WO2025043211A1 - Method for manufacturing catheters and other embodiments - Google Patents

Abstract

Catheters and methods for manufacturing using modified lost wax casting are provided. The catheters may be formed using 3D printing to create a mold of a catheter within a consumable crucible. Plaster is added between the crucible and the catheter and then the print is burned out forming a layered void. Once the print is removed, a polymer is added to the layered void and the plaster is removed.

Description

METHOD FOR MANUFACTURING CATHETERS AND OTHER EMBODIMENTS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63/578,641 , filed on August 24, 2023, and which is incorporated by reference herein in its entirety.

FIELD OF THE DISCLOSURE

[0002] This disclosure relates to catheters and a method for manufacturing catheters.

BACKGROUND OF THE DISCLOSURE

[0003] Hydrocephalus is an imbalance between cerebrospinal fluid (CSF) production and absorption, leading to brain compression and increased intracranial pressure. Every year, nearly 400,000 people are diagnosed. Eighty percent of those diagnosed will suffer long-term neurological deficits.

[0004] The common treatment for hydrocephalus is CSF drainage by shunting. However, shunts have the highest failure rate of any neurological device with 50% failing within two years. A shocking 98% of shunts fail after just ten years, a rate increased by the 80% of patients who suffer from tens if not hundreds of repetitive shunt failures. These failures may lead to diminished quality of life and long-term neurologic deficits.

[0005] While many factors such as infection and disconnection may lead to shunt obstruction and eventual failure, most shunts fail due to blockage of the holes with cells and tissues. Even without occlusion, shunts are far from ideal, and patients often experience discomfort such as headaches and pain on a regular basis which directly impacts their quality of life. There is an ongoing urgent need to improve hydrocephalus treatment.

[0006] The current shunt manufacturing process is expensive, inconsistent, and only compatible with a limited range of catheter geometries. Thus, there is a need to develop a catheter manufacturing technology that can address the limitations of the current catheter manufacturing processes.

SUMMARY OF THE DISCLOSURE

[0007] This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify all key features or essential features of the claimed subject matter, nor is it intended to be used alone as an aid in determining the scope of the claimed subject matter.

[0008] The present disclosure provides catheters and a method for manufacturing catheters. A catheter is a flexible hollow tube including a funnel at a first end and an insertion tip at a second, opposite end. In some aspects, a catheter may additionally include drainage eyelets or lateral holes along the length of the catheter between the funnel and the insertion tip. While catheters are generally cylindrical in shape, the traditional shape may not be appropriate in all circumstances.

[0009] A common cause of catheter failure is occlusion in which cells or tissue block the lateral holes, impeding the flow of bodily fluids. Using the methods described herein, the lateral holes may be designed to decrease cell adhesion and/or proliferation as well as provide altered fluid dynamic profiles in comparison to current catheters. In some aspects, the shape, number, location, and spacing of the lateral holes may be altered depending on a variety of factors including the intended location at which the catheter is to be placed, the anatomy of a particular patient, and the length of time the catheter is to be inserted. In some aspects, there may be one or more rows of lateral holes along the length of the catheter. In some aspects, the shape of the lateral holes may be altered depending on a variety of factors including flow dynamics and cell adhesion. In some examples, the shape of an individual lateral hole can be round, square, or any other suitable shape. The shape of each lateral hole may be the same or different. In some aspects, the holes may have the same diameter. In other aspects, the holes may have different diameters. Examples of the diameter of an individual hole can include 600 pm, 750 pm, 450 pm, 460 pm, 275 pm, or the like. In some aspects, the diameter of the lateral holes may be 100 pm to 2 mm, 275 pm to 2 mm, 450 pm to 1.75 mm, 500 pm to 1 mm, 600 pm to 0.75 mm, 0.1 mm to 1.5 mm, 0.1 mm to 1.4 mm, 0.5 mm to 1 mm, or any fraction thereof. In some examples, the lateral holes may be placed at constant intervals. In some examples, the lateral holes may be placed at various intervals. In some examples, the intervals between the holes can be between 0.5 mm to 4 mm. Examples of the intervals can include 3.7 mm, 3.45 mm, 1.1 mm, 0.8 mm, or the like. Adjustments may also be made to the edges of the holes. In some aspects, modifications may be made to the interior surface of the catheter as well. For example, one or more areas of the interior surface may be modified to decrease or increase the size of the lumen. Such lumen obstructions may allow for modification of flow patterns of bodily fluids moving through the catheters as well as provide other desirable features.

[00010] The use of additive printing and modified lost wax casting as described herein allows for the creation of novel, customizable catheters. Such catheters may have designs tailored to specific anatomical locations, or the specific anatomy of a particular individual. In some aspects, the catheters may be designed to decrease cell adhesion and/or proliferation relative to conventional catheters. Further, the geometries of such catheters may be adapted based on the length of time for which the catheter will be inserted. [0011] In some embodiments, a design file is generated via computer-aided design (CAD) software. The design file is printed of resin or other solid or semisolid fusible substance using additive manufacturing to form a print catheter. The resin print is then filled with plaster and the plaster is allowed to cure. In some aspects, the print includes a crucible as well as catheter and plaster may be inserted in a void between the crucible and the catheter. Once the plaster is cured, the resin is burned out or otherwise removed, leaving behind a layered mold that allows for the formation of the interior lumen as well as the exterior of the catheter and the related lateral holes. The mold is then filled with a polymer such as silicone, latex, urethane, or rubber and the like. Once the polymer is cured, the plaster is dissolved leaving behind the catheter.

[0012] In some embodiments, the solid or semisolid fusible substance includes at least one of wax, photopolymer, or resin. In some embodiments, the print catheter includes a blend of wax and resin. In some embodiments, the blend comprises 35% of wax and 65% of resin. In some embodiments, the print is generated via Digital Light Processing (DLP) printing. In some embodiments, the polymer includes at least one of polydimethylsiloxane (PDMS) elastomer, polytetrafluoroethylene (PTFE), resin, silicone, rubber, or latex.

BRIEF DESCRIPTION OF DRAWINGS

[0013] The detailed description is set forth with reference to the accompanying figures. In the figures, the left-most digit(s) of a reference number identifies the figure in which the reference number first appears. The use of the same reference numbers in different figures indicates similar or identical items or features. Some of the drawings submitted herein may be better understood in color. Applicant considers the color versions of the drawings as part of the original submission and reserves the right to present color images of the drawings in later proceedings.

[0014] FIG. 1 illustrates an example process for manufacturing the catheter in accordance with the implementations of this disclosure.

[0015] FIG. 2 is a detailed process for manufacturing the catheter in accordance with the implementations of this disclosure.

[0016] FIGs. 3A-3I are images of the various steps of the manufacturing method in accordance with implementations of this disclosure showing (FIG. 3A) a cross-section of a sacrificial porous shell; (FIG. 3B) a cross section of the plaster mold from the porous consumable crucible showing the porous consumable crucible, the catheter, and a two-part sacrificial support system 306 stabilizing the lumen which will be removed after catheter extraction; (FIGs. 3C-3D) sectional views of the interior of the molds; (FIGs. 3E-3G) are views the two-part high-throughput disposable crucible holding chamber (HTDCHC) showing (FIG. 3E) the mold used for plaster and/or polymer investment; (FIG. 3F) the mold used to form the HTDCHC via vacuum forming, and (FIG. 3G) the combined two molds with a slight clearance between; (FIG. 3H) HTDCHC holding nineteen catheters before plaster investment; and (FIG. 31) plaster molds in secondary chambers prior to polymer investment, t in accordance with the implementations of this disclosure. [0017] FIG. 4 illustrates a picture of a catheter manufactured in accordance with the implementations of this disclosure.

[0018] FIGs. 5A-5C are images of manufactured catheters in accordance with various implementations of this disclosure showing a rougher version of a catheter at FIG. 5A, a smoother catheter at FIG. 5B with some artifacts inside the hole and a smooth catheter in comparison to FIG. 5A at 5C.

[0019] FIGs. 6A-6C illustrate a (FIG. 6A) 3-dimensional (3D) computational fluid dynamics simulation of the wall shear pressure contour of the CSF flow through holes of a conventional cylindrical catheter 602 showing a variation in the amount of shear seen at 606 and the amount of shear shown at 604 as liquid moves along the Y direction towards the tip of the catheter 602; (FIG. 6B) illustrates a 3D computational fluid dynamics simulation of the wall shear pressure contour of the CSF flow through holes of a flow-optimized catheter 608 prepared according to implementations of this disclosure with shear forces remaining consistent through the holes 610; (FIG. 6C) illustrates a side-by-side comparison of the 2D computational fluid dynamics simulation comparison of the velocity contour of the CSF flow through the lumens of the conventional cylindrical catheter 602 and the flow-optimized catheter 608.

[0020] FIGs. 7A-7C are images of (FIG. 7A) confocal microscopy of an explanted catheter from a shunt bank with tissue mass obstructing the catheter segment; (FIG. 7B) lateral holes as created using conventional methods in 50 shore A polymer showing uneven and partially occluded holes; (FIG. 7C) a catheter with circular holes manufactured by the improved process via the modified lost wax casting technique of this disclosure showing evenly spaced and formed holes.

[0021] FIG. 8 illustrates an embodiment of a catheter according to an embodiment.

[0022] FIGs. 9A-9D are images of catheters manufactured via the modified lost wax casting technique of this disclosure using (FIGs. 9A-B) solvated latex and (FIG. 9C-D) two-part silicone with lateral holes 906 having a diameter of 0.55mm, lateral holes 908 having a diameter of 0.775 mm, and lateral holes 910 having a diameter of 1.44 mm.

[0023] FIG. 10 is a print of a resin catheter/crucible combination.

[0024] FIGs. 11 A-1 1 C are images of catheters formed under a variety of conditions in accordance with the modified lost wax casting technique of this disclosure.

[0025] FIGs. 12A-12Q variations in catheter obstruction as described in Table 3, below. [0026] Fl Gs. 13A-13B are cross-sectional views of CAD and real manufactured catheters according to the parameters of FIGs. 12A-12Q. FIG. 13A shows CAD cross-sectional view of inner lumen variations LD1 (1302), S (1304), and LD2 (1306) and inner lumen obstruction LO1 (1308), LO2 (1310), LO3 (1312). 13B shows an actual cross-sectional view of inner lumen variations LD1 (1314), S (1316), and LD2 (1318) and inner lumen obstruction LO1 (1320), LO2 (1322), LO3 (1324).

[0027] FIG. 14 is a graph comparing commercial and manufactured standard time elapsed time for a fixed pressure drop as a measure of resistance to fluid flow increases with commercial catheters having an average time elapsed of 11.0789 seconds and manufactured catheters having an average time elapsed of 9.1654 seconds.

[0028] FIGs. 15A-15B are graphs showing the effect of different types of obstruction including a plot of the row obstructed catheter’s time elapsed (FIG. 15A) and a plot of segment obstructed catheters in comparison to standard catheter’s time elapsed (15 B).

