplanted into a recipient. The composition of the final flush solution is described in detail above.

In certain embodiments, before the liver is removed from the organ care system 600, the liver is cooled again to a temperature within a range of about 4°C to 10°C, 5°C to 9°C, 5°C to 8°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C or 10°C, or any range defined by the values described herein. The liver can be cooled by contact with ice or by refrigeration of the liver storage chamber. In some embodiments, the system 600 can include a cooling unit configured to cool the liver directly and/or to cool the fluid circulating in the system 100. The final flush solution can also be refrigerated first and then used to flush the liver to cool the liver. Thus, in these embodiments, the liver can be subjected to a final flush and cooling at the same time. Once the liver is prepared and cooled to the appropriate temperature, it can be prepared for transplantation into a suitable recipient.

For example, in some embodiments, the liver is cooled and flushed while being positioned on system 600. The user can connect a one-liter cooling flush solution bag to the flush port (e.g., port 4301) of the hepatic artery, but close the port. The user connects two one-liter cooling flush solution bags to the flush port (e.g., port 4302) of the portal vein, but closes the port. The user connects the flushing collection bag to the perfusion module, the perfusate collection port (e.g., port 4309) just after the pump of the perfusion module complies with the chamber. Then, the user can apply a standard surgical clamp to the perfusion module tube just before being shunted to the hepatic artery and portal vein while closing the circulating pump 106. The hepatic artery and portal vein flush ports can be opened so that flushing solution will enter the hepatic artery and portal vein. The perfusate collection bag can be unclamped so that the mixture of perfusate and flushing solution fills the bag instead of filling the organ chamber.

If the decision is made to cool the liver at the end of storage, the following exemplary procedure may be used:

1. Obtain and set up the heater cooler unit (place near the OCS, plug in the power cord, turn on the power, turn on the water circuit controls, and close the water circuit valves). Do not connect the heater cooler water line to the liver perfusion module gas exchanger water line.

2. Set the heater cooler water circuit temperature to close to the current liver temperature (eg, approximately 37°C) and allow it to reach that temperature.

3. Connect the heater cooler water line equipped with Hansen quick-connect fittings to the liver perfusion module oxygenator water line.

4. Turn off the heater 100.

5. Set the heater cooler water circuit temperature to a temperature that is lower than the liver's temperature, but not more than 10°C lower, and open the valve of the water line to allow flow to the liver perfusion module gas exchanger 114. As the actual temperature of the perfusion fluid, as reflected on the user interface, approaches the heater cooler water temperature set point, adjust the heater cooler water temperature set point to be lower than the perfusate/liver temperature, but not more than 10°C lower, by increments and hold, repeatedly adjusting until the blood/liver has reached the desired temperature.

6. When the liver temperature has reached the desired temperature, the liver is removed from the system 600.

While the foregoing focuses on the final flush and cooling of the liver, similar or identical processes may be used when preserving other organs. For example, in some embodiments, the foregoing final flush/cooling techniques may be applied to a heart and/or lung being preserved by system 600.

VII. Evaluation

In some embodiments of the disclosed subject matter, various techniques or methods are provided for evaluating the viability of a liver (e.g., transplant viability) while the liver is stored on an organ care system 600. Typically, biological indicators known in the art for evaluating liver function (e.g., liver enzymes) and known imaging techniques can be used to evaluate the biological function and status of the liver. In addition, because the liver stored on the organ care system 600 is easily accessible to the operator, techniques that are not easily adopted by healthcare professionals in vivo, such as visual observation of the liver or palpation of the liver, can also be used. Based on the evaluation results, one or more parameters of the organ care system 600, such as the nutrient or oxygen content in the perfusion fluid or the flow rate and flow pressure of the perfusion fluid, can be adjusted to improve the viability of the liver.

In some embodiments, perfusion parameters of the organ care system 600 can be used to assess liver viability. Specifically, in certain embodiments, the perfusion fluid flow pressure in the cannulated hepatic artery and/or portal vein can be measured as an indicator of liver viability. In some embodiments, a stable flow pressure in the hepatic artery line within the range of 50 mmHg to 120 mmHg can indicate that the preserved liver is receiving adequate essential nutrients. For example, in some embodiments, a stable flow pressure of approximately 50 mmHg, 60 mmHg, 70 mmHg, 80 mmHg, 90 mmHg, 100 mmHg, 110 mmHg, 120 mmHg, or any pressure within the range defined by the values herein can indicate that the preserved liver is receiving adequate essential nutrients. Flow pressures outside of this range can indicate a leak or blockage in the system or may suggest to the operator that the flow pressure be adjusted to ensure adequate nutrient delivery to the liver. In other embodiments, the perfusion fluid flow rate in the cannulated hepatic artery and/or portal vein can be measured as an indicator of liver viability. In other embodiments, a flow rate in the range of 0.25 L/min to 1 L/min of the hepatic artery can indicate that the preserved liver is receiving an adequate supply of essential nutrients. For example, in some embodiments, a flow rate in the range of approximately 0.25 L/min, 0.30 L/min, 0.35 L/min, 0.40 L/min, 0.45 L/min, 0.50 L/min, 0.55 L/min, 0.60 L/min, 0.65 L/min, 0.70 L/min, 0.75 L/min, 0.80 L/min, 0.85 L/min, 0.90 L/min, 0.95 L/min, 1.00 L/min of the hepatic artery, or a flow rate within any range bounded by the values specified herein, can indicate that the preserved liver is receiving an adequate supply of essential nutrients. A flow rate outside of this range can indicate a leak or blockage in the system or suggest to the operator that the flow rate be adjusted to ensure proper nutrient supply to the liver. Flow rate and pressure may be measured using the pressure sensors and/or flow rate sensors described herein.

In some embodiments, visual observation or inspection of the liver can be used to assess liver viability. For example, a pink or red liver can indicate that the liver is functioning normally, while a black or cyan liver can indicate that the liver is functioning abnormally or deteriorating (e.g., ongoing hypoperfusion). In other embodiments, palpation of the liver is used to assess its viability. When the liver feels soft and flexible, the liver is likely functioning normally. On the other hand, if the liver feels tight or stiff, the liver is likely functioning abnormally or deteriorating (e.g., ongoing hypoperfusion).

A. Bile production

In some embodiments, because bile duct is cannulated and is connected to the reservoir of organ care system 600, therefore can easily check the color and amount of bile produced by liver to assess liver viability.In certain embodiments, black or dark green bile can indicate normal liver function, and light or colorless bile can indicate that liver is not working properly or deteriorating.In other other embodiments, bile production can also be utilized to assess liver viability (and/or the determination that liver is producing bile can be a good indicator completely). Although any bile output can be an indicator of healthy liver, in general, the more bile produced, the better liver function.In certain embodiments, bile output of about 250mL to 1L, 500mL to 1L, 500mL to 750mL, 500mL, 750mL or 1L per day or the bile output in any range defined by the value noted herein shows that the liver preserved on organ care system 600 is working normally and can survive.

B. Blood gas, liver enzyme, and lactate measurements/trends

In some embodiments, various biomarkers or compounds in the perfusion fluid can be used to assess liver viability. For example, metabolic assessment of the liver can be performed by calculating oxygen delivery, oxygen consumption, and oxygen demand. Specifically, the amount of dissolved oxygen and carbon dioxide in the perfusion fluid can be monitored as indicators of liver function. The concentrations of these gases in the perfusion fluid (or blood product) before and after liver perfusion can be measured and compared. In certain specific embodiments, the concentrations of oxygen and carbon dioxide can be measured by various sensors within the flow modules or subsystems of the organ care system 600.

In some embodiments, the perfusion fluid (e.g., the perfusion fluid entering the hepatic artery and leaving the IVC) before and after liver perfusion can be sampled using a corresponding oxygen concentration sensor (or other sensor), and the relevant concentrations of oxygen and/or carbon dioxide can be measured. A significant increase in carbon dioxide concentration in the perfusion fluid after liver perfusion and/or a significant decrease in oxygen concentration after liver perfusion can indicate that the liver is performing its oxidative metabolic function well. On the other hand, a small increase or no increase in carbon dioxide concentration in the perfusate after liver perfusion and/or a slight decrease or no decrease in oxygen concentration after liver perfusion can indicate that the liver is not performing its oxidative metabolic function properly. The difference between _PvO2 and _PaO2 can indicate metabolic activity, active aerobic metabolism, and oxygen consumption.

In some embodiments, a liver function blood test (LEFT) can be performed to assess liver viability. Specifically, in some embodiments, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, albumin, bilirubin (direct and indirect) can be measured to assess liver function. In other embodiments, fibrinogen blood levels can be measured and indicate the ability of liver cells to produce clotting factors.

AST and ALT are liver enzymes and widely accepted clinical liver biomarkers for assessing liver function and/or suitability for transplantation. However, measuring AST and ALT is often complex and time-consuming, and is typically performed in a hospital or laboratory setting. Therefore, there is a need for a sensitive and simple indicator for determining the status of a preserved liver. Lactate, also known as lactic acid, is a byproduct/end product of anaerobic metabolism in living cells/tissues/organs. Lactate is produced when cells lack oxygen or have low oxygen levels to metabolize glucose for energy generation via the glycolytic pathway. Applicants have discovered that, instead of measuring AST levels, lactate levels in perfusion fluid, such as that exiting the IVC, can be measured. Lactate concentration can be measured quickly and simply, offering significant advantages over time-consuming liver enzyme measurements. Based on the rapid feedback provided by lactate measurements, one or more parameters of the organ care system 600—such as flow rate, pressure, and nutrient concentration—can be adjusted to maintain or rapidly improve liver viability. In other words, lactate values (e.g., arterial lactate trends) can be correlated with and indicative of AST levels. For example, a series of lactate measurements (over time) trending lower can be correlated with and/or indicate that AST is trending lower. In some embodiments, lactate measurements can be made in the measurement drain 2804, but this is not required and can be made at any other location in the system 100. Additionally, in some embodiments, the system 600 can be configured to obtain lactate measurements over time at a single location, the difference between the lactate values entering the liver and leaving the liver, and lactate measurements over time at multiple locations.

C. Imaging

In yet other embodiments, various other methods known in the art can be utilized to assess liver viability. In some specific embodiments, ultrasound analysis of the liver can be performed to assess the liver parenchyma, intrahepatic, and extrahepatic bile duct trees. Other non-limiting examples of imaging techniques include magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), fluoroscopy, and transjugular intrahepatic portosystemic shunt (TIPS), all of which can be used to assess the liver and detect abnormalities. For example, when examining an ultrasound of the liver, a physician can examine sinusoidal size, potential obstructions in the bile ducts, and/or general blood flow.

