WO2001085295A2

WO2001085295A2 - Use of magnetic particles or other particles having relatively high density in a fluid for mixing and/or leak detection

Info

Publication number: WO2001085295A2
Application number: PCT/US2001/014415
Authority: WO
Inventors: Stephen R. Ash; Donald E. Blake; David J. Carr; Fritz J. Friedlaender
Original assignee: Hemocleanse Inc
Current assignee: Hemocleanse Inc
Priority date: 2000-05-05
Filing date: 2001-05-04
Publication date: 2001-11-15
Anticipated expiration: 2002-11-05
Also published as: WO2001085295A3; AU2001259469A1

Abstract

A device and methods for extracorporeal treatment of fluids, such as blood, for effective plasmafiltration or hemofiltration alone or in combination with dialysis. The preferred devices (10) is a circuit that may include a dialyzer (20), a plasmafilter (30), a sorbent pump (40) to circulate a treatment sorbent solution, a sorbent container (32), and a leak detector (50) may be located downstream from the filtration member.

Description

USE OF MAGNETIC PARTICLES OR OTHER PARTICLES

HAVING RELATIVELY HIGH DENSITY IN A FLUID FOR

MIXING AND/OR LEAK DETECTION

This invention claims priority to United States Provisional Application Serial No. 60/202,238 filed May 5, 2000.

BACKGROUND OF THE INVENTION

This invention generally relates to the use of magnetic particles or particles having relatively high density in a treatment fluid that is separated from a fluid being treated by a membrane or other barrier. In certain aspects of the invention, magnetic particles are used for mixing the treatment fluid. In other aspects of the invention, particles having relatively high density are used for mixing a treatment fluid. In other aspects of the invention, magnetic particles are used for leak detection. As used herein, the term "magnetic" is intended to refer to a property of the particles whereby a force is exerted thereon by the application of a magnetic field thereto. The invention also relates to devices, methods and compositions for treating a fluid, wherein the fluid to be treated is separated by a membrane or other barrier from a treatment fluid, and wherein magnetic particles are included in the treatment fluid for mixing and/or for leak detection. The invention is particularly suitable, useful and applicable to devices, methods and compositions for extracorporeally treating blood, a blood fraction such as blood filtrate or plasma, or other biological fluid, to remove toxins therefrom.

Improved manners of mixing fluids, particularly suspensions, are continuously sought. For example, those of ordinary skill in the art recognize the importance of mixing fluids used for extracorporeal blood treatment. Extensive efforts have been made to discover safe and effective methods for removing toxins from patients by extracorporeal treatment of their blood. These efforts have included many studies directed to methods for extracorporeal treatment of hepatic failure, and many methods have been proposed with the goal of removing small molecular toxins, protein-bound molecules or larger molecules thought to be responsible for the coma and illness of hepatic failure. Extracorporeal treatment of blood and blood fractions is also used in the treatment of renal failure. This type of technique is also useful for the treatment of certain types of blood poisoning. One manner of treating hepatic failure involves the use of filtration techniques, e.g., hemofiltration, wherein small and middle molecular weight molecules (i.e. having molecular weights of up to 70,000) are filtered across a membrane and/or plasmafiltration, wherein plasma proteins having molecular weights of up to about 1,000,000 or more are filtered across a membrane. Plasma separation processes are carried out in a device referred to herein as a plasmafilter. When a plasmafilter is used in conjunction with powdered sorbents, blood or a blood fraction is placed in contact with one side of a membrane (referred to herein as the "blood side"), and a sorbent suspension is placed in contact with the opposite side of the membrane (referred to herein as the "sorbent side"). Toxins in the blood or blood fraction are then caused to pass through the membrane and into contact with sorbent particles in the sorbent suspension, whereupon the toxins are adsorbed to the particles and removed from the blood or fraction. Movement of the toxins across the membrane from the blood side to the sorbent side and into contact with the sorbent particles may be effected by application of a positive pressure upon the blood side, or a negative pressure upon the sorbent side, whereupon plasma or other fluid carrying the toxin passes through the membrane to the sorbent side.

One problem commonly encountered in this type of process is insufficient mixing of the toxins with the sorbent suspension on the sorbent side of the plasmafilter after the toxins have passed the membrane, and therefore inefficient removal of toxins from the blood or blood fraction. For chemical transfer in the plasmafilter, it is desirable that toxins in the plasma moving across the membranes and into the sorbent side contact as many of the sorbent particles as possible. It has been determined that some of the chemical transfer reactions in which protein-bound toxins to pass from sites of binding to charcoal require up to one minute. Therefore, it is desirable that the toxins in the plasma permeating the membranes be well mixed with the sorbent particles, and it is preferred that the mixing occur at a distance from the membranes and even within a sorbent container positioned remotely from the membrane or membranes. Otherwise, a stagnant layer of plasma or other fluid harboring the toxins may form adjacent the membrane, resulting in unacceptable removal of toxins. Therefore, it is desirable that the contents of the sorbent side of the plasmafilter be continuously and effectively mixed. One manner of attempting to achieve this mixing is to rapidly flow fluid past the membrane surface; however, it has been found that the fluid adjacent the membrane surface is typically not well mixed. The sorbent suspension tends to flow through the plasmafilter case at some distance from the membranes rather than impinge on the membrane surfaces. For example, in a hollow fiber device, the flow may be around bundles of fibers rather than through and between the individual fibers.

Mixing is also desirable in other types of treatments in which blood, a blood fraction or other fluid to be treated is separated from a treatment fluid by a membrane. For example, in hemodialysis treatments, where small molecular toxins are removed from blood or a blood fraction by diffusion, mixing of the dialysate composition is also desirable as an aid to the diffusion process. It is readily understood that, as toxins diffuse from the blood side of the membrane to the dialysate side of the membrane, the toxins will be present at higher concentrations adjacent the membrane than at more remote locations, thus slowing the diffusion of additional toxins across the membrane. A stagnant layer may also form adjacent dialysis membranes during a dialysis treatment. Mixing of the dialysate would therefore be expected to more quickly disperse the toxins throughout the dialysate, thereby increasing the rate of diffusion across the membrane.

It is also important when using a plasmafilter, or other type of device in which blood, a blood fraction or other fluid is separated from a treatment fluid by a membrane or other barrier, to have some manner of detecting when a leak has occurred in the membrane or other barrier. In the case of hemodialysis, hemofiltration or plasmafiltration, it is readily understood that a leak would result in the loss of a portion of the blood or blood fraction to the sorbent/dialysate side, and/or, perhaps more problematically, the movement of materials from the sorbent/dialysate side into the blood or blood fraction on the blood side, which may render the blood or blood fraction unsuitable for introduction or reintroduction into a patient. The same concern exists for processes in which other biologic fluids are treated, and also applies to treatment systems for non-biologic fluids, in which contamination of fluids is undesirable. In light of this background, there remain needs for improved manners of mixing fluids and improved devices and methods for the extracorporeal treatment of blood or of blood fractions to effectively remove toxins, including both soluble and protein-bound toxins. There also remain needs for effective manners for detecting leaks. The present invention addresses these needs.

SUMMARY OF THE INVENTION

In certain preferred embodiments of the present invention there are provided systems and technique for treating a biologic fluid wherein a biologic fluid is separated from a treatment fluid, such as, for example, a dialysate or a sorbent suspension, by a membrane, the treatment fluid having a plurality of solid particles therein. In certain embodiments, a fraction of the biologic fluid is passed through a membrane to contact and mix with a sorbent suspension having a plurality of solid particles therein. After interacting with the sorbent suspension the biologic fluid passes back through the membrane as a treated fluid. In certain preferred embodiments, the plurality of solid particles are more dense than the remainder of the suspension and cause mixing of the suspension as they move through the suspension. In certain other preferred embodiments the plurality of solid particles are magnetic particles, and are caused to move through the suspension by application of one or more magnetic fields, thereby mixing the treatment fluid. In another aspect of the present invention there is provided a system and technique for treating a biologic fluid wherein a biologic fluid is separated from a treatment fluid, such as, for example, a dialysate or a sorbent suspension, by a membrane, the treated fluid having a plurality of solid magnetic particles therein. In certain preferred embodiments, a downstream leak detector captures and detects magnetic particles that pass into the biologic fluid side of the membrane.

In other preferred embodiments a novel sorbent suspension is provided including solid sorbent particles and solid magnetic particles in water or a normal saline solution. The suspension can be used with the systems and techniques of the present disclosure to treat blood or other fluid. It is an object of the invention to provide devices, methods and compositions for treating fluids.

It is another object of the invention to provide devices, methods and compositions for treating fluids whereby a treatment fluid includes solid particles.

An additional object of the invention is to provide devices, methods and compositions for treating fluids whereby a treatment fluid includes solid magnetic particles. Further objects, advantages and features of the present invention will be apparent from the detailed description herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a schematic illustration of a blood treatment system including a leak detector.

Figure 2 is a schematic illustration of a plasmafilter having a magnetic field source associated therewith in alternate states.

Figure 2a is a schematic illustration of an alternative configuration for a plasmafilter in accordance with one aspect of the invention.

Figure 3 is a schematic illustration of a leak detector in accordance with one embodiment of the invention. Figure 4 is an illustrative plot of the fractional clearance versus time for a plasmafilter according to an embodiment of the invention.

Figure 5 is a schematic illustration of a system according to an embodiment of the invention.

Figure 6 is partial schematic illustration of an alternative configuration for the plasmafilter in the Figure 5 system.

