High-strength biomaterials

Abstract

A method for producing high strength hydrophilic nanoporous biomaterials for medical devices is provided. [Solution] A method for producing a hydrophilic material includes heating a mixture comprising at least one water-soluble polymer and a solvent to a temperature above the melting point of the polymer, forming the mixture, and passing the formed mixture through a solvent removal environment.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION This application relates to porous biomaterials, including high strength hydrophilic nanoporous biomaterials for medical devices. Summary of the Invention

[0002] Disclosed herein are biomaterials useful for manufacturing medical devices. Materials and methods are provided herein for the production of durable, smooth, biocompatible biomaterials for various medical device applications. New processing techniques have been used to create biomaterials with superior properties, such as strength and hemocompatibility. Included herein are methods for extruding hydrophilic polymers to create high-strength, hemocompatible, nanoporous biomaterials or other materials. These methods can be performed without the use of chemical crosslinkers or radiation crosslinking.

[0003] One embodiment is a method for producing a hydrophilic material, comprising heating a mixture comprising at least one water-soluble polymer and a solvent to a temperature above the melting point of the polymer, forming a mixture, and passing the mixture through a solvent-removing environment. Extrusion is used to form the mixture, and the mixture is formed into a continuous porous solid as it passes through a die. Nanoporous solids having a Young's modulus of at least 5 MPa at the equilibrium water content (EWC) of the porous solid can be produced. Extrusion can be used to form high-aspect-ratio, high-strength materials, including tubing useful as catheters.

[0004] One embodiment is a polymeric material comprising a hydrophilic porous solid, the porous solid having a solids content of at least 33% w / w and a Young's modulus of at least 5 MPa at equilibrium water content (EWC). The material may be formed with a high aspect ratio, e.g., 10:1 or greater, including materials formed as catheters. [Brief explanation of the drawings]

[0005] [Figure 1] FIG. 1 is a schematic diagram of an extrusion apparatus for forming a continuous form with a cross-sectional side view of a bath. [Figure 2] FIG. 2 is an enlarged view of a portion of the apparatus of FIG. 1, showing the die head in perspective view from outside the bath. [Figure 3] FIG. 3 is an enlarged view of a portion of the apparatus of FIG. 1, showing the die head mounted on the bath. [Figure 4] FIG. 4 is a longitudinal cross-sectional view of a portion of a continuous porous solid formed in the apparatus of FIG. [Figure 5] FIG. 5 is a plot showing the stress-strain curve of a polymeric material. [Figure 6] FIG. 6 is a plot of tensile test data for a porous solid produced with the apparatus of FIG. [Figure 7] FIG. 7 is a scanning electron microscope image (SEM) of the surface of the porous solid. [Figure 8] FIG. 8 is an SEM of a cross section of the porous solid of FIG. [Figure 9] FIG. 9 is a plot of data for dehydration of porous solid catheters, with the y-axis being weight and the x-axis being time in minutes. [Figure 10] FIG. 10 is a plot of tensile test data for porous solids prepared according to Example 4, with the higher molecular weight polymer (PVA67-99) providing a higher modulus and tensile strength than the lower molecular weight polymer (PVA28-99). [Figure 11]FIG. 11 is a plot of tensile test data for porous solids produced according to Example 4, showing that the highest polymer concentration (26%) provides the material with the greatest modulus and tensile strength relative to lower polymer concentrations (22% or 18%). [Figure 12A] FIG. 12A is a photograph of a control (Bard POWERPICC) porous solid incorporating a radiopaque agent. [Figure 12B] Figure 12B is a photograph of an unannealed porous solid incorporating 5.7 wt% bismuth subcarbonate radiopaque agent. [Figure 12C] Figure 12C is a photograph of the unannealed porous solid incorporating 12.1 wt% bismuth carbonate radiopaque agent. [Figure 12D] Figure 12D is a photograph of the annealed porous solid incorporating 12.1 wt% bismuth subcarbonate radiopaque agent. [Figure 12E] Figure 12E is a photograph of an annealed porous solid incorporating 5.7 wt% bismuth subcarbonate radiopaque agent. [Figure 12F] Figure 12F is a photograph of a porous solid incorporating 4.2 wt% bismuth subcarbonate radiopaque agent. [Figure 13] FIG. 13 is a photograph of the first set of test samples described in Example 7. [Figure 14] FIG. 14 is a photograph of the second set of test samples described in Example 7. [Figure 15A] FIG. 15A is a scanning electron micrograph (SEM) of a widthwise cross section of the extruded porous solid described in Example 8. [Figure 15B] FIG. 15B is a scanning electron micrograph (SEM) of a longitudinal cross section of the extruded porous solid described in Example 8. [Figure 16]16A-16D are SEMs of the hydrophilic nanoporous material prepared as described in Example 9, provided at various magnifications indicated by the scale bar. [Figure 17A] FIG. 17A is a plot of tensile test data for samples produced as described in Example 10. [Figure 17B] FIG. 17B is a plot of tensile test data for samples produced as described in Example 10. [Figure 18A] FIG. 18A is a plot of tensile data for various blends of the polymer described in Example 11, with the data shown in N / mm. [Figure 18B] FIG. 18B is a plot of tensile data for various blends of the polymer described in Example 11, with the data shown in N / mm. [Figure 19] FIG. 19 is a plot of tensile data for various blends of the polymer described in Example 12, with the data shown in N / mm. [Figure 20A] FIG. 20A is a photograph of the PEG / PVA copolymer extrudate described in Example 12 showing the surface with a PEG molecular weight of 8k. [Figure 20B] FIG. 20B is a photograph of the PEG / PVA copolymer extrudate described in Example 12 showing the surface with a PEG molecular weight of 20k. [Figure 20C] FIG. 20C is a photograph of the PEG / PVA copolymer extrudate described in Example 12 showing the surface with a PEG molecular weight of 35K. [Figure 21A] FIG. 21A provides the results of the blood contact test described in Example 15 as a photographic plot of relative thrombus accumulation. [Figure 21B] FIG. 21B provides the results of the blood contact test described in Example 15 as a photograph of the test sample. DETAILED DESCRIPTION OF THE INVENTION

[0006] Materials, methods, and uses are described herein for biomaterials comprising medically acceptable porous solids. These materials can be fabricated as tough, high-strength materials with smooth, biocompatible surfaces. Nanoporous and microporous solids with particularly high Young's modulus and tensile strength are described herein. Nanoporous materials are solids containing interconnected pores (or pores) up to 100 nm in diameter. Methods for fabricating hydrogels are also described. Hydrophilic polymers can be used to fabricate these various porous solids, resulting in hydrophilic solids. The water content of nanoporous or microporous solids can be as high as 50% w / w in EWC. The water content of hydrogels can, in principle, be as high as 90% w / w. Porous solid materials can be used to fabricate various devices, including medical catheters and implants, with significantly reduced adsorption and / or adhesion of biological components to the surface.

[0007] The process for producing the material can include extrusion to create devices with high aspect ratios. One embodiment of a method for producing the material includes heating a mixture comprising at least one water-soluble polymer and a solvent to a temperature above the melting point of the polymer solution, forming the mixture in a solvent-removing environment to produce a crosslinked matrix, and continuing to remove the solvent until the crosslinked matrix becomes a microporous or nanoporous solid material. Crosslinking can occur while the mixture is cooling and / or in the solvent-removing environment.

[0008] (Extrusion of polymeric materials) Various techniques are known for producing solid plastic materials. These traditionally involve extruding a polymeric material through an opening under conditions that shape it into a solid plastic as it passes through the opening. Typically, there is a heating phase to soften or melt the polymer, a shaping / forming phase in which the polymer is in a flowable form and under some kind of constraint, and a cooling phase in which the shaped / formed polymer is cooled to a temperature at which it retains its shape. Plastics may undergo some changes after passing through the opening, such as shrinkage, solvent removal, or crosslinking, but their shape is fixed upon solidification. Thermoplastics can be remelted. Some thermosetting resins form strong inter- and / or intra-chain bonds that are non-covalent crosslinks, referred to as physical crosslinks to distinguish them from covalent bonds. Thermosetting resins are formed irreversibly by covalent crosslinks. Examples of forming processes are thermoforming, molding processes, and extrusion processes. The extrusion process typically involves forcing a polymeric material through a shaped die under pressure. Usually, polymer pellets are fed into a hopper into a screw extruder, which compresses and melts the polymer as it passes through the die. After passing through the opening in the die, the polymer is rapidly cooled and becomes a solid shape. Extrusion can also include a drawing process. Many complex shapes can be formed in the extrusion process. Many shapes include objects with one or more lumens, coatings, layered coatings, filaments, hollow contoured objects, objects with round, square, or complex cross sections, and copolymeric extrusions that combine multiple polymers in the extruder or die.The term "die" is used broadly herein to encompass the opening through which a polymer passes to form a solid during the extrusion process, and includes a mandrel, a die combination, a die containing one or more of port-hole dies, a die with multiple openings that cooperate to produce an extruded product, a die that cooperates with a core, a core tubing, a core wire, a die that cooperates with air or gas acting as a core, or a slit die. Cores are useful for providing a lumen for a continuously extruded product and may be temporary for devices with hollow lumens or permanent in the case of coated devices (e.g., coated wire). Almost any shape can be produced with a die, as long as the shape produced has a continuous profile. The term "continuous" is a technical term referring to the theoretical production of an unlimited length of material, although semi-continuous, intermittent, or other processes may be used.