D. Pathology/biopsy

In yet other embodiments, a liver biopsy can be used to assess liver viability. In a liver biopsy, a small piece of liver tissue is removed so that it can be examined under a microscope for signs of damage or disease. Because the liver is stored ex vivo on the organ care system 600, the liver is easily accessible and can be biopsied easily.

VIII. Cloud

During operation, the system 600 generates information about the system itself and/or the organ being preserved. In some embodiments of the system 600, this information can be stored in internal memory such as RAM or ROM. In some embodiments, the information generated by the system 600 can also be transmitted to a remote storage location such as in the cloud. The cloud can be, for example, a series of remotely interconnected computers configured to provide data and/or services via the Internet. The cloud can store the information, perform analysis on the information, and/or provide the information to one or more third parties and/or stakeholders.

In some embodiments of system 600, the system can include a multimodal communication link between itself and one of more other locations, such as a server in the cloud. This communication link can be controlled by controller 150 (e.g., via data management subsystem 151), but this is not required, and other components can be used to control the communication. Controller 150 can be configured to provide real-time information about system 600 and/or the organ contained therein to one or more remote locations while the system is at a donor hospital, in transit, and/or at a recipient hospital. In some embodiments, communication can be achieved using communication links such as wired network connections (e.g., Ethernet), wireless network connections (e.g., IEEE 802.11), cellular connections (e.g., LTE), Bluetooth connections (e.g., IEEE 802.15), infrared connections, and/or satellite-based network connections. In some embodiments, controller 150 can maintain a connection priority list, favoring more reliable connections such as hardwired internet and/or Wi-Fi over less reliable cellular and/or satellite connections. In other implementations, the priority list may be generated with a preference for low-cost transmission mediums such as Wi-Fi.

System 600 can be configured to communicate with the cloud and ultimately with remote parties via one or more technologies. For example, system 600 can be configured to communicate with a server in the cloud and/or directly with one or more remote computers. In some embodiments, system 600 can be configured to: i) send information, such as email and/or text messages, to a predetermined address; ii) upload data files to a remote storage location using, for example, FTP; iii) communicate with a dedicated remote server to provide information in a proprietary format; and iv) receive information downloaded from the cloud and/or other remote computers. In some embodiments, controller 150 can send/receive information on a regular schedule that can vary depending on the system's operational phase. For example, controller 150 can be configured to provide updates every five minutes when system 600 is at a donor hospital, every 15 seconds during transport, and/or every 15 seconds when system 600 is at a recipient hospital. Controller 150 can also be configured to send/receive information securely, such as using encryption and/or timestamping.

The controller 150 can be configured to provide various types of information to the cloud and/or remote location, such as: price quotes for organs, system readiness information, battery charge level, gas tank level, status of the solution infusion pump, flow rate, pressure level, oxygenation rate, hematocrit level, lactate level, temperature level, flow rate set for the pump 106, temperature set for the heater 110, position of the flow fixture 190, some or all of the information displayed on the user interface (e.g., circulation and infusion flow rates, pressure, oxygenation level, hematocrit level), geographic location, altitude, a copy of the displayed interface itself, waveforms displayed on the user interface, alarm limits, active alarms, screen captures of the user interface, photos (e.g., photos captured using an onboard camera), HAP/HAF/lactate trends, historical usage information about the system 600 (e.g., number of hours the system has been used), and/or donor information. In cardiac/pulmonary embodiments, additional information such as AOP and/or PEEP can be provided. Essentially, any piece of information collected, generated, and/or stored by the system 600 can be sent to the cloud and/or a remote computer.

The controller 150 may be configured to receive various types of information from the cloud and/or remote locations such as: instructions from a remote user, "pull" requests for data from a remote location, control inputs, information about organ receptors, and/or system updates.

In some embodiments, using the information provided by system 600, users remote from system 600 can effectively and remotely view the same user interface displayed on system 600. Furthermore, in some embodiments, users remote from system 600 can remotely control system 600 as if they were physically present. In some embodiments, the remote view can be an enhanced version of what is observed by an in-person user. For example, the user interface can be presented in a similar format so that the remote user sees what the in-person user sees, but the remote view can be enhanced so that it also displays additional information to provide context for the remote viewer. For example, donor demographics, geographic location, trends, and/or assessment results can also be displayed. The remote user can also be provided with virtual buttons and/or controls that match those provided on system 600, which can be used to remotely control the operation of system 600.

In some embodiments, one or more technicians can remotely connect to the system 600 and access the system 600 to perform diagnostics, update the system, and/or remotely troubleshoot problems. In some embodiments, remote technical assistance can be limited to times when the system 600 is not being used to preserve an organ.

In some implementations, information provided by system 600 can be presented to remote users via a web portal, mobile application, and/or other interface.

In some embodiments, access to the information provided by the system 600 can be limited to one or more registered users, such as surgical staff, technical support teams, and/or administrators at the recipient's hospital. In some embodiments, access to the information provided by the system 600 can be dependent on the recipient's electronic medical files. For example, a cloud-based server can access one or more electronic medical files of the recipient to determine, for example, parties explicitly identified as having access to the recipient's health data, parties associated with organizations identified as having access to the recipient's health data, and/or individuals working at medical facilities within a specific geographic distance of the recipient.

As described herein, samples of the perfusion fluid may sometimes be extracted during transport for external analysis. However, in these cases, the data obtained through external analysis is not correlated with the information contained within system 600. Therefore, in some embodiments, the user interface provided by system 600 can be configured to allow the user to input and store externally generated data about the organ. For example, if an on-site user extracts a sample of the perfusion fluid to perform a lactate measurement in an external analyzer, the on-site user can then input and store the results, along with data generated by system 600 itself, within system 600. Along with the results themselves, the user can also provide timestamp information and a description of the information. The information entered by the user can be stored, processed, downloaded, and/or transmitted by system 600 as if the information were generated internally. In this way, system 600 can maintain a complete record of all information related to the organ while it is ex vivo, regardless of whether the information was generated internally or externally by system 600.

26 , in operation, process 6600 describes an exemplary embodiment of how system 600 can be used with a cloud-based communication/storage system. Process 6600 is exemplary only and not limiting. For example, the stages described herein may be modified, altered, rearranged, and/or omitted. Process 6600 assumes that system 600 is in communication with a cloud-based remote server and that the system is being used to transport an organ, but this is not required. The process may be suitable for use, for example, when an organ is being processed ex vivo for transplantation back to the original patient rather than into a new recipient.

At stage 6605, an organization controlling organ allocation (e.g., an organ procurement organization) may provide a quote for an organ to the retrieval hospital. Through a web portal to system 600, retrieval hospital staff may query the system 600's readiness status (e.g., battery charge level, gas levels) and may enter information about the donor. This information may be transmitted to system 600 via a server.

At stage 6610, clinical support on-call personnel may be registered with the server via email, text message, automated phone call, and/or any other communication means for upcoming transmission session reminders. The clinical support personnel may be, for example, staff employed by the manufacturer of the system 600.

At stage 6615, which typically occurs during transport, system 600 can send system/organ status information to a cloud-based server via a communication link. The information sent to the server can be viewed in an online portal by third parties, such as transplant surgeons, support staff, and/or any other permitted parties (all of which may be located in different geographical locations). In some embodiments, the server can perform additional processing on the information received from system 600 to generate new information, which can then be presented back to system 600 and/or third parties. The information displayed to the user on system 600 (e.g., the underlying data and/or the images themselves) can be proactively sent to the server, for example, every two minutes. This data can then be stored on the server with a timestamp. For example, in some embodiments, each time the server receives information from system 600, the information can be placed in a row of an Excel spreadsheet. Additionally, during stage 6615, a remote user viewing information through the portal can "pull" (request) a refresh/snapshot of the data from the OCS, rather than waiting for the next two-minute sample to be "pushed." Additionally, in some embodiments, a remote party can remotely control the operation of system 600 via a remote interface.

The remote view can be an enhanced version of what is displayed on the monitor of system 600. The remote view can be presented in a similar format so that the remote user can see what the in-person user is observing. However, in some embodiments, the remote view can be enhanced so that the remote view also displays additional information to provide context for the remote viewer, such as donor personnel statistics, trends, and assessment results.

System 600 can send alerts to remote third parties such as transplant surgeons and/or clinical support teams via a server. A live user can trigger contact with one or more remote third parties via a monitor menu action. For example, a live user can send a request for assistance to technical support, which receives the alert and calls or otherwise contacts the live user via, for example, a text message and/or email.

System 600 can automatically sound an alarm under certain critical conditions (e.g., HAP > 120, or PVP > 20 mmHg). On-site users can also take photos using a camera integrated into system 600 (e.g., into operator interface module 146). Images can be automatically pushed to a server by system 600.

During stage 6615, the system 600 can automatically provide information to the server and/or other remote computers at regular intervals, such as every 15 seconds, every two minutes, every five minutes, or every 10 minutes. In some embodiments, the transmission of information between the system 600, the server, and/or the third party can be performed in real time so that the remote party can access and/or control the system 600 in real time, just as if they were there in person. In some embodiments, the on-site user and/or any other remote party can initiate an unscheduled transmission of information. In some embodiments, if the communication link of the system 600 has been disabled or is inoperable (e.g., during air transportation), the controller 150 can be configured to continue generating regular status updates and store them for transmission once the communication link has been re-enabled.

At stage 6620, which typically occurs at the end of a transmission session, session files from the system 600 can be pushed to the server. Information provided to the server may include, for example, trends, errors, blood samples, and event files. WiFi can be prioritized over cellular links for data transmission to minimize costs.

IX. Possible Benefits

Some embodiments of the system 600 described herein may provide one or more benefits. For example:

Depending on the type of procedure being performed, manually controlling the organ preservation system may be a labor-intensive process that requires specialized training. In addition, as with any medical procedure, manual control is also susceptible to error by the person controlling the system. Therefore, in some embodiments, the system 600 can automatically control itself in real time. For example, the controller 150 can be configured to automatically control the flow rate of the pump 106, the operation of the gas exchanger 114, the temperature of the heater 110, the operation of the flow clamp 190 (in the case of using an automatic clamp) and/or the transmission of information to the cloud. The controller 150 can be configured to control the operation of the system 600 based on feedback information from, for example, sensors housed in the system 600.