[0029] FIGs. 16A-16D are graphs showing the results of lateral hole and lumen diameter variation including the mean time elapsed for catheters varying in lateral hole diameter (FIG. 16A); the trend in relative resistance between each lateral hole diameter variation (FIG. 16B); the mean time elapsed for catheters varying in lumen diameter (FIG. 16C); and the trend in relative resistance between each lumen diameter variation (FIG. 16D).

[0030] FIGs. 17A-17B are graphs showing the experimental results of mean time-elapsed for the lumen obstruction group including the mean time elapsed of catheters that have varying sizes of lumen obstructions compared to the standard (FIG. 17A); and trends in relative resistance as the lumen obstruction increases in diameter (FIG. 17B).

[0031] FIGs. 18A-18B are graphs showing the results of a blood assay on varying lumen diameter including a plot showing the mean time until complete flow obstruction for catheters with varying lumen diameters compared to the standard (FIG. 18A); and time to failure in a blood assay showing that the design of the catheter has an impact on the longevity of the catheter (FIG. 18B).

DETAILED DESCRIPTION

[0032] Hydrocephalus, an imbalance between cerebrospinal fluid production and absorption, is diagnosed in more than 400,000 people annually and arises from a variety of causes including genetic diseases, meningitis, subarachnoid hemorrhage, stroke, traumatic brain injury, or tumors. Eighty percent of those diagnosed will suffer long-term neurological deficits.

[0033] The common treatment for all hydrocephalus patients is CSF drainage by shunting. However, shunts have the highest failure rate of any neurological device with 98% failing after ten years. Shunts fail for a variety of reasons including infection, disconnection, fracture, migration, valve failure, over drainage, under drainage, and occlusion of the shunt and the shunt tubing or catheter. Most failures are due to a blockage or some obstruction within the shunt system. For example, catheters may become obstructed with attaching glia which form a substrate for more glia or other cells and tissues (e.g., choroid plexus) to secondarily bind and block the flow of CSF through the shunt.

[0034] A shunt catheter is an implantable hollow tube that redirects excessive fluid build-up to a different compartment where the fluid may be absorbed. In some aspects it may redirect cerebrospinal fluid from the brain or the spine. While commonly used, the current shunt manufacturing process is expensive, inconsistent, and only compatible with a limited range of catheter geometries.

[0035] Traditionally, catheters are made from extruded polymer tubing. The tubing is cut into appropriately sized pieces and the tubing is stretched over a fixture so that holes may punched in the tubing to allow for bodily fluids including CSF to drain. While stretching allows for a more consistent hole to be punched, once the tubing is removed from the fixture, the holes shrink and may deform as shown in FIG. 7B. Hole deformity problems are more pronounced in softer polymers as the increased stretchiness of the softer polymers makes it challenging to make clean cuts through the polymer using a mechanical punch. Mechanical punching also limits the hole size and placement. Further, punching holes creates a surface roughness which may increase the incidence of occlusion. For example, the roughness average (Root Mean Square (RMS)) of a lateral hole of a commercial catheter is 1 .12 ± 0.5 (Harris, C.A., McAllister, J.P., Childs Nerv Syst 27, 1221-1232 (2011 ). //doi.org/10.1007/s00381 -011 -1430-0). The roughness average of a lateral hole produced according to the methods described herein may have an average surface roughness (RMS) less than 1.12 ± 0.5. For example, the catheters produced according to the methods described herein may have a decreased surface roughness of 5%, 10%, 15%, 20%, 30% relative to conventional catheters.

[0036] The shape of the lateral holes in the conventional catheters as shown in FIG. 7B are visibly different than the lateral holes in the catheters manufactured using the modified lost wax casting method described herein and shown in FIGs. 5A-C, FIGs. 9A-D, and FIGs. 12A-12Q. Further, the use of the modified lost wax casting method as described herein allows for more flexibility in the type and hardness of the materials used to form the catheter in comparison to a conventional extrusion process. For example, many conventional catheters have a shore hardness of 60A, resulting in a device that is significantly harder than the tissue surrounding it. Such hardness may cause discomfort to a patient and potential damage to the surrounding tissue. [0037] Provided is an improved catheter manufacturing process is described in this disclosure that can produce ventricular catheters with any architecture, spacing, and lateral hole geometry. Another advantage of the catheter manufacturing process disclosed herein is the ability to consistently produce holes of the desired geometry. The improved catheter manufacturing process would eliminate the limitations of conventional catheter manufacturing processes, thus offering considerably more opportunity for catheter material that is more biocompatible and geometries that do not excessively provoke cellular proliferation such as astrocyte proliferation.

[0038] Provided are shunt catheters and methods of manufacturing shunt catheters. A shunt catheter (referred to herein as a catheter) is a flexible hollow tube including a funnel at a first end and an insertion tip at a second, opposite end. A catheter may additionally include drainage eyelets or lateral holes along the length of the catheter between the funnel and the insertion tip. As shown in FIG. 8, a catheter 802 may have a funnel end 804 opposite an insertion tip 808 with a plurality of lateral holes or eyelets 806 along the length of the catheter in the y direction as shown by axis 810. The methods of manufacturing as described herein may be used to alter one or more dimensions of a catheter. For example, the length; thickness of the lumen; obstructions within the lumen, size of the openings; shape, number, spacing, pattern, orientation, and dimensions of the lateral holes; and shape and size of the catheter as a whole may be altered.

[0039] While a single row of lateral holes 806 are shown, there may be a plurality of rows, including two, three, four, five, or more rows of lateral holes. In some examples, the shape of an individual hole may be the same or a different shape than another hole on the same catheter. Holes may be round, square, or any other suitable shape. Further, the interior of the hole may be cylindrical, conical, or barrel shaped. In some aspects, the holes on a catheter may have the same diameter. In other aspects, the lateral holes may have different diameters. Examples of the diameter of an individual lateral hole may include 600 pm, 750 pm, 450 pm, 460 pm, 275 pm, or the like. 600 pm, 750 pm, 450 pm, 460 pm, 275 pm, or the like. In some aspects, the diameter of the lateral holes may be 100 pm to 2 mm, 275 pm to 2 mm, 450 pm to 1 .75 mm, 500 pm to 1 mm, 600 pm to .75 mm, 0.1 mm to 1 .5 mm, 0.1 mm to 1 .4 mm, 0.5 mm to 1 mm, or any fraction thereof. In some aspects, the holes may be 0.55 mm, 0.775 mm, 1 mm, or 1 .4 mm. In some aspects the interior shape and/or profile of the lateral holes may be altered to improve flow dynamics or decrease cell adhesion. For example, the profile of the hole may be made smoother or may be internally tapered to reduce shear forces in the lumen or central channel of the catheter. In some examples, the lateral holes of a catheter may be placed at constant intervals. In some examples, the lateral holes of a catheter may be placed at various intervals. In some examples, the intervals between the holes can be between 0.5 mm to 4 mm. Examples of the intervals can include 3.7 mm, 3.45 mm, 1.1 mm, 0.8 mm, or the like. While the lateral holes are shown in a linear fashion in FIG. 8, in some examples, the multiple rows of holes may be arranged in a spiral manner. In some examples, the holes may be arranged in a staggered manner.

[0040] In some aspects, the methods described herein allow for the creation of catheters of specific dimensions with specific lateral hole geometries and spacing. Such a design may take into consideration 3D modeling and flow dynamics. The design of the lateral holes in the catheter may be tailored to the intended use of the device. For example, the size, number, shape, and spacing of the lateral holes may be modified depending on flow and cell adhesion which may be impacted by the intended location of the device. In some aspects, the shape of the interior walls of the holes may be altered to influence flow dynamics. In some aspects, the size of the lumen (e.g. the internal diameter of the catheter) may be altered. In some aspects, the profile of the catheter may be altered. For example, curved catheters may reduce contact with ventricular walls. Cone shaped catheters as shown in FIGs. 6B and 6C may have improved flow dynamics in comparison to conventional catheter shapes.

[0041] As shown in FIGs. 5A-C and 9A-9D, the use of the modified lost wax casting method as described herein creates smoother edges to the lateral holes. For example, FIG. 9A is an image of a catheter manufactured using solvated latex with a catheter hole size of 0.55mm. As shown in FIG. 9A, the edges of the lateral holes 902 are much smoother than the edges of the lateral hole in a conventional catheter as shown in FIG. 7B. FIG. 9B shows a series of lateral holes in a catheter manufactured using latex. A similar smoothness to the smoothness of FIG. 9A is seen at 904 of FIG. 9C which depicts a catheter made from two-part silicone with a hardness of 37 shore 00 hardness. The modified lost wax casting method also allows for variation in the size of the holes. As can be seen in FIG. 9D, the modified lost wax casting method as described herein allows for the creation of catheters with highly specific lumen spacing and sizes. In FIG. 9D, the topmost catheter 906 depicts a catheter with a hole size of 0.55 mm as would be seen in a conventional catheter. The middle catheter 908 depicts a catheter with a 0.775 mm lateral hole size. The bottom catheter 910 has a 1.4 mm hole size. The modified lost wax casting based on 3D printed designs may also allow changes to the interior of the catheter. For example, one or more areas of the interior surface may be modified to decrease or increase the size of the lumen at one or more locations as described in further detail with reference to FIGs. 120-12Q and shown in FIG. 13 in the various states of simulated obstruction at 1308-1312. Such lumen obstructions may allow for modification of flow patterns of bodily fluids moving through the catheter as well as other desirable features. In some aspects, the obstructions may be used for modeling the effects of different conditions on catheter function. [0042] In some aspects, there may be macro or micro patterning on an interior or exterior of the catheter. Micro and macro patterning of the surface of the catheters creates features that may lead to a redistribution of cerebrospinal fluid flow in the region immediately adjacent to the drainage holes. As described herein, macropatterning is on the scale of 100s of microns and micropatterning is on a scale of microns or nanometers and tens of microns or nanometers. The shunt catheters described herein may have either or both micro and macro patterning.

[0043] Macro and micro patterning may be located at any useful location on the shunt catheter. The locations may be contiguous or non-contiguous. In some aspects, the patterning may cover the majority or the entirety of the exterior surface area of the shunt catheter. In other embodiments, the patterning may be applied locally. In some aspects, the patterning may be located around the interior and/or exterior of a lateral hole.

[0044] In some aspects, the design of the catheter may depend on the intended use of the catheter. For example, the usefulness of different types of modifications may depend on whether the catheter is to be used for short or long term implantation, that is catheters intended to be used for days, weeks, or months may have different designs than catheters intended to be used for years. Other parameters may depend on the placement location, or the particular anatomy of an individual patient.