[0009] The extrusion process typically involves heating a polymer and forcing it through a die while it is hot so that it cools rapidly and sets a plastic shape. The selection of temperature and conditions depends on factors such as the polymer's chemical composition and molecular weight, melting temperature (Tm), glass transition temperature (Tg), the presence of crosslinks, and the effect of solvents, if any. Tm indicates the transition between the crystalline or semi-crystalline phase and the liquid amorphous phase. Tg indicates the temperature at which an amorphous polymer transitions from a rubbery, viscous liquid to a brittle, glassy, ​​amorphous solid upon cooling. Amorphous polymers have a Tg but do not have a specific melting point, Tm. Conventional extrusion processes generally involve treating the polymer at high temperatures (typically above 150°C) while it is in the extruder.

[0010] Disclosed herein is a novel process for extruding high-strength materials. Certain aspects of this process provide for one or more of removing solvent from the hydrophilic polymer-solvent mixture when the material is extruded, extruded at a low temperature, or extruded into a solvent-removing environment, and further removal at a time after extrusion. Additionally, an annealing step may be included.

[0011] 1-4 show one embodiment of an apparatus for producing a material. The illustrated device 100 includes a syringe pump 102 that accepts at least one syringe 104, an optional heating jacket (not shown) for heating the syringe, a die head 106, a heating element 108 and power cable 109 that provide the necessary heat for the die head 106 (details not shown in FIG. 1), a dispensing spool 110 for a core tube 112, an intake spool 114 and motor (not shown) for the core tube, and a bus 116 for extrusion material 117 (the bus having temperature control for cooling or heating shown as a heat exchanger 118 comprising heat exchange piping 120 in the bus 116). The die head 106 accepts the core tube 110 passing therethrough. A supply line 122 from the syringe to the die head 106 provides the supply to the device 100. The system of this embodiment may further include a metering station, a jacketed vessel for heating and mixing the solution for loading into the syringe, and a solvent removal environment for further drying the tubing after removal from the bath 116. The system may also have a heating station for thermally annealing the tubing or other extruded product, if desired. PTFE core tubes are useful, and wire, air, non-solvent liquids, or other materials may also be used for the core.

[0012] In use, for example, a polymer is heated in a suitable solvent in a jacketed vessel and placed in a syringe 104. More than one polymer may be present, and radiopaque agents or other additives may be added. More than one syringe may be used with the same or different mixtures. The polymer syringe is heated to a predetermined temperature, typically between 80 and 95°C, and degassed prior to extrusion. The syringe 104 is attached to a syringe pump 102 with a wrap heater to maintain the temperature during extrusion. The core 112 is looped through a die head 106, e.g., a heated out-dwelling die head, and fed into an extrusion bath 116, attached to a motor-driven puller wheel 114. The bath temperature is controlled using a heat exchanger 118, such as a chiller. The extruded material is typically extruded at temperatures ranging from -30°C to 75°C. Other temperatures may be used, with 0°C being a generally useful temperature setting for extrusion. Those skilled in the art will recognize that all ranges and values ​​between the explicitly defined boundaries are contemplated, e.g., any of -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, and 75°C may be utilized as upper or lower limits. The motor speed of the puller wheel 114 can be controlled to adjust the outer diameter gauge size around the core 112. Adjustments to the die size, material feed rate, tubing core diameter, and puller speed can serve to adjust the final tubing gauge, for example, in embodiments where a catheter is being manufactured. The polymer feed rate can be adjusted, for example, by controlling the syringe pump 102 in this embodiment. A connector 122 connects one or more syringes to the die head 106. Many pumps and other tools for controllably delivering polymer solutions are known. The apparatus and method can be adapted to the drawing process, although other feeding processes are available.Through this disclosure, those skilled in the art will be able to apply its principles, in light of what is known about extrusion or other molding techniques, to fabricate alternative processes and devices that achieve the same end product as described herein. Scaled-up versions of this process may be adapted for use, for example, in a multizone screw extruder, with the solvent mixture fed through appropriate injectors or hoppers and controlled zones to deliver the cooled extrudate. Features such as syringe pumps can be replaced with appropriately metered and controlled liquid or solid polymer feed systems. This system has been used to fabricate a variety of porous solid products, such as 6F catheters, with the properties shown in Table 1. Samples were fabricated using 13% w / w 85 kDa PVA containing either 0.1% w / w 450 kDa PAA or 1% w / w 20 kDa PVP-iodine. In all cases, samples were extruded into cooled ethanol at 0°C to 15°C, soaked in ethanol overnight, and then dried. The samples were then annealed in glycerol at 120°C for 6 to 17 hours and then rehydrated before testing. For PVA-PAA and PVP-iodine, samples were prepared with an average outer diameter of 1.59 mm (5F), as well as average outer diameters of 1.86 mm and 2.01 mm after hydration in aqueous solution for several days. 6F catheters were fabricated with PVA. The tensile strength of several formulations was evaluated at equilibrium water content (EWC), demonstrating that increased strength compared to ISO-10555 standard requirements is readily achievable. These samples not only met but exceeded the ISO standard (see Table 1). [Table 1]

[0013] The tensile results in Table 1 were obtained from one batch of samples. The minimum strength required by ISO 10555-1:2013 is 2.25 lbs (15 N) for catheters with ODs between 1.14 and 1.82 mm and 3.37 lbs (15 N) for catheters with ODs greater than 1.82 mm. The average strength of samples fabricated using the final casting process (approximately 12 F) resulted in samples with a tensile strength 164% greater than the required minimum. Catheters can be graded using the French nomenclature, where F stands for inner diameter. Fukumori et al. (Open J. Organic Polymer Materials 3:110-116 (2013)) reported a freeze-thaw process that produced a poly(vinyl alcohol) (PVA) material with a Young's modulus of 181 MPa, with a Young's modulus of approximately 5 MPa or greater requiring at least three cycles in the samples tested. The process for producing these gels required multiple freeze-thaw cycles. The resulting material was tested in a dry state and does not correspond to the strength measured by EWC. Fukumori et al. found that the crystalline content of the material increased with the number of freeze-thaw cycles, and attributed the material's strength to large crystals that formed as the freeze-thaw cycles progressed, which formed excellent cross-links that increased the Tg of the material. The nature of these processes produces a dry material. Furthermore, as described below, the freeze-thaw process produces macropores.

[0014] In contrast, the process herein does not employ a freeze-thaw process and / or does not employ a freezing process and / or does not employ a melting process. Furthermore, this process can be used to produce solid porous materials with little or no swelling at EWC, e.g., 0% to 100% w / w swelling, even in the absence of a covalent crosslinker. Those skilled in the art will recognize that ranges and values ​​between the explicitly stated boundaries are contemplated, e.g., 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 95, and 100% w / w can be used as upper or lower limits. Swelling is measured as % swelling = 100 × (total weight at EWC dry weight) / dry weight, where dry weight is the weight of the material without moisture.

[0015] Figure 5 shows the different regions of a stress-strain curve for a polymeric material. There are three main regions: Young's modulus, strain hardening, and break point. Young's modulus is defined as the slope of the linear elasticity of a material (change in stress / change in strain). Strain hardening is defined as the strengthening of a material with deformation. Break point is the point of maximum elongation. As shown in Figure 6, tensile load and travel were plotted for a PVA (5F) sample. The shape of the load curve was representative of other samples subjected to tensile testing. The sharp initial slope and eventual leveling out of elongation may indicate the viscoelastic properties of the extruded PVA, which indicates that the material undergoes strain hardening and ultimately strain softening until break. This particular sample exhibited a maximum tensile load of 14.9 N and a travel of 115 mm (454% elongation). Other samples prepared in the same manner with an average diameter of 2.03 mm (6.4 F) have an average ultimate tensile strength of 24.6 N (5.52 lbs). This substantial increase in tensile strength with such a small increase in cross-sectional area indicates that catheters made with these materials significantly exceed the minimum standard of ISO 10555. The extruded samples possess horizontal orientation and alignment along the length of the samples (in the direction of extrusion), as supported by the SEM of the nanoporous material shown in Figure 7. The orientation of the polymer chains was produced by the extrusion process. Figure 8 is an SEM image of a cross section of the same material prepared according to Example 1A, showing pore sizes of 100 nm or less.

[0016] Qualitative observations of sample strength, radiopacity, and surface finish and symmetry yield very good results. The sample surfaces, while not substantially perfect, are free of imperfections. When used to create cast samples containing severe parting lines, the results obtained with the extrudates outperformed the same components; no significant lines, bumps, or other imperfections were observed. The extrusion process was observed to be efficient and useful for producing strong, high-tensile strength tubing with high aspect ratios that would not be possible using conventional molds. A similar drawing process to extrusion may also be employed.

[0017] Example 1A describes a general method for extruding porous solids. Surprisingly, this process was effective. A cold extrusion process was created, with the die held at the extrusion side in a bath at only 13°C. The polymer is hydrophilic and viscous at low temperatures. Cold extrusion was effective in producing very strong materials with other good properties, including smoothness, defect-freeness, and consistent pore size. Extrusion was achieved using a mixture of polymer in a solvent, including PVA in water, as used in Example 1A. Extrusion into a solvent-removing environment, which in this example was an alcohol bath, contributed to the desired properties. In general, it is useful to use one or more combinations of extrusion of a hydrophilic polymer into a solvent, cold extrusion, and extrusion into a bath that rapidly removes the solvent from the extrudate. Furthermore, additional solvent-removal and / or annealing processes provide further utility for producing desired porous solids.