Providing automatic control of system 600 can result in improved usability, reduce the possibility of errors, and reduce the labor intensity of transporting organs. For example, automating the control process can compensate for user variability that can exist when different personnel control the system. For example, even if two users receive the same training, the judgment of one user may still differ from that of another user, which may lead to inconsistent levels of care between the two users. By automating the control process, a consistent level of care can be achieved between operators in a way that would otherwise be difficult to achieve. In addition, providing automated control can also provide better care for isolated organs by updating the operating parameters of system 600 more quickly than can be provided using manual control.

The technology described herein can also improve the utilization rate of donor organs that are currently unused due to the limitations of cold storage methods. In existing cold storage methods, many organs are wasted because they cannot be transported to recipients before they suffer damage caused by cold storage. This causes many organs that were originally suitable for transplantation to be wasted every year. Using the technology described herein, the amount of time an organ can be kept in a healthy ex vivo state can be greatly extended, thereby increasing the number of potential donors and recipients.

The technology described herein can also help improve the assessment of whether an organ is suitable for transplantation into a recipient. For example, using the example of a liver, visual observation or inspection of the liver can be used to assess liver viability. For example, a pink or red liver can indicate that the liver is functioning normally, while a gray or black liver can indicate that the liver is functioning abnormally or has deteriorated. In other embodiments, palpation of the liver can be used to assess its viability. If the liver feels soft and flexible, the liver is likely functioning normally. On the other hand, if the liver feels tight or stiff, the liver is likely functioning abnormally or has deteriorated.

In other embodiments, because the bile duct is cannulated and connected to the reservoir of system 600, the color and amount of bile produced by the liver can be easily checked to assess liver viability. In certain embodiments, black or dark green bile indicates normal liver function, while light or colorless bile indicates that the liver is not functioning normally or is deteriorating. In other embodiments, bile production can also be utilized to assess liver viability. Generally, the more bile produced, the better the liver function. In certain embodiments, bile production of about 250mL to 1L, 500mL to 1L, 500mL to 750mL, 500mL, 750mL or 1L per day or bile production in any range defined by values described herein indicates that the liver stored on the organ care system 600 is functioning normally and can survive. When the organ is in vivo, many of the aforementioned techniques would still be difficult even if possible.

X. Example

The following describes experimental testing and results related to some embodiments. As described below, the experimental testing included multiple studies and phases. Phase I included a 12-hour study of 27 liver samples on the above OCS system, including two groups of organs. Phase II included a simulated transplant process that replicated the clinical steps of liver resection, preservation, and simulated transplantation of multiple sample livers for 4 hours. Phase III included a simulated transplant process that replicated the clinical steps of liver resection, preservation, and simulated transplantation of multiple sample livers for 24 hours.

A. Phase I

Organ Set A and Organ Set B were used for Phase I. The goals of Phase I included: (1) optimally perfusing and preserving the liver on the OCS system with a nutrient-rich perfusate based on expansion-regulated red blood cells ("RBCs") for up to 12 hours; (2) maintaining stable near-physiologic hemodynamics (pressure and flow) for both the portal and hepatic arterial circulations; (3) enabling monitoring of organ function and stability on the OCS by monitoring bile production rates, liver enzyme trends, stable pH, and arterial lactate levels; and (4) performing histopathological assessment of the organs after OCS.

The animal model used for testing is a porcine model consisting of Yorkshire hogs weighing 70 to 95 kg. Yorkshire hogs are used as a model due to their similarities to human anatomy and organ size comparable to that of adult humans. The perfusate used for testing is based on red blood cells. Given that the liver is a highly metabolically active organ, a perfusate with oxygen-carrying capacity and rich nutrients is ideal for the organ in order to simulate its in vivo environment and meet its high metabolic demands.

The liver is unique due to its dual blood supply. As previously described, the liver obtains its blood supply through the portal vein (PV) and the hepatic artery (HA). The portal circulation is a low-pressure circulation (5mmHg to 10mmHg), while the hepatic artery circulation delivers high-pressure pulsating blood flow (70mmHg to 120mmHg). Stable perfusion parameters and hemodynamics indicate stable perfusion. Lactate levels are used as an indicator of adequate perfusion because lactate is one of the most sensitive physiological parameters and is therefore a good indicator of adequate perfusion. Lactate is produced under hypoxic conditions, which indicate inadequate perfusion, and the trend of lactate levels is a sensitive indicator for adequate perfusion assessment. Aspartate aminotransferase ("AST") is a standard indicator for evaluating the liver clinically and is also used as an indicator of viability. The trend of AST levels is another indicator and an indicator of organ viability. Bile production is a unique function of the liver. Bile production monitoring is another indicator of organ viability and function.

Phase I included a study of 27 liver samples. Group A included 21 samples that were stored on OCS for 8 hours using a cell-based perfusate, and Group B included 6 samples that were stored on OCS for 12 hours using a cell-based perfusate.

The following protocol was applied to both Group A and Group B testing during Phase I.

First, animal preparation, organ excision, intubation and advance OCS flushing have been described.By according to the combination of following dosage intramuscular injection of Telazol (Telazol) and xylazine (Xylazine), every 70kg to 95kg Yorkshire pig is sedated in its cage: 6.6mg/kg Telazol and 2.2mg/kg xylazine.Then animal is intubated, IV (venous) line is set up, then animal is transferred to OR platform with supine position, then connected to ventilator and anesthesia machine.Liver is exposed by right rib lower edge incision, and heart is exposed by midline sternotomy.Hepatic artery (HA), portal vein (PV) and common bile duct are separated.Then right atrium and superior vena cava are separated and intubated for blood collection.Then 40Fr intravenous cannula is used to collect 2 liters to 3 liters of blood from animal by right atrium.Then collected blood is processed to collect RBC through blood recovery machine (Haemonetics Cell Saver5+).During blood collection time, local cooling is applied to liver. The liver was then harvested.

After harvesting the liver, the hepatic artery (HA), portal vein (PV), common bile duct, suprahepatic vena cava, and infrahepatic vena cava are isolated and cannulae of appropriate size are utilized for each. Exemplary cannulae sizes include 14Fr, 16Fr, 18Fr hepatic artery cannulae, 40Fr and 44Fr portal vein cannulae, 12Fr and 14Fr common bile duct cannulae, 40Fr suprahepatic vena cava, and 40Fr infrahepatic vena cava.

The liver is then flushed with 3 L of a cold solution, each containing 10 mml/L sodium bicarbonate (NHCO ₃ ), 2 mics/L epoprostenol sodium, and 160 mg/L methylprednisolone. One liter is delivered through the hepatic artery and pressurized to approximately 50 to 70 mmHg. Two liters are delivered by gravity through the portal vein.

After cannulation, the organ was maintained on OCS at 34°C for 12 hours using a turgor-adjusted RBC-based perfusate. The OCS liver system perfusate included washed red blood cells, 25% albumin, solution, dexamethasone, 8.4% sodium bicarbonate (NaHCO ₃ ), 10% calcium gluconate (100 mg/ml) for adult multivitamins for infusion, Gram-positive antibiotics such as cefazolin, and Gram-negative antibiotics such as ciprofloxacin. Table 7 below summarizes the composition and dosage of the liver perfusate.

Table 7. Composition and dosage of OCS liver perfusion solution

In addition to the OCS liver circulating perfusate mentioned above, the following were delivered to the perfusate as a continuous infusion using an integrated Alaris infusion pump: Total parenteral nutrition (TPN): CLINIMIX E (4.25% amino acids/10% dextrose); plus insulin (30 IU), glucose (25 g), and 40,000 units of heparin; Prostacyclin infusion as needed : (epoprostenol sodium) to optimize hepatic artery pressure; Bile salts (sodium taurocholate): as needed for bile salt supplementation. Table 8 below shows the infusions and rates of the liver perfusate.

Table 8. OCS liver perfusate infusion and rate

The liver is perfused on the OCS by delivering a warm, oxygenated, and nutrient-rich blood-based perfusate through the hepatic artery and portal vein. Once the liver is mounted on the OCS and all cannulas are connected, the pump flow rate is gradually and very slowly increased to achieve the target flow rate over 10 to 20 minutes. As the liver warms to the temperature set point, the flow control clamp is adjusted to maintain a 1:1 to 1:2 flow ratio between the HA and PV. The vasodilator flow rate is adjusted as needed to manage hepatic artery pressure. Arterial blood samples are collected within the first 15 to 20 minutes.

The following perfusion parameters were maintained during perfusion on the liver OCS device: hepatic artery pressure (mean HAP): 75 mmHg to 100 mmHg; hepatic artery flow (HAF): 300 ml/min to 700 ml/min; portal vein pressure (mean PVP): 4 mmHg to 8 mmHg; portal vein flow (PVF): 500 ml/min to 900 ml/min; perfusion temperature (Temp): 34°C; oxygen flow 400 ml/min to 700 ml/min.

Lactate levels were collected from the OCS liver perfusion according to the following sampling protocol. One OCS hepatic artery sample was collected between 10 and 20 minutes after initiation of perfusion on the liver OCS device. Samples were collected from the device at approximately hourly intervals until lactate levels trended downward, at which point lactate samples were obtained every two hours or after any active HAF or HAP manipulation. Baseline liver enzymes were measured from the animal. Liver enzymes were collected and assessed every two hours on the OCS starting at the second hour.

Histopathological sampling after OCS

At the end of the storage time, OCS perfusion was terminated. The liver was disconnected from the device and all cannulas were removed. Samples were collected from the liver and stored in 10% formalin for histopathological evaluation. Liver sections were collected to obtain the wet/dry ratio. The section weights were recorded before and after 48 hours in an 80°C oven. The wet/dry ratio was then calculated according to the following formula: water content (W/D ratio) = 1 - (final weight / starting weight).

The liver was considered acceptable if acceptance criteria were met, which included: stable perfusion parameters for HAF, HAP, PVF, and PVP throughout the storage period on OCS; stable or declining arterial lactate; continuous bile production at a rate >10 ml/hr.; stable or declining liver enzymes (AST); and normal and stable perfusate pH.

The 21 samples of Phase I, Group A successfully met the acceptance criteria for the above confirmation. The data of hepatic artery flow during 8 hours of OCS liver perfusion shown in the graph of Figure 31 indicate that the pig liver perfused with OCS showed stable perfusion, as demonstrated by the hepatic artery flow (HAF) trend throughout the 8 hours of storage on OCS. Figure 32 shows the PVF trend throughout the 8 hours of storage on OCS, and the data of portal vein flow during 8 hours of OCS liver perfusion shown in the graph of Figure 32 indicate stable perfusion, as demonstrated by the stable portal vein flow (PVF) trend throughout the 8 hours of storage on OCS. Figure 33 shows a graphical depiction of hepatic artery pressure and portal vein pressure during 8 hours of OCS liver perfusion. Figure 33 shows the stable perfusion pressure demonstrated by the pig liver perfused with OCS, as demonstrated by the stable portal vein pressure and hepatic artery pressure throughout the 8 hours of storage.