Figure 6a is a partial schematic illustration of an alternative configuration for the sorbent container in the Figure 5 system.

Figure 7 is a partial schematic illustration of another alternative configuration for the plasmafilter in the Figure 5 system. Figure 8 is a partial schematic illustration of a hollow fiber membrane.

Figure 9 is a top sectional view of a hollow fiber plasma filtration device according to an embodiment of the present invention. DESCRIPTION OF THE PREFERRED EMBODIMENTS

For the purposes of promoting an understanding of the principles of the invention, reference will now be made to certain embodiments and figures (with like reference numerals intended to indicate like structures), and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alterations, further modifications and applications of the principles of the invention as described herein being contemplated as would normally occur to one skilled in the art to which the invention relates.

The present invention provides in certain aspects devices, methods and compositions for improving the mixing of fluids in a fluid treatment system. The invention is particularly useful in systems in which a fluid flows through a circuit, and optionally through a chamber, in which undesirable stagnant layers can form. The invention relates to the placement in the fluid of solid particles having magnetic properties and/or having relatively high density. The invention also relates in certain aspects to system configurations whereby the particles are utilized to aid in the breaking of stagnant layers and/or the general mixing of the fluid.

The present invention in one aspect involves methods for mixing a fluid in which magnetic particles are provided in the fluid. The fluid is positioned in relation to one or more magnetic field sources such that, when the sources are actuated, the magnetic field causes the particles to move through the fluid to mix the fluid. It is preferred, although not required, that the fluid to be mixed be essentially non-magnetic, and that the magnetic particles are the only materials substantially affected by the magnetic field. It is also preferred, of course, that the fluid being mixed by the magnetic particles be compatible with the magnetic particles selected for use, and that the fluid is not detrimentally impacted by application of a magnetic field.

The magnetic field source or sources are preferably configured such that the magnetic field is intermittently or continuously altered to periodically change the direction that the particles move through the fluid. Placing magnetic field sources at various locations relative to the fluid, and intermittently actuating the respective sources may achieve this, for example. Another way of achieving this result is by providing a single magnetic field source configured to move in relation to the fluid. Alternatively, the source or sources may be positioned such that actuation causes the particles to move against the force of gravity, whereupon removal of the field will cause the particles to move by the force of gravity in a different direction. In this arrangement, the field can be applied in pulses to achieve movement of the particles in directions that periodically change. It is understood that one condition for causing movement of the magnetic particles is the presence of a magnetic gradient, which can be produced by a moving or periodically applied magnet or similar magnetic field generator. Accordingly, the phrase "changing magnetic field" is used herein to indicate the desired condition, however generated. It is well within the purview of a person skilled in the art to select an appropriate magnetic field source, and it is not intended that the invention be limited by a particular configuration thereof.

The movement of the particles through the fluid advantageously mixes the fluid. Accordingly, the particles preferably move several to many times their own length. In addition to bulk mixing of the fluid, the moving magnetic particles can break stagnant layers that may form in the fluid. This function is important in various preferred uses of the invention, such as, for example, in extracorporeal blood treatment techniques, such as filtration techniques or hemodialysis techniques, as described more fully below, in which stagnant layers on the dialysate- or sorbent- side surfaces of membranes limit efficiency of heat and mass transfer.

Another advantage of inventive magnetic mixing techniques arises in systems where it is desirable that the fluid to be mixed is caused to flow through a system. The magnetic particles can be moved magnetically in a direction that is independent of the bulk fluid flow through the system. Thus, mixing may advantageously be achieved at a discreet location along a fluid's flow path. An inventive mixing method would have particular application, for example, in situations where mixing is desired, but where the bulk fluid flow cannot be high enough to result in turbulent flow. Another application is in situations where ordinary mechanical means of mixing are impractical. The invention may be advantageously used in connection with methods, devices and compositions by which a body fluid is treated outside the body, such as extracorporeal blood treatment techniques, in which blood, a blood fraction or other biologic fluid is contacted with a treatment fluid across one or membranes and is separated from the treatment fluid by the membrane or membranes. The treatment fluid may be, for example, a sorbent suspension (for filtration, e.g. plasmafiltration or hemofiltration techniques), a dialysate (for dialysis techniques) or a combination thereof. To achieve mixing of the treatment fluid in accordance with this aspect of the invention, thereby improving the efficacy of the treatment system, magnetic particles are positioned in the treatment fluid, and one or more magnetic fields are intermittently applied to the fluid, preferably at the location of the membrane or membranes.

It is readily understood that in an extracorporeal blood treatment system, the membrane or membranes are positioned at discrete locations, typically within a cartridge, case or other type of container having separate fluid flow paths for the blood or blood fraction and for the treatment fluid. In a preferred aspect of the invention, the one or more magnetic fields are applied to the treatment fluid at this location to improve mixing of the fluid at the location where transfer of components occurs. Furthermore, some systems include a treatment fluid circuit that includes a reservoir, from which the treatment fluid is propelled into contact with the membrane or membranes before the fluid returns to the reservoir. In some systems, such as, for example, filtration systems, it is desirable to mix the fluid at the location of the reservoir alternatively or in addition to mixing at the location of the membrane or membranes.

To further describe one preferred aspect of the invention, there are provided systems for extracorporeal treatment of blood or a blood fraction by filtration in a manner that provides the safe, consistent and effective removal of toxins. Referring to Figure 5, to practice this aspect of the invention a device 110 (referred to herein as a "plasmafilter") is provided which defines a space 112 for receiving a flow of blood or a blood fraction (referred to herein as the "blood side"), separated by one or more membranes 114 from a space 116 for receiving a flow of sorbent solution (referred to herein as the "sorbent side"). For purposes of the present invention, it is understood that the term "blood" is intended to refer to blood or a blood fraction and can also be substituted with other types of biologic fluids, such as, for example, spinal fluid or lymph fluid.

The blood side is fluidly connected to a source of blood 118 and to a receptacle for treated blood 120. For example, the invention may be advantageously used to treat to a patient by inserting a vascular access device into the bloodstream of the patient. Blood is extracted from the patient's circulatory system through the access, passed through the plasmafilter, and returned, often through the same vascular access device, to the patient's bloodstream. Such vascular access devices are well known in the relevant field, and are commonly used for extracorporeal blood treatment procedures known in the art. The blood side of a plasmafilter and the vascular access device are preferably connected by flexible conduits, and a pump 122 (for example a roller pump) may be used to control the flow of blood from the patient, through the blood side 112 of the plasmafilter, and back into the patient's bloodstream. The sorbent side 116 may be fluidly connected to a sorbent suspension container 124, preferably by flexible conduits. In this arrangement, a second pump 126 (for example also a roller pump) may be used to control the flow of sorbent suspension from the container 124, through the sorbent side 116 of the plasmafilter, and back into the container 124.

Passage of toxins, carried by blood plasma, across the membrane 114 from the blood side 112 to the sorbent side 116 is preferably achieved by application of a pressure gradient across the membrane, which gradient may be applied by increasing the pressure on the blood side and/or by decreasing the pressure on the sorbent side. The pumps may be used to alter the pressure, commonly in conjunction with valves or other flow regulators, as is well known in the art. Alternatively or in addition, as is also known in the art an expansion chamber 128 having a flexible membrane 129 can be coupled to a pressure and vacuum source 126 and to one side of the membrane 114, for example the sorbent side 116, to draw a volume of fluid from one side to the other. Once the plasma and the entrained toxins pass to the sorbent side 116, they are preferably thoroughly mixed with the sorbent suspension to provide time for transfer of protein-bound toxins to the sorbents, before return of proteins to the blood. Turning now to Figures 6 and 6a, mixing may optionally be achieved within the plasmafilter itself by including magnetic particles in the sorbent suspension and applying intermittent magnetic fields to the suspension, thereby moving the magnetic particles in the suspension. A magnetic field can be applied, for example, via a magnetic field source 130, which is schematically shown in Figure 6 associated with the sorbent side 116. Further mixing and contact between the toxins and the sorbent agent may be achieved by passing the mixture comprising plasma, toxins and the sorbent agent into the container 124, and optionally applying intermittent magnetic fields to the fluid in the container 124, as depicted for example in Figure 6a wherein a magentic field source 130 is schematically shown associated with container 124. The residence time of the toxins in the fluid in contact with the sorbent agent results in toxins being adsorbed onto sorbent particles, and thereby prevents the toxins from moving back into the blood. The fluid of the sorbent side mixture, free from a significant amount of the toxins, is then passed back into the blood by an opposite pressure gradient across the membrane 114, which urges the fluid back to the blood side of the plasmafilter. This opposite pressure gradient can be applied by increasing the pressure on the sorbent side and/or by decreasing the pressure on the blood side by the same or different means as for applying the first pressure gradient. It is readily understood that a separate sorbent suspension container 124 or reservoir is not critical to the invention, and that alternative arrangements may be used to achieve the advantageous result of the invention. For example, in an alternative embodiment, the sorbent side 116 of the plasmafilter is configured to have a sufficient volume to contain an amount of sorbent suspension that may be used for an entire treatment. In this embodiment, of course, the magnetic field source or sources can be simply positioned in locations relative to the plasmafilter to apply the desired intermittent magnetic fields to the sorbent suspension fluid therein. In this embodiment, a desired pressure gradient across the membrane or membranes for the passage of plasma and other materials across the same may be achieved by controlling flow and pressure in the blood side alone, or by utilizing a plasmafilter design featuring a sorbent side pressure controller. For example, turning now to Figure 7, the sorbent suspension may be placed in a container having a flexible boundary 132, which itself is encased in a rigid container 134. In such a system, the pressure on the sorbent side may be controlled by increasing or decreasing the pressure in the rigid container 134 in a wide variety of ways known in the art, including, for example, by simply utilizing a pump 136 to pump air or another gas into or out of the rigid container 134 exterior to the flexible container 116. It is readily understood that either a positive or a negative pressure may be applied in this manner, thereby providing for the control of the passage of plasma and other materials across the membrane or membranes. It is of course not intended that the invention be limited by this particular design.