[0018] The process of Example 1A produced a nanoporous solid. Requirements for a nanoporous material include a high polymer concentration of greater than about 10% w / w in the polymer-solvent mixture with a high level of crosslinking. Those skilled in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, and that any of the following values ​​can be used as upper or lower limits: 10, 12, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 95, or 99% w / w by weight of polymer in the total weight of the polymer-solvent mixture. The polymer should be substantially solvated, meaning a true solution or at least half of the polymer is dissolved and the remainder is at least suspended. Polymer solvation contributes to polymer chain alignment and interpolymer crosslinking during extrusion. Without being bound by theory, it is believed that a high starting polymer-solvent mixture concentration aids in this. Additionally, potential chain alignment of the material as it passes through the die is believed to promote more intrapolymer to interpolymer crosslinking. Entering the extrudate or other formed mixture into a gas or liquid desolvation environment is believed to further collapse the pore structure before the closely packed polymers are fully crosslinked, thereby improving chain proximity and further increasing crosslink density. It is useful to deposit the extruded or otherwise formed material directly into a solvent removal environment. Further solvent removal can be used to collapse the material until the desired end point in structure and / or properties is reached. An annealing process can further contribute to strength.

[0019] On the other hand, freezing increases strength by forcing superconcentrated microregions to achieve chain proximity and improve crosslink density, but retain macroporosity due to the presence of ice crystals throughout the gel structure. Desolvation creates forced superconcentrated microregions, but these do not generate macropores. In contrast, gels pre-established before dehydration or freezing are inherently formed with macropores. Furthermore, our studies have shown that such nanoporous solids possess greater strength than macroporous materials.

[0020] Hydrogels can also be produced by using lower polymer concentrations in the polymer-solvent mixture, generally less than 10% w / w of polymer in the polymer-solvent mixture. Those skilled in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, and that, for example, any of 2, 5, 7, 8, 9, or 10% w / w of polymer by weight of the total weight of the polymer-solvent mixture can be used as an upper or lower limit. Additionally or alternatively, the polymer-solvent mixture is not extruded into a solvent removal environment.

[0021] Microporous materials can be produced using process conditions intermediate between those of nanoporous solids and hydrogels. One aspect is to prepare the material using conditions equivalent to those used to produce nanoporous materials, but to stop solvent removal before it reaches a nanoporous solid structure.

[0022] Extrusion of hydrophilic polymers in solvents, including PVA (Example 1A), is useful for producing high-strength materials. The use of solvents in the starting material is uncommon, at least for extrusion starters. Typically, extrusion uses solid materials that are heated to a flowable temperature, then extruded, and later cooled by various methods. For example, extrusion of pure PVA is believed possible. However, such extrusion lacks the polymer structure required to produce porous solids and instead behaves like conventional plastics. According to theory of operation, pure PVA extrusion would lack the hydrogen-bonding qualities that occur in aqueous ionic solvent states. Temperatures suitable for preparing PVA to be flowable in extrusion produce a poorly cohesive (or absorbent, cohesive) material at the die head, preventing the formation of continuous shapes. It has been difficult to form high-aspect shapes, such as tubes, from extrusion processes using extruded PVA. The high viscosity of PVA and other hydrophilic polymers makes them difficult to penetrate into solution. A narrow working band in temperature, e.g., 85-95°C, has been observed to be useful. Below about 85°C, the PVA was unable to truly melt and therefore did not become completely amorphous for extrusion. Above about 95°C, boiling and evaporation losses rendered the process ineffective. These temperature ranges can be offset by increasing the pressure above atmospheric, but pressurized systems are difficult to use and scale. This method is usefully carried out at temperatures below the boiling point of the polymer-solvent material.

[0023] The flowing polymer-solvent mixture had weak cohesion upon exiting the die. The use of a core to support the mixture in the mold helped maintain its shape in the die. This contrasts with typical core extrusion processes used, for example, as coating processes for coating wires in cell phone chargers. Typical processes that avoid the use of solvents or significant solvent concentration have relatively high cohesion upon exiting the die, which can easily hold the tube, and do not rely on active bonds, such as hydrogen bonding in hydrophilic polymers, to form the solid material into a coherent shape upon exiting the die.

[0024] Passing the formed polymer-solvent mixture through a solvent-removal environment has been useful. In Example 1A, for example, the use of a cold ethanol bath is atypical compared to conventional extrusion. Most extrusions do not use bath temperatures below room temperature. Furthermore, the use of a solvent-removal bath is typical compared to conventional processes; the bath or other solvent-removal environment helps to solidify the extruded material sufficiently to stabilize and concentrically form the core; otherwise, the melt would teardrop-like. Attempts to recover it at the end of extrusion would destroy it because it is still molten. Conventional baths containing water cause PVA or similar hydrophilic polymeric materials to lose their shape by swelling, dissolving, or both. Example 1B demonstrates a molding process, which involves preparing a polymer-solvent mixture that is formed in a mold and then subjected to a solvent-removal environment. These methods do not have the advantage of chain alignment observed in extrusion. However, properly controlled temperature and solvent removal can produce materials with high strength and controlled pore structure.

[0025] Example 2 demonstrates the effectiveness of this method when incorporating a radiopaque agent; barium sulfate was the material used in this case. In Example 3, the porous material lost moisture when exposed to air at ambient conditions (Figure 9), but retained its desired properties and could be effectively transported / stored in a sealed package or solution, or left in the ambient environment for a reasonable storage period, or as needed after the user unpackages it for end use. Example 4 demonstrates increasing strength (modulus and ultimate break) as the molecular weight of the hydrophilic polymer (PVA) increases from 140kJ to 190kJ (Table 3). Bismuth subcarbonate was used as the radiopaque agent. In the same example, increasing the concentration of the polymer in the polymer mixture used for extrusion showed increased strength toward the highest concentration compared to lower concentrations (Table 5 and Figures 10-11).

[0026] Porous solids are very smooth, can be used in a hydrated state, and can be conveniently bonded to other materials. For catheters, for example, extensions, luer locks, suture wings, etc. are useful. Example 5 demonstrates that conventional processes are effective for bonding other materials to porous materials. Examples 6 and 7 demonstrate that porous solids are suitable for radiopaque medical devices and have good burst strength in pressure tests. Contact drop tests (Example 8) demonstrate that various porous solids are hydrophilic (PVA test). SEM images (15A-15B, Example 8) are of nanoporous solids. Example 9 demonstrates nanoporous solids (Figures 16A-16D).

[0027] Without being limited to a particular theory, the observations of the test samples suggest that crosslinking within the material provided by the first hydrophilic polymer (PVA) increases through interactions with the chains of the second polymer (PAA or PEG) until the second polymer begins to form domains with itself within the material. This is believed to be due to the ability of the second polymer (PAA or PEG) to incorporate higher molecular weight species, providing additional material strength. The results indicate that extrusion of copolymers is useful in the range of 0.1% to 10% w / w of the second polymer or less than 10% w / w of the first polymer, with ranges of less than 5% w / w of the first polymer also being useful. Those skilled in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, e.g., 0.1, 0.2, 0.4, 0.5, 0.8, 1, 2, 3, 4, 5, 6, 8, and 10% w / w can be used as upper or lower limits.

[0028] The effect of various salts on the properties of the porous solids was evaluated as described in Example 10 (Figures 17A-17B). Salts were useful for manipulating the strength of the material. Without being limited to a particular theory, it is believed that the salts are part of the physical crosslinks, acting as low molecular weight crosslinkers between the polymer chains. Monosodium phosphate yielded the highest Young's modulus, and phosphoric acid produced the highest tensile strength. Boric acid increased both Young's modulus and ultimate tensile stress, while citric acid and phosphoric acid were comparable. Boric acid forms high-strength crosslinks but is not a covalent crosslinker.

[0029] Further tensile tests were performed on coextrudates of a given concentration of a first hydrophilic polymer and a relatively low concentration of a second hydrophilic partner (Example 11). Figure 18A shows tensile tests of PVA blends with low concentrations of 450 kDa PAA (0.1, 0.4, or 4.0% w / w PAA, 16% w / w PVA, where percentages refer to the w / w concentration of polymer in solvent). PAA concentrations of 0.1 to 0.4% w / w had higher strengths, supporting the conclusions described for Examples 9 and 10 above. Higher molecular weight (MW) PAA (3 million Da) was also tested (Figure 18B). However, they generally had only about half the strength of the lower MW PAA. The decrease in tensile strength with increasing PAA molecular weight may be due to a decrease in bonding and / or entanglement interactions between PVA and PAA due to chains longer than 3 million MW. No significant differences in strength were observed when three different MW PEGs were blended with PVA (8k, 20k, and 35k PEG) (Figures 19 and 20A-C, Example 12). Porous plastics made from PVA without a radiopaque agent were superior to control catheters in terms of non-thrombogenicity (Example 13, Figures 21A-B).