[0045] In traditional lost wax casting, a mold is built around a sacrificial wax model, in this case, a 3D print of a catheter. The mold created using traditional lost wax casting is of the outside of the wax model. However, in this instance, a catheter is a hollow tube. The appropriate geometries of the inside surface or lumen of the catheter are therefore also needed to produce a device that will function as desired. The modified lost wax casting methods as described herein allow for a burnout on an object with a complex inside and outside geometry. Further, in traditional lost wax casting, the resulting cast may be manually buffed or otherwise sanded to improve the finish. Such methods do not work with elastomers as used to form the catheters herein. Thus, the lost wax casting process has been modified to improve the quality of the print and the resulting cast. [0046] In some aspects, the design may be generated using computer-aided design (CAD). The design may be printed using a 3D printer such as a DLP printer or other additive manufacturing system. In some aspects, various aspects of the print including the orientation, layer height, and temperature may be adjusted to tailor the resulting catheter to a desired flow dynamic or cell adhesion profile. For example, thinner layers in the print lead to a smoother surface which may decrease the incidence of cell adhesion. In some aspects, the layer height of the designs may be 25-50 pm, 25-40 pm, 25 pm, 30 pm, 35 pm, 40 pm, 45 pm, 50 pm or any fraction thereof. In some aspects the orientation of the catheter may be altered to decrease peel force and reduce layer lines. For example, the print may be oriented between 10^e to 45^s, 10^s to 35^s, or 10^s to 25^s from normal. In some aspects, the print orientation is 10^s from normal. In other aspects, the temperature of the 3D printer may be adjusted. For example, DLP printing is usually done at ambient temperature, however in some aspects, the resin may be warmed to 40^eC. In some aspects, the temperature of 40^sC may be maintained during the print process. In some aspects, an anchor point may be used as part of the print. In some aspects, a buffer zone such as a segment of sacrificial material that may be added to one or both ends of the catheters and which may be sanded or otherwise removed prior to the burnout cycle.

[0047] The design may be printed using a resin to create a model catheter or “print.” In some aspects, the resin may include wax, for example 35% wax. As shown in FIG. 3H and FIG. 10, in some aspects, the print may include the catheter and a consumable crucible. After printing, the model catheter or catheter/crucible is inserted into or filled with a plaster slurry respectively. In some aspects, the plaster is Dental Plaster Type IV though other plasters may also be used. Once the plaster is cured, the resin print is burned out leaving a layered hollow portion in the center (that is, as shown at 314 in FIG. 3D, a mold having an exterior plaster surface 322, a first inner surface 324 and a second inner surface 326, where there is a void between the first inner surface and the second inner surface, allowing for the creation of a tube) of the plaster and an exterior space between the plaster surface 316 and a container, allowing for easy extraction of the plaster mold. A polymer may then be injected into the central layered hollow portion or void in the plaster. Once the polymer is cured, the plaster is removed yielding a catheter. In some aspects, the polymer catheter may be washed or otherwise processed to remove any lingering plaster.

[0048] In some aspects, the material used to form the catheter may be a polymer that stimulates regrowth or improves vascularization. In some aspects, an elastomer such as rubber, for example solvated latex or nitrile; polyurethane; silicone; polydimethylsiloxane (PDMS); or polytetrafluorethylene (PTFE). In some aspects, the elastomer may be selected to mimic or have a similar softness or rigidity as the tissue which will be adjacent to the catheter in the body of a patient. For example, the polymer may have a shore 00 hardness of 0-40, for example, a shore 00 hardness of 10, 20, 30, 37, or 50.

[0049] During production, one or more aspects are altered to provide a catheter of the desired shape, hardness, and complexity. For example, the amount of resin used, the type of resin used, plaster mixing time, plaster mixing pressure, type of plaster used, plaster powder:water ratio, plaster curing time, plaster mixing time, the pressure at which the plaster is being mixed, the viscosity of the plaster, plaster additives such as aluminum oxide and fumigated silica, centrifugation speed, centrifugation time, curing time, kiln temperature, kiln time, forced aging time, moisture content of plaster at time of mixing, and moisture of resin immediately prior to the burnout cycle all impact the resulting catheter. For example, the amount of plaster may be from 74% to 76%.

[0050] As shown in FIGs. 11 A-C, change in the one or more variables results in surprising differences in the produced catheters. For example, in FIG. 1 1 A, the catheters were printed rightside up on a printer that had a pixel size of 35 pm XY. FIG. 11 B was printed upside down on supports. FIG. 110 was also printed upside down on supports, but was produced with a printer that had a pixel size of 22 pm. Further, while all three catheters used the same dental type IV plaster, burn out procedure, and 00-30 silicone rubber, the plaster powder: water ratios, mixing pressure, centrifugation, and ageing temperature were all varied. For example, to produce the catheter shown in FIG. 11 A the plaster was prepared using an 82.6:17.4 powder to water ratio, the plaster powder and water was mixed in a vacuum mixer for 60 at 650 RPM without vacuum prior to filling or submerging the resin, the plaster/resin composition was allowed to dry at room temperature and the plaster/resin composite was placed in a kiln for curing. The temperature of a kiln was raised from room temperature to 300^eF over two hours. Once the temperature reached 300^eF, the plaster/resin composite was baked for 60 minutes. The temperature was then raised to 700^eF over 60 minutes and then baked at 700^BF for sixty minutes. The temperature was then raised from 700°F to 1350°F over 120 minutes. Once the kiln reached 1350°F, the composite was baked for 120 minutes. The kiln was then be allowed to return to room temperature. The plaster was then subjected to vacuum at -25 °Hg for 1 minute, allowed to dry at room temperature, aged at 45°C for 90 hours, and the resulting mold was filed 00-30 silicone rubber and allowed to cure for 24 hours at room temperature prior to removing the plaster. To produce the catheter shown in FIG. 11 B, the plaster powdenwater ratio was changed to 74:26, vacuum mixed for 60 seconds at -0.09 MPa, centrifuged for 5 minutes at 300 RPM, allowed to dry at room temperature and aged at 70°C for 5 days. The resulting mold was filed 00-30 silicone rubber and allowed to cure for 24 hours at room temperature prior to removing the plaster. The catheter of FIG. 11 C was produced using a plaster powder:water ratio of 74:26, vacuum mixed for 60 seconds at -0.09 MPa, centrifuge spun the catheters for 5 minutes at 500 RPM, aged at 45°C for 6 days and the resulting mold was filled with 00-30 silicone rubber and allowed to cure for 24 hours at ambient temperature prior to removing the plaster. As shown in FIGs. 1 1A-11 C, the catheters of FIG. 1 1 B and 11 C appear to have much smoother surfaces than the catheter of FIG. 11 A.

[0051] One of the advantages of the catheter manufacturing process disclosed herein is its versatility in producing a variety of catheter designs and sizes. Research indicates that the shunt revision rate is not consistent across various etiologies of hydrocephalus (Cummins DD et al. Available from: //doi.org/10.1016/j.wneu.2022.05.008; Nigim F et al. J Surg Res [Internet]. Elsevier Inc; 2014;191 :140-7. Available from: //dx. doi.org/10.1016/j.jss.2014.03.075, Holwerda JC et al. Child’s Nerv Syst. Child’s Nervous System; 2020;36:577-82). Further, standard shunts may not fit all anatomies. A customizable manufacturing process allows for tailoring to achieve specific effects, such as differences in flow dynamics, cell adhesion, or cell proliferation relative to conventional catheters.

[0052] Aspects of the current disclosure are now described in additional detail, as follows: (I) Overview of the Process; (II) Details of the Process of Manufacturing Catheter; (III) Simulation Results; (IV) Experiments Related to Optimizing the Catheter Manufacturing Process; (V) Experiments Related to Manufacturing and Testing of Flow-Optimized Catheter; (VI) Kits; (VII) References; (VIII) Example Clauses; and (IX) Closing Paragraphs. These headings are provided for organization purposes only and do not limit the scope or interpretation of the disclosure.

[0053] (I) Overview of the Process. As described above, CSF drainage by shunting is a common treatment for hydrocephalus patients. The shunt usually includes a ventricular catheter which includes multiple holes along its length. In some cases, hydrocephalus patients can experience a high failure rate of shunts due to blockage of the catheter, which can lead to diminished quality of life and suffering from long-term neurologic deficits.

[0054] Evidence indicates that astrocytes make up a vast majority of cells in the tissue that block catheters. In the tissue obstructed shunts, increased cell proliferation is observed, with astrocyte markers highly co-localized suggesting that astrocytes are actively populating. In some tissue obstructed shunts, more than a 2000% increase in cell proliferation has been observed.

[0055] This disclosure provides a process for manufacturing flow-optimized ventricular catheters. The goal is to reduce shunt obstruction by reducing astrocyte proliferation and thus cell density on the shunt surface. Preliminary data indicates that the uneven flow of CSF is primarily attributed to the cylindrical shape of the commercial catheters and altering the profile of the ventricular catheters will allow uniform CSF flow through all catheter holes as shown in FIGs. 6B and 6C. The flow-optimized catheter may diminish astrocytic activation, downstream pro-inflammatory cytokine secretion, and ultimately shunt obstruction by distributing even flow through all catheter holes. In some aspects, the flow-optimized ventricular catheters may have decreased tissue pull relative to conventional catheters.

[0056] This disclosure describes a manufacturing process that can rapidly prototype and manufacture ventricular catheters to manufacture novel catheters that reduce astrocyte proliferation relative to conventional catheters. The modified catheter is optimized in its overall profile to allow fluid distribution through all catheter holes. In some aspects, the fluid flowing through the catheter includes biological fluids such as such as cerebrospinal fluid (CSF) in brain tissue, blood in the circulatory system, and so on.

[0057] In some examples, the catheter 104 may be part of a shunt system for treating hydrocephalus. In some examples, the catheter 104 may be used downstream from the proximal (ventricular) tip of a ventriculoperitoneal shunt, a ventriculoatrial shunt, a lumbar peritoneal shunt, or the like.

[0058] FIG. 1 illustrates an example process 100 for manufacturing the catheter in accordance with the implementations of this disclosure. In some examples, the fluid flowing through the catheter 104 includes biological fluids in organs or tissues, such as cerebrospinal fluid (CSF) in brain tissue, blood in the circulatory system, and so on. In some examples, the catheter 104 may be a part of a shunt system for treating hydrocephalus. In some examples, the catheter 104 may be used for downstream from the proximal (ventricular) tip of a ventriculoperitoneal shunt, a ventriculoatrial shunt, a lumbar peritoneal shunt, or the like.

[0059] Referring to FIG. 1 , at 102, the process includes designing the catheter 104. In some examples, the design process may be performed using computer-aided design (CAD) software. CAD software is a digital product for the creation, modification, analysis, or optimization of a design. Commercially available CAD tools include but are not limited to, AutoCAD, SolidWorks, FreeCAD, CATIA, Siemens NX, and so on.

[0060] The catheter design tailors the architecture of the ventricular catheters to reduce excessive flow and shear. The catheter is parametrically designed to address the uneven flow of CSF through the catheter and to distribute flow through all lateral catheter holes. Preliminary data using computational fluid dynamics of the optimized catheter as shown in FIG. 6B demonstrates uniform flow, pressure, and shear rate throughout the catheter in comparison to the catheter of FIG. 6A such that the maximum shear in any catheter hole of the catheter of FIG. 6B is reduced significantly compared to conventional catheters.