In one preferred aspect of the invention, the membrane used is a hollow fiber plasmafilter membrane 38 (see Figure 8 and Figures 2, 2a and accompanying description below) defining an interior portion 142 and an exterior portion 140. Blood is passed through the interior portion 142 (blood side) of the membrane while a sorbent suspension contacts the exterior portion 140 (sorbent side) of the membrane. A fraction of the blood or other fluid is caused to alternately exit and re-enter the interior portion of the membrane through the membrane. The fraction that exits the interior portion 142 of the membrane contains the toxins, which contact and mix with the sorbent suspension so as to remove the toxins from the fraction and deliver the toxins into the sorbent suspension. As described above, the exiting and re-entering of the fraction of blood may desirably be facilitated by creating intermittent pressure differentials across the membrane 38, which pressure differentials may preferably be created by the alternating positive and negative pressure applied on the sorbent side of the membrane. Information relating to systems that may be used in connection with the present invention is found in U.S. Patent Nos. 5, 919,369; 5,536,412; and 5,277,820, all to Ash, each of which is hereby incorporated herein by reference in its entirety for all purposes.

There are many suitable hollow fiber membranes which are known for use in plasmafiltration or hemofiltration of blood, and those skilled in the area will be readily able to select and utilize a suitable membranes in the present invention. Such membranes can be, for example, cellulosic membranes (e.g. cellulose acetates), and will have pore sizes sufficiently large to allow passage of plasma proteins (e.g. in plasmafiltration with molecular weight cutoffs of up to 2-5,000,000 m.w.) and/or middle molecular weight blood toxins (e.g. in hemofiltration with molecular weight cutoffs of up to about 70,000). Suitable plasmafiltration and hemofiltration membranes include, for example, those known under the designations F-80 (60,000 m.w. cutoff, Fresenius USA, Inc., Walnut Creek, CA), Altrex 140 (70,000 m.w. cutoff, Althin Medical, Inc., Miami Lakes, FL)), CT190G (60,000 m.w. cutoff, Baxter, Deerfield, IL), and Plasmaflow AP-05H(L) (about 1,000,000 m.w. cutoff, Asahi Medical Co., Ltd., Tokyo, Japan). Alternate preferred plasmafiltration or hemofiltration membranes have pore sizes which transmit albumin or middle molecular weight molecules with selectivity over larger molecules, and thus will provide removal of toxins while minimizing potential interference with other blood functions. For example, the Plasmaflow AP-05H(L) plasma separator (0.5 square meters) has about a 5% rejection of albumin during unidirectional filtration, but about an 80% rejection of macroglobulins. When used, a moving magnetic field should ideally extend over the entire chamber to be mixed, though the magnetic field has no particular limitations other than to be of sufficient strength and orientation to move the magnetic particles. Magnetic field strengths that result in successful operation can readily be determined empirically and are generally of the order provided by permanent magnets located 0.01 to 10cm from the particles.

In an alternative embodiment depicted in Figure 9, several magnets 230 are placed radially around the circumference of a hollow fiber device 30 (for example device 30 of Figure 2a described below). In this embodiment, by sequentially actuating the magnets 230 one at a time around the circumference of the case, the magnetic particles are driven in a rotational manner to generate a cyclone-type effect and to thereby impinge on the membrane surfaces. In yet another embodiment, one or more permanent magnets are used, which include mechanisms to change their positional relationship to the plasmafilter case. In this embodiment, the simple movement of the magnets causes the magnetic particles in the sorbent solution to move, thereby mixing the fluid. A sorbent suspension used for plasmafiltration or hemofiltration in accordance with the invention includes a solid particulate sorbent agent, a solid particulate magnetic material and an aqueous liquid. It is also understood that sorbent suspensions can be made "on-site" by providing a dry mixture of solids and adding an aqueous liquid to prepare the suspension for use. As such, another aspect of the invention is a dry mixture including a solid particulate sorbent agent and a solid particulate magnetic material.

The particulate magnetic material is selected such that the magnetic properties of the particles are effective to achieve the advantageous results of the invention. In particular, it is important that the magnetic particles have a susceptibility to a magnetic field that is sufficiently high to allow the particles to be moved about in the fluid upon application of a magnetic field, preferably a moderate magnetic field. It is also important, however, that the material not have a remanent magnetization that is too high, because such particles may undesirably cling to one another. For example, if a ferrimagnetic material is used, after the particles have been fully magnetized, and after all applied magnetic fields are removed, the particles will exhibit a remanent magnetization. If the remanent magnetization is too low, the particles will not respond very well to an applied filed. If the remanent is too high, the particles may cling to each other and may not separate enough to exhibit desirable characteristics for use in accordance with the present invention. It is within the purview of a person skilled in the art to select a magnetic material having properties suitable for use in the present invention.

It is also preferred that the magnetic particles selected in accordance with the invention be paramagnetic, so that if electric current is used to create the magnetic field, the current can be either direct or alternating current. In order to prevent excessive agglomeration of particles under the magnetic field it is preferred that the field be applied in an A/C pulse. Application of an A/C pulse with increasing intensity will avoid magnetization of the individual particles, and avoid agglomeration of the particles. Magnetic particles selected for inclusion in a sorbent suspension in accordance with the invention are kept from entering blood through the filtration membrane by choosing particles that are larger, preferably only slightly larger, than the threshold upper pore size of the membrane. In one preferred aspect of the invention, the particles are magnetite particles, which are ferrimagnetic and paramagnetic. When magnetite is used, it is preferred that the particles be from about 0.1 to about 0.5 microns in diameter, provided that this range may be expanded if necessary to accommodate a membrane having a higher or a lower threshold pore size. It is also understood that the preferred particle size may be different when a different magnetic material is used. It is within the purview of a person skilled in the art to vary the particle sizes as needed in accordance with the invention when alternate magnetic materials are used. The magnetic particles can be isolated from an inventive sorbent suspension after use by sedimentation, centrifugation, or applying a constant magnetic field on a container holding the suspension.

In one preferred embodiment, magnetite particles are present in the sorbent suspension in an amount of from about 5 to about 15 grams per liter. In another embodiment, magnetite particles are present in the sorbent suspension in an amount of from about 8 to about 12 grams per liter. In. yet another embodiment, magnetite particles are present in the sorbent suspension in an amount of about 10 grams per liter. It is understood that it may be preferred, particularly when alternate magnetic materials are used, to include the magnetic material in amounts outside of these ranges, depending upon, for example, the magnetic susceptibility and other characteristics of the material selected. It is within the purview of a person of ordinary skill in the art to select a suitable amount of such other material to achieve the advantageous results of the invention. The sorbent agent in the sorbent suspension can be one of many known to those practiced in this area, but is preferably a powdered surface adsorptive agent. A preferred powdered surface adsorptive agent is powdered activated charcoal. Further, for the plasmafilter application, the powdered surface adsorptive agent preferably has an average particle diameter just above the pore size of the membrane of 0.2-0.5 microns, with 90% or more of the particles having diameters not greater than about 75 microns. Particles exceeding 75 microns in diameter can be screened if desired. Most preferably, the powdered charcoal used in plasmafiltration and hemofiltration in accordance with the invention has an average particle diameter of not greater than about 25 microns. As one example, a suitable finely powdered activated charcoal is available from American Norit Company, Inc. of Jacksonville, Florida, U.S.A., which can be screened to remove particles larger than those desired. Alternatively, the sorbent agent may be particulate silica of minimum size of 0.2 micron or greater, as described in U.S. Patent Application No. 09/237,476, filed January 26, 1999 by Ash, which is hereby incorporated by reference herein in its entirety for all purposes.

In addition, the sorbent agent may have one or more substances bound thereto, for example to improve or increase the removal of blood components which are known to have affinity for the bound substance(s). For example, activated charcoal may be pre- treated to have antigens or antibodies ionically or covalently bound thereto to increase removal of corresponding antibodies or antigens, or may have DNA sequences ionically or covalently bound thereto which are known to bind to selected plasma proteins, for example plasma proteins such as regulatory proteins that are known to be present in various clinical settings.