[0030] Embodiments of polymer blends include at least one first hydrophilic polymer and at least one second hydrophilic polymer in a solvent extruded as described herein. Examples include one or more combinations of PVA, PAA, PEG, PVP, polyalkylenes, hydrophilic polymers, and combinations thereof. Example concentrations include at least one second hydrophilic polymer present in a range of 1 part to 10,000 parts of the first hydrophilic polymer. Those skilled in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, and that any of the following may be used as upper or lower limits: 1, 2, 10, 100, 1,000, 1,500, 2,000, 2,500, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 parts. Exemplary concentrations of polymers in polymer-solvent mixtures include a first polymer present at a first concentration and one or more additional polymers present at a second concentration, where the first polymer concentration and the additional polymer concentration are independently selected from, for example, 0.1 to 99%, e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 33, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95% w / w. Additionally, non-hydrophilic polymers and / or non-hydrophilic blocks in the block polymer may be present, with the concentration of such polymers and / or such blocks generally being less than about 10% w / w, e.g., 0.1, 0.2, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10% w / w.

[0031] (Process systems and parameters for making materials) Provided herein are processes for producing biocompatible porous solids, such as microporous or nanoporous solid materials, that have low protein adsorption properties and serve as the basis for non-biofouling devices. Modifications of starting polymer concentration, molecular weight, solvent removal, formation process, and curing / annealing process may provide surface properties with reduced protein adsorption and other characteristics. Particular embodiments include extruding polymer mixtures to produce various continuous shapes. The mixtures may be further cured and annealed. These processes can be used to produce strong, highly lubricious materials. Embodiments include polymer mixtures extruded into single- or multi-lumen shapes of various diameters and wall thicknesses.

[0032] An embodiment of the process for producing a nanoporous solid material involves heating a mixture comprising a polymer and a solvent (polymer mixture), extruding the mixture into a solvent-removing environment, and removing the solvent from the crosslinked matrix until a nanoporous solid is formed. Depending on the process, one or more of these actions may be combined. Additionally, it is useful to cool the mixture as it exits the die. Without being limited to a particular theory of operation, crosslinking the polymer while passing through the die initially forms a porous matrix with gaps between the polymer strands but no pore structure, and therefore is not a true nanoporous solid. As the solvent is removed under appropriate conditions, the crosslinked structure becomes a nanoporous solid. Crosslinking begins when the polymer mixture is extruded through the die and the mixture is cooled. Crosslinking may continue as the solvent is removed. The transition to form a nanoporous material occurs when the solvent is removed and is generally considered complete or essentially (meaning 90% or more) complete at this stage. The resulting material may be further processed by annealing with or without additional solvent or plasticizer. This process, as well as other extrusion or other forming processes and / or materials described herein, may be free of one or more of the following: covalent crosslinking agents, agents that promote covalent crosslinking, radiation to crosslink polymer chains, freezing, thawing, freeze-thaw cycles, one or more freeze-thaw cycles, ice crystal formation, foaming agents, surfactants, hydrophobic polymers, hydrophobic polymer segments, reinforcements, wires, braids, non-porous solids, and fibers.

[0033] Porous materials may be produced by an extrusion process comprising forcing the polymer mixture through a die and into a cooling environment. The cooling environment may further be a solvent removal environment, or a dehydration environment if the solvent is water. The die may have a core therethrough such that the polymer mixture forms around the core. Additional solvent removal and / or annealing environments may be used.

[0034] The extrusion process of the polymer-solvent mixture may be carried out as cold extrusion. The term "cold extrusion" refers to a process that involves passing the polymer-solvent mixture through a die, without the need to heat the polymer-solvent mixture above its boiling point during the entire process of preparing and extruding the polymer-solvent mixture. Thus, in cold extrusion, the die head is kept below the boiling point of the polymer-solvent mixture. While many solvents may be used, water is often a useful solvent, and in this case, the die head is kept below 100°C, although lower temperatures may be useful as described above. The term "polymeric mixture" refers to a polymer in solution or dissolved or suspended in a solvent. The solvent may be, for example, water, an aqueous solution, or an organic solvent. Heating the polymer mixture may comprise heating the mixture to a temperature above the melting point of the polymer. Generally, a solution transitions from a cloudy to a clear state upon reaching the melting point.

[0035] Extrusion is a useful process for forming materials. Other forming processes, such as molding, casting, or thermoforming, may also be used with polymer-solvent mixtures. Generally, the polymer-solvent mixture is prepared without boiling and formed into a shape that is subjected to solvent removal conditions controlled to produce nanoporous or microporous materials using the guidelines provided herein. Annealing processes may also be included. Hydrogels that are not microporous or nanoporous may also be produced.

[0036] A heated polymer mixture may be molded or otherwise formed when it is cooled or molded / formed and immediately cooled. The term "formed" is a broad term that refers to passing a material from an amorphous molten state into a final product or an intermediate shape for further processing. Forming encompasses casting, laminating, coating, injection molding, stretching, and extrusion. Forming can be accomplished using injection molding equipment made of materials with heat-conducting properties that allow them to be easily heated and rapidly cooled in a cooling environment to enhance the flow of the injected polymer mixture. In other embodiments, the molding process can be achieved by extruding the polymer mixture through a die to form a continuous material.

[0037] Cooling the polymer mixture may include cooling extruded material, such as by passing the polymer material through a die. Examples of cooling methods include a liquid bath at least 20°C below the boiling point of the polymer mixture or below the Tm of the polymer mixture, e.g., 20, 30, 40, 50, 60, 70, 80, 90, 100, or 110°C, a liquid bath at the boiling point or below the Tm of the polymer, or a bath or other environment at temperatures between -50 and 30°C. Those skilled in the art will recognize that all ranges and values ​​between the explicitly defined boundaries are contemplated, e.g., -50, -45, -25, -20, -10, -5, -4, 0, 15, 20, 25, or 30°C may be used as upper or lower limits. Cooling may be performed in a solvent-removing environment. Freezing temperatures may be avoided. Without being limited to a particular theory of operation, the polymer chains are cooled to a point that promotes crosslinking and locks in chain transfer. This can occur at temperatures above 30°C, or even higher if time permits. The bath may be aqueous and may be osmotically adjusted with salts or other osmotic agents to effect solvent removal for aqueous materials with relatively low osmolality values ​​through osmotic pressure and diffusion. The bath may also be other solvents that freeze at lower temperatures than water, thereby allowing temperatures below 0°C to be used without freezing the solvent or material. When hydrophilic copolymers are used in combination with PVA, for example, temperatures above 20°C are used for crosslinking, with chain immobilization occurring at much higher temperatures.

[0038] A "solvent-removing environment" refers to an environment that significantly accelerates solvent removal compared to drying under ambient conditions. Such an environment may be unheated, meaning that it does not exceed ambient temperature, e.g., 20°C. Such an environment may be a vacuum, e.g., a vacuum chamber, a salt bath, or a bath that removes the solvent from the polymer mixture. For example, an aqueous polymer mixture can be introduced into an ethanol bath, where ethanol replaces water. The ethanol may then be removed. The salt bath may be, for example, a high salt concentration bath (1M to 6M). The process time in the solvent-removing environment and / or the cooling process may be independently selected to be 1 to 240 hours. Those skilled in the art will recognize that all ranges and values ​​between the explicitly defined boundaries are contemplated, and for example, 1, 2, 5, 10, or 24 hours, or 1, 2, 5, 7, or 10 days can be used as upper or lower limits. The salt may dissociate to form singly, doubly, or triply charged ions.

[0039] One or more solvent removal environments may be used, or one environment may be adjusted in terms of temperature. Thus, a cooling bath may be used, followed by solvent removal in an oven or vacuum oven. For example, a washing step may be performed before or after cooling or solvent removal, for example, by immersion in a series of solvents at various concentrations, various salt solutions, various proportions of ethanol or other solvents.

[0040] In one embodiment, the extruded material undergoes a solvent removal process involving exposure to a salt bath. The material is immersed in a series of diH2O baths (either fresh or replaced) for a period of time (e.g., 2-48 hours, 4-24 hours) to remove excess salt from the cast material or end-user device. The material is then removed from the wash step and dehydrated to remove excess water. Dehydration can be performed, for example, using temperatures ranging from 20-60°C. Dehydration is typically performed at 37°C for 24 hours or longer.

[0041] In one embodiment, the extruded or otherwise formed polymer mixture is then exposed to a high salt bath (1M-6M) for an inversely correlated period of time. The higher the salt content, the shorter the soaking time. For example, soaking in a 6M solution of NaCl for 16-24 hours. After soaking, the material is not rinsed with a salt solution. The material is already strengthened and can be removed from any mold pieces carried over from the initial formation. Alternatively, after the salt or other bath, the material is immersed in a water bath and dehydrated to remove excess water. Dehydration can be performed using temperatures ranging from 20-60°C. Dehydration can be performed at 37°C for more than 4 hours, more than 24 hours, or from 4 hours to 150 hours. Those skilled in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, e.g., 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120, 144, 150 hours, any of which may be used as upper or lower limits. For example, dehydration at 40°C for 6 to 24 hours has been observed to be useful.

[0042] In another embodiment, NaCl is incorporated into the starting polymer solution at a concentration ranging from 0.1 to 3M of the final polymer mixture volume. The polymer is dissolved in a heated solution under stirring, then brought above its melting point. Dry NaCl is slowly added to this solution under stirring until completely dissolved. The slightly cloudy solution is then drawn into a feed for shape creation via either injection molding, casting, extrusion, and / or stretching. A quench is performed at the end of each process to rapidly reduce the temperature and form a solid material. In this embodiment, no additional salt soaks are required. After the material hardens, it is removed from the molding process, rinsed with water to remove salt, and dehydrated, if necessary.