[0061] At 106, the process includes generating mold 108 based on the design. In some instances, the mold may be created using modified lost wax casting. For example, a catheter may be printed using additive printing, for example Digital Light Processing (DLP) printing. DLP is a 3D printing technology used to rapidly produce photopolymer parts. In some aspects the catheter may be printed using a blend of resin or wax. In some aspects, the percentage of wax in the blend can be 35% and the rest of the blend can be resin. In some aspects, the print includes a crucible surrounding the catheter as shown in FIG. 10. Commercially available DLP printers include, but are not limited to, Formlabs Form, Anycubic Photon, Peopoly Moai, Wanhao Duplicator, Elegoo Mars, ELEGOO Saturn 2 8K, Phrozen Shuffle, B9Creator, Kudo3D Titan 2, XYZprinting Nobel, and so on. One obstacle in catheter design was providing sufficient support for the thin lumen. In some aspects, the lumen is completely separated from the rest of the mold on all sides with the small lateral holes providing the only point of contact suspending the lumen of the catheter. Sufficient support is provided to avoid cracking and collapse of the plaster mold when the resin is removed.

[0062] At 110, the catheter/crucible resin mold 112 is filled with plaster. In some aspects, the plaster is Dental IV plaster. In some aspects, in order to form the plaster slurry, water is placed in a vacuum mixer container and the plaster powder is added at a plaster powder:water ratio of 74%:26%. The vacuum mixer is then set to a first pressure and mixed for a first time. In some aspects, the vacuum mixer is set to -0.09 MPa for 1 -3 minutes. In some aspects, the catheter/crucible print is placed on a vibrating base while the plaster is poured in, allowing the plaster to integrate with the 3D print. The plaster/print combination is then centrifuged for a first time at a first speed. For example, the plaster/print combination may be centrifuged for 300 rpm to 900 rpm. In some aspects, the plaster/print combination was centrifuged for 7 min at 700 rpm or 5 min at 800 rpm.

[0063] After the plaster/print combination is centrifuged, the plaster is allowed to dry at room temperature for 48 hours before the burnout stage. The resin-wax crucible may limit the drying time of the plaster, extending the time needed fo achieve the desired result. The plaster/print combination is then placed in a kiln to undergo the burnout cycle at 114 resulting in a negative plaster mold 116. During the burnout stage, the plaster is heated in a controlled manner to gradually eliminate the printed material. The burnout cycle may be a single or multi-stage process taking place at one or more different temperatures for one or more lengths of time. For example, the plaster/resin composite may be placed in a kiln and the temperature of a kiln raised to 300^eF over two hours. Once the temperature reaches 300^eF, the plaster/resin composite may be baked for 60 minutes. The temperature may then be raised to 700^eF over 60 minutes and then baked at 700^eF for 60 minutes. The temperature may then be raised again from 700°F to 1350°F over 120 minutes. Once the kiln reaches 1350°F, the composite may be baked for 120 minutes. The kiln may then be allowed to return to room temperature. The void left by the removed material is where the catheter forming material will be poured during casting. After the burnout process, the empty plaster mold is ready for the casting step.

[0064] Once cooled, the mold is placed into a sealed plastic container and filled with catheter forming material at 118 forming filled molds 120. The sealed container is centrifuged to force the catheter forming material to fill the hollow catheter impression and force any bubbles to rise to the top. As an example, the sealed containers are centrifuged at a speed of 3000 to 5000 revolutions per minute (rpm) for 3-5 minutes. The catheter forming material takes the shape of the intricate pattern left behind after the printed catheter was burned out. The catheter forming material is left to cure under ambient conditions for 24 hours. Once the catheter forming material has solidified, the plaster is dissolved at 122 to form a catheter 124. While the plaster may be removed using any process generally used, in some aspects the plaster/polymer composite can be removed from the sealed container and placed in solvent to allow the plaster to dissolve, releasing the final catheter with the desired shape and details.

[0065] In some examples, the catheter forming material includes polymers such as polydimethylsiloxane (PDMS) elastomer, polyurethane, polytetrafluoroethylene (PTFE), resin, silicone, rubber, or latex, or any combination thereof.

[0066] (II) Details of the Process of Manufacturing Catheter. As described above, the uneven flow of CSF is primarily attributed to the shapes and dimensions of the traditional catheters and the lateral holes. Thus, the catheter design may be improved in terms of the shape of the catheter and/or the hole sizes, which can be tailored to manipulate the flow velocity and shear rate/shear stress through the catheter holes and the internal lumen of the ventricular catheter. Initial designs lacked sufficient support to avoid cracking and collapse of the plaster mold. Further, the removal of the plaster was hampered by the limited surface area between the plaster and the solvent. The process described herein provides sufficient support from the crucible to avoid cracking and collapse of the 3D printed wax mold as well as support of the plaster mold when the wax mold is removed, improves drying time of the plaster, decreases fracture propagation, and allows curing and separation of the catheter. Using the process described herein, a surprising increase in yield and usable catheters was obtained.

[0067] FIG. 2 illustrates a detailed process 200 for manufacturing the catheter in accordance with the implementations of this disclosure. Generally, a catheter is designed using a variety of information on catheters available from universities, research centers, health institutions, hospitals, clinics, governmental agencies, or the like. Such information may include designs, failure rates, causes of failures and the like. Additional information such as computational fluid dynamics (CFD) and patient anatomy may also be used to design a catheter. The manufacturing process described herein allows for modifications to the shape of the catheter that are not possible with conventional catheter manufacturing.

[0068] At 206, the process includes generating a CAD file of a catheter with the selected features including lumen size and placement. In some examples, the catheter can be designed to distribute flow among catheter holes more evenly than conventional catheters. [0069] At 208, the process includes 3D printing a resin catheter or combination catheter/crucible. As described herein, DLP 3D printing can be used to print the catheter. While DLP printing is usually done at ambient temperature, the resin may be warmed to 40^eC and the temperature maintained during the printing process.

[0070] At 210, the process includes submerging the printed resin catheter in a plaster slurry or filling the catheter/crucible with a slurry. Once the plaster is cured at 212, the printed resin catheter is burned out at 214 to form a plaster mold. For example, the plaster/resin composition can be heated in a kiln to burn out the mold. In some aspects, the burn out may be a multi-stage process in which the temperature is raised one more times before cooling in a step wise manner. For example, the plaster/resin composite may be placed in a kiln and the temperature of a kiln may be raised to 300^eF over two hours. Once the temperature reaches 300^eF, the plaster/resin composite may be baked for 60 minutes. The temperature may then be raised to 700^eF over 60 minutes and may then bake at 700^eF for sixty minutes. The temperature may then be raised again from 700°F to 1350°F over 120 minutes. Once the kiln reaches 1350°F, the composite may be baked for 120. The kiln may then be allowed to return to room temperature.

[0071] At 216, the process includes forming the catheter using the plaster mold. For example, silicone elastomer (or other materials suitable to form the catheter) can be injected into the cavity left behind in the plaster. The polymer may then be cured under any suitable conditions. In some aspects, the polymer may be cured at ambient temperature for 24 hours.

[0072] At 218, the process includes dissolving the plaster. For example, after the silicone elastomer is cured, the plaster can be dissolved or otherwise removed using solvent such as DP2400 resulting in a functional catheter including a cap and lateral holes.

[0073] FIG. 3A illustrates a cross-section of a sacrificial porous shell including a false crucible bottom 302, lateral holes 304 and a sacrificial support system 306 with resin fins (measurements are in millimeters). The sacrificial support for the lumen in both the resin and plaster phase maintains the structure of the catheter. The wax-resin catheter is supported with an equal amount of plaster from all sides. The resin fins shown at 306 connect the catheter to the interior of the crucible shell, supporting, centering, and stabilizing the catheter.

[0074] FIG. 3B is a cross-section of the plaster mold from the porous consumable crucible after the burnout cycle with a sacrificial support system 308, high-throughput attachment points 310, and the lumen of the catheter 312. Three plaster fins connect the plaster in the lumen of the catheter with the rest of the plaster in the back of the catheter, supporting the plaster piece in place. The sacrificial support system stabilizes the lumen of the catheter and is removed after the catheter extraction [0075] FIG. 30 illustrates a picture of a catheter 320 and a sectional view of mold having an exterior plaster surface 316 in accordance with implementations of this disclosure. The mold having an exterior plaster surface 316 has been broken sectionally to show the inside. It can be seen that the cavity 318 inside the mold 316 has the shape of the intricate pattern of the desired catheter.

[0076] FIG. 3D is a picture of a catheter 320 and a sectional view of a plaster mold 322 having a first inner surface 324 and a second inner surface 326 with a void between the first inner surface and the second inner surface, allowing for the creation of the catheter in accordance with implementations of this disclosure. It can be seen that the first inner surface 324 inside the plaster mold 322 has the shape of the intricate pattern of the desired catheter.

[0077] FIG. 3E is a first part of a high-throughput disposable crucible holding chamber (HTDCHC) for plaster and/or polymer investment. The high-throughput attachment points 310 provide anchoring points between the individual catheters allowing the molds to be processed as batches or individually.

[0078] FIG. 3F is a mold that forms the HTDCHC shown in FIG. 3E.

[0079] FIG. 3G is the combined HTDCHC including the molds shown in FIGs. 3E and 3F. While the combined molds are shown in a hexagonal shape, other shapes may also be used.

[0080] FIG. 3H is an HTDCHC holding nineteen catheters before plaster investment.

[0081] FIG. 3I plaster molds placed in secondary chambers prior to polymer investment.

[0082] FIG. 4 is a picture 400 of a catheter 402 in accordance with the implementations of this disclosure. Referring to FIG. 4, the catheter 402 has holes 406, 408, 410, 412, 414, and 416. In some examples, the holes 406-416 can have the same dimension (the same diameter) or different dimensions (different diameters). While the holes 406-416 are circular and barrel shaped, other shapes may also be used. For example, the holes 406-416 may be other geometric shapes such as a rectangle, oval, irregular shapes, or the like. The interior of the hole may also have a variety of shapes such as conical, tapered, truncated cone, and the like. Moreover, it should be understood that the dimensions and the shapes of the catheter 402 and the holes 406-416 are exemplary rather than limiting.

[0083] Though FIG. 4 shows six holes 406-416 in the catheter 402, it should be understood that the catheter 402 can include other numbers of holes. Though FIG. 4 shows that the holes 406- 416 are distributed evenly along the catheter 402, it should be understood that holes 406-416 can be distributed unevenly or in a pattern. For example, the holes may be in a spiral pattern.

[0084] FIG. 5A, FIG. 5B, and FIG.5C are illustrative images of sections of manufactured catheters with holes in accordance with implementations of this disclosure showing a rougher version of a catheter at FIG. 5A, a smoother catheter at FIG. 5B with some artifacts inside the hole and a smooth catheter in comparison to FIG. 5A at 5C.

[0085] Advantages of the catheter manufacturing process include versatility in producing a variety of catheter designs and sizes. Another advantage of the manufacturing process is the ability to design, manufacture, and test catheters all within the lab rather than using a third party for manufacturing processes.

[0086] (III) Simulation Results. Catheter failure may be influenced by uneven flow of CSF through the catheter holes, high flow and shear in shunt catheter holes with the most occlusion, and high flow and shear directly causing astrocyte expression of IL-6 and enhanced cell proliferation. In some aspects, the catheters described herein may reduce IL-6 production compared to current catheters.