Figure 34 is a graphical depiction of arterial lactate levels during 8 hours of OCS liver perfusion. Figure 34 shows that pig livers perfused with OCS exhibit excellent metabolic function, as demonstrated by their ability to clear lactate and the trend of lactate decreasing throughout the 8 hours of storage on OCS. Figure 35 is a graphical depiction of total bile production during 8 hours of OCS liver perfusion. Figure 35 shows that the OCS-perfused livers continued to produce bile at a rate of >10 ml/hr. throughout the 8 hours of storage on OCS, indicating preserved organ function. Figure 36 is a graphical depiction of AST levels during 8 hours of OCS liver perfusion. Aspartate aminotransferase (AST) is a standard indicator used clinically to evaluate the liver. The graph of Figure 36 shows that the OCS-perfused livers exhibited a trend of decreasing AST levels during the 8 hours of perfusion on OCS, indicating good liver function. Figure 37 is a graphical depiction of ACT levels during 8 hours of OCS liver perfusion. As shown in Figure 37, the activated clotting time (ACT) remained above 300 seconds during the 8-hour perfusion on OCS. Figure 38 is a graphical depiction of the colloid osmotic pressure throughout the 8-hour storage on OCS. As shown in Figure 38, the colloid osmotic pressure remained stable on OCS.

FIG39 is a graphical depiction of bicarbonate levels during 8 hours of OCS liver perfusion. As shown in FIG39 , bicarbonate (HCO 3 ) levels remained within the normal physiological range during the 8 hours of perfusion on OCS, requiring very small doses of HCO 3 for correction, indicating a stable liver metabolic profile. FIG40 is a depiction of pH levels detected during 8 hours of storage on OCS. As shown in FIG40 , a stable and normal pH remained during the 8 hours of perfusion on OCS, with no or minimal need for addition of HCO 3 for correction, indicating a well-functioning and adequately perfused organ.

Figure 41 shows images of tissue taken from samples in Phase I, Group A. Histological examination of parenchymal and bile duct tissue showed normal liver sinusoidal architecture with no signs of necrosis or ischemia, as well as normal bile duct epithelial cells, indicating adequate perfusion and the absence of ischemic injury.

The results observed for organs from Phase I, Group B, maintained for 12 hours showed acceptable results similar to those observed for organs from Group A.

As in Group A above, in Phase I Group B, livers were considered acceptable if they met acceptance criteria, which included: stable perfusion parameters of HAF, HAP, PVF, and PVP throughout the period of preservation on OCS; stable or declining arterial lactate; continuous bile production at a rate >10 ml/hr.; stable or declining liver enzymes (AST); and normal and stable perfusate pH.

Figure 42 depicts hepatic artery flow for 12 hours of OCS liver perfusion.As shown, the graph of Figure 42 shows that OCS-perfused pig livers demonstrated stable perfusion as evidenced by the trend of hepatic artery flow (HAF) throughout the 8 hours of storage on OCS.

Figure 43 depicts portal vein flow for 12 hours of OCS liver perfusion. As shown, the graph of Figure 43 shows that OCS-perfused pig livers demonstrated stable perfusion, as evidenced by the stable portal vein flow (PVF) trend throughout the 12 hours of storage on OCS.

Figure 44 depicts hepatic artery pressure and portal vein pressure during 12 hours of OCS liver perfusion. The graph of Figure 44 demonstrates that pig livers perfused with OCS exhibit stable perfusion pressure, as evidenced by stable portal vein flow (PVP) and hepatic artery pressure (HAP) trends throughout the 12 hours of OCS storage.

Figure 45 depicts arterial lactate during 12 hour OCS liver perfusion. The graph of Figure 45 shows that OCS perfused pig livers demonstrated excellent metabolic function as evidenced by their ability to clear lactate and the decreasing trend in lactate levels throughout the 12 hour period of storage on OCS.

Figure 46 depicts bile production during 12 hours of OCS liver perfusion.The graph of Figure 46 demonstrates that OCS-perfused livers continued to produce bile at a rate of >10 ml/hr throughout the 12 hours of preservation on OCS, indicating good function of the preserved organ.

Figure 47 depicts AST levels during 12 hours of OCS liver perfusion. Aspartate aminotransferase (AST) is a standard indicator used clinically to evaluate the liver. The graph in Figure 47 shows that livers perfused with OCS showed a trend toward decreased AST levels over the course of 12 hours of perfusion on OCS. This indicates good liver function.

Figure 48 depicts ACT levels in 12-hour OCS liver perfusion. The activated clotting time (ACT) remained above 300 seconds during the 12-hour perfusion on OCS, as shown in Figure 48.

B. Phase II

Phase II, or Group C, included 12 liver samples. Six samples were stored on OCS for 8 hours using a cell-based perfusate followed by 4 hours of simulated transplantation using whole blood as the perfusate. The other six samples were stored in UW solution for 8 hours and then simulated transplantation using whole blood as the perfusate for 4 hours on OCS.

The goals of Phase II included preserving the liver via OCS with 8 hours of warm perfusion using an RBC-based perfusate, followed by 45 minutes of cold ischemia, and then an additional 4 hours of warm OCS liver perfusion using whole blood, (a) optimally perfusing and preserving the liver on the OCS system for 8 hours with a nutrient-rich perfusate based on expansion-regulated RBCs, (b) maintaining stable near-physiological hemodynamics (pressure and flow) for both the portal and hepatic arterial circulations, c) enabling monitoring of organ function and stability on OCS by monitoring bile production rates, liver enzyme trends, stable pH, and arterial lactate levels; and (d) subjecting the organ to 45 minutes of cold ischemia after the initial 8 hours on OCS, (e) followed by 4 hours of simulated transplantation on OCS using whole blood while monitoring and evaluating organ hemodynamic and perfusion parameters and monitoring organ function.

Mock transplantation on OCS was used to minimize confounding variables associated with orthotopic transplantation and to isolate these variables from ischemia/reperfusion effects alone.

The preclinical simulated transplantation test of this group (C) was expanded to include a control device in which a standard liver care cold preservation solution was used to cold store pig livers. Except for the cold preservation phase, the protocol for this device of this group was identical to the OCS simulated transplantation device of the same group (C). The detailed protocol and results are described below.

Similar to Phase I, Yorkshire pigs weighing 70 to 95 kg were used as test subjects in Phase II. For this phase, two animals were used per study, with the first animal serving as the organ donor and the second animal serving as the blood donor for the perfusion simulation phase performed on the OCS.

In this simulated animal transplant model, the donor organ is exposed to the conditions of organ excision, preservation and final cooling for transplantation identical with in situ transplantation.The only difference is: in the transplantation stage, the organ is reperfused in the ex vivo OCS perfusion system with the unmodified whole blood of another animal to control all the confounding variables that may hide the real influence of preservation injury on the donor organ of in situ transplantation.The donor organ function and injury index monitored during the simulated transplantation stage are identical with the donor organ function and injury index monitored during the in situ transplantation.The acceptance criteria to the sample of stage II are identical with the acceptance criteria outlined above and are measured during the 4-hour simulated transplantation.

Phase II, simulated transplantation of OCS equipment, 6 samples (N=6).

This setup was achieved by replicating all key clinical steps of the liver retrieval, preservation, and simulated transplantation process in the following sequence:

Donor Organ Retrieval (30-45 minutes): During this phase, the donor organ is harvested and cold flushed for 30-45 minutes to replicate the clinical conditions of donor liver retrieval and setup on the OCS Liver System. The same preparation, organ retrieval, cannulation, and pre-OCS flushing are performed as described in Phase I.

Donor livers were stored on OCS (8 hours): During this phase, donor organs were perfused and assessed ex vivo using the OCS liver system. During this phase, livers were monitored hourly for indicators of liver damage (AST levels), metabolic function (lactate levels), and bile production rate as an indicator of liver function/viability, and the livers were assessed. This group underwent the same organ storage as the 8-hour storage samples described in Phase I.

Post-OCS cold storage ischemia (45 minutes): During this phase, the donor liver is flushed with a cold flush solution as specified in the proposed clinical protocol to replicate the final cooling required for re-transplantation of the donor liver. The donor liver is kept cold for 45 minutes to replicate the time required for the re-transplantation process in the recipient. Using the final flush line included in the OCS liver perfusion terminal device, the liver is flushed and cooled on the OCS with a 3L cold perfusion solution supplemented with 10mml/L sodium bicarbonate (NHCO3), 2mcg/L sodium prostaglandin and 160mg/L methylprednisolone, wherein 1 liter is supplied to the hepatic artery at approximately 50mmHg to 70mmHg and 2 liters are gravity drained to the portal vein. The liver is then disconnected from the OCS and placed in a cold saline bath for 45 minutes.

Final reperfusion of donor liver (4 hours): Transplantation was replicated/simulated by the following process so that graft assessment indicators of local ischemia and reperfusion due to preservation technique were independent of other confounding variables associated with the transplant model (described above). Liver grafts were reperfused ex vivo for 4 hours at 37°C using normothermic fresh whole blood from different pigs in a new OCS liver perfusion module. For the simulated transplantation phase, the organs were perfused on the OCS using a new perfusion module. The perfusion pressure/flow was controlled to near physiological levels and the temperature was maintained at 37°C. The liver was monitored every hour for the same indicators as during the preservation period. In addition, liver tissue samples were histologically evaluated in the same manner as described above in Phase I to assess liver tissue structure and any signs of damage.

Phase II, simulated transplant cold storage control arm (N=6).

This is achieved by replicating all key clinical steps of the liver retrieval, preservation, and simulated transplantation process in the following sequence:

Donor Organ Retrieval (30-45 min): During this phase, the donor organ is harvested, which lasts 30-45 min to replicate the clinical conditions of donor liver retrieval. The same preparation, organ retrieval, cannulation, and pre-OCS flushing as described in Phase I are performed.

Donor Liver Cold Preservation: During this phase, donor livers were stored for 8 hours using standard of care cold storage solution Belzer (UW solution) for liver flushing and stored at 2°C to 5°C to simulate standard of care for cold preservation of livers.