In an alternate aspect of the invention, magnetic particles themselves may be modified to exhibit adsorptive properties. It is therefore understood that the described sorbent function and magnetic function may indeed be provided by a single magnetic/sorbent composition. With respect to particulate matter having magnetic characteristics and also binding characteristics, U.S. Patent No. 5,123,901 to Carew, U.S. Patent No. 4,910,148 to Sorensen, et al, U.S. Patent No. 5,980,479 to Kutushov and U.S. Patent No. 5,536,475 to Moubayed, et al. are hereby incorporated herein by reference in their entireties for all purposes. The sorbent suspension formulation may also include an ion-exchanger to bind ionic chemicals, e.g. ammonium, etc., which may occur in the patient's blood. Many suitable ion exchangers including both resins and other materials such as zeolites or zirconium silicates are known in the art. When included, the ion- exchanger may preferably be a cation-exchange resin, which is desirably loaded with sodium or calcium or both. For example, to date, sodium polystyrene sulfonate has been a preferred material for removing various potentially toxic cations such as manganese or copper. Cation exchangers can also remove viruses from plasma. Alternately, anion exchangers may be included in the sorbent suspension. An example is cholestyramine, which has a high binding capacity for bilirubin, cholesterol, and endotoxins. A sorbent suspension selected for use in a plasmafiltration protocol in accordance with the invention preferably also includes physiologic electrolytes and may also preferably include macromolecular flow inducing agents. In general, these components are present in effective amounts to achieve the desired removal of substances from and electrolyte balance in the blood of the patient while maintaining the stability and fluidity of the sorbent suspension. Because plasmafiltration membranes as used in the invention can potentially pass endotoxins, it is preferred that the sorbent suspension be free from measurable endotoxins. While general sorbent suspension production techniques have been sufficient for these purposes, if necessary, measures can be taken to sanitize or sterilize the suspension, for example using heat or radiation (e.g. gamma-radiation), to assure that the sorbent suspension is substantially free from bacteria or other microbial growth which could potentially generate endotoxins or other harmful substances.

The types and amounts of electrolytes included in the suspension formulation will depend upon the specific needs of the patient and will be readily determinable by physicians or others skilled in the area. Typically, the electrolytes will include sodium and chloride (e.g. optionally provided as sodium chloride), and can also include bicarbonate, potassium, calcium, or any other electrolytes to be regulated in the patient. As indicated, however, the types and amounts of electrolytes may vary widely depending on patient needs. Where the sorbent suspension is not intended to correct electrolyte imbalance, for example where the electrolyte imbalance is corrected in a dialyzer upstream from the plasmafilter, electrolytes are preferably present in the sorbent suspension in physiologic concentrations. In one preferred aspect, the sorbent and magnetic particles are suspended in a solution of normal saline at the beginning of a blood treatment procedure. More generally, the electrolyte concentration can be between about 0.45% and 2.0% by weight NaCl, more preferably about 0.9% by weight NaCl. Macromolecular flow inducing agents may also be included in the sorbent suspension to aid in maintaining the stability of the sorbent suspension formulation (i.e. to prevent solids from settling out of suspension) and maintaining the flow properties of the suspension. One desirable flow-inducing agent is a nonionic, hydroxyl-containing polymer such as a glycol derivative. Suitable agents of this type are available from BASF Wyandotte of Parsippany, New Jersey, U.S.A. under the trademark "Pluronic" polyols. These Pluronic polyols are polyoxyalkylene derivatives of propylene glycol. Pluronic F68, for example, functions both as a flow inducing agent and a defoaming agent. Another flow agent that may be included in preferred suspensions is macroreticular polyvinylpyrrolidone.

The magnetic particles, sorbent agent, electrolytes, flow inducing agents and any other additives will usually comprise about 5% to 40% by weight of the sorbent suspension formulation as a whole, with the remainder being water. In one embodiment of the invention, magnetic particles comprise from about 1% to about 20% by weight of the suspension formulation and solid sorbents comprise from about 2% to 25% by weight of the suspension formulation. In another embodiment, magnetic particles comprise from about 1% to about 20% by weight of the suspension formulation, solid sorbents comprise from about 2% to 25% by weight of the suspension formulation and electrolytes comprise about 1% to 5% of the suspension formulation. In another embodiment, a sorbent suspension formulation is provided that comprises from about 1% to about 20% magnetic particles, from about 2% to about 20% powdered surface adsorptive agent, up to about 10% ion- exchanger, and up to about 1% flow agent. One preferred sorbent suspension of the invention includes magnetic particles and charcoal, and is free from ion-exchangers or macromolecular flow inducing agents. Another preferred sorbent suspension of the invention includes about 70 grams per liter powdered charcoal, and about 10 grams per liter magnetite particles, preferably from about 0.1 to about 0.5 microns in diameter, depending upon the pore size of the membrane.

The sorbent suspension can also include viable hepatic cells, e.g. xenogenic or allogenic cells, alone or in combination with one or more of the solid adsorbents and other materials described above, to assist in the effective removal of toxins. For example, hepatocytes can be isolated from suitable donor tissue, purified and microencapsulated in polymer as described by Dixit et al., Hepatology 1990: 12: 1342. These microencapsulated cells can then be used directly in the sorbent suspension, or can be cryopreserved until use, for example as described by Dixit et al., Transplantation 1993; 55: 616-22. When hepatic cells are so used, plasma is effectively separated from the blood by passage through the plasmafilter membrane, and proteins and toxins are convected into contact with the cells circulating exterior of the membrane. After the cells have acted upon the toxins, the plasma is returned through the membrane and back into the patient. Filtration treatment can be performed alone, or in connection with other treatments, such as, for example, dialysis of blood or a blood fraction. In connection with dialysis when used in the present invention, there are many dialyzer membranes which are known for use in dialyzing body fluids such as blood, and those skilled in the area will be readily able to select and utilize a suitable membranes in the present invention. One suitable membrane is a cellulosic membrane, particularly one composed of regenerated cuproammonium cellulose (Cuprophan). Examples of dialysis devices and methods are provided in U.S. Patent No. 5,277,820 to Ash; U.S. Patent No. 4,661,246 to Ash; U.S. Patent No. 4,581,141 to Ash; U.S. Patent No. 4,348,283 to Ash; U.S. Patent No. 4,071,444 to Ash; U.S. Patent No. 3,734,851 to Matsumura; U.S. Patent No. 4,897,189 to Greenwood et al.; U.S. Patent No. 4,267,041 to Schael; U.S. Patent No. 4,118,314 to Yoshida; U.S. Patent No. 3,989,625 to Mason; and U.S. Patent No. 3,962,075 to Fialkoff et al., each of which is hereby incorporated by reference in its entirety

In one preferred aspect of the invention, a blood treatment device is provided that includes a dialyzer and a plasmafilter, both having a blood side that is fluidly connected in a circuit with conduits to a blood source. (See Example 1). It is of course understood that the present invention is not limited to a device having a dialyzer, but is also directed to a device including only an inventive plasmafilter fluidly connected to the blood source. In addition to or in place of the moving magnetic field, mixing can be accomplished by periodically or continuously vibrating or otherwise mechanically shaking a sorbent suspension containing chamber and/or the membrane. The shaking can be accomplished, for example, with a vibrating or shaking member 400 (see Figure 2a) in contact with a portion of the device or by manual shaking the device. In addition, the sorbent suspension can be caused to flow through the chamber and past the membrane through successive reversals of the flow of the sorbent suspension through the chamber to facilitate mixing and continual suspension of solid particles in the sorbent suspension.

In another aspect of the present invention, therefore, there are provided devices, methods and compositions for fluid mixing wherein particles are provided in a fluid, the particles having a relatively high density relative to the density of other solids and liquids in the suspension. This aspect of the invention is particularly useful for a plasmafiltration system that utilizes a hollow fiber membrane device, as described herein. In this aspect of the invention, it is not necessary that the particles be magnetic; however, magnetic particles can be used. A plasmafilter can be configured such that the sorbent suspension is caused to flow through the hollow fiber chamber in a manner that causes relatively high density particles to fall under the force of gravity from the sorbent inlet, through the sorbent suspension and into contact with the hollow fibers, thereby causing a disruption of a stagnant layer and mixing of the fluid in the plasmafilter chamber. The relative movement of the particles through the suspension facilitates mixing in the suspension.

In a preferred configuration for gravitational mixing, depicted in Figure 2a, the plasmafilter 30 is positioned with the longitudinal axes of the hollow fiber membranes 38 angled from horizontal. It is of course understood that, although Figure 2a and other Figures herein depict only a few hollow fibers 38, a hollow fiber filter will typically include a relatively large number of such fibers. In this embodiment, sorbent outlet 36 is positioned at or near the lower end of the device 30. The axes are preferably at least about 10° and more preferably at least about 30° from horizontal. In another preferred embodiment the axes are within about 10° of about 45° from horizontal. In this configuration, sorbent inflow 34 can be placed at the upper portion and on the opposite side of device 30 so as to provide the sorbent suspension and magnetic particles at approximately the highest point in the device. It is understood that the heavier particles will fall through the suspension and at least a portion of the particles will impinge upon the membranes 38 under the force of gravity.

In addition, the net flow of sorbent in chamber 31 is generally from inlet 34 to outlet 36, co-current with the blood flow inside membranes 38 which is from inlet 24 to outlet 26. Periodically, the flow of sorbent is reversed. This reversed flow is performed at a reduced flow rate which is preferably below that which would cause the heavier magnetic particles to completely reverse their bulk flow. The relative movement of the heavier particles through the now upward flow of the sorbent suspension further increases the mixing in the chamber 31 around the fibers 38. As an example, the sorbent flow from inlet 34 to outlet 36 can occur at approximately 200ml/min whereas reversed flow can occur at approximately lOOml/min, with approximately 6-12 seconds between flow reversals.

It is understood that the relative speed with which heavier particles fall through the sorbent suspension is dependent on a variety of factors including the relative density differential, the size of the particles, and their shape. In the preferred application, the sorbent suspension has a density approximately equivalent to water. The relatively high density particles, such as, for example, 0.5 micron magnetite particles, which are generally rod shaped, preferably have a density about 4-6 times that of the sorbent suspension. Another advantage of including a relatively high density particulate material in a sorbent suspension is that mixing can also be achieved by mechanical means, such as, for example, by shaking or vibrating a chamber in which the suspension is contained. It is readily understood that the shaking of such a chamber causes higher density particles therein to move through the fluid relative to materials therein having lower densities. Thus, in this aspect of the invention, a treatment system can include a means for mechanically shaking or vibrating a hollow fiber device to facilitate mixing of a sorbent suspension therein.