[0087] Thus, optimizing the architecture of the ventricular catheters for CSF drainage will allow uniform CSF flow through all catheter holes and reduce excessive flow and shear. Therefore, an improved catheter manufacturing process is required to produce the flow-optimized catheter with a modified architecture and lateral hole geometry. This process will provide the flexibility and accuracy required to produce hypothesis-driven, ventricular catheters that are optimized to drain CSF as efficiently as possible.

[0088] FIG. 6A, FIG. 6B, and FIG. 6C illustrate simulation results of CSF flow through different types of catheters. In some examples, the simulation can be conducted using commercial software such as ANSYS Fluent, OpenFOAM, COMSOL Multiphysics, SimScale, Converge CFD, or the like.

[0089] FIG. 6A illustrates a 3-dimensional (3D) computational fluid dynamics simulation of the wall shear pressure contour of the CSF flow through holes of a cylindrical catheter 602. Referring to FIG. 6A, more than 86% percent of CSF flow is conducted through the three rows furthest from the catheter tip including holes 603, 605, and 606, resulting in very high shear forces.

[0090] FIG. 6B illustrates a 3D computational fluid dynamics simulation of the wall shear pressure contour of the CSF flow through holes of a flow-optimized catheter 604. The flow-optimized catheter 604 described herein was parametrically designed to address the uneven flow of CSF through the catheter and to distribute flow through catheter holes more evenly. Referring to FIG. 6B, flow-optimized catheter 604 demonstrates uniform flow through all catheter holes such as hole 610 and a fifty-fold decrease in maximum wall shear.

[0091] FIG. 6C illustrates a 2D computational fluid dynamics simulation a comparison of the velocity contour of the CSF flow through the lumens of a cylindrical catheter 612 and a flow- optimized catheter 614. Referring to FIG. 6C, the CSF flow distribution in the lumen of the flow- optimized catheter 614 is more even than the CSF flow distribution in the lumen of the cylindrical catheter 612.

[0092] The flow-optimized catheter 614 incorporates improvements in many variables including the geometry and the size of catheter holes. Several studies have underscored the importance of catheter holes in the uniform conductance of CSF. Studies indicated the importance of catheter hole diameter and geometry in astrocyte and macrophage adhesion and activation to the proximity of catheter holes (Harris CA, McAllister JP. Child’s Nerv Syst. 2011 ;27:1221-32; Galarza M et al. Acta Neurochir (Wien). 2016;158:109-16; Gimenez A et al. Biomed Eng Online. BioMed Central; 2016;15:5-19). Preliminary data using computational fluid dynamics of flow- optimized catheter 604 demonstrate uniform flow, pressure, and shear rate throughout the catheter such that the maximum shear in any catheter hole is reduced by more than fiftyfold compared to commercial catheters. Such substantial reduction in shear forces will significantly reduce shunt failure caused by astrocytic activation, proliferation, and ultimately obstruction formation.

[0093] FIG. 7A is an image of an explanted catheter from a shunt bank with tissue mass obstructing the catheter segment taken using confocal microscopy. FIG. 7B is an image of a conventional catheter in which the holes have been mechanically punched. As can be seen in FIG. 7B, the holes are of an inconsistent shape and are partially occluded. FIG. 7C is an image of a catheter with circular holes manufactured by the improved process via the modified lost wax casting technique showing the spacing between the holes.

[0094] The manufacturing process may reduce the burden of current treatments by lowering the failure rate of shunts by designing and producing catheters optimized for CSF drainage, a major shift from catheters designed based on manufacturing limitations, reducing the frequency of shunt revision surgeries and improving the quality of life for hydrocephalus patients through improving ventricular catheters.

[0095] (IV) Experiments Related to Optimizing the Catheter Manufacturing Process. To optimize the catheter manufacturing process, several experiments were conducted. Here, a tested and validated protocol for modified lost wax casting to produce catheters was developed. Commercial catheters (control) and manufactured shunt catheters may be statistically correlated by defining data normality using the Anderson-Darling test. Once data are separated into parametric and nonparametric forms, the student-t or one-way analysis of variance (ANOVA, parametric), multivariate/repeat measures ANOVA with Holm correction (parametric), or the Kruskal-Wallis H test with a planned comparison of mean rank (non-parametric) may be used. For all tests, a confidence interval was set at 0.95 (a = 0.05). In all repeat measures analyses, the Greenhouse-Geisser correction can be used following a measure of sphericity. Following cases in which a paired t-test or ANOVA is used, a post hoc Tukey test is performed if the null hypothesis is. Scientific Rigor can be that when feasible in the preliminary study, researchers address data quality, statistical power, sample size, and limitations and alternatives

[0096] The proposed flow-optimized catheter may improve the longevity of ventricular catheters by reducing astrocyte activating shear forces by more than fifty-fold on catheter surfaces.

[0097] Experiment 1 : Protocol for Manufacturing Silicone Catheters with Consistent Lateral Holes. The objective of this these experiments was to produce catheters with consistent and reproducible holes. Catheters were designed using CAD and 3D printed using ultraviolet (UV) cured resin wax. The printed catheters and/or crucible/catheters were then cleaned with isopropyl alcohol, dried, and cured with UV light. As the multilayer nature of the crucible may inhibit UV curing, lateral holes were provided as shown in FIG. 3A at 304. Such holes also provided access for isopropyl alcohol or other cleaning agents during the resin-wax catheter preparation. The design of the crucible/catheters additionally included a false crucible bottom as shown at 302 in FIG. 3A. The use of a false crucible bottom may allow for pressure reduction preventing the cracking in the burnout cycle as shown in FIGs. 3C and 3D during the burnout cycle.

[0098] A high throughput disposable crucible holding chamber (HTDCHC) for use in the investment process was produced using two resin printed molds as shown in FIGs. 3E-3G.

[0099] Plaster was prepared using deionized water (DI)(ASTM type 2 water) and dental type IV plaster according to the criteria shown in Table 1 .

Table 1

Plaster Preparation

The plaster was mixed using a ZKJ-3 Mixing Vibrating Machine (PuTian City OuBo E-Business Co., Ltd., Putian Chengxiang District, Fuzhou, China) at 270RPM. Experiments with other types of water and plater resulted in broken casts.

[0100] The HTDCHC holding the wax catheter as shown in FIG. 3G and 3H was placed on a vibrating plate and the mixed plaster was added until the plaster reached half the height of the catheter. The plaster was then manually stirred to remove any pockets of air and debris. Additional plaster was then added until the catheter was full. The plaster-filled inserts were then put inside a Thermo Scientific Sorvall Legend XTR Challenge centrifuge and spun at 500rpm for 3 mins (Thermo Fisher Scientific, Inc., Waltham, MA, USA). The HTDCHC was then placed into a vacuum chamber at -0.0847 mPa for 1 minute. The plaster was then allowed to cure for 24 hours and the plaster/catheters were removed from the HTDCHC and placed into a forced air oven at 70°C for 1 -2 days. The presence of the lateral holes in the wax-resin mold as shown in FIG. 3A at 304 allowed for reduced plaster drying time.

[0101] The specific conditions of each batch are shown in Table 2, below.

Table 2

Plaster Investing

After the plaster was dried in the forced air oven, excess wax was sanded from the mold with a belt sander, the sanded catheters were placed in a kiln and the wax was burned out leaving an empty cavity of the catheter within the plaster shells.

[0102] The desired catheter material (silicone, latex, urethane, or rubber) was prepared according to package instructions and mixed at 3200rpm for three minutes. The negative mold plaster catheters were then placed in the HTDCHC as shown in FIG. 3I with and without polyvinyl alcohol (PVA) coating and the catheter material was added until the HTDCHC was filled. The HTDCHC was then placed into a centrifuge at a relative centrifugal force (RCF) of 7 (200 rpm) for two minutes. The speed was increased to 300 rpm until the polymer material was fully invested. Some HTDCHCs were placed into a vacuum chamber at -0.0847MPa until bubbles were no longer present. Once the cast catheter dried, it was treated with plaster solvent and cleaned with a DK sonic DK sonic ultrasonic cleaner at full waves for 90 minutes (Shenzhen Dekang Cleaning Electronic Appliance Co., Ltd., Shenzhen, Guangdong, China).

[0103] Seventeen catheter variations, including the standard model, were produced with the variations shown in Table 3. All catheters are described relative to the tip to the tail of the catheter.

Table 3

Catheter Variations

The catheters were cut to 30mm in length, and labeled by name and sample number, with each type having a sample size of five (n=5).

[0104] Experiment 3: Strength and Hardness Testing. Catheters were made using Shore 00 50 durometer silicone, Shore 00 30 durometer silicone, Shore 00 10 durometer silicone, costume latex, polyurethane, and Latex using the procedure of Experiment 1 , . A uniaxial hydraulic press was used to pull the catheters apart until the sample breaks in two to determine total elongation (American Society for Testing and Materials ASTM d412-16 (2021 ) (ach material was tested 5 times as shown in Table 5.

Table 4

Elastomer Data

[0105] As shown in Table 4, the modified lost wax casting method described herein is compatible with materials of different physical properties. 5.

[0106] (V) Experiments Related to Manufacturing and Testing of Flow-Optimized Catheter. The parametric design of the proposed catheter is driven by comprehensive computational flow analysis and confocal analysis of over 300 explanted ventricular catheters. The catheters diminish astrocytic activation, downstream pro-inflammatory cytokine secretion, and ultimately shunt obstruction by distributing even flow through all catheter holes.

[0107] Experiment 1 : Static Cytotoxicity Assay. Static in vitro cytotoxicity assays are performed to evaluate the biocompatibility of the manufactured catheters. Control catheters and flow-optimized catheters are placed in 24 well-plates with human astrocytes. The assay is incubated for seven days in incubators and the cells are observed with bright-field microscopes at the end of the experiment. Logistic regression can be used to statistically analyze the results of the experiment.

[0108] Experiment 2: In-vitro Astrocyte Proliferation. The purpose of this experiment is to evaluate the efficacy of flow-optimized catheters at diminishing astrocytic activation and attachment compared to standard catheters. The high throughput bioreactors are used to expose flow-optimized and standard catheters to pulsatile artificial CSF flow for 14 days. After the exposure period, the samples are removed and fixed in paraformaldehyde. Immunofluorescence is employed to identify the cell nuclei. After fluorescent staining, confocal microscopy is used to obtain images of the exterior surface of the catheter. To compare adhesion across standard and flow-optimized catheters, attachment in the proximity of catheter holes is investigated. Cell density is measured using image analysis software.

[0109] Example 3: Stimulation of Artificial Hemorrhagic Hydrocephalus. Catheters LD1

(FIG. 12M), S (FIG. 12A), and LD2 (FIG. 12N) were selected because of their general increase in mean time elapsed as shown in Table 4 and subjected to a blood assay that simulates an artificial state of hemorrhagic hydrocephalus. Additionally, they were selected because they had the largest impact on resistance. Changing the lumen diameter had the biggest statistical significance across the evaluated architectural changes. The catheters were placed in PETG chambers designed to mimic the real-life scenario of blood-induced blockages to assess the practical impact of design variations on catheter performance in the face of obstructions as shown in FIGs 18A and 18B.