After cold storage, organ flushing and preparation (45 minutes): During this stage, the donor liver is flushed with cold flush solution using the final flush line included in the OCS liver perfusion terminal device. The liver is flushed using 3L of cold perfusion solution supplemented with 10mml/L sodium bicarbonate (NaHCO3), 2mcg/L prostaglandin sodium, and 160mg/L methylprednisolone, wherein 1 liter is supplied to the hepatic artery at approximately 50mmHg to 70mmHg and 2 liters are gravity drained into the portal vein. The liver is then disconnected from the OCS and placed in a cold saline bath for 45 minutes.

Final reperfusion of donor liver (4 hours): Transplantation was replicated/simulated by the following process so that graft assessment indicators of ischemia and reperfusion due to the preservation technique were independent of other confounding variables associated with the transplant model (described above). Liver grafts were reperfused ex vivo for 4 hours using normothermic fresh whole blood from different pigs in a new OCS liver perfusion module. Perfusion pressure/flow was controlled to near physiological levels and temperature was maintained at 37°C. The liver was monitored every hour for the same indicators as during preservation. In addition, liver tissue samples were histologically evaluated in the same manner as described above in Phase I to assess liver tissue structure and any signs of damage.

Results observed for Phase II indicate that samples perfused using the OCS system achieved better post-perfusion outcomes than samples subjected to cold storage. Compared to the OCS arm of this group, samples subjected to cold storage did not meet the previously described acceptance criteria for the 4-hour simulated transplantation period.

In the cold-storage control arm, liver metabolic function exhibited an unstable and deteriorating profile over the four hours of simulated transplantation, as evidenced by a trend toward decreasing arterial lactate, compared to the OCS arm of the group, which exhibited much better metabolic function. This suggests that the OCS arm livers had significantly better metabolic function than the cold-storage control arm. The profile of liver enzymes (AST), a sensitive indicator of liver damage, was unstable and trended toward much higher levels in the cold-storage control arm compared to the OCS arm of the group. This suggests that, compared to the better-preserved and better-functioning liver grafts in the OCS arm (as evidenced by the much lower liver enzyme (AST) trend in the OCS arm), the control arm liver grafts had impaired liver function. In the cold-storage control arm, pH trends required a much higher HCO3 dose than that required for the OCS arm of the group to achieve and maintain a stable metabolic profile. This suggests that the OCS arm was able to maintain a much better metabolic profile than the cold-storage control arm. Bile production rates were lower in the cold-storage control arm than in the OCS arm. This suggests that liver graft function was better in the OCS arm compared to the cold storage control arm. Perfusion parameters were comparable for both arms in this group. Based on these comparisons, the OCS arm successfully met the proposed pre-specified acceptance criteria, while the cold storage control arm did not meet the same acceptance criteria.

Figure 49 depicts hepatic artery flow on a simulated transplant OCS liver preservation apparatus versus a simulated transplant controlled cold preservation apparatus. As shown, the graph of Figure 49 depicts stable hepatic artery flow (HAF) during a 4-hour perfusion on OCS during simulated transplantation.

Figure 50 depicts portal vein flow on a simulated transplant OCS liver preservation apparatus versus a simulated transplant controlled cold preservation apparatus. As shown in Figure 50, the graph demonstrates stable portal vein flow (PVF) during a 4-hour perfusion on OCS during simulated transplantation.

Figure 51 depicts hepatic artery pressure and portal vein pressure in a simulated transplant OCS liver preservation apparatus and a simulated transplant controlled cold preservation apparatus. The graph of Figure 51 demonstrates the stable hepatic artery pressure (HAP) and portal vein pressure (PVP) trends during a 4-hour perfusion on OCS.

Figure 52 depicts arterial lactate in simulated transplant OCS-perfused livers versus simulated transplant control cold-preserved livers. The graph in Figure 52 demonstrates that OCS-perfused livers have significantly better metabolic function, as evidenced by a trend toward decreased arterial lactate. This suggests that OCS-perfused livers have significantly better metabolic function compared to cold-preserved livers.

Figure 53 depicts bile production in simulated transplant livers perfused with an OCS device and simulated transplant livers perfused with a cold storage device. The graph in Figure 53 demonstrates that livers perfused with the OCS device had a higher rate of bile production compared to cold-stored livers. This suggests that liver graft function was better in the OCS group than in the cold-stored group.

Figure 54 depicts AST levels in simulated transplant livers perfused with OCS versus simulated transplant livers perfused with cold storage. The graph in Figure 54 demonstrates that OCS-perfused livers had significantly lower AST levels throughout the 4-hour simulated transplant period. This suggests that liver damage to the graft was significantly less in the OCS group compared to the cold storage group.

Figure 55 depicts ACT levels for a simulated transplant OCS liver preservation arm versus a simulated transplant control cold preservation arm. The activated clotting time (ACT) remained above 300 seconds during 8 hours of perfusion on OCS.

Figure 56 depicts the colloid osmotic pressure of the simulated transplant OCS liver preservation device and the simulated transplant control cold preservation device. As depicted in Figure 56, there is a stable colloid osmotic pressure on the OCS liver preservation device.

Figure 57 depicts bicarbonate levels in a simulated transplant OCS liver preservation arm versus a simulated transplant control cold preservation arm.

Figure 58 depicts pH levels in a simulated transplant OCS liver preservation apparatus versus a simulated transplant control cold preservation apparatus. The graph in Figure 58 demonstrates that OCS-perfused livers had better pH values over the 4-hour perfusion period on OCS compared to cold-stored livers. OCS-perfused livers required significantly less HCO3 correction compared to the cold-stored group, indicating that the liver graft functioned better in the OCS apparatus compared to the control apparatus.

As shown in FIG59 , histological examination of parenchymal and bile duct tissues revealed normal liver sinusoidal architecture with no signs of necrosis or ischemia, as well as normal bile duct epithelial cells, indicating adequate perfusion and the absence of ischemic injury.

As shown in FIG60 , histological examination of the parenchymal and bile duct tissues showed marked hemorrhage and congestion within the parenchyma, interlobular hemorrhage, multifocal widely diffused interlobular hemorrhage, and lobular congestion.

C. Phase III

The preclinical simulation transplantation test of this group is carried out to compare the liver (3 samples) of OCS preservation for 12 hours with the control equipment liver cold preservation (3 samples) of using standard liver care cold preservation solution (UW solution) for 12 hours. Then, the leukocyte-reduced blood from different animals is used on OCS to simulate the transplant model to evaluate the OCS equipment and cold storage equipment for 24 hours. Except for the cold preservation stage, the scheme of the two equipments of this group is identical. In the simulated transplantation stage, organ function and stability are evaluated by monitoring and measuring the stable perfusion parameters, bile production, liver biomarkers, pH level and arterial lactate level that are maintained within the pre-specified range. Liver biomarkers include AST, ALT, ALP, GGT and total bilirubin. After the simulated transplantation stage, the liver is sampled for histopathological evaluation. The acceptance criteria of this stage are the same as the acceptance criteria outlined in Phase I.

OCS equipment :

Donor Organ Retrieval: During this phase, the donor organ is harvested and cold flushed to replicate the clinical conditions of donor liver retrieval and setup on the OCS Liver System. The same preparation, organ retrieval, cannulation, and pre-OCS flushing are performed as described in Phase I.

Donor livers were stored on OCS (12 hours): During this phase, donor organs were perfused and evaluated ex vivo using the OCS liver system. This group underwent organ storage similar to the 8-hour storage samples described in Phase I. The perfusate consisted of 1500 ml to 2000 ml of RBCs (Haemonetics Cell Saver), 400 ml of 25% albumin, 700 ml of Promali, antibiotics of 1 g cefazolin (Gram-positive) and 100 mg levofloxacin (Gram-negative), 500 mg of succinate sodium, 20 mg of dexamethasone, 50 mmol HCO3, 1 vial of multivitamins, and 10 ml of calcium gluconate (4.65 mEq).

During storage, 80% O2 was started at a rate of 450 ml/min just before the start of organ preparation and adjusted according to arterial pCO2 and pO2. The temperature was maintained at 34°C.

Continuous infusions were delivered using an integrated OCS-SDS. Flolan was added to the HA inflow (0.05 mg of Flolan "1 mic/ml" in 50 ml of Flolan diluent) at 0 to 20 mic/hr (0 to 20 ml/hr) as needed. CLINIMIX E TPN supplemented with 30 IU insulin, 25 g glucose, and 40,000 U heparin was continuously infused into the PV at a rate of 30 mL/h as priming began. Taurocholate sodium salt, a gamma-sterilized bile salt, was infused at a rate of 3 mL/h (1 g/50 ml of sterile water) as priming began.

Target pressures and flows: portal vein pressure, 1 mmHg to 8 mmHg; portal vein flow, 0.7 L/min to 1.7 L/min; hepatic artery pressure, 85 mmHg to 110 mmHg; and hepatic artery flow, 0.3 L/min to 0.7 L/min.

Using the final flush line included in the OCS liver perfusion terminal, the liver was flushed and cooled on the OCS with 3 L of cold bolus solution, with 1 L delivered to the hepatic artery at approximately 50 to 70 mmHg and 2 L gravity drained into the portal vein. The liver was then disconnected from the OCS and placed in a cold saline bath for 45 minutes.

Cold static storage equipment:

The same preparation, organ extraction, cannulation, and pre-OCS flushing were performed as described in Phase I.

After flushing the organ with 3 L of UW, it was stored cold in UW solution at approximately 5°C for 12 hours. Using the final flush line included in the OCS liver perfusion terminal, the liver was flushed and cooled on the OCS with 3 L of cold paracentesis solution, with 1 liter delivered to the hepatic artery at approximately 50 to 70 mmHg and 2 liters gravity drained into the portal vein. The liver was then disconnected from the OCS and placed in a cold saline bath for 45 minutes.

Both groups of livers underwent a 24-hour post-transplantation phase in which they were mounted on an OCS machine and supplied with a post-perfusion solution consisting of 1500 to 3000 ml of leukopenia-reduced blood, 100 ml of 25% albumin, 1 g of cefazolin (Gram-positive) and 100 mg of levofloxacin (Gram-negative) antibiotics, 500 mg of succinate sodium, 20 mg of dexamethasone, 50 mmol of HCO₃, a vial of multivitamins, and 10 ml of calcium gluconate (4.65 mEq). During the simulated transplantation, 80% O₂ was initiated at a rate of 450 ml/min just before the organ was mounted and regulated according to arterial pCO₂ and pO₂. The temperature was maintained at 37°C.