Since the suspension of sorbent particles and plasma is well mixed around the fibers in accordance with the invention, there is no need for rapid flow of sorbent suspension through the plasmafilter. It is preferred that the sorbent suspension flows at a rate of from about 50 ml/min to about 400 ml min through the plasmafilter. A flow of about 100 ml min through the case can be created by the plasma filtered across the membranes, if one-way valves are placed in the lines connecting the plasmafilter case to the sorbent suspension reservoir. Each time 20 ml of plasma exits the fibers, it pushes 20 ml of sorbent suspension through a one- way valve on one end of the plasmafilter case. When 20 ml of plasma returns to the blood, the plasma enters the plasmafilter case through a one-way valve at the opposite end of the case. A fluid stream is thereby provided that flows into, through and out of the plasmafilter, and also into, through and out of the container. A roller pump or diaphragm pump can also be used to create flow through the plasmafilter and sorbent reservoir. The sorbent agent or agents will therefore be in contact with the plasma in the container for a period of time adequate to effect removal of an acceptable proportion of the toxins from the plasma. It is, of course, understood, as described above, that the plasmafilter may alternatively be a self-contained system, in which case it is not necessary to have a separate sorbent suspension container or devices, such as pumps and valves, for causing the sorbent solution to flow.

In circumstances where only plasmafiltration or hemofiltration (and not dialysis) of the blood is desired, a dialysis machine as known in the relevant field may be employed with the proviso that the membrane in the dialysis instrument need not be a dialysis membrane, and thus may be one which is permeable to all solutes and proteins but impermeable to blood cellular components, e.g. a membrane formed from a suitable plastic film. Moreover, where only plasmafiltration or hemofiltration is desired, the dialysis instrument need not be employed at all, and any means of contacting the sorbent suspension with the exterior of the hollow fiber membranes or other membrane while passing the blood or other fluid through the blood side (with bidirectional flow of the blood or fluid across the membranes) will be suitable. For example, as described above, a roller pump could be used to pass blood continuously through the hemofilter or plasmafilter membranes. A hollow fiber membrane cartridge could have sorbent side connections to a container filled with sorbent suspension, or may be a self-contained unit large enough to contain the entire volume of the sorbent suspension fluid. In a system wherein the sorbent suspension is circulated through the cartridge, for example by a roller pump, the pressure changes in the sorbent side (created automatically by roller pumps) could create the desired bidirectional flow of plasma or other fluid across the membranes. Alternately, application of pressure and vacuum to the accumulator (described above) could actuate passage of plasma into and out of a sorbent suspension enclosed in a rigid case. Such systems provide high clearance of protein-bound or middle molecular weight toxins simply and at relatively low cost.

In another advantageous aspect of the invention, there is provided a fluid treatment system including a membrane or other barrier that separates the blood, blood fraction or other fluid to be treated from a treatment fluid, and further including a leak detection device associated with the blood side. The treatment device can be, for example, a plasmafilter, a dialysis machine or other treatment device configured to maintain separation of fluids by a membrane or other barrier. An example of such a treatment system is an extracorporeal blood treatment system that features a treatment device including a membrane separating a blood side and a treatment fluid side, and a leak detection device associated with the blood side downstream from the treatment device. In this embodiment, the treatment fluid is a sorbent suspension, a dialysate, or other type of treatment fluid prepared to remove toxins from blood or a blood fraction when mixed therewith. This aspect of the invention is particularly useful for treatment protocols in which blood, a blood fraction or other biological fluid is continuously returned to a patient after treatment. For example, a system including a leak detector finds advantageous use, and is described below, in connection with plasmafiltration of blood. More particularly, a system is described that includes a dialyzer, a plasmafilter and a leak detector. It is understood, however, that the principles of the invention are not limited to this embodiment.

For purposes of describing the invention, as stated above, reference is made to a plasmafilter system, in which blood or a blood fraction is separated by a membrane from a sorbent suspension. It is, of course, understood that the leak detection device may be used in a wide variety of applications of the invention, and is not intended to be limited to use in connection with a plasmafilter. It is readily understood that in a treatment system such as a plasmafilter, a breach in the membrane or other barrier between the blood or blood fraction and the treatment fluid can have catastrophic consequences. A compromised membrane in a plasmafilter, for example, would result in the loss of blood or blood fraction into the sorbent circuit of the plasmafilter system and, perhaps more significantly, the leak of materials from the sorbent suspension into the blood or blood fraction. Because blood exiting a plasmafilter is commonly returned right away to a patient undergoing treatment, the leak of sorbent materials into the blood side can result in the return of contaminated blood to the patient which can have extreme consequences. It is therefore desired that a plasmafilter system, or other like system, be able to detect small amounts of sorbent or other treatment fluid that leak into the blood or blood fraction if the plasmafilter membrane or membranes fail. However, detection of sorbents in blood has historically proven difficult because a typical sorbent suspension, which may comprise primarily powdered activated charcoal, is itself very difficult to detect non-invasively. Many physical properties (i.e., density and particle size) of typical sorbents, such as charcoal, are similar to properties of blood. Furthermore, the optical absorption spectrum of charcoal does not lend itself to positive identification of low concentrations of charcoal in blood. In accordance with this aspect of the invention, the leak detection device is configured to detect magnetic particles in the blood or blood fraction downstream from the plasmafilter, the presence of which indicates that a leak has occurred in the membrane separating the sorbent suspension from the blood or blood fraction in the plasmafilter. In this aspect of the invention, therefore magnetic particles in the sorbent suspension are used as a tracer for leak detection. More particularly, the magnetic particles are used to detect the presence of a leak in a non-magnetic flow system, because when the magnetic particles are carried along with the sorbent suspenion through a leak in the membrane, they can be detected in the contaminated blood or blood fraction downstream of the plasmafilter. In one manner of detecting magnetic particles, the particles are trapped in a magnetic field and detected by sensing the collection of particles. The collection of particles can be sensed, for example, using an optical detector, an ultrasound detector, or other type of detector known in the art and configured to sense the presence of collected particles. Another alternative is to use the electromagnetic properties of the particles to detect them in the contaminated fluid by detecting the magnetic field generated thereby.

The general design of a preferred leak detector 50 in accordance with the invention is shown in Figure 3, although it is not intended that the invention be limited to this design. In this embodiment, a light source 52 passes a beam of light through a tube 26 carrying the blood. Small permanent magnets 55 are placed near the beam of light. The preferable orientation of the magnets is close to and parallel to the blood tubing with a North pole on one side of the light beam and a South pole on the other side of the light beam. When magnetic particles are in the blood, they are collected by the magnets at a location within the path of the light beam and obstruct the light beam. A sensor 58 opposite the light source may be configured to record data at preselected intervals, and an operator of the system may review this data for a decrease in the amount of light passing through the tube, which indicates a leak and the resulting contamination. The decrease in light (below a predetermined noise threshold) may also preferably actuate a signal indicating the appearance of the particles. A wide variety of sensors and signaling devices may be used in a detector in accordance with the invention as are well known to those of ordinary skill in the art. The detector on the effluent tube thus provides an operator with an effective way to monitor the system for leaks, thereby ensuring that the membranes or procedures to remove the particles remain intact and effective.

With a detector that actively collects magnetic particles, the detector can determine quantitatively the amount of particles that have passed through the membranes, even though this passage may occur over several hours of treatment (proportional to the ratio of concentration of magnetic particles to other particles in the suspension). Because the configuration described above accumulates the magnetic particles, it provides a sensitive measure of low concentration of contaminants in the blood. Methods that measure concentration of contaminants must be much more sensitive to detect low contaminant levels. The closer the North and South poles of magnets are to the light path, the more effective the collection of magnetic particles and the greater decrease in measured light transmission with accumulation of magnetic particles. From experiments conducted to date, it has been found that small, independent, powerful permanent magnets will retain magnetic particles effectively against very rapid flow of fluid through a small effluent tube (900 ml/min peak flow in a 3 mm ID. tube). These magnets accumulate most of the magnetic particles within a flowing solution. As described above, if the magnets are sufficiently powerful, they can be positioned only near the LED, or only near the detector. Having magnets near each element provides greater total magnetic field and provides a redundant system, protecting against the single failure of a magnet or the possibility of a magnet falling out of position. Another advantage of this type of detector is that the detector not only detects magnetic particles in the blood or blood fraction, but also collects magnetic particles by the force of the magnetic field applied, thereby isolating the particles from the blood prior to its reintroduction into the bloodstream of a patient.

When the magnetic particles are of smaller size than other particles in the sorbent suspension, magnetic particles can be expected to exit through leaks in the system, such as leaks in the membrane in particular, in greater numbers or proportions than the larger particles. Furthermore, the magnetic particles would be expected to exit first through leaks having relatively small dimensions. Accordingly, in one advantageous aspect, the magnetic particles can be collected and identified by the optical detector at the beginning of a leak before a hole or tear in the system becomes dangerously large. This allows corrective action to be taken by the operator, who can be signaled when the amount of collected magnetic particles exceeds a threshold amount, before a significant amount of non-magnetic solid particles are introduced into the patient's blood. In this aspect, the magnetic particles are preferably smaller than non-magnetic particles, for example at least 2 and more preferably at least 5 or 10 times smaller than the average size of the non-magnetic particles.