[0110] The results of the experiments showed a significant difference in relative resistance when lateral hole, lumen, and lumen obstruction diameter varied; all following a non-linear trend. Variations in row obstructions showed slight changes in resistance. However, different variations in the segmental lateral hole were not significant.

[0111] Experiment 2: Evaluation. This experiment shows the capability of the disclosed processes to accommodate designs that are non-standard and to show ranges of the catheter designs. The experiment quantifies impacts of architectural changes of the catheter. These changes were mostly "negative" such as obstructing the lumen or blocking a row of lateral holes. These "negative" changes to the catheter did not impact flowrate equally (i.e. blocking the lumen had more impact than blocking a row of lateral hole)s. "Positive" changes such as increasing the size of the lumen while keeping the outer diameter constant were also tested. This change was only accessible utilizing the lost wax manufacturing process.

[0112] Catheters were tested using the Ventricular Catheter Testing Device (VCTD), a gravity- driven, benchtop model that uses a fixed hydrostatic pressure range to quantitatively analyze resistance to fluid flow. The VCTD acquires pressure, flow rate, and time data; the time elapsed for a fixed pressure drop increases as resistance to fluid flow increases; hence, the time elapsed was referred to as “relative resistance” and used as a proxy measurement (Gopalakrishnan, P., Faryami, A., & Harris, C. A. (2023). A novel, benchtop model for quantitative analysis of resistance in ventricular catheters. PLoS ONE, 18(1 1 November), //doi. org/10.1371/journal. pone.029481 1 ). Each catheter was tested three times, with the results averaged. One control group of unused, unexpired catheters of a common commercial brand was also tested to provide a reference frame against the catheters specifically manufactured for this study.

[0113] Obstruction. As shown in FIGs. 13A and 13B, lateral row obstruction (RO) was seen in 3 variations: 1 RO (3 rows open), 2RO (2 rows open), and 3RO (1 row open). Complete obstruction (CO) catheters were also made (n=3) to depict cases where all rows were completely obstructed. Lateral Segment (Sg.) obstruction has 4 variations with each Sg, obstructed individually. Sg.1 , Sg.2, Sg.3, and Sg.4 are illustrated in Table 5. Additional views of these catheters are shown in FIGs. 12O-12Q.

Table 5

Time elapsed data and resistance calculations for all variants

[0114] A notable increase in resistance was observed when three rows (3RO) were blocked (see FIG. 15A). This is consistent with our previous study on increasing lateral row occlusions, however, this study builds on that by obstructing the holes through CPS rather than manual obstruction which has innate limitations (Gopalakrishnan, P., Faryami, A., & Harris, C. A. (2023). A novel, benchtop model for quantitative analysis of resistance in ventricular catheters. PLoS ONE, 18(11 November), //doi.org/10.1371/journal. pone.0294811 ). Complete occlusion (CO), achieved by blocking all four rows, resulted in unmeasurable flow through the VCTD, simulating a scenario of 100%-hole occlusion where flow ceases entirely. Therefore, it is logical to conclude that as a catheter gets close to complete obstruction the resistance will be at its highest (Ginsberg, H. J., Sum, A., Drake, J. M., & Cobbold, R. S. C. (2000). Ventriculoperitoneal Shunt Flow Dependency on the Number of Patent Holes in a Ventricular Catheter. Pediatric Neurosurgery, 33(1 ), 7-11. //doi.org/10.1159/000028979). A study from Lee et al. also found results that suggested a drastic increase in resistance when the catheter nears 100% occlusion (Lee, S., Vinzani, M., Romero, B., Chan, A. Y., Castaneyra-Ruiz, L., & Muhonen, M. (2022). Partial Obstruction of Ventricular Catheters Affects Performance in a New Catheter Obstruction Model of Hydrocephalus. Children, 9(10), 0-7. //doi.org/10.3390/children9101453).

[0115] From a design perspective, catheters with at least one unobstructed row maintain substantial flow. This finding suggests that partial occlusion of the holes does not significantly affect catheter flow resistance. Contrary to the common assumption that partially blocked catheters require immediate replacement, our data reveal that these catheters can still facilitate flow, indicating that partial occlusion doesn't equate to total blockage.

[0116] As shown in FIG. 15A, there is a significant difference in the meantime elapsed for the 3RO compared to all other RO variations and the standard (P<.0001 ). In three samples (n=3), full obstruction (CO) occurred, resulting in no recorded flow within 10 minutes. These fully obstructed samples were excluded from the statistical analysis. However, it is reasonable to assume that its time elapsed is significantly higher than the standard and all RO variations, consistent with findings from prior studies (Gopalakrishnan, P., Faryami, A., & Harris, C. A. (2023). A novel, benchtop model for quantitative analysis of resistance in ventricular catheters. PLoS ONE, 18(11 November), //doi.org/10.1371/journal. pone.0294811 ). Moreover, the time elapsed data for all variations with lateral hole segment obstructions (Sg.1 , Sg.2, Sg.3, Sg.4) and the standard did not exhibit significant differences from each other as shown in FIG. 15B.

[0117] Impact of Lateral Hole and Lumen Diameter on Resistance to Flow. Among the manipulated parameters, those that had the greatest impact on relative resistance were lumen diameter and lumen obstruction (Fig. 16C and 17A). The lateral hole diameter group has 3 variations from the standard catheter, these include HD1 (,3482mm), S (.5475mm), HD2 (0.7458mm), and HD3 (1.0421 mm). The inner lumen diameter group has 2 variations from the standard 1.36mm, where LD1 is 0.86mm, and LD2 is 1.86mm. Architectural dimensions of diameter for both the lateral holes and the inner lumen were manipulated to discern how much the resistance of a catheter is affected by these variables.

[0118] Lateral hole diameter also showed marked decreases in relative resistance as the diameter was increased. (Fig. 16A) Most notably, the results of all these experiments show nonlinear changes in relative resistance, even when parameters are changed linearly (e.g., lumen diameter). This nonlinear trend matches the nonlinear trend reported in the literature, which lends further support to the hypothesis that catheters must approach complete obstruction before CSF outflow is significantly reduced. Indeed, analysis of the lumen obstruction data presented in this study shows that significant increases in relative resistance only occurs once the catheter lumen is more than 75% obstructed (Fig 17A). Even a catheter whose lumen is more than half blocked is capable of sufficient fluid outflow.

[0119] Changes in lateral hole diameter (FIG. 16A) revealed significant discrepancies in the time- elapsed data across various hole diameter variations (HD1 , S, HD2, and HD3) (P<.05). Notably, as the hole diameter increased, the time elapsed exhibited an exponential decrease. Similarly, the experiments focusing on altering the inner lumen diameter (as shown in FIG. 16B) displayed significant differences in time-elapsed data among different inner lumen diameter variations (LD1 , S, and LD2) (P<.05). It was observed that with an increase in the inner lumen diameter, the time elapsed decreased exponentially.

[00120] (VI) Kits. Also provided are kits useful for treating hydrocephalus patients. An example of the kit includes one or more: a wearable device, a shunt valve that can be sterile and vacuum sealed, and a lithium battery pack which is sterile, and vacuum sealed.

[00121] More generally, kits can include instructions, for example, written instructions, on how to use the material(s) therein. Material(s) can be, for example, any substance, composition, polynucleotide, solution, etc., herein or in any patent, patent application publication, reference, or article that is incorporated by reference.

[00122] A kit can include a device as described herein, and optionally additional components such as buffers, reagents, and instructions for carrying out the methods described herein. The choice of buffers and reagents will depend on the particular application, e.g., the setting of the assay (point-of-care, research, clinical), analyte(s) to be assayed, the detection moiety used, the detection system used, etc.

[00123] The kit can also include informational material, which can be descriptive, instructional, marketing, or other material that relates to the methods described herein and/or the use of the devices for the methods described herein. In embodiments, the informational material can include information about the production of the device, physical properties of the device, date of expiration, batch or production site information, and so forth.

[00124] (VII) References.

[00125] 1. Drake JM, Kestle JRW, Tuli S. CSF shunts 50 years on - Past, present and future. Child’s Nerv Syst. 2000;16:800-4.

[00126] 2. Browd SR, Ragel BT, Gottfried ON, Kestle JRW. Failure of cerebrospinal fluid shunts: Part I: Obstruction and mechanical failure. Pediatr Neurol. 2006;34:83-92.

[00127] 3. Kestle J, Drake J, Milner R, Sainte-Rose C, Cinalli G, Boop F, et al. Long-term followup data from the shunt design trial. Pediatr Neurosurg. 2000;33:230-6. [00128] 4. Pujari S, Kharkar S, Metellus P, Shuck J, Williams MA, Rigamonti D. Normal pressure hydrocephalus: Long-term outcome after shunt surgery. J Neurol Neurosurg Psychiatry. 2008;79:1282-6.

[00129] 5. Harris C, Pearson K, Hadley K, Zhu S, Browd S, Hanak BW, et al. Fabrication of three- dimensional hydrogel scaffolds for modeling shunt failure by tissue obstruction in hydrocephalus. Fluids Barriers CNS. BioMed Central; 2015;12:1-15.

[00130] 6. And B editing: precision chemistry on the genome, Cells transcriptome of living.

' 'WTIMX HHS Public Access. Physiol Behav. 2016;176:139-48.

[00131] 7. Hariharan P, Sondheimer J, Petroj A, Gluski J, Jea A, Whitehead WE, et al. A multicenter retrospective study of heterogeneous tissue aggregates obstructing ventricular catheters explanted from patients with hydrocephalus. Fluids Barriers CNS [Internet]. BioMed Central; 2021 ;18:1-13. Available from: //doi.org/10.1186/s12987-021 -00262-3

[0132] 8. Khodadadei F, Liu AP, Harris CA. A high-resolution real-time quantification of astrocyte cytokine secretion under shear stress for investigating hydrocephalus shunt failure. Commun Biol [Internet]. Springer US; 2021 ;4:1-11. Available from: //dx.doi.org/10.1038/s42003-021 -01888-7 [0133] 9. Gluski J, Zajciw P, Hariharan P, Morgan A, Morales DM, Jea A, et al. Characterization of a multicenter pediatric-hydrocephalus shunt biobank. Fluids Barriers CNS [Internet]. BioMed Central; 2020 ; 17:1-11 . Available from: //doi.org/10.1186/s12987-020-00211 -6

[0134] 10. Harris CA, Resau JH, Hudson EA, West RA, Moon C, Black AD, et al. Reduction of protein adsorption and macrophage and astrocyte adhesion on ventricular catheters by polyethylene glycol and N-acetyl- L -cysteine. J Biomed Mater Res - Part A. 2011 ;98 A:425-33.

[0135] 11. Harris CA, Resau JH, Hudson EA, West RA, Moon C, McAllister JP. Mechanical contributions to astrocyte adhesion using a novel in vitro model of catheter obstruction. Exp Neurol [Internet]. Elsevier Inc.; 2010;222:204-10. Available from: //dx.doi.org/10.1016/j.expneurol.2009.12.027

[0136] 12. Horbatiuk J, Alazzawi L, Harris CA. The flow limiting operator: A new approach to environmental control in flow bioreactors. RSC Adv. 2020;10:31056-64.