A continuous infusion was delivered using an integrated OCS-SDS. Flolan was added to the HA inflow at 0 to 20 mic/hr (0 to 20 ml/hr) as needed (0.05 mg of Flolan at 1 mic/ml in 50 ml of Flolan diluent). CLINIMIX E TPN supplemented with 30 IU insulin, 25 g glucose, and 40,000 U heparin was continuously infused into the PV at a rate of 30 mL/h as priming began. Taurocholate sodium salt, a gamma-sterilized bile salt, was infused at a rate of 3 mL/h (1 g/50 ml of sterile water) as priming began.

Target pressures and flows: portal vein pressure, 1 mmHg to 8 mmHg; portal vein flow, 0.7 L/min to 1.7 L/min; hepatic artery pressure, 85 mmHg to 110 mmHg; and hepatic artery flow, 0.3 L/min to 0.7 L/min.

Using the final flush line included in the OCS liver perfusion terminal, the liver was flushed and cooled on the OCS with 3 L of cold perfusate solution, wherein 1 liter was delivered to the hepatic artery at approximately 50 to 70 mmHg and 2 liters were gravity drained into the portal vein. Each liter was supplemented with 10 mmol HCO3 and 150 mg succinate sodium. The liver was then disconnected from the OCS and placed in a cold saline bath for 45 minutes. Table 9 below shows the infusate and rate of the liver perfusate.

Table 9. OCS liver perfusate infusates and rates

FIG61 is a sample location diagram showing the location of samples from pig liver.

Sample livers were evaluated according to the following liver histopathology sampling protocol.

Sample collection time: at the end of the experiment (at the end of the 24-hour simulated transplantation period).

Collection methods and samples:

1. Gross images: Photographs of the capsule and lower surface of OCS and CS livers at the beginning of the study after gross examination.

2. Bile Duct: The entire extrahepatic bile duct and as much adherent surrounding tissue as possible (without surgical removal from the surrounding tissue) in a jar of neutral buffered formalin.

3. Electron Microscopy (EM) : 0.1 cm (1 mm) segments of liver tissue from the periphery and deep side of the left lateral lobe and right inner lobe. Tissue specimens were placed in electron microscopy fixative.

4. Liver Parenchyma (LM): Obtain 1 x 1 cm sections from the circumference and deep side of each lobe (8 lobes total) and preserve in formalin. Sections should be no thicker than 3 mm to 5 mm, and the fixative volume should be 15 to 20 times greater than the specimen volume. Any obvious defects should be sampled.

Sample location:

Two samples were collected from each lobe according to Figure 61 to access the liver parenchyma, and each sample was stored in a separate jar filled with 10% formalin and labeled accordingly.

1. Left lateral lobe peripheral limbus-- LM (LLLP--LM)

2. Left lateral lobe periphery-- EM (LLLP--EM)

3. Left lateral lobe deep side - LM (LLLD--LM)

4. Left lateral lobe deep-- EM (LLLD--EM)

5. Left Medial Lobe Periphery- LM (LMLP-LM)

6. Left medial lobe deep side - LM (LMLD--LM)

7. Right Medial Lobe Peripheral- LM (RMLP-LM)

8. Right Medial Lobe Peripheral-- EM (RMLP--EM)

9. Right medial lobe deep side - LM (RMLD-LM)

10. Right Medial Lobe Deep- EM (RMLD-EM)

11.Right lateral lobe periphery-- LM (RLLP--LM)

12. Deep side of right lateral lobe-- LM (RLLD--LM)

13. Extrahepatic bile duct (EHBD)

Data acquisition and analysis

For each variable, the stored data was summarized in tabular and graphical form. Continuous variables were then analyzed using mean, median, standard deviation, minimum, and maximum values. Afterwards, AST, ALT, GGT, and ALP test results were collected, recorded, and attached. Next, arterial lactate was collected, recorded, and attached. Next, pH was measured, recorded, and attached. Next, HCO3 levels were measured, recorded, and attached. Finally, total bile production was collected and recorded.

Results of Phase III.

The OCS arm of this group (N=3) successfully met all pre-specified acceptance criteria in the protocol by demonstrating the following throughout the 24-hour simulated transplantation phase: stable perfusion parameters for HAF, HAP, PVF, and PVP during storage on OCS, stable or declining arterial lactate, continuous bile production at a rate of >10 ml/hr., stable or declining liver enzymes (AST), and normal and stable perfusate pH. For example, Figure 62 shows the hepatic artery pressure (HAP) trend during 24 hours of perfusion on OCS.

Figure 63 shows portal vein pressure in the OCS liver preservation arm and the control cold preservation arm. Figure 63 demonstrates portal vein pressure (PVP) trends during 24 hours of perfusion on OCS; the cold preservation arm showed an increase in PVP over time compared to the stable PVP of the OCS preservation arm.

Figure 64 shows hepatic artery flow in an OCS liver preservation apparatus versus a control cold preservation apparatus. Figure 64 demonstrates stable hepatic artery flow (HAF) trends during 24 hours of perfusion on OCS.

Figure 65 shows portal vein flow in the OCS liver preservation apparatus and the control cold preservation apparatus. Figure 65 demonstrates the stable portal vein flow (PVF) trend during 24 hours of perfusion on OCS.

In contrast, the simulated transplant OCS arm (N=3) performed better than the control arm. Perfusion parameters were comparable for the two arms in this group, however, the control arm had higher vascular resistance than the OCS arm. The peak lactate level of the control arm, 7.8 mmol/L, was much higher than the 2.4 mmol/L of the OCS arm. Throughout the simulated transplant phase, both arms continued to produce bile at a rate of >10 ml/hr. For example, Figure 66 depicts arterial lactate in the OCS liver preservation arm and the control cold preservation arm. Figure 66 shows arterial lactate in the OCS liver preservation arm and the control cold preservation arm. This indicates that the OCS arm liver has significantly better metabolic function than the cold storage arm.

Liver enzymes (AST, ALT, and GGT), which are sensitive biomarkers of liver damage, showed much higher peak values in the OCS arm compared to the group. The average AST peak value in the OCS arm was 88.7, while it was 1188 for the control arm. The average ALT level peaked at 31.3 for the OCS arm, while it peaked at 82 for the control arm. The average GGT level peaked at 28.7 for the OCS arm, while it was 97 for the control arm. This indicates that the livers were well preserved and had less cell damage for the liver transplants stored on the OCS arm compared to the control arm. For example, Figure 67 shows the AST levels for the OCS liver preservation arm versus the control cold preservation arm. Figure 67 demonstrates that the OCS perfused livers had significantly lower AST levels throughout the 24-hour simulated transplant period. This indicates that there was significantly less liver damage to the transplants in the OCS group compared to the cold storage group.

Figure 68 shows ALT levels in the OCS liver preservation arm versus the control cold storage arm. Figure 68 demonstrates that OCS-perfused livers had lower ALT levels with a mean peak of 31.3, compared to a mean peak of 82 in the control arm. This suggests that there was less liver damage to the transplants in the OCS arm compared to the control cold storage arm.

Figure 69 depicts GGT levels in the OCS liver preservation arm versus the control cold storage arm. Figure 69 demonstrates that OCS-perfused livers had significantly lower GGT levels throughout the 24-hour period. This suggests better hepatobiliary protection for transplants in the OCS arm compared to the control cold storage arm.

The OCS arm showed a better metabolic profile than the control arm, as indicated by a stable and normal pH level compared to the lower pH of the control arm. This suggests that the OCS arm was able to maintain a much better metabolic profile than the control arm. For example, Figure 70 depicts the pH levels of the OCS liver preservation arm versus the pH levels of the control cold preservation arm. As shown in Figure 70, the OCS-perfused livers had normal and stable pH values over the course of 24 hours of perfusion compared to the control cold preservation arm livers.

In addition, compared to the control arm, which showed lower HCO3 throughout the simulated transplant period, the OCS arm demonstrated better liver metabolic function, as indicated by higher HCO3 levels over the 24-hour simulated transplant. This suggests that the OCS arm livers have better metabolic function than the control arm. For example, Figure 71 depicts HCO3 levels in the OCS liver preservation arm versus HCO3 levels in the control cold preservation arm. As shown in Figure 71, the OCS-perfused livers had higher HCO3 levels over the 24-hour perfusion period compared to the control cold preservation arm livers.

Figure 72 depicts bile production from the OCS liver preservation device versus the control cold preservation device. Figure 72 demonstrates that both devices maintained a bile production rate of >10 ml/hr. Based on the data presented above, OCS demonstrated stable perfusion and metabolic profiles for up to 12 hours of OCS preservation and good preservation of liver graft function. Furthermore, when compared to the cold static preservation control device, in the simulated transplant model, OCS-perfused pig livers demonstrated significantly better metabolic function as demonstrated by their ability to metabolize lactate to baseline levels compared to cold-stored livers where lactate consistently rose to significantly higher levels. Furthermore, OCS-perfused pig livers had significantly lower AST levels compared to the much higher AST levels in the simulated transplant control device, suggesting that liver graft function was better in the OCS device compared to the control cold storage device. The results of this preclinical OCS liver device testing demonstrate that the OCS device is safe and effective in preserving pig livers, as demonstrated by meeting the specified acceptance criteria. In Phase III, the differences observed between the control arm and the OCS arm were similar to those observed in Phase II, indicating that the OCS arm had better results.

Other Uses

Although the preservation of donor organs intended for transplantation has been described above, some embodiments of the organ care system 600 described herein can be used for other purposes. For example, the system 600 can also be used to maintain organs during repair or other types of surgery, treatment and/or processing (e.g., complex, high-risk surgery and/or processing). That is, if the surgery is performed on an organ in a living body, some surgeries, treatments and/or processing may damage the human body. Therefore, it would be beneficial to remove the organ from the patient's body, perform surgery and/or processing on the organ outside the living body, and then transplant the organ back into the patient's body. For example, certain radiation treatments may damage the tissue surrounding the organ. Therefore, by removing the organ, the organ can be subjected to enhanced radiation treatment without causing collateral damage to the patient's body. Other embodiments are possible.

D. Ex vivo treatment of liver diseases including cancer, fatty liver, and infection by delivering therapeutic agents to the organ

In some embodiments, a liver preserved on the organ care system 600 can be treated for extra-organ treatment of liver disease. Non-limiting examples of liver disease include cancer, fatty liver disease, and liver infection. Treatment can be performed by adding a therapeutic agent to the perfusion fluid circulating through the organ care system 600, thereby providing the therapeutic agent to the liver itself. Alternatively, the therapeutic agent can be added directly to one or more nutrient solutions described herein. In some embodiments, the temperature of the perfusion fluid and/or the liver can be maintained at 40°C or 42°C, which can accelerate the rate of fat cell breakdown and dissolution in the liver.