[0043] The term "annealing" in the context of semicrystalline polymers or solid porous materials refers to heat treatment at an annealing temperature corresponding to the melting temperature of the polymer in the nanoporous material. This temperature is typically lower than the melting temperature, within about 0-15% of the melting temperature. Plasticizers or other materials may affect the melting temperature, usually by compressing it. For example, for pure PVA, the annealing temperature would be within about 10% of the PVA's melting point. If other materials are present, the annealing temperature will generally be lower. The theory of operation is that annealing is a process of stress relief combined with an increase in the size of crystalline domains in the annealed material. Unlike metals, annealing increases the strength of the annealed material. Annealing may be performed in air, gas, or in the absence of oxygen or water (e.g., in nitrogen, vacuum nitrogen, argon, oxygen scavenger, etc.). For example, dehydrated PVA nanoporous materials have been tested by annealing. Annealing is used to increase the crystallinity of the PVA network, further reducing the pore size of the PVA network and reducing the adsorption properties of the final gel surface. Annealing can be performed at temperatures ranging from 100 to 160°C, for example. In a preferred embodiment, this step is performed by immersing the dehydrated gel in a mineral oil bath.

[0044] Annealing can be performed in a gas or liquid at ambient, elevated, or low (vacuum) pressure. The liquid can be a low-molecular-weight polymer (up to 2000 Da) or other material (e.g., mineral oil). Examples of low-molecular-weight polymers are glycerin, polyols, and polyethylene glycols less than 500 MW. A useful embodiment is annealing in a glycerin bath, for example, at 140°C for 1-3 hours. The glycerin acts to further reduce the fouling properties of the gel by interacting with and neutralizing the free hydroxyl end groups of the PVA network. The annealed nanoporous material is cooled, removed from the annealing bath, and rinsed from the bath medium using a series of extended immersions. The product is then dehydrated and prepared for terminal sterilization.

[0045] Various types of dies may be used, including longitudinal, angular, transverse, and spiral extrusion heads, as well as single-polymer extrusion heads used to extrude a single polymer and multilayer extrusion heads used to coextrude multiple polymer or other layers. Continuous operation heads (or periodic operation heads) may be used, as well as periodic ones. Various materials, such as reinforcing materials, fibers, wires, braiding materials, braided wires, braided plastic fibers, etc., may be incorporated into or as layers. Similarly, such materials may be excluded. Furthermore, porous solids may be manufactured with specific properties, such as Young's modulus, tensile strength, solids content, polymer composition, porous structure, or measurable solvent content, known and excluding various other materials. Thus, embodiments include the materials disclosed herein described in terms of their properties, regardless of various other incorporated materials. For example, nanoporous solids may have reinforcing wires that contribute additional strength to the material, yet have a known specific Young's modulus. Cores may be used with extrusion dies. The core may be air, water, a liquid, a solid, a non-solvent, or a gas. Given this disclosure, one skilled in the art will understand that a variety of extrusion processes may be useful using these various types of cores. Cores made from polytetrafluoroethylene tubing (PTFE) are useful.

[0046] Multi-lumen tubing has multiple channels running through its profile. These extrusions can be custom designed to fit device designs. Multi-lumen tubing has variable outer diameters (ODs), numerous custom inner diameters (IDs), and various wall thicknesses. This tubing comes in numerous shapes, such as round, oval, triangular, square, and crescent. These lumens can be used for guidewires, fluids, gases, wires, and various other needs. The number of lumens in multi-lumen tubing is limited only by the size of the OD. In certain embodiments, the OD can be as large as 0.5 inches, the ID as small as 0.002 inches, and the web and wall thickness can be as thin as 0.002 inches. Tight tolerances can be maintained to + / - 0.0005 inches. Those skilled in the art will recognize that all ranges and values ​​between the explicitly defined boundaries are contemplated, for example, any of 0.002, 0.003, 0.004, 0.007, 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, and 0.5 inches can be used as upper or lower limits for OD and / or ID. Tolerances may be, for example, 0.0005 to 0.1 inches. Those skilled in the art will recognize that all ranges and values ​​between the explicitly defined boundaries are contemplated, for example, any of 0.0005, 0.001, 0.002, 0.003, 0.006, 0.01, 0.02, 0.03, 0.06, 0.8, 0.9, and 1 inch can be used as upper or lower limits.

[0047] Braided tubing can be made in a variety of configurations. For example, it can be braided using round or flattened single or double wires as thin as 0.001 inches. A variety of materials can be used to manufacture braided tubing, including stainless steel, beryllium copper, and silver, as well as monofilament polymers. Braids can be wrapped with a variety of plastic-insulated cables (PICs) per inch over many thermoplastic substrates, such as nylon or polyurethane. The advantages of braided catheter shafts are their high torque capacity and kink resistance. By varying certain factors during the braiding process, the tubing's properties can be tailored to meet performance requirements. After the braid is complete, a second extrusion can be applied to the top of the braided tubing to encapsulate the braid and provide a smooth finish. Braided tubing can be manufactured with walls as thin as 0.007 inches, if desired.

[0048] (Porous, Microporous and Nanoporous Materials) The term "porous solid" is used broadly herein to refer to a material having a solid phase containing large spaces, and is used to describe true porous materials and hydrogels with an open matrix structure. Some terms related to "porosity" are used somewhat loosely in the scientific literature, so it is useful to provide a specific definition herein. The term "nanoporous material" or "nanoporous solid" is used herein to refer to a solid made with interconnected pores having a pore size of up to about 100 nm in diameter. The term "diameter" is broad and, as is customary in these technologies, encompasses pores of any shape. The terms "microporous solid" or "microporous material" are similarly used herein to specifically refer to a solid made with interconnected pores having a pore size of up to about 10 μm in diameter. These nano- or microporous materials are characterized by an interconnected porous structure. Some hydrogels, sometimes referred to by those skilled in the art as hydrogel sponges, are truly porous materials with a continuous, solid network of material filled through voids, the voids being pores. However, the open matrix structure found in many hydrogels is not truly porous, and they are generally referred to as porous materials for convenience, or by analogy with pores when characterizing diffusion or other properties. For example, hydrogels, as those terms are used herein, are not nanoporous or microporous solids. The spaces between the strands of an open-matrix hydrogel and those of the matrix are not interconnected pores. Hydrogels are crosslinked gels with solid-like properties that are not true solids, but because they are crosslinked, insoluble in solvents, and have significant mechanical strength, it is convenient for those skilled in the art to refer to them as solids. Hydrogels may have high water contents, e.g., 25% w / w or higher at EWC.Those skilled in the art of hydrogel technology use the term "porous" to characterize the net molecular weight cut off or to refer to the spacing between the strands of an open hydrogel matrix when the hydrogel does not have a true porous structure and is not a nanoporous or microporous material as used herein. The definitions of nanoporous and microporous materials used herein are also in contrast to the statements that microporous materials are sometimes described as having pore diameters of less than 2 nm, macroporous materials are described as having pore diameters of more than 50 nm, and the mesoporous category is somewhere in between.

[0049] The extrusion process for producing the materials of the present invention has several advantages. Extrusion has been observed to align polymers in a parallel orientation, which contributes to high tensile strength. Extruded and stretched polymer molecules align in the direction of the tube or fiber. The tendency to return to a random orientation is countered by strong intermolecular forces between the molecules. Furthermore, extrusion allows for the creation of materials or devices with high aspect ratios compared to injection molding or other molding processes. Furthermore, extrusion provides good dimensional control, allowing for control of wall thickness, lumen, and lumen placement. The use of high concentrations of polymer above its melting point in a solvent has been useful to enable extrusion. Attempts to produce high-strength materials using similar polymers have used other techniques that do not allow extrusion, are inefficient, and are often not suitable for producing practical end products.

[0050] For example, polyvinyl alcohol (PVA) was used herein to fabricate nanoporous materials with superior properties, especially compared to traditionally used PVA biomaterials. Indeed, PVA is widely used throughout the medical device industry and has an established track record of biocompatibility. PVA is a linear molecule with a rich history as a biocompatible biomaterial. PVA hydrogels and membranes have been developed for biomedical applications such as contact lenses, artificial pancreases, hemodialysis, and synthetic vitreous humor, as well as implantable medical materials to replace cartilage and meniscus tissue. Its biocompatibility and low protein adsorption properties make it an attractive material for these applications, resulting in low cell adhesion compared to other hydrogels.

[0051] Other attempts have been made to improve the properties of PVA for biomedical purposes. For example, freeze / thaw processes have been tested. Techniques for forming hydrogels from PVA, such as "salting out" gelation, have been shown to form useful polymer hydrogels using different molecular weights and concentrations. Manipulation of Flory interactions has also been investigated in the formation of PVA gels by combining two solutions (U.S. Patent No. 7,845,670; U.S. Patent No. 8,637,063; U.S. Patent No. 7,619,009) for use as an injectable, in-situ-forming gel for intervertebral disc repair. Generally, a conventional process for producing tough PVA materials is investigated in U.S. Patent No. 8,541,484. Methods for doing this without the use of radiation or chemical crosslinkers have also been previously investigated, as shown in U.S. Patent No. 6,231,605. Other research related to this PVA did not result in the invention described herein. Some of these other materials were useful in terms of tensile strength, but were nonetheless macroporous in nature.