[0137] 13. Harris CA, McAllister JP. Does drainage hole size influence adhesion on ventricular catheters? Child’s Nerv Syst. 201 1 ;27: 1221-32.

[0138] 14. Faryami A, Menkara A, Viar D, Harris CA. Testing and validation of reciprocating positive displacement pump for benchtop pulsating flow model of cerebrospinal fluid production and other physiologic systems. PLoS One [Internet]. 2022;17:e0262372. Available from: //dx.doi.org/10.1371 /journal. pone.0262372 [0139] 15. Cummins DD, Morshed RA, Goldschmidt E, Kuo YH. Comparison of Shunt Outcomes for Nonbacterial Infection Hydrocephalus with Common Hydrocephalus Etiologies: A Retrospective Case-Control Study. World Neurosurg [Internet]. The Author(s); 2022;1— 8. Available from: //doi.org/10.1016/j.wneu.2022.05.008

[0140] 16. Nigim F, Critchlow JF, Schneider BE, Chen C, Kasper EM. Shunting for hydrocephalus: Analysis of techniques and failure patterns. J Surg Res [Internet]. Elsevier Inc; 2014;191 :140-7. Available from: //dx.doi.org/10.1016/j.jss.2O14.03.075

[0141] 17. Holwerda JC, van Lindert EJ, Buis DR, Hoving EW. Surgical intervention for hydrocephalus in infancy; etiology, age and treatment data in a Dutch cohort. Child’s Nerv Syst. Child’s Nervous System; 2020;36:577-82.

[0142] 18. Galarza M, Gimenez A, Amigo JM, Schuhmann M, Gazzeri R, Thomale U, et al. Next generation of ventricular catheters for hydrocephalus based on parametric designs. Child’s Nerv Syst. 2018;34:267-76.

[0143] 19. Galarza M, Gimenez A, Pellicer O, Valero J, Amigo JM. Parametric study of ventricular catheters for hydrocephalus. Acta Neurochir (Wien). 2016;158:109-16.

[0144] 20. Gimenez A, Galarza M, Pellicer O, Valero J, Amigo JM. Influence of the hole geometry on the flow distribution in ventricular catheters for hydrocephalus. Biomed Eng Online. BioMed Central; 2016;15:5-19.

[0145] 21 . Khodadadei, Fatemeh CH. How Is Hydrocephalus Treatment Dependent on Astrocyte Phenotype Expression? 2020 AIChE Annual Meeting; Available from: //aiche.confex.com/aiche/2020/meetingapp.cgi/Paper/605618

[0146] 22. Achyuta AKH, Stephens KD, Lewis HGP, Murthy SK. Mitigation of reactive human cell adhesion on poly(dimethylsiloxane) by immobilized trypsin. Langmuir. 2010;26:4160-7.

[0147] 23. Kovach KM, Capadona JR, Gupta A Sen, Potkay JA. The effects of PEG-based surface modification of PDMS microchannels on long-term hemocompatibility. J Biomed Mater Res - Part A. 2014; 102:4195-205.

[0148] 24. Zhou J, Khodakov DA, Ellis A V., Voelcker NH. Surface modification for PDMS-based microfluidic devices. Electrophoresis. 2012;33:89-104.

[0149] 25. Lee, S., Vinzani, M., Romero, B., Chan, A. Y., Castaheyra-Ruiz, L., & Muhonen, M. (2022). Partial Obstruction of Ventricular Catheters Affects Performance in a New Catheter Obstruction Model of Hydrocephalus. Children, 9(10), 0-7. //doi.org/10.3390/children9101453 [0150] 26. Isaacs, A. M., Riva-Cambrin, J., Yavin, D., Hockley, A., Pringsheim, T. M., Jette, N., Lethebe, B. C., Lowerison, M., Dronyk, J., & Hamilton, M. G. (2018). Age-specific global epidemiology of hydrocephalus: Systematic review, metanalysis and global birth surveillance. In PLoS ONE (Vol. 13, Issue 10). Public Library of Science, //doi.org/10.1371/journal. pone.0204926 [0151] 27. Rekate, H. L. (2009). A Contemporary Definition and Classification of Hydrocephalus. In Seminars in Pediatric Neurology (Vol. 16, Issue 1 , pp. 9-15). //doi.org/10.1016/j.spen.2009.01 .002

[0152] 28. Brinker, T., Stopa, E., Morrison, J., & Klinge, P. (2014). A new look at cerebrospinal fluid circulation. Fluids and Barriers of the CNS, 11 (1), 1-16. //doi.org/10.1186/2045-8118-11 -10 [0153] 29. Greitz, D., Wirestam, R., Franck, A., Nordell, B., Thomsen, C., & Stahlberg, F. (1992). Pulsatile brain movement and associated hydrodynamics studied by magnetic resonance phase imaging. The Monro-Kellie doctrine revisited. Neuroradiology, 34(5), 370-380. //doi.org/10.1007/BF00596493

[0154] 30. Milhorat, T. H. (1975). The third circulation revisited. Journal of Neurosurgery, 42(6), 628-645. //doi.org/10.3171 /jns.1975.42.6.0628

[0155] 31. Penn, R. D., Basati, S., Sweetman, B., Guo, X., & Linninger, A. (2011 ). Ventricle wall movements and cerebrospinal fluid flow in hydrocephalus: Clinical article. Journal of Neurosurgery, 1 15(1 ), 159-164. //doi.org/10.3171/2010.12. JNS10926

[0156] 32. Stone, J. J., Walker, C. T., Jacobson, M., Phillips, V., & Silberstein, H. J. (2013). Revision rate of pediatric ventriculoperitoneal shunts after 15 years: Clinical article. Journal of Neurosurgery: Pediatrics, 11 (1 ), 15-19. //doi.org/10.3171/2012.9. PEDS1298

[0157] 33. Kulkarni, A. V, Riva-Cambrin, J., Butler, J., Browd, S. R., Drake, J. M., Holubkov, R., Kestle, J. R. W., Limbrick, D. D., Simon, T. D., Tamber, M. S., Wellons, J. C., & Whitehead, W. E. (2013). Outcomes of CSF shunting in children: Comparison of Hydrocephalus Clinical Research Network cohort with historical controls. Journal of Neurosurgery: Pediatrics, 12(4), 334- 338. //doi.org/10.3171/2013.7.PEDS12637

[0158] 34. Hanak, B. W., Bonow, R. H., Harris, C. A., & Browd, S. R. (2017). Cerebrospinal Fluid Shunting Complications in Children. In Pediatric Neurosurgery (Vol. 52, Issue 6, pp. 381—400). S. Karger AG. //doi.org/10.1159/000452840

[0159] 35. Borgbjerg, B. M., Gjerris, F., Albeck, M. J., Hauerberg, J., & Borgesen, S. E. (1995). Frequency and causes of shunt revisions in different cerebrospinal fluid shunt types. Acta Neurochirurgica, 136(3), 189-194. //doi.org/10.1007/BF01410625

[0160] 36. Malm, J., Lundkvist, B., Eklund, A., Koskinen, L. O. D., & Kristensen, B. (2004). CSF outflow resistance as predictor of shunt function. A long-term study. Acta Neurologica Scandinavica, 1 10(3), 154-160. //doi.org/10.111 1/j.1600-0404.2004.00302.x [0161] 37. Cheatle, J. T„ Bowder, A. N„ Agrawal, S. K„ Sather, M. D„ & Hellbusch, L. C. (2012). Flow characteristics of cerebrospinal fluid shunt tubing: Laboratory investigation. Journal of Neurosurgery: Pediatrics, 9(2), 191-197. //doi.org/10.3171/2011 .11.PEDS11255

[0162] 38. Gopalakrishnan, P., Faryami, A., & Harris, C. A. (2023). A novel, benchtop model for quantitative analysis of resistance in ventricular catheters. PLoS ONE, 18(11 November). //doi.org/10.1371/journaLpone.0294811

[0163] 39. Hanak, B. W., Ross, E. F., Harris, C. A., Browd, S. R., & Shain, W. (2016). Toward a better understanding of the cellular basis for cerebrospinal fluid shunt obstruction: Report on the construction of a bank of explanted hydrocephalus devices. Journal of Neurosurgery: Pediatrics, 18(2), 213-223. //doi.org/10.3171/2016.2.PEDS15531

[0164] 40. Bigner, S. H., Elmore, P. D., Dee, A. L., & Johnston, W. W. (1985). The cytopathology of reactions to ventricular shunts. Acta Cytologica, 29(3), 391-396.

[0165] 41. Del Bigio, M. R., & Bruni, J. E. (1986). Reaction of rabbit lateral periventricular tissue to shunt tubing implants. Journal of Neurosurgery, 64(6), 932-940.

//doi.org/10.3171 /jns.1986.64.6.0932

[0166] 42. Schoener, W. F., Reparon, C., Verheggen, R., & Markakis, E. (1991 ). Evaluation of Shunt Failures by Compliance Analysis and Inspection of Shunt Valves and Shunt Materials, Using Microscopic or Scanning Electron Microscopic Techniques. In S. Matsumoto & N. Tamaki (Eds.), Hydrocephalus (pp. 452-472). Springer Japan.

[0167] 43. Sekhar, L. N., Moossv, J., & Guthkelch, A. N. (1982). Malfunctioning ventriculoperitoneal shunts Clinical and pathological features. In J. Neurosurg (Vol. 56).

[0168] 44. Thomale, U. W., Hosch, H., Koch, A., Schulz, M., Stoltenburg, G., Haberl, E. J., & Sprung, C. (2010). Perforation holes in ventricular catheters-is less more? Child’s Nervous System, 26(6), 781-789. //doi.org/10.1007/s00381 -009-1055-8

[0169] 45. Hanak, B. W., Hsieh, C. Y., Donaldson, W., Browd, S. R., Lau, K. K. S., & Shain, W. (2018). Reduced cell attachment to poly(2-hydroxyethyl methacrylate)-coated ventricular catheters in vitro. Journal of Biomedical Materials Research - Part B Applied Biomaterials, 106(3), 1268-1279. //doi.org/10.1002/jbm.b.33915

[0170] 46. Harris, C. A., & McAllister, J. P. (201 1 ). Does drainage hole size influence adhesion on ventricular catheters? Child’s Nervous System, 27(8), 1221-1232. //doi.org/10.1007/s00381 - 011 -1430-0

[0171] 47. Ginsberg, H. J., Sum, A., Drake, J. M., & Cobbold, R. S. C. (2000). Ventriculoperitoneal Shunt Flow Dependency on the Number of Patent Holes in a Ventricular Catheter. Pediatric Neurosurgery, 33(1 ), 7-1 1 . //doi.org/10.1 159/000028979 [0172] 48. Ros, B., Iglesias, S., Linares, J., Cerro, L., Casado, J., & Arraez, M. A. (2021 ). Shunt overdrainage: Reappraisal of the syndrome and proposal for an integrative model. In Journal of Clinical Medicine (Vol. 10, Issue 16). MDPI. ://doi.org/10.3390/jcm10163620

[0173] 49. Kraemer, M. R., Koueik, J., Rebsamen, S., Hsu, D. A., Salamat, M. S., Luo, S., Saleh, S., Bragg, T. M., & Iskandar, B. J. (2018). Overdrainage-related ependymal bands: A postulated cause of proximal shunt obstruction. Journal of Neurosurgery: Pediatrics, 22(5), 567-577. //doi.org/10.3171/2018.5.PEDS18111

[0174] 50. Menkara, A., Faryami, A., Viar, D., & Harris, C. (2022). Applications of a novel reciprocating positive displacement pump in the simulation of pulsatile arterial blood flow. PLoS ONE, 17(12 December). //doi.org/10.1371/journal.pone.0270780

[0175] 51. Lintula, L. (2008). How shunts are made. It's about life: 10th National Conference on Hydrocephalus, Park City, Utah.