Alternatively, the magnetic particles are selected to be approximately the same size as the smallest of the solid sorbent particles. Typical charcoal particles useful in the present invention range in size, for example at typical confidence interval of 95% or 99%, between 0.5 and 75 microns with a mean of about 3-4 microns. Advantageously, magnetic particles can be used of approximately 0.5 microns in size to assure that effectively no charcoal particles are smaller than the magnetic particles. In practice, it is preferable that no more than 5%, and preferably no more than 1% of the non-magnetic particles are smaller than the magnetic particles.

The sensitivity of the detector 58 to the amount of accumulated magnetic particles could vary depending on the type and quality of the detector. Thus, it might be expected that some small amount of leaking could occur before a sufficient amount of magnetic particles are accumulated to overcome the detector threshold and signal a leak. The proportion of magnetic particles in the sorbent suspension relative to non-magnetic particles is therefore preferably selected such that a non-harmful amount of sorbent particles are passed through the system prior to the detector signaling a leak. Where approximately 20mg of collected magnetic particles constitute the detector threshold, the magnetic particles preferably are between 3% and 20%, more preferably between 7-15%, and most preferably about 10% of the total weight of the solids in the sorbent suspension.

An alternative collector could use the magnetic properties of the particles to measure their passage through the effluent tubing. Application of a magnetic field over the tubing magnetizes the particles, and the moving particles create electric fields that can be detected by coils near the tubing.

As can be appreciated by those of skill in the art, in one embodiment there has been described a system for treating a biologic fluid comprising: a housing defining a chamber and having a first fluid inlet and a first fluid outlet, the first fluid inlet and outlet adapted to transmit a biologic fluid to be treated, at least one membrane positioned in the chamber and defining a boundary between a first and a second side of the chamber, the first side of the chamber in fluid communication with the first fluid inlet and the first fluid outlet and adapted to receive the biologic fluid, the a second side of the chamber adapted to receive a sorbent suspension; a sorbent suspension in the second side chamber, the sorbent suspension including solid sorbent particles suspended in a fluid and a plurality of magnetic particles, and wherein the membrane defines pores sized to substantially prevent passage of sorbent particles and magnetic particles into the first side of the chamber while permitting passage of at least a portion of the biologic fluid into the second side of the chamber whereby portions of the biologic fluid can contact the sorbent particles to be treated. The sorbent suspension can include from about 1% to about 20% by weight magnetic particles, from about 2% to about 25% by weight solid sorbents, from about 0.45% to about 2.0% by weight electrolytes, from about 60% to about 95% by weight water, and where the magnetic particles are from between about 3% and about 20% of the total weight of the solids in the suspension. In another embodiment there has been described a plasmafilter system comprising: a membrane defining a boundary between a blood side and a sorbent side, and a sorbent suspension on the sorbent side of the membrane, the sorbent suspension including; from about 1% to about 20% by weight magnetic particles, from about 2% to about 25% by weight solid sorbents, and from about 60% to about 95% by weight water, wherein the membrane defines pores sized to substantially prevent passage of the solid sorbent particles and magnetic particles to the blood side while permitting passage of at least a portion of the blood to the sorbent side whereby portions of the blood can contact the solid sorbents to be treated. In one refinement of either of the embodiments above the systems include means for moving the magnetic particles relative to the membrane in the sorbent side of the chamber, such as a source of a changing magnetic field or a mechanical shaker, to facilitate mixing in the sorbent side. In another refinement the systems include an outflow line fluidly connected to the first fluid outlet and a source of a magnetic field associated with the outflow line for collecting at least a portion of any magnetic particles in the outflow line, a detector to sense the presence of magnetic particles collected by the magnetic field, and means to generate a signal when the amount of detected magnetic particles collected by the magnetic field exceeds a predetermined amount. In still other refinements, the systems include a second fluid inlet and a second fluid outlet in fluid communication with the second side of the chamber and adapted to transmit the sorbent suspension into and out of the chamber respectively, and means for causing a fluid fraction of the biologic fluid to pass from the first side of the chamber through the membrane into the sorbent suspension in the second side of the chamber to provide a mixture; and means for causing a fluid fraction of the mixture to pass from the second side of the chamber through the membrane into the biologic fluid in the first side of the chamber to provide a treated biologic fluid. In still other refinements at least a portion of the solid sorbent particles are non-magnetic, and the plurality of magnetic particles have an average particle size substantially smaller than the average particle size of the non-magnetic solid sorbents and/or no more than about 1% of the non-magnetic solid sorbents have a particles size smaller than the average size of the plurality of magnetic particles.

In another embodiment there has been described a sorbent composition comprising; from about 60% to about 95% by weight water; from about 0.45% to about 2% by weight electrolytes dissolved in the water, the electrolytes proportioned in physiologic concentrations, from about 1% to about 20% by weight magnetic particles, and from about 2% to about 25% by weight solid sorbent particles. In various refinements, the plurality of electrolytes comprises a plurality of members selected from the group consisting of magnesium ions, potassium ions, sodium ions, chloride ions, acetate ions and bicarbonate ions or consist essentially of about 0.9% by weight NaCl. In other refinements the composition comprises from about 2% to about 20% powdered surface adsorptive agents as at least a portion of the solid sorbent particles, up to about 10% ion-exchangers, and up to about 1% flow agents, the solid sorbent particles include at least about 70 grams per liter of powdered charcoal, and the magnetic particles include at least about 10 grams per liter of magnetite particles between about 0.1 to about 0.5 microns in size.

In still another embodiment there is provided a filtration process for removing blood toxins, comprising: passing a fluid containing protein bound and/or middle molecular weight blood toxins through the interior of a hollow fiber membrane, during the passage of fluid, circulating a sorbent suspension against exterior surfaces of the hollow fiber membrane, the sorbent suspension including magnetic particles, during the passage of fluid and circulating of sorbent suspension, periodically creating magnetic fields upon the sorbent suspension so as to cause the magnetic particles to move in the suspension, thereby mixing the suspension. In various refinements the hollow fiber membrane is a plasmafiltration membrane, whereby middle molecular weight toxins and protein- bound toxins are removed from the fluid and the fluid is blood.

In still another embodiment a blood treatment device comprises: a hollow fiber membrane; a pump fluidly connected to the interior of the hollow fiber membrane and adapted to pass a fluid containing middle molecular weight and/or protein-bound blood toxins through the interior of the hollow fiber membrane; a chamber surrounding the hollow fiber membrane, the chamber further being fluidly connected to a supply of a first sorbent suspension including magnetic particles; a pump adapted to circulate the sorbent suspension through the chamber and against exterior surfaces of the hollow fiber membrane; and a device for applying a dynamic magnetic field to the sorbent suspension to cause the magnetic particles to move about in the sorbent suspension and thereby increase mixing of the sorbent suspension as it is circulated against exterior surfaces of the hollow fiber membrane. In various refinements the hollow fiber membrane is a plasmafiltration membrane and the device includes a dialysis instrument adapted to dialyze the fluid fluidly connected in series with the device, upstream of the device. In still other embodiments the device includes a sorbent suspension leak detector fluidly connected in series with the device, downstream of the device, the leak detector including a source of a magnetic field for collecting magnetic particles and a detector to detect the presence of collected magnetic particles. In still other refinements the pump adapted to circulate the first sorbent suspension is a roller pump and/or the first sorbent suspension is circulated counter-current to the fluid in the hollow fiber membrane.

There is also provided a blood treatment device which comprises: a hollow fiber membrane; a pump fluidly connected to the interior of said hollow fiber membrane and adapted to pass a fluid containing middle molecular weight and/or protein-bound blood toxins through the interior of said hollow fiber membrane; a chamber surrounding said hollow fiber membrane, said chamber further being fluidly connected to a supply of a first sorbent suspension including a plurality of solid particles, the plurality of solid particles having a density at least two times the density of the remainder of the sorbent suspension; a pump adapted to circulate said sorbent suspension through said chamber and against exterior surfaces of said hollow fiber membrane; and wherein the hollow fiber membrane includes portions in the chamber orientated at least about 30° from horizontal such that the magnetic particles pass through the sorbent suspension and around the hollow fiber membrane under the force of gravity thereby increase mixing of the sorbent suspension as it is circulated against exterior surfaces of the hollow fiber membrane. In various refinements the plurality of solid particles have a density at least about 4 times the density of the remainder of the sorbent suspension. In other refinements the plurality of solid particles are magnetic particles, and the device includes a sorbent suspension leak detector fluidly connected in series with said device, downstream of said device, wherein the sorbent suspension leak detector includes a source of a magnetic field for collecting magnetic particles and a detector to detect the presence of collected magnetic particles. In other refinements the case of the plasmafilter or hemofilter is shaken during use. The acceleration forces of shaking have the effect of improving mixing near the membranes of sorbent particles with density slightly higher than water (such as charcoal). However the acceleration forces of shaking increase mixing much more effectively when dense particles such as magnetite are included in the suspension.