[0052] In contrast, the process herein provides high-strength materials with true porous structures and other useful properties, such as an unexpectedly good combination of biocompatibility and mechanical properties. Porous solid material embodiments are provided with a combination of structural features independently selected from pore size, tensile strength, Young's modulus, solids concentration, crosslinking type and degree, internal orientation, hydrophilicity, and material composition, and optionally, end-user devices or intermediate materials with desired aspect ratios, lumens, multiple lumens, concentrically arranged lumens, or tubes with thickness tolerances, or specific medical devices, each of which is described in detail herein.

[0053] Embodiments include nanoporous materials having pore sizes less than or equal to 100 nm or in the range of 10-100 nm. One of skill in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, e.g., any of 1, 2, 3, 4, 5, 10, 20, 50, 60, 70, 80, 90, 100 nm can be used as an upper or lower limit.

[0054] Embodiments include nanoporous or microporous materials having a tensile strength at break, as measured by EWC, of ​​at least about 50 MPa or 1-300 MPa. One of skill in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, and that, for example, any of 10, 20, 30, 40, 50, 60, 70, 100, 200, or 300 MPa can be used as an upper or lower limit.

[0055] Embodiments include nanoporous or microporous materials having a Young's modulus, as measured by EWC, of ​​at least about 1 MPa or between 1 and 100 MPa. One of skill in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, and that any of 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100 MPa can be used as an upper or lower limit.

[0056] Embodiments include nanoporous or microporous materials or hydrogels having an elongation at break, as measured by EWC, of ​​at least about 100% or 50-500%. One of skill in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, e.g., any of 50, 60, 70, 80, 90, 100, 200, 300, 400, 450, or 500% can be used as an upper or lower limit.

[0057] Embodiments include nanoporous or microporous materials or hydrogels having at least 20% solids or 20-90% w / w solids, as measured by EWC. One of skill in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, and that any of the following solids values ​​can be used as upper or lower limits: 5, 10, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90% w / w. Percent solids are measured by comparing the total weight at EWC to the dry weight.

[0058] Tensile strength, modulus and elongation values ​​may be mixed and matched in combination within the ranges set forth in this disclosure.

[0059] Embodiments include nanoporous or microporous materials or hydrogels with physical or covalent crosslinks, or combinations thereof. The physical crosslinks are non-covalent, e.g., ionic, hydrogen, electrostatic, van der Waals, or hydrophobic packing. These materials may be free of covalent crosslinks, their covalent crosslinking products, and chemical products. Chemicals may be added during processing to create covalent crosslinks, as is known in the polymerization art. Alternatively, the process and materials may not be the same.

[0060] Embodiments include hydrogels with nanoporous or microporous materials or internal alignment of polymer structures. Alignment may be visualized using SEM images of cross sections along the direction of extrusion (i.e., along the length of the tube). "Alignment" refers to the orientation of the majority of horizontal chains and along the length of the sample (in the direction of extrusion).

[0061] Embodiments include hydrogels having nanoporous or microporous materials or hydrophilic surfaces and / or hydrophilic materials. Materials made from water-soluble polymers are hydrophilic. A water-soluble polymer is a polymer that dissolves in water at a concentration of at least 1 g / 100 ml. A surface is hydrophilic if the contact angle of a water droplet on the surface is less than 90 degrees (the contact angle is defined as the angle passing through the interior of the droplet). Embodiments include hydrophilic surfaces having contact angles between 90° and 0°. Those skilled in the art will recognize that all ranges and values ​​between the explicitly defined boundaries are contemplated, e.g., 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 2, and 0° can be used as upper or lower limits.

[0062] Materials for use in the process and / or biomaterial may include polymers. Hydrophilic polymers are beneficial. For example, one or more polymers may be selected from polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyacrylic acid (PAA), polyacrylamide, hydroxypropylmethacrylamide, polyoxazoline, polyphosphate, polyphosphazene, and polysaccharides, as well as variations of the same with added iodine (e.g., PVA-I, PVP-I) or variations with pendant groups, copolymers with one or more of PAA, PVA, PVP, or PEG, and combinations thereof. Two or more hydrophilic polymers may be mixed together to form a nanoporous material. The molecular weight of the polymer may affect the properties of the biomaterial. Higher molecular weights tend to increase strength, decrease pore size, and reduce protein adsorption. Thus, embodiments include polymers or hydrophilic polymers with a molecular weight of 40kDa to 5000kDa. One of ordinary skill in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, e.g., any of the following molecular weights can be used as upper or lower limits: 40k, 50k, 100k, 125k, 150k, 250k, 400k, 500k, 600k, 750k, 800k, 900k, 1 million, 1.5 million, 2 million, 2.5 million, 3 million.

[0063] The term "PEG" refers to all polyethylene oxides, regardless of molecular weight or whether the polymer is hydroxyl-terminated. Similarly, the terms "PVA," "PVP," and "PAA" are used without restriction regarding terminal chemical moieties or MW range. References to polymers described herein include all forms of polymers, including linear, branched, unactivated, and derivatized polymers. Branched polymers have a linear backbone and at least one branch, and thus encompass star, brush, comb, and combinations thereof. Derivatized polymers have a backbone comprising the indicated repeat unit and one or more substituents or pendant groups, collectively referred to as derivatized moieties. "Substitution" refers to the replacement of one atom with another. "Pendant groups" are chemical moieties attached to a polymer and may be the same or different from the polymer repeat unit. Thus, references to polymers include highly derivatized polymers and polymers having less than 0.01-20% w / w of derivatized moieties (calculated as the total MW of the moiety compared to the total weight of the polymer). One of skill in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, e.g., any of 0.01, 0.05, 0.1, 0.2, 0.3, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20% w / w can be used as upper or lower limits.

[0064] A porous solid may be formed as a monolithic material, as a layer on another material, device, or surface, as multiple layers, or as one or more layers of material comprising nanoporous material. Thus, for example, multiple layers may be extruded and the layers may be independently selected to form one or more of a nanoporous material, a microporous material, a hydrogel, a single polymer material, a material having two or more polymers, and a non-nanoporous material.

[0065] The process for producing the material can also affect material properties, including the concentration of polymer in the polymer mixture passing through the die. The starting concentration of PVA or other hydrophilic polymer can range, for example, from 5 to 70% by weight (w / w) in water, with approximately 10 to 30% (w / w) generally preferred. Those skilled in the art will recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, and any of the following can be used as upper or lower limits: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70%.

[0066] The processes described herein may be truncated before the polymer is crosslinked and processed to become a true nanoporous material, or adapted to avoid nanoporous structures. Generally, such materials have lower strength and toughness and lower solids content. Such materials are generally hydrogels when hydrophilic polymers are used at relatively low solids. Therefore, such materials, even hydrogels, are contemplated herein and may have somewhat lower properties compared to nanoporous materials, but may nevertheless produce materials superior to conventional processes and materials using the same polymers. Similarly, as a generalization, microporous solids will approach the properties of nanoporous materials and have strength superior to that of hydrogels.

[0067] Embodiments include methods for producing polymeric materials, including heating a mixture comprising a water-soluble polymer and a solvent to a temperature above the melting point of the polymer, extruding the mixture, and cooling the mixture while removing the solvent and / or while crosslinking. When multiple polymers are present in a solvent, the melting point of the combined polymer in the solvent, with or without other additives, can be readily determined by one of ordinary skill in the art by observing the mixture as it heats, for example, as the mixture changes appearance from a cloudy state to a significantly translucent state. Additionally, some or all of the solvent may be removed from the mixture during cooling after or as part of a forming process using the mixture. Embodiments include removing at least 50% w / w of the solvent in less than 60 minutes (or less than 1, 2, 5, or 10 minutes). Embodiments include removing at least 90% w / w (or at least 70% w / w or at least 80% w / w) of the solvent in less than 60 minutes (or less than 1, 2, 5, 10, or 30 minutes).

[0068] (product) With reference to the materials described herein, including nanoporous materials, microporous materials, and hydrogels, final or intermediate products or products containing the materials may be manufactured with a desired aspect ratio, e.g., at least 3:1. The aspect ratio increases as the length of the device increases and as the width decreases. Those skilled in the art will recognize that all ranges and values ​​between the explicitly defined boundaries are contemplated, e.g., 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 50:1, 100:1, and 1000:1 may be used as upper or lower limits. High aspect ratios are highly advantageous for certain devices, e.g., many types of catheters. In principle, thin tubes can be continuously extruded without limit in length. Such devices include, for example, tubes, rods, cylinders, and cross-sections with square, polygonal, or circular profiles. One or more lumens may be provided in any of them. The device may be made of a single material, essentially a single material, or multiple materials including the various layers already described, or reinforcing materials, fibers, wires, braided materials, braided wires, braided plastic fibers.

[0069] In particular, the extrusion process provides concentric placement of the lumens. Concentricity is in contrast to eccentricity, meaning that the lumen is off-center. In the case of multiple lumens, the lumens may be positioned such that they are symmetrically positioned. Symmetry is in contrast to eccentric placement of the lumens, which is the result of an insufficiently controlled process. Embodiments include the aforementioned devices having an aspect ratio of at least 3:1 with lumens positioned without eccentricity or one lumen concentric with the longitudinal axis of the device.