[0176] 52. Medtronic Inc. (2006) Rivulet. United States Patent Serial No. 78887628. (n.d.).

[0177] 53. Suresh, S., & Black, R. A. (2015). Electrospun polyurethane as an alternative ventricular catheter and in vitro model of shunt obstruction. Journal of Biomaterials Applications, 29(7), 1028-1038. //doi.org/10.1 177/0885328214551587

[0178] 54. Harinarayana, V., & Shin, Y. C. (2021 ). Two-photon lithography for three-dimensional fabrication in micro/nanoscale regime: A comprehensive review. Optics & Laser Technology, 142, 107180. //doi.org/10.1016/j.optlastec.2021 .107180

[0179] 55. Bunea, A. -I., del Castillo Iniesta, N., Droumpali, A., Wetzel, A. E., Engay, E., & Taboryski, R. (2021 ). Micro 3D Printing by Two-Photon Polymerization: Configurations and Parameters for the Nanoscribe System. Micro, 1 (2), 164-180. //doi.org/10.3390/micro1020013.

[0180] (VIII) Example Clauses.

[0181] 1 . A method, including:

[0182] generating a design file for a catheter, wherein the catheter is within a crucible and wherein there is a first void between the crucible and catheter and a second void within the catheter;

[0183] combining plaster powder and water at a ratio in a vacuum mixer to form plaster;

[0184] pouring the plaster into the voids;

[0185] curing the plaster;

[0186] burning out a print to create a mold, the burning out including increasing a temperature in a step wise manner to a temperature of 1350^eF;

[0187] filling the void with a polymer; and

[0188] removing the plaster. [0189] 2. The method of embodiment 1 , wherein the print includes at least one of wax, photopolymer, or resin.

[0190] 3. The method of embodiment 2, wherein the print includes a blend of wax and resin.

[0191] 4. The method of embodiment 3, wherein the blend includes 35% of wax and 65% of resin.

[0192] 5. The method of any of embodiments 1-4, wherein the plaster powder is Dental IV plaster.

[0193] 6. The method of embodiment 5, wherein the plaster powder further includes aluminum oxide or fumigated silica.

[0194] 7. The method of any of embodiments 1 -6, wherein a height of a print layer is 25 pm- 50 pm.

[0195] 8. The method of embodiment 7, wherein the print layer height is 25 pm.

[0196] 9. The method of any of embodiments 1 -8, wherein the print is oriented 10^e from normal.

[0197] 10. The method of any of embodiments 1 -9, wherein the ratio of plaster powder to water is 74%:26%.

[0198] 1 1. The method of embodiment 10, wherein the plaster powder and water are vacuum mixed for 60 seconds at -0.09 MPa.

[0199] 12. The method of any of embodiments 1-11 , wherein after the plaster is poured into the void in the print, the plaster/print combination is centrifuged.

[0200] 13. The method of any of embodiments 1-12, wherein after the void is filled with the polymer, the plaster/polymer combination is centrifuged for 5 minutes at 800 rpm.

[0201] 14. The method of any of embodiments 1 -13, wherein the polymer includes at least one of polydimethylsiloxane (PDMS) elastomer, polytetrafluoroethylene (PTFE), resin, silicone, rubber, or latex.

[0202] 15. The method of any of embodiments 1 -14, wherein the plaster is removed with a solvent.

[0203] 16. The method of embodiment 15, wherein the solvent is DP2400.

[0204]

[0205] 17. The method of any of embodiments 1-16, wherein the consumable crucible is porous.

[0206] 18. The method of any of embodiments 1 -7, wherein the consumable crucible includes lateral holes. [0207] 19. The method of any of embodiments 1-18, wherein the consumable crucible includes a false bottom.

[0208] 20. The method of any of embodiments 1-19, wherein the catheter includes holes configured to allow fluid flow therethrough.

[0209] 21. The method of embodiment 20, wherein the fluid includes cerebrospinal fluid (CSF).

[0210] 22. The method of any of embodiments 1 -21 , wherein the mold has a first inner surface and a second inner surface and a void between the first inner surface and the second inner surface.

[0211 ] 23. A catheter prepared according to any of embodiments 1 -22.

[0212] While the example clauses described above are described with respect to one particular implementation, it should be understood that, in the context of this document, the content of the example clauses can also be implemented via a method, device, system, a computer-readable medium, and/or another implementation.

[0213] The processes are illustrated as logical flowgraphs, which represent sequences of operations that can be implemented in hardware, software, or a combination thereof. In the context of software, the blocks represent computer executable instructions stored on one or more computer-readable storage media that, when executed by processor(s), perform the recited operations. Generally, computer-executable instructions include routines, programs, objects, components, data structures, and the like that perform particular functions or implement particular abstract data types. The order in which the operations are described is not intended to be construed as a limitation, and any number of the described operations can be combined in any order and/or in parallel to implement the processes. In some embodiments, one or more operations of the process can be omitted entirely. Moreover, the processes can be combined in whole or in part with each other or with other processes.

[0214] (IX) Closing Paragraphs. Specific descriptions provided herein and in the herewith filed documents are included to demonstrate particular embodiments of the disclosure. Those of ordinary skill in the art should recognize in light of the present disclosure that many changes can be made to the specific embodiments disclosed herein and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[0215] As will be understood by one of ordinary skill in the art, each embodiment disclosed herein can comprise, consist essentially of or consist of its particular stated element, step, ingredient or component. Thus, the terms “include” or “including” should be interpreted to recite: “comprise, consist of, or consist essentially of.” The transition term “comprise” or “comprises” means has, but is not limited to, and allows for the inclusion of unspecified elements, steps, ingredients, or components, even in major amounts. The transitional phrase “consisting of” excludes any element, step, ingredient, or component not specified. The transition phrase “consisting essentially of” limits the scope of the embodiment to the specified elements, steps, ingredients or components and to those that do not materially affect the embodiment.

[0216] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. When further clarity is required, the term “about” has the meaning reasonably ascribed to it by a person skilled in the art when used in conjunction with a stated numerical value or range, i.e. denoting somewhat more or somewhat less than the stated value or range, to within a range of ±20% of the stated value; ±19% of the stated value; ±18% of the stated value; ±17% of the stated value; ±16% of the stated value; ±15% of the stated value; ±14% of the stated value; ±13% of the stated value; ±12% of the stated value; ±11 % of the stated value; ±10% of the stated value; ±9% of the stated value; ±8% of the stated value; ±7% of the stated value; ±6% of the stated value; ±5% of the stated value; ±4% of the stated value; ±3% of the stated value; ±2% of the stated value; or ±1% of the stated value.

[0217] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0218] The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0219] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0220] Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0221] Furthermore, numerous references have been made to patents, printed publications, journal articles, other written text, and web site content throughout this specification (referenced materials herein). Each of the referenced materials are individually incorporated herein by reference in their entirety for their referenced teaching(s), as of the filing date of the first application in the priority chain in which the specific reference was included. For instance, with regard to chemical compounds, nucleic acid, and amino acids sequences referenced herein that are available in a public database, the information in the database entry is incorporated herein by reference as of the date of an application in the priority chain in which the database identifier for that compound or sequence was first included in the text.

[0222] It is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

[0223] The particulars shown herein are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of various embodiments of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for the fundamental understanding of the invention, the description taken with the drawings and/or examples making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

[0224] Definitions and explanations used in the present disclosure are meant and intended to be controlling in any future construction unless clearly and unambiguously modified in the example(s) or when application of the meaning renders any construction meaningless or essentially meaningless. In cases where the construction of the term would render it meaningless or essentially meaningless, the definition should be taken from Webster's Dictionary, 3rd Edition, or a dictionary known to those of ordinary skill in the art.

Claims

LISTING OF CLAIMS What is claimed is:

1 . A method, comprising: generating a design file for a catheter, wherein the catheter is within a consumable crucible and wherein there is a first void between the consumable crucible and catheter and a second void within the catheter; combining plaster powder and water at a ratio in a vacuum mixer to form plaster; pouring the plaster into the voids; curing the plaster; burning out a print to create a mold, the burning out comprising increasing a temperature in a step wise manner to a temperature of 1350^eF; filling the void with a polymer; and removing the plaster.

2. The method of claim 1 , wherein the print comprises at least one of wax, photopolymer, or resin.

3. The method of claim 2, wherein the print comprises a blend of wax and resin.

4. The method of claim 3, wherein the blend comprises 35% of wax and 65% of resin.

5. The method of claim 1 , wherein the plaster powder is Dental IV plaster.

6. The method of claim 5, wherein the plaster powder further comprises aluminum oxide or fumigated silica.

7. The method of claim 1 , wherein a height of a print layer is 25 pm-50 pm.

8. The method of claim 7, wherein the print layer height is 25 pm.

9. The method of claim 1 , wherein the print is oriented 10^e from normal.

10. The method of claim 1 , wherein the ratio of plaster powder to water is 74%:26%.

11 . The method of claim 10, wherein the plaster powder and water are vacuum mixed for 60 seconds at -0.09 MPa.

12. The method of claim 1 , wherein after the plaster is poured into the void in the print, the plaster/print combination is centrifuged.

13. The method of claim 1 , wherein after the void is filled with the polymer, the plaster/polymer combination is centrifuged for 5 minutes at 800 rpm.

14. The method of claim 1 , wherein the polymer comprises at least one of polydimethylsiloxane (PDMS) elastomer, polytetrafluoroethylene (PTFE), resin, silicone, rubber, or latex.

15. The method of claim 1 , wherein the plaster is removed with a solvent.

16. The method of claim 15, wherein the solvent is DP2400.

17. The method of claim 1 , wherein the consumable crucible is porous.

18. The method of claim 1 , wherein the consumable crucible comprises lateral holes.

19. The method of claim 1 , wherein the consumable crucible comprises a false bottom.

20. The method of claim 1 , wherein the catheter comprises holes configured to allow fluid flow therethrough.

21 . The method of claim 20, wherein the fluid comprises cerebrospinal fluid (CSF).

22. The method of claim 1 , wherein the mold has a first inner surface and a second inner surface and a void between the first inner surface and the second inner surface.

23. A catheter prepared according to any of claims 1 -22.