Non-limiting examples of anticancer therapeutic agents suitable for ex vivo treatment of liver cancer include microtubule binding agents, DNA intercalators or crosslinking agents, DNA synthesis inhibitors, DNA and/or RNA transcription inhibitors, antibodies, enzymes, enzyme inhibitors, gene regulators and/or angiogenesis inhibitors. Anticancer "microtubule binding agents" refer to agents that interact with tubulin to stabilize microtubule formation or destabilize microtubule formation, thereby inhibiting cell division. Examples of microtubule binding agents include, but are not limited to, paclitaxel, docetaxel, vinblastine, vindesine, vinorelbine (Navelbine), epothilone, colchicine, Aplysia 15, nocodazole, podophyllotoxin and rhizoxin. Analogs and derivatives of such compounds can also be used and are known to those of ordinary skill in the art.

Anticancer DNA and/or RNA transcription regulators include but are not limited to actinomycin D, daunorubicin, doxorubicin and its derivatives and analogs. DNA intercalators and cross-linkers include but are not limited to cisplatin, carboplatin, oxaliplatin, mitomycins such as mitomycin C, bleomycin, chlorambucil, cyclophosphamide and its derivatives and analogs. DNA synthesis inhibitors include but are not limited to methotrexate, 5-fluoro-5'-deoxyuridine, 5-fluorouracil and its analogs. Examples of suitable enzyme inhibitors include but are not limited to camptothecin, etoposide, formestane, trichostatin and its derivatives and analogs. Other anti-permeability agents can include doxorubicin, apigenin, rapamycin, zebularine, cimetidine and its derivatives and analogs. Any other suitable liver cancer therapeutic agent known in the art is considered.

Another advantage of the above chemotherapy is its specificity: the anticancer agent is delivered specifically to the diseased organ, the liver, without any undesirable toxicity to other healthy organs or tissues.

Non-limiting examples of therapeutic agents suitable for ex vivo therapeutic treatment of fatty liver disease include pioglitazone, rosiglitazone, orlistat, ursodiol, and betaine.Any other suitable fatty liver therapeutic agent known in the art is contemplated.

Non-limiting examples of therapeutic agents suitable for ex vivo therapeutic treatment of liver infection include interferon alpha-2b, interferon alpha-2a, ribavirin, telaprevir, boceprevir, simeprevir, and sofobuvir. Any other suitable therapeutic agent for liver infection known in the art is contemplated.

E. Regenerative Methods Involving Stem Cells or Gene Transfer

In other embodiments, the organs preserved by the organ care system 600 described herein can be subjected to regenerative treatment. Non-limiting examples of organ regenerative treatment include stem cell therapy or gene transfer therapy. Stem cells are undifferentiated biological cells that can differentiate into specific cells such as hepatocytes. Adult stem cells can be collected from the blood, fat and bone marrow of liver donors with various types of liver diseases, or obtained from another adult with compatible stem cells (stem cell transplantation). Isolated stem cells, such as bone marrow cells, can be used to infuse damaged or diseased livers preserved on the organ care system 600 to repair the liver to a healthier state. For example, isolated stem cells can be separated from a donor and included in a blood product in the perfusion fluid.

In some other embodiments, the liver preserved by the organ care system 600 described herein can be subjected to gene transfer therapy. Gene transfer is the process of introducing exogenous DNA into host cells, such as liver cells, to achieve disease treatment. In certain embodiments, gene transfer therapy is a virus-mediated gene transfer that uses viruses to inject their DNA into the interior of liver cells. Non-limiting examples of suitable viruses include retroviruses, adenoviruses, adeno-associated viruses, and herpes simplex viruses. In some embodiments, genes for treating certain liver diseases are packaged into vectors (viral or other) and are included as part of the perfusion fluid used to perfuse the liver, or are directly added to the circulation of the organ care system 600.

F. In vitro immunomodulation

In other embodiments, the donor liver preserved by the organ care system 600 described herein can be immunomodulated. The immune response within the liver and its regulation may affect the outcome of a liver transplant. More importantly, liver disease can be treated by inducing, enhancing, or suppressing the immune response from the liver. For example, the liver immune system can be activated to attack malignant tissue and thereby treat liver cancer. On the other hand, the liver immune system can be suppressed to treat autoimmune liver diseases such as autoimmune hepatitis. Any immunosuppressant or immune activator known in the art can be used to treat the preserved liver to achieve the desired effect.

G. Extracorporeal surgical treatment of the liver

In other embodiments, a donor liver preserved by the organ care system 600 described herein can undergo surgical treatment, such as liver tumor resection or split transplantation between two recipient patients. In other embodiments, a donor liver preserved by the organ care system 600 described herein can undergo radiation therapy to treat certain liver diseases such as liver cancer.

XI. Conclusion

Other embodiments are within the scope and spirit of the disclosed subject matter. In some embodiments, a perfusion circuit for ex vivo perfusion of a liver is disclosed, the perfusion circuit comprising: a pump for providing a pulsatile fluid flow of a perfusion fluid in the circuit; a gas exchanger; a distributor in fluid communication with the pump and configured to divide the perfusion fluid flow into a first branch and a second branch, wherein the first branch comprises a hepatic artery interface, wherein the first branch is configured to provide a first portion of the perfusion fluid to a hepatic artery of the liver via the hepatic artery interface at a high pressure and a low flow rate, wherein the first branch is in fluid pressure communication with the pump, wherein the second branch comprises a portal vein interface, wherein the second branch is configured to provide a second portion of the perfusion fluid to the liver via the portal vein interface at a low pressure and a low flow rate. The portal vein provides a high flow rate to the liver, the second branch further includes a clamp located between the distributor and the portal vein interface for selectively controlling the flow rate of the perfusion fluid flowing to the portal vein, the second branch further includes a compliance chamber configured to reduce the pulsatile flow characteristics of the perfusion fluid from the pump to the portal vein, wherein the pump is configured to transmit fluid pressure to the liver through the first and second branches; a drain configured to receive perfusion fluid from the uncannulated inferior vena cava of the liver; and a reservoir positioned below the liver and between the drain and the pump, the reservoir configured to receive the perfusion fluid from the drain and store a certain amount of fluid.

In some embodiments, the second branch of the perfusion circuit includes a plurality of compliance chambers. In some embodiments, the compliance chambers in the perfusion circuit are located between the distributor and the portal vein interface. In some embodiments, the portal vein interface of the perfusion circuit has a cross-sectional area that is larger than the cross-sectional area of the hepatic artery interface. In some embodiments, the perfusion circuit includes at least one flow rate sensor and at least one pressure sensor located in the second branch. In some embodiments, the pump includes a pump driver, and the position of the pump driver is adjustable to control the pattern of pulsatile flow to the liver. In some embodiments, the clamp includes an engaged position and a disengaged position, and when the clamp is in the disengaged position, the clamp can be adjusted to select a desired clamping force and corresponding flow rate, and the clamp can be moved to the engaged position to apply the selected clamping force when in the engaged position without further adjustment, so that the user can quickly engage and disengage the clamp while still precisely controlling the amount of clamping force applied to the perfusion circuit.

In some embodiments, a system for perfusing an isolated liver under near-physiological conditions is disclosed, the system comprising a perfusion circuit comprising: a pump for pumping a perfusion fluid through the circuit, the pump being in fluid communication with a hepatic artery interface and a portal vein interface, wherein the pump provides the perfusion fluid to the hepatic artery of the liver via the hepatic artery interface at a high pressure and a low flow rate, and wherein the pump provides the perfusion fluid to the portal vein of the liver via the portal vein interface at a low pressure and a high flow rate; a gas exchanger; a heating subsystem for maintaining the temperature of the perfusion fluid at a normothermic temperature; a drain configured to receive the perfusion fluid from the inferior vena cava of the liver; and a reservoir configured to receive the perfusion fluid from the drain and store a quantity of the fluid. In some embodiments, the heating subsystem is configured to maintain the perfusion fluid at a temperature between 34° C. and 37° C. In some embodiments, the perfusion circuit comprises an inferior vena cava cannula. In some embodiments, a control system for controlling the operation of a system is disclosed, the control system comprising: an onboard computer system connected to one or more components of the system; a data acquisition subsystem comprising at least one sensor for acquiring data related to the organ; and a data management subsystem for storing and maintaining data related to the operation of the system and data related to the liver. In some embodiments, the heating subsystem comprises a dual feedback loop for controlling the temperature of the perfusion fluid within the system.

In some embodiments, a system for preserving a liver ex vivo under physiological conditions is disclosed, the system comprising: a multiple-use module comprising a pulsatile pump; a single-use module comprising: a perfusion circuit configured to provide perfusion fluid to the liver; a pump interface assembly for transmitting pulsations pumped by the pump to the perfusion fluid; a hepatic artery interface configured to deliver the perfusion fluid to the hepatic artery of the liver; a portal vein interface configured to deliver the perfusion fluid to the portal vein of the liver; a distributor for supplying a flow of perfusion fluid from the pump interface assembly at a high pressure and a low flow rate to the hepatic artery interface and at a low pressure and a high flow rate to the portal vein interface; an organ chamber assembly configured to hold the ex vivo organ, the organ chamber assembly comprising: a housing; a flexible support surface suspended within the organ chamber assembly; and a bile container configured to collect bile produced by the liver.

In some embodiments, the flexible support surface is configured to conform to organs of different sizes, and the flexible support surface also includes protrusions for stabilizing the liver in the organ chamber assembly. In some embodiments, the flexible support surface includes a top layer, a bottom layer, and a deformable metal substrate located between the top layer and the bottom layer. In some embodiments, the flexible support surface is configured to support and controllably support the liver without applying undue pressure to the liver. In some embodiments, the single-use module also includes a wrapping that is configured to cover the liver in the organ chamber assembly. In some embodiments, the single-use module includes a sensor for measuring the amount of bile collected in the bile container. In some embodiments, the single-use module can be sized and shaped to interlock with the portable base frame of the multiple-use module for electrical, mechanical, gas, and fluid interoperability with the multiple-use module. In some embodiments, the multiple-use module and the single-use module can communicate with each other via an optical interface that automatically performs optical alignment when the disposable single-use module is being installed into the portable multiple-use module.