[0070] Porous solids, such as nanoporous materials, microporous materials, and strong hydrogels, may be used to fabricate catheters or medical textiles. Examples of catheters include central venous, peripheral central, midline, peripheral, tunneled, dialysis access, urinary, neurological, peritoneal, intra-aortic balloon pump, diagnostic, interventional, drug delivery, shunts, wound drains (external ventricular, intraperitoneal, and intraperitoneal), and infusion ports. Porous solids may be used to fabricate implantable devices, either fully implantable or percutaneously implanted, permanently or temporarily. The porous solid material may be used to fabricate devices that contact bodily fluids or devices that come into contact with bodily fluids, including extracorporeal devices and / or intracorporeal devices, and including blood-contacting implants. Examples of such devices include drug delivery devices (e.g., insulin pumps), tubing, contraceptive devices, feminine hygiene, endoscopes, grafts (including grafts with small diameters <6 mm), pacemakers, implantable cardiovascular defibrillators, cardiac resynchronization devices, cardiovascular device leads, ventricular assist devices, catheters (cochlear implants), endotracheal tubes, tracheostomy tubes, drug delivery ports and tubing, implantable sensors (intravascular, transcutaneous, intracranial), ventilator pumps, and ophthalmic devices, including drug delivery systems. Catheters can comprise tubular nanoporous materials with fasteners that cooperate with other devices (e.g., Luer fasteners or fittings). Radiopaque agents may be added to materials, fibers, or devices. The term "radiopaque agent" refers to agents commonly used in the medical device industry to impart radiopacity to materials (e.g., barium sulfate, bismuth, or tungsten).

[0071] Medical fibers made from porous solid materials include applications such as sutures, threads, medical fibers, braids, meshes, knitted or woven meshes, nonwoven fabrics, and devices based thereon. The fibers are strong and flexible. Materials may be manufactured using these fibers to withstand fatigue and wear.

[0072] (Further definitions) The term "medically acceptable" refers to a material that is highly purified to be free of contaminants and is nontoxic. The term "consists essentially of," when used in the context of a biomaterial or medical device, refers to a material or device having less than 3% w / w of other materials or components, provided that such 3% does not render the device unsuitable for its intended medical use. "Equilibrium water content" (EWC) refers to the water content of a material when the hydrogel's wet weight is constant and before degradation. Materials with high solids are generally observed to reach equilibrium water content in 24 to 48 hours. Physiological saline refers to a phosphate buffer solution with a pH of 7 to 7.4 and a human physiological osmolality at 37°C. For purposes of measuring equilibrium water content, distilled water is used. The term "w / v" refers to weight per volume, e.g., g / L or mg / mL. The terms "biomaterial" and "biomedical material" are used interchangeably herein and can be used in the biomedical field, such as implants, catheters, blood contacting materials, tissue contacting materials, diagnostic assays, medical kits, tissue sample processing or other medical purposes. Furthermore, while materials are suitable for biomedical applications, they are not limited to the same and may be manufactured as general-purpose materials.

[0073] The term "molecular weight (MW)" is measured in g / mol. The MW of a polymer refers to the weight average MW unless otherwise specified. If the polymer is part of a porous solid, the term "MW" refers to the polymer before crosslinking. When the distance between crosslinks is specified, it is the weight average MW between the crosslinks unless otherwise indicated. The abbreviation "k" stands for thousand, M stands for million, and "G" stands for billion; for example, 50kMW means 50,000 MW. Dalton is also a unit of MW and similarly refers to the weight average when used for polymers.

[0074] The publications, journal articles, patents, and patent applications referenced herein are incorporated herein for all purposes, and the present specification controls in case of conflict. Features of the embodiments described herein may be mixed and matched based on the needs of creating a workable process or product. [Example]

[0075] Example 1A: Extrusion of PVA Porous Solid In the examples, unless otherwise indicated, the apparatus shown in Figure 1 is used when extrusion is described. A 17 wt. % PVA solution was prepared using 100 ml of deionized water and 20 g of PVA (85 kDa, Sigma-Aldrich). The water was heated (100 °C) until it began to boil, and then the dry PVA was added slowly (over approximately 5-10 minutes) with moderate mixing (mixer speed approximately 40). A boil-free process involves turning off the heat as soon as boiling begins to occur to prevent boiling. Once all the PVA was added and the solution began to thicken, the heat was reduced to approximately 90 °C and the stirring speed was increased to ensure the polymer was completely dissolved and thoroughly blended. The PVA solution was stirred for approximately 2 hours. Upon completion, the solution was viscous and slightly opaque. The solution was poured into a 20 cc syringe and degassed in a 90 °C oven. Heating / degassing typically does not exceed 2 hours.

[0076] The polymer sample was extruded into a bath of 13°C ethanol (Fisher, 190 proof) using a PTFE monofilament pulling speed of 7 (ARDUINO specific motor movement software, 84 mm diameter pulling wheel). After extrusion, the sample was allowed to rest in the cold ethanol for approximately 30 minutes before being removed. The sample was then transferred to another container of ethanol and placed in a -25°C freezer for 24 hours. The monofilament was then removed from the sample by clamping the end of the monofilament with tongs and slowly sliding the sample. A mandrel slightly smaller than the sample's inner diameter (0.033 in.) was inserted into the sample, and the sample was allowed to dry flat in a 50°C incubator for approximately 3 hours. After complete drying, the sample was annealed by immersing it in glycerol (Sigma-Aldrich) in a sealed container at 120°C for 24 hours ± 4 hours in an oven. After annealing, the sample was removed from the glycerol and gently rinsed with deionized water. The sample was then transferred to a new container of deionized water and allowed to rehydrate for approximately 24 hours. The sample can be dehydrated and rehydrated without any adverse effects or changes to the porous solid observed. This process produced a nanoporous solid material.

[0077] Example 1B: Molded PVA PVA gels were prepared by weighing 10 g of 85 kMW PVA (88% hydrolyzed PVA) and adding it to 100 mL of diH2O heated to 80 °C under stirring. The PVA was slowly added and mixed, then the temperature was increased to 90 °C. The PVA solution was stirred until clarity was achieved. Approximately 5 mL of the PVA solution was drawn into a syringe and degassed to remove trapped air. The PVA solution was poured into a preheated mold at 60 °C and rapidly cooled using a refrigerated cooling source. The PVA gel was then removed from the mold intact on the mandrel.

[0078] The PVA gel was quenched in a 6 M solution of NaCl. The PVA gel was immersed in the salt solution overnight (16–24 h) and then removed. The hardened gel was then removed from the mandrel in a hydrated state to remove excess salt and immersed in diH2O for an additional 24 h. The gel was then dehydrated to remove residual water by drying at 25 °C for 24 h.

[0079] Some of these gels were then annealed by immersing in mineral oil and heating at 140°C for 1 hour. The gels were thoroughly rinsed and submerged in oil to ensure no exposed areas were present. The gels were allowed to cool, rinsed with 20 mL of diH2O, and then rehydrated with an additional 20 mL of diH2O at 37°C. Other samples of the gels were annealed by immersing in glycerin and heating at 120-130°C for 3-24 hours. The gels were thoroughly rinsed and submerged in glycerin to ensure no exposed areas were present. The gels were allowed to cool, rinsed with 20 mL of diH2O, and then rehydrated with an additional 20 mL of diH2O at 37°C.

[0080] Example 2: Extrusion of PVA-Barium A PVA-barium polymer solution was prepared using 100 ml of deionized water, 16 g of barium sulfate (Sigma-Aldrich), and 4 g of 85 kDa PVA (Sigma-Aldrich). The water was heated to a boil (100 °C). The dry barium sulfate was added slowly first and mixed until no clumps were observed. The dry PVA was then added slowly (over approximately 5 minutes) to the water with moderate mixing. Once all the PVA was added and the solution began to thicken, the heat was reduced to approximately 90 °C and the stirring speed was increased to ensure the polymer was completely dissolved and thoroughly blended. The PVA-barium solution was stirred vigorously for approximately 2 hours. Upon completion, the solution was viscous and white. The solution was poured into a 20 cc syringe and degassed in a 90 °C oven. Heating during degassing typically does not exceed 2 hours.

[0081] The sample was extruded in a manner similar to that described in Example 1 and then allowed to rest in cold ethanol for approximately 30 minutes before being moved. The sample was then transferred to another container of ethanol and placed in a freezer set at -25°C for 24 hours. The monofilament was then removed from the sample by clamping the end of the monofilament with tongs and slowly sliding the sample. A mandrel slightly smaller than the inner diameter of the sample was inserted into the sample, and the sample was allowed to dry flat in an incubator at 50°C for approximately 3 hours. After complete drying, the sample was annealed by immersing it in glycerol (Sigma-Aldrich) in a sealed container at 120°C for 24 hours ± 4 hours in an oven.

[0082] After annealing, the samples were removed from the glycerol and gently rinsed with deionized water. They were then transferred to a new container of deionized water and allowed to rehydrate for approximately 24 hours. Samples can be dehydrated and rehydrated without any adverse effects or changes observed.

[0083] (Example 3: Rehydration rate / dehydration rate of PVA porous material) Over a 23-hour period, a percent loss of 55% was observed in a PVA sample prepared as described in Example 1A for a 3.5 French catheter. A plot of weight loss over time in ambient air is shown in Table 2 below and Figure 9. [Table 2]

[0084] Example 4: Example of tensile test PVA extrusion samples were prepared by heating a slurry of 17.6 g of bismuth carbonate and 100 g of a 6.2 g / L monosodium phosphate solution in a jacketed reactor at 95 °C. To this, 25.8 g of PVA (Mowiol 28-99 or Sekisui Selvol 165, also known as 67-99) was added over 5 minutes while mixing at 70% run (DITCV2 mixer). The polymer was mixed at 70% run for 1-1.5 hours. The polymer was degassed at 90 °C for less than 2 hours. The polymer was then extruded into 190-proof ethanol at 5-10 °C and stored at ambient conditions for at least 30 minutes.