The invention will be further described with reference to the following specific Examples. It will be understood that these Examples are also illustrative and not restrictive in nature. EXAMPLES

EXAMPLE 1 As a representative example of a system in accordance with the invention, the system depicted in Figure 1 (referred to herein as a "Liver Dialysis Unit / Plasma Filter" or "LDU/PF") is an extracorporeal blood treatment system that includes two membrane-based blood treatments, a dialyzer 20 and a plasmafilter 30. Each of these components preferably contains a separate suspension of sorbents, including charcoal in both and also a cation exchanger in the dialyzer sorbent circuit. As shown in Figure 1, the blood leaving the dialyzer through conduit 24 passes through plasmafilter 30, preferably a hollow-fiber membrane device, and exits through blood outlet 26. Sorbent pump 40 continually or sequentially pumps a sorbent suspension through the plasmafilter 30 through sorbent lines 34 and 36 and back to the sorbent container 32. In the device shown, the dialyzer 20 serves as the blood pump. Decreasing the pressure in the sorbent suspension causes the dialyzer to draw in about 50 ml of blood through a single-lumen access in a vein (inflow). Increasing the pressure in the same suspension causes the membranes to compress, passing about 50 ml of blood through plasmafilter 30 and ultimately back to the patient through single-lumen access (outflow).

The plasmafilter 30 separates plasma from the blood and treats blood plasma with a sorbent suspension, which surrounds the plasmafilter membranes 38 as shown in Figure 2. During each outflow cycle of the dialyzer, as 50 ml of blood passes through the blood side of the plasmafilter membranes 38, about 20 ml of plasma passes out of the membranes into the sorbent suspension. During each inflow cycle, about 20 ml of plasma passes back from the sorbent suspension to the blood side of the membranes. An expandable membrane within a chamber, also known as an accumulator, is preferably attached to the otherwise rigid sorbent side container 32. An example of an accumulator is chamber 128 in Figure 5. The expansion and collapse of the membrane allows a viewer to monitor the system to ensure that the amount of plasma passing into the sorbent suspension is the same as that returning to the blood during each inflow/outflow cycle. Pressure gradients created within the blood side of the circuit or on the dialysate side assure that the passage of plasma across the membranes is timed with inflow and outflow cycles of the device. Instead of using the LDU to pump blood intermittently through the plasmafilter/sorbent device, a more standard blood circuit containing a roller pump and a dual-lumen catheter could be used. In this case, the roller pump passes blood through the plasmafilter at a constant rate. Alternate application of vacuum or pressure to the accumulator on the sorbent suspension alternately removes plasma from the blood passing through the plasmafilter, then returns an equal volume of plasma to the blood.

EXAMPLE 2 As discussed above, for chemical transfer in the plasmafilter, it is important to have the plasma exiting the blood side through the membranes contact as many of the sorbent particles as possible. Therefore, the fluid on the sorbent side of the plasmafilter (i.e., the plasma/sorbent mixture) is preferably mixed at or near the membrane surface. This mixing is preferably accomplished by applying a magnetic field to the area adjacent the membrane, thereby moving the magnetic particles within the sorbent suspension. Preferably, different magnetic fields are intermittently applied to this area to thereby move the magnetic particles intermittently in different directions, and optionally at different speeds, thereby improving the mixing action of the particles. Alternatively, the magnetic field may be altered by moving the source of the field, such as, for example, by using moving electrical coils or permanent magnets.

In one preferred embodiment, electromagnets 70 are placed on opposite sides of the plasmafilter, and the electromagnets are energized on one side at a time so that the magnetic particles are drawn first to one side of the plasmafilter, then the other, thereby featuring a bidirectional motion. During the passage of magnetic particles through the plasmafilter, they bounce and reflect off of the membranes in the device, moving the stagnant layer away from the membrane surfaces and mixing plasma with the general sorbent suspension. An example of a preferred design of electromagnets and their relationships to the plasmafilter is depicted in Figure 2.

Typical electromagnet actuation is from about 0.1 to about 0.3 seconds. A preferred cycle of operation for the magnetic fields of this system is about 2 seconds, with actuation of electromagnets on one side one second, and on the other side the next second. Since the magnetic particles in this embodiment are paramagnetic, current can be either direct or alternating current. The mixed fluid on the sorbent side then flows, by action of the pump, from the plasmafilter and into the container. EXAMPLE 3 To test the effect of moving magnetic particles on diffusive mass transfer in a plasmafilter, experimental data were obtained as follows. A plasmafilter was thoroughly washed with water to remove hemoglobin from both the blood and filtrate compartments. The plasmafilter was then perfused with an aqueous solution of hemoglobin (150 mg/1) flowing through the blood circuit at about 200 ml/min. The filtrate compartment of the plasmafilter was filled with water. All of the solution flowing out of the plasmafilter blood circuit was collected and samples were taken at various times from the outflow from the blood circuit and analyzed for hemoglobin content. Based upon a comparison of the outflow hemoglobin content and the known inflow hemoglobin content, the cleared fraction of the hemoglobin was calculated.

Figure 4 sets forth a plot of the experimental data, depicted as cleared fraction at given times. Shown in Figure 4 are three sets of data, two sets obtained in the absence of magnetic mixing, and one set obtained with magnetic mixing. For the magnetic mixing experiment, 5 grams of magnetite were injected into the filtrate compartment of the plasmafilter and distributed throughout the filtrate compartment as much as possible by flowing water through the filtrate compartment. While the hemoglobin solution was perfusing the plasmafilter, two sets of electromagnets along the length of the plasmafilter were alternately actuated using a 6 second cycle. The electromagnets were opposed on a diameter of the plasmafilter. The goal was to have the magnetic particles move from one side of the plasmafilter to the other during perfusion.

Most of the first two minutes of each experiment was dominated by the filling of the blood circuit with the hemoglobin solution. The relatively high data points obtained during this period and shown in Figure 4 may be explained by the fact that the blood compartment of the plasmafilter contained only water prior to the introduction of hemoglobin thereinto. This water is flushed from the blood compartment for about the first two minutes of the experiment, and samples taken from the outflow during this period therefore have low hemoglobin content, resulting in artificially high "clearance" data. For this reason, the pertinent data in Figure 4 is believed to be the data from about 2 minutes to about 10 minutes on the horizontal axis.

In the data collected for the experiments in which magnetic mixing was not used (referred to herein as the "diffusion only" data), the fraction of the hemoglobin flowing into the plasmafilter after the filling was complete decreased steadily. In the data collected for the experiments in which magnetic mixing was used (referred to herein as the "mixing" data), the fraction of hemoglobin lost to the filtrate compartment was stable after the initial filling. After only a short period of time elapsed for each experiment, the transfer rate shown by the mixing data was about twice the transfer rate shown by the diffusion only data. The data therefore show that moving magnetic particles in the filtrate compartment enhance the transfer of hemoglobin from the blood compartment to the filtrate compartment.

All references, including publications, patents, and patent applications, cited or listed in this specification are herein incorporated by reference as if each individual reference were specifically and individually indicated to be incorporated by reference and set forth in its entirety herein. Further, any theory, proposed mechanism of operation, or finding stated herein is meant to further enhance understanding of the present invention, and is not intended to in any way limit the present invention to such theory, proposed mechanism of operation, or finding. While the invention has been illustrated and described in detail in the drawings and foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only the preferred embodiments have been shown and described and that all changes and modifications that come within the spirit of the invention are desired to be protected. Although the invention is described above in terms of various preferred embodiments, it is understood that the invention is not limited to mixing fluids in systems for the treatment of blood and blood fractions, but is equally applicable to the mixing of other fluids, including other biological or non-biological fluids. This invention is, of course, particularly useful in systems and techniques that involve the passage of fluid or other materials across a membrane and mixing thereof with another fluid; however, the invention is also applicable to systems and techniques that do not utilize such membranes, but which benefit from the effective mixing of a fluid for a wide variety of reasons.

Claims

What is Claimed

1. A system for treating a biologic fluid comprising: a housing defining a chamber and having a first fluid inlet and a first fluid outlet, the first fluid inlet and outlet adapted to transmit a biologic fluid to be treated, at least one membrane positioned in the chamber and defining a boundary between a first and a second side of the chamber, the first side of the chamber in fluid communication with the first fluid inlet and the first fluid outlet and adapted to receive the biologic fluid, the a second side of the chamber adapted to receive a sorbent suspension; a sorbent suspension in the second side chamber, the sorbent suspension including solid sorbent particles suspended in a fluid and a plurality of magnetic particles, and wherein the membrane defines pores sized to substantially prevent passage of sorbent particles and magnetic particles into the first side of the chamber while permitting passage of at least a portion of the biologic fluid into the second side of the chamber whereby portions of the biologic fluid can contact the sorbent particles to be treated.

2. The system of claim 1 further comprising means for moving the magnetic particles relative to the membrane in the sorbent side of the chamber to facilitate mixing in the sorbent side.

3. The system of claim 2 wherein the means for moving the magnetic particles comprises a source of a changing magnetic field whereby the magnetic particles move in response to a generated magnetic filed.

4. The system of claim 2 wherein the means for moving comprises a means for mechanically shaking the chamber.

5. The system of claim 1 wherein the magnetic particles have a density substantially different than the remainder of the suspension.

6. The system of claim 5 wherein the magnetic particles have a density at least double the density of the remainder of the suspension and the magnetic particles travel through the suspension in the chamber under the force of gravity to thereby mix the suspension.

7. The system of claim 6 wherein the membrane is a hollow fiber membrane oriented at least about 30 degrees from horizontal.

8. The system of claim 1 further comprising an outflow line fluidly connected to the first fluid outlet and a source of a magnetic field associated with the outflow line for collecting at least a portion of any magnetic particles in the outflow line.

9. The system of claim 8 further comprising a detector to sense the presence of magnetic particles collected by the magnetic field.