The subject matter described herein can be implemented using digital electronic circuits or implemented in computer software, firmware or hardware or a combination thereof, the hardware including the structural devices disclosed in this specification and their structural equivalents. The subject matter described herein can be implemented as one or more computer program products for being executed by a data processing device (e.g., a programmable processor, a computer or multiple computers) or for controlling the operation of the data processing device, such as one or more computer programs tangibly embodied in an information carrier (e.g., in a machine-readable storage device) or embodied in a propagation signal. A computer program (also referred to as a program, software, software application or code) can be written in any form of programming language, including compiled or interpreted languages, and the computer program can be deployed in any form, including as an independent program or as a module, component, subroutine or other unit suitable for use in a computing environment. A computer program does not necessarily correspond to a file. A program can be stored in a portion of a file that stores other programs or data, in a single file dedicated to the program in question, or in multiple collaborative files (e.g., files storing one or more modules, subroutines or partial codes). A computer program can be deployed to be executed on one computer or on multiple computers at one site or distributed across multiple sites and interconnected by a communication network.

The processes and logic flows described in this specification (including the method steps of the subject matter described herein) can be performed by one or more programmable processors executing one or more computer programs to perform the functions of the subject matter described herein by operating on input data and generating output. The processes and logic flows can also be performed by special purpose logic circuitry, such as an FPGA (field programmable gate array) or an ASIC (application-specific integrated circuit), and the apparatus of the subject matter described herein can be implemented as such special purpose logic circuitry.

Processors suitable for executing computer programs include, for example, general-purpose and special-purpose microprocessors, and any one or more processors of any type of digital computer. Typically, a processor will receive instructions and data from a read-only memory or a random access memory, or both. The essential elements of a computer are a processor for executing instructions and one or more memory devices for storing instructions and data. Typically, a computer will also include one or more mass storage devices for storing data, such as magnetic, magneto-optical, or optical disks, or the computer will be operatively coupled to receive data from or transfer data to, or both receive and transfer data to, the one or more mass storage devices. Information carriers suitable for containing computer program instructions and data include all forms of non-volatile memory, including, for example, semiconductor memory devices (e.g., EPROM, EEPROM, and flash memory devices); magnetic disks (e.g., internal hard disks or removable disks); magneto-optical disks; and optical disks (e.g., CDs and DVDs). The processor and memory may be supplemented by or incorporated into dedicated logic circuitry.

To provide for interaction with a user, the subject matter described herein can be implemented on a computer having a display device (e.g., a CRT (cathode ray tube) or LCD (liquid crystal display) monitor) for displaying information to the user, and a keyboard and pointing device (e.g., a mouse or trackball) through which the user can provide input to the computer. Other types of devices can also be used to provide for interaction with the user. For example, the feedback provided to the user can be any form of sensory feedback (e.g., visual feedback, auditory feedback, or tactile feedback), and input from the user can be received in any form, including sound input, voice input, or tactile input.

The technology described herein can be implemented using one or more modules. As used herein, the term "module" refers to computing software, firmware, hardware and/or its various combinations. However, at a minimum, a module need not be interpreted as software that is not implemented on hardware, firmware or recorded on a non-transitory processor-readable recordable storage medium (that is, a module is not the software itself). In fact, a "module" is interpreted as always including at least some physical, non-transitory hardware, such as a part of a processor or a computer. Two different modules can share the same physical hardware (for example, two different modules can use the same processor and network interface). The modules described herein can be combined, integrated, separated and/or copied to support various applications. In addition, the function described herein as being performed at a specific module can be performed at one or more other modules and/or performed by one or more other devices to replace the function performed at a specific module or to supplement the function performed at a specific module. In addition, a module can be implemented across multiple devices and/or other local or remote components of each other. In addition, a module can be moved from one device and added to another device, and/or can be included in two devices.

The subject matter described herein can be implemented in a computing system that includes a back-end component (e.g., a data server), a middleware component (e.g., an application server), or a front-end component (e.g., a client computer with a graphical user interface or a web browser through which a user can interact with an implementation of the subject matter described herein), or any combination of such back-end components, middleware components, and front-end components. The components of the system can be interconnected by any form or medium of digital data communication, such as a communication network. Examples of communication networks include local area networks ("LANs") and wide area networks ("WANs"), such as the Internet.

Claims (20)

1. A perfusion circuit for ex vivo perfusion of liver, the perfusion circuit comprising: A pump, the pump being used to provide a pulsating fluid flow of infusion fluid in the infusion circuit; Gas exchanger; A distributor, which is in fluid communication with the pump and configured to divide the pulsating fluid flow into a first branch and a second branch; The first branch includes a hepatic artery interface; The first branch is configured to supply a first portion of the perfusion fluid to the hepatic artery of the liver via the hepatic artery interface at a high pressure of 25 mmHg to 150 mmHg and a low flow rate of 0.25 L/min to 1 L/min. The first branch is connected to the pump fluid pressure; The second branch includes a portal vein interface; The second branch is configured to supply a second portion of the perfusion fluid to the portal vein of the liver via the portal vein interface at a low pressure of 1 mmHg to 25 mmHg and a high flow rate of 0.75 L/min to 2 L/min; The second branch also includes a clamp located between the dispenser and the portal vein interface for selectively controlling the flow rate of perfusion fluid flowing to the portal vein; The second branch also includes a compliance chamber configured to reduce the pulsating flow characteristics of the perfusion fluid from the pump to the portal vein; The pump is configured to provide a pulsating flow of perfusion fluid, wherein a first portion of the perfusion fluid is supplied to the hepatic artery of the liver at a high pressure of 25 mmHg to 150 mmHg and a low flow rate of 0.25 L/min to 1 L/min via a first branch including the hepatic artery interface, and a second portion of the perfusion fluid is supplied to the portal vein of the liver at a low pressure of 1 mmHg to 25 mmHg and a high flow rate of 0.75 L/min to 2 L/min via a second branch including the portal vein interface; Discharge device, the discharge device being configured to receive perfusion fluid from the inferior vena cava of the liver; and A reservoir, located below the liver and between the discharge device and the pump, is configured to receive perfusion fluid from the discharge device and store a certain amount of fluid. 2. The infusion circuit according to claim 1, wherein the second branch comprises a plurality of compliant chambers. 3. The perfusion circuit according to claim 1, wherein the compliance chamber is located between the dispenser and the portal vein interface. 4. The perfusion circuit according to claim 1, wherein the portal vein interface has a larger cross-sectional area than the hepatic artery interface. 5. The infusion circuit according to claim 1, further comprising at least one flow rate sensor and at least one pressure sensor located in the second branch. 6. The perfusion circuit of claim 1, wherein the pump includes a pump driver, and wherein the position of the pump driver is adjustable to control the pattern of pulsating fluid flow to the liver. 7. The infusion circuit according to claim 1, wherein the clamp includes an engaged position and an unengaged position; The clamp is configured such that when the clamp is in the disengaged position, the clamp is adjusted to select a desired clamping force and a corresponding flow rate. The clamp is movable to the engagement position to apply a selected clamping force when in the engagement position without further adjustment, thereby maintaining precise control over the amount of clamping force applied to the infusion circuit when engaging and disengaging the clamp. 8. A system for perfusing an isolated liver under near-physiological conditions, the system comprising: Infusion circuit, the infusion circuit comprising: Pump, the pump being used to pump a pulsating fluid flow of infusion fluid in the infusion circuit; A distributor, which is in fluid communication with the pump and configured to divert the perfusion fluid into the hepatic artery interface and the portal vein interface; The pump delivers the perfusion fluid to the hepatic artery of the liver via the distributor and the hepatic artery interface at a high pressure of 25 mmHg to 150 mmHg and a low flow rate of 0.25 L/min to 1 L/min; and The pump delivers the perfusion fluid to the portal vein of the liver via the distributor and the portal vein interface at a low pressure of 1 mmHg to 25 mmHg and a high flow rate of 0.75 L/min to 2 L/min. Gas exchanger; A heating subsystem for maintaining the temperature of the perfusion fluid at normal body temperature; Discharge device, the discharge device being configured to receive perfusion fluid from the inferior vena cava of the liver; and A storage device configured to receive and store the infusion fluid from the discharge device. 9. The system of claim 8, wherein the heating subsystem is configured to maintain the infusion fluid at a temperature between 34°C and 37°C. 10. The system of claim 8, wherein the perfusion circuit further includes an inferior vena cava cannulation. 11. The system of claim 8, further comprising a control system for controlling the operation of the system, the control system comprising: An airborne computer system, the airborne computer system being connected to one or more components of the system; A data acquisition subsystem, comprising at least one sensor for acquiring data related to the liver; and A data management subsystem is provided for storing and maintaining data related to the operation of the system and data concerning the liver. 12. The system of claim 8, wherein the heating subsystem further comprises a dual feedback loop for controlling the temperature of the infusion fluid. 13. A system for the ex vivo preservation of liver under physiological conditions, the system comprising: A reusable module, the reusable module including a pulsating pump; Single-use module, the single-use module includes: A perfusion circuit configured to provide perfusion fluid to the liver; A pump interface assembly for transmitting the pulsations generated by the pump to the perfusion fluid; A hepatic artery interface configured to deliver the perfusion fluid to the hepatic artery of the liver; A portal vein interface configured to deliver the perfusion fluid to the portal vein of the liver; A distributor for supplying a pulsating fluid flow from the pump interface assembly at a high pressure of 25 mmHg to 150 mmHg and a low flow rate of 0.25 L/min to 1 L/min to the hepatic artery interface and at a low pressure of 1 mmHg to 25 mmHg and a high flow rate of 0.75 L/min to 2 L/min to the portal vein interface; and Organ compartment assembly, configured to hold an isolated liver, the organ compartment assembly including case; A flexible support surface, the flexible support surface being suspended within the organ chamber assembly; and A bile container configured to collect bile produced by the liver. 14. The system of claim 13, wherein the flexible support surface is configured to conform to livers of different sizes, and the flexible support surface further includes protrusions for stabilizing the liver in the organ chamber assembly. 15. The system of claim 13, wherein the flexible support surface comprises a top layer, a bottom layer, and a deformable metal substrate located between the top layer and the bottom layer. 16. The system of claim 13, wherein the flexible support surface is configured to support and controllably support the liver without damaging the liver. 17. The system of claim 13, wherein the single-use module further includes a package configured to cover the liver within the organ chamber assembly. 18. The system of claim 13, wherein the single-use module further includes a sensor for measuring the amount of bile collected in the bile container. 19. The system of claim 13, wherein the single-use module is sized and shaped to interlock with the portable base of the multiple-use module for electrical, mechanical, gaseous and fluid interoperability with the multiple-use module. 20. The system of claim 13, wherein the reusable module and the single-use module are configured to communicate with each other via an optical interface that automatically performs optical alignment when the single-use module is being installed into the portable reusable module.