10. The system of claim 9 wherein the detector is an optical detector.

11. The system of claim 9 further comprising: means to generate a signal when the amount of detected magnetic particles collected by the magnetic filed exceeds a predetermined amount.

12. The system of claim 9 further comprising: a second fluid inlet and a second fluid outlet in fluid communication with the second side of the chamber and adapted to transmit the sorbent suspension into and out of the chamber respectively.

13. The system of claim 12 further comprising: means for causing a fluid fraction of the biologic fluid to pass from the first side of the chamber through the membrane into the sorbent suspension in the second side of the chamber to provide a mixture; and means for causing a fluid fraction of the mixture to pass from the second side of the chamber through the membrane into the biologic fluid in the first side of the chamber to provide a treated biologic fluid;

14. The system of claim 1 wherein the plurality of magnetic particles include ferrimagnetic particles.

15. The system of claim 14 wherein the plurality of magnetic particles include paramagnetic particles.

16. The system of claim 1 wherein the plurality of magnetic particles include paramagnetic particles.

17. The system of claim 1 wherein at least a portion of the solid sorbent particles are non-magnetic, and wherein the plurality of magnetic particles have an average particle size substantially smaller than the average particle size of the non- magnetic solid sorbents.

18. The system of claim 17 wherein no more than about 1% of the nonmagnetic solid sorbents have a particles size smaller than the average size of the plurality of magnetic particles.

19. The system of claim 1 wherein the sorbent suspension includes from about 1% to about 20% by weight magnetic particles, from about 2% to about 25% by weight solid sorbents, from about 0.45% to about 2.0% by weight electrolytes, and from about 60% to about 95% by weight water.

20. The system of claim 19 wherein magnetic particles comprise between about 3% and about 20% of the total weight of the solids in the suspension.

21. The system of claim 19 wherein the sorbent suspension further comprises from about 2% to about 20% by weight powdered surface adsorptive agents as at least a portion of the solid sorbents, up to about 10% by weight of ion-exchangers, and up to about 1% by weight of flow agents.

22. The system of claim 19 wherein the sorbent suspension comprises at least about 70 grams per liter of powdered charcoal as a portion of the solid sorbents, and at least about 10 grams per liter of magnetic particles.

23. The system of claim 22 wherein the plurality of magnetic particles include magnetite particles.

24. The system of claim 22 wherein the plurality of magnetic particles are between about 0.1 to about 0.5 microns in size.

25. The system of claim 24 wherein no more than about 1% of the nonmagnetic solid sorbents have a particles size smaller than the average size of the plurality of magnetic particles.

26. The system of claim 1 wherein the membrane is a hollow fiber membrane.

27. A plasmafilter system comprising: a membrane defining a boundary between a blood side and a sorbent side, and a sorbent suspension on the sorbent side of the membrane, the sorbent suspension including; from about 1% to about 20% by weight magnetic particles, from about 2% to about 25% by weight solid sorbents, and from about 60% to about 95% by weight water wherein the membrane defines pores sized to substantially prevent passage of the solid sorbent particles and magnetic particles to the blood side while permitting passage of at least a portion of the blood to the sorbent side whereby portions of the blood can contact the solid sorbents to be treated.

28. The system of claim 27 wherein the sorbent suspension includes from about 2% to about 20% by weight powdered surface adsorptive agents as at least a portion of the solid sorbents, up to about 10% by weight ion-exchangers, from about 0.45% to about 2.0% by weight electrolytes, and up to about 1% by weight flow agents.

29. The system of claim 27 wherein the solid sorbents include at least about 70 grams per liter of powdered charcoal, and the magnetic particles include at least about 10 grams per liter of magnetite particles.

30. The system of claim 29 wherein the magnetic particles include magnetite particles between about 0.1 to about 0.5 microns in size.

31. The system of claim 27 wherein no more than about 1% of the nonmagnetic solid sorbents have a particles size smaller than the average size of the plurality of magnetic particles.

32. The system of claim 27 wherein the magnetic particles are ferrimagnetic.

33. The system of claim 27 wherein the magnetic particles are paramagnetic.

34. The system of claim 27 further comprising: means for moving the magnetic particles relative to the membrane and to the solid sorbents to facilitate mixing on the sorbent side of the membrane.

35. The system of claim 30 wherein the means for moving the magnetic particles comprises a source of a changing magnetic field whereby the magnetic particles move in response to a generated magnetic gradient.

36. The system of claim 34 wherein the means for moving comprises a means for mechanically shaking the chamber.

37 The system of claim 27 further comprising an outflow line fluidly connected to the blood side of the membrane and a source of a magnetic field associated with the outflow line for collecting at least a portion of any magnetic particles in the outflow line.

38. The system of claim 37 further comprising a detector to sense the presence of magnetic particles collected by the magnetic field.

39. The system of claim 38 wherein the detector is an optical detector.

40. A sorbent composition comprising; from about 60% to about 95% by weight water; from about 0.45% to about 2% by weight electrolytes dissolved in the water, the electrolytes proportioned in physiologic concentrations, from about 1% to about 20% by weight magnetic particles, and from about 2% to about 25% by weight solid sorbent particles,

41. The composition of claim 40 wherein the plurality of electrolytes comprises a plurality of members selected from the group consisting of magnesium ions, potassium ions, sodium ions, chloride ions, acetate ions and bicarbonate ions.

42. The composition of claim 41 wherein the plurality of electrolytes consists essentially of about 0.9% by weight NaCl.

43. The sorbent suspension of claim 40 further comprising: from about 2% to about 20% powdered surface adsorptive agents as at least a portion of the solid sorbent particles, up to about 10% ion-exchangers, and up to about 1% flow agents.

44. The sorbent suspension of claim 40 wherein the solid sorbent particles include at least about 70 grams per liter of powdered charcoal, and the magnetic particles include at least about 10 grams per liter of magnetite particles.

45. The sorbent suspension of claim 44 wherein the magentite particles are between about 0.1 to about 0.5 microns in size.

46. A filtration process for removing blood toxins, comprising: passing a fluid containing protein bound and/or middle molecular weight blood toxins through the interior of a hollow fiber membrane, during said passage of fluid, circulating a sorbent suspension against exterior surfaces of the hollow fiber membrane, the sorbent suspension including magnetic particles, during said passage of fluid and circulating of sorbent suspension, periodically creating magnetic fields upon the sorbent suspension so as to cause the magnetic particles to move in the suspension, thereby mixing the suspension.

47. The process of claim 46 wherein said hollow fiber membrane is a plasmafiltration membrane, whereby middle molecular weight toxins and protein- bound toxins are removed from said fluid.

48. The process of claim 46 wherein said fluid is blood.

49. A blood treatment device thatcomprises: a hollow fiber membrane; a pump fluidly connected to the interior of said hollow fiber membrane and adapted to pass a fluid containing middle molecular weight and/or protein-bound blood toxins through the interior of said hollow fiber membrane; a chamber surrounding said hollow fiber membrane, said chamber further being fluidly connected to a supply of a first sorbent suspension including magnetic particles; a pump adapted to circulate said sorbent suspension through said chamber and against exterior surfaces of said hollow fiber membrane; and a device for applying a dynamic magnetic field to the sorbent suspension to cause the magnetic particles to move about in the sorbent suspension and thereby increase mixing of the sorbent suspension as it is circulated against exterior surfaces of the hollow fiber membrane.

50. The device of claim 49 wherein said hollow fiber membrane is a plasmafiltration membrane, hemofiltration membrane, or high-permeability dialysis membrane.

51. The device of claim 49 further comprising a dialysis instrument adapted to dialyze said fluid fluidly connected in series with said device, upstream of said device.

52. The device of claim 49 further comprising a sorbent suspension leak detector fluidly connected in series with said device, downstream of said device.

53. The device of claim 52 wherein said sorbent suspension leak detector includes a source of a magnetic field for collecting magnetic particles and a detector to detect the presence of collected magnetic particles.

54. The device of claim 49 wherein the pump adapted to circulate the first sorbent suspension is a roller pump.

55. The device of claim 54 wherein the first sorbent suspension is circulated counter-current to the fluid in the hollow fiber membrane.

56. A blood treatment device which comprises: a hollow fiber membrane; a pump fluidly connected to the interior of said hollow fiber membrane and adapted to pass a fluid containing middle molecular weight and/or protein-bound blood toxins through the interior of said hollow fiber membrane; a chamber surrounding said hollow fiber membrane, said chamber further being fluidly connected to a supply of a first sorbent suspension including a plurality of solid particles, the plurality of solid particles having a density at least two times the density of the remainder of the sorbent suspension; a pump adapted to circulate said sorbent suspension through said chamber and against exterior surfaces of said hollow fiber membrane; and wherein the hollow fiber membrane includes portions in the chamber orientated at least about 30° from horizontal such that the magnetic particles pass through the sorbent suspension and around the hollow fiber membrane under the force of gravity thereby increase mixing of the sorbent suspension as it is circulated against exterior surfaces of the hollow fiber membrane.

57. The device of claim 56 wherein the plurality of solid particles have a density at least about 4 times the density of the remainder of the sorbent suspension.

58. The device of claim 57 wherein the plurality of solid particles are magnetic particles, the device further including a sorbent suspension leak detector fluidly connected in series with said device, downstream of said device.

59. The device of claim 58 wherein said sorbent suspension leak detector includes a source of a magnetic field for collecting magnetic particles and a detector to detect the presence of collected magnetic particles.