[0085] The polymer was dried at 55° C. for 3 hours and annealed in a forced convection oven at 140° C. for 1.5 hours. The sample was then rehydrated in 1×PBS at 37° C. for 2 hours.

[0086] Tensile strength (stress) was measured in Newtons on a Mark 10 tensile tester (Model DC4060) using a 100 N digital force gauge (Model# M5-1006). Cross-sectional area was measured for the samples using a caliper (Mark 10 Model# 500-474) to measure the outer diameter and a pin gauge set to measure the inner diameter. PVA 67-99 exhibits a nominal viscosity of 67 cP (nominal viscosity as a 4% solution in water) with 99% or greater hydrolysis. PVA 28-99 exhibits a nominal viscosity of 28 cP (nominal viscosity as a 4% solution in water) with 99% or greater hydrolysis. Viscosity of PVA is positively correlated with the molecular weight of the polymer. Table 3 and Figure 10 show the increase in Young's modulus and maximum tensile stress with increasing PVA viscosity. [Table 3]

[0087] An 18% PVA extrusion sample was prepared by heating a 100 g slurry of 17.6 g of bismuth subcarbonate and 1.6 g of monosodium phosphate solution in a jacketed reactor at 95 °C. To this, 25.8 g of PVA (MOWIOL 28-99) was added over 5 min with mixing at 70% run setting (DITCV2 mixer).

[0088] A 22% PVA extrusion sample was prepared by heating a slurry of 23.3 g of bismuth subcarbonate and 100 g of 6.2 g / L monosodium phosphate solution in a jacketed reactor at 95 °C. To this, 35.0 g of PVA (MOWIOL 28-99) was added over 5 minutes with mixing at 70% run setting (DITCV2 mixer).

[0089] A 26% PVA extrusion sample was prepared by heating a slurry of 35.4 g of bismuth carbonate and 115.9 g of 6.2 g / L monosodium phosphate solution in a jacketed reactor at 95 °C. To this, 53.2 g of PVA (MOWIOL 28-99) was added over 5 minutes with mixing at 70% run setting (DITCV2 mixer).

[0090] Each set of polymers was mixed for 1.5-2 hours at a 70% run setting. The polymers were degassed at 90°C for less than 2 hours. The polymers were then extruded into 190-proof ethanol at 5-10°C and stored at ambient conditions for at least 30 minutes.

[0091] The polymer was dried in a vacuum oven at 40°C for 24 hours and annealed in silicone oil at 140°C for 1 hour. The samples were rinsed three times with 190-proof ethanol and then rehydrated in 1x PBS at 37°C for 2 hours. The various preparations are described in Table 4. [Table 4]

[0092] The PVA in the mixtures in Table 4 was increased in the batch process relative to the monobasic salt solution. Increasing the PVA provided higher ultimate tensile strength and Young's modulus. As the ratio of PVA to monobasic sodium phosphate increases, stronger materials can be prepared. Figure 11 and Table 5 show that 26% PVA 28-99 has an increased Young's modulus and ultimate tensile stress compared to 22% and 18% PVA 28-99. [Table 5]

[0093] Example 5: Attaching an extension tube / Luer lock to a hydrogel The luer lock was attached to a polyurethane (PU) extension tube via cyanoacrylate. The extension tube was mated to the PVA catheter body by sliding it approximately 0.5 inches. A heat gun was used at approximately 300°F, the PU / PVA was exposed 10 times with 0.5 second intervals and overlaps, and repeated until an infusion bond between the PU and PVA occurred. Tensile data was evaluated on multiple samples. [Table 6]

[0094] Further testing showed that traditional ethylene-vinyl acetate (EVA) bonding processes for attaching extensions or other devices to catheters were effective for bonding such devices to extruded porous PVA material. Table 7 shows results where the attachment points exceeded the PVA strength or otherwise exceeded all design requirements. A standard natural-color EVA melt liner (OD: 3 / 16 inch, wall: 0.014 inch) and polyolefin RNF (heat shrink: 0.25 inch) were used with PVA tubing (ID: 0.050 inch / OD: 0.063 inch to 0.065 inch) and a Luer hub (ID: 0.062 inch / OD: 0.101 inch) with tubing assembly. A Steinel HG2310 LCD heat gun (0.25 inch diameter nozzle with a tip modified by compression to 0.12 inch width to provide a narrow heat zone area) set at 400°F and a 0.050 inch stainless steel mandrel was inserted through the luer hub / tubing assembly into the ID of the PVA tubing.

[0095] Three samples using a PE hub and PVA tubing butt weld were fabricated at 400°F. The joints were observed to be very strong.

[0096] The clear luer hub and tubing assembly was slid into approximately 0.75 inches of PVA extrusion, and an ethyl vinyl acetate melt liner and polyolefin were added to the assembly. The melt was prepared and joined at 400°F. Once the PVA extrusion and melt liner were melted, a more controlled shrinkage method was applied using gentle hand rolling of the melted joint to form a flat surface and prevent melting of the PVA tubing.

[0097] The PVA extrusion was inserted into the hub and tubing and bonded using the method described above. Strength was excellent; the assembly could not be pulled apart by hand. Two samples were formed, hydrated, and used for testing. After conditioning in PBS at 37°C for 2 hours, the samples were tensile tested. The results are shown in Table 7. [Table 7]

[0098] The suture wing overmold was also successfully attached. EVA (Ateva 2803G with 20% bismuth subcarbonate) was used for injection molding of the suture wings. A tension line (HTP Meds #2006-0335 Rev A) and PVA tubing were attached. A maximum break force of 27 N (6.1 lbf) (Wagner Instruments #FDK 30) was required to remove the PVA tubing and EVA suture wings. When the assembled PICC was hydrated, the break force was 28 N (6.2 lbf).

[0099] Example 6: Radiopacity Samples were prepared according to the method of Example 2. The samples are shown in Figures 12A-12F. The samples are the control (12A, BARD PowerPICC), unannealed 5.7 wt% bismuth subcarbonate (12B), unannealed 12.1 wt% bismuth carbonate (12C), annealed 12.1 wt% bismuth subcarbonate (12D), annealed 5.7 wt% bismuth subcarbonate (12E), and 4.2 wt% bismuth subcarbonate (12F).

[0100] All samples B through E exceeded the radiopacity of the control sample. The 4.2% bismuth subcarbonate sample (12F) exhibited radiopacity at or below the same level and is considered minimal for the samples. Radiopacity testing was performed at Mount Auburn Hospital in Cambridge, Massachusetts.

[0101] Example 7: Power Infusion Pressure testing showed that the extruded porous plastic exceeded all design requirements. Power injection testing was performed on samples of the PVA-RO (radiopacifying) agent-incorporated nanoporous solid prepared according to Example 2 using a Medrad MARK V PLUS POWER INJECTOR. The samples were attached to a barb / luer fitting with silicone tubing.

[0102] Water was injected at 5 mL / sec for 1 second, but the sample did not clog (it was free flowing) and passed through without breaking. Another identical sample of the same PVA-RO formulation was clogged and tested using the same parameters. The sample broke at the extension tubing joint due to pre-existing damage from the heat shrink process.

[0103] Another set of samples, shown in Figure 13, was then heat-shrunk onto silicone tubing using the method described in Example 5, with barbed fittings containing Loctite 4902. Barbs were attached to each end of the samples to allow for capping for occlusion testing. Samples 1 and 2 were tested using a 5 ml / sec flow rate with a total liquid volume of 5 ml at 100 PSI. The samples failed near the heat shrink joint due to the bonded heat exposure (failure locations shown in Figure 14).

[0104] Sample 3 was tested with decreasing injection rates and volumes and passed two of three cycles: Cycle 1 used a 0.4 mL / sec flow rate with 100 maximum PSI and a 1 mL total volume, while Cycle 2 used the same parameters with 200 maximum PSI. Both cycles were completed. Cycle 3 used a 5.0 mL / sec flow rate with 1 mL total volume and 350 maximum PSI. The tubing broke due to separation from the silicone and heat shrinkage. No damage to the hydrogel was observed, indicating that the PVA extruded tubing could withstand power injection when using the appropriate mounting method (i.e., overmolding).

[0105] Example 8: Contact angle The contact angle was measured for PVA-RO incorporating a hydrogel prepared according to Example 2. A 1 cm section of the extruded material was cut from the main strand using a precision knife. The sample was then carefully cut along the length of the cross section. Loctite 406 was used to carefully adhere the sample to a glass slide. Once fully adhered, Loctite 406 was tapped along the edge of the sample, and the wall of the sample was gently pressed onto the glass slide using forceps until it formed a flat shape. A single droplet of colored water was placed on the surface of the material using a 20 μL pipettor. The droplet was immediately photographed and imported into an image viewer for measurement of the contact angle. All surfaces and the camera were leveled prior to testing. The sample had a contact angle of 60° as measured by the drop test (taken through the drop).

[0106] Example 9: SEM Results Additionally, Figures 15A-15B are SEM images of a 17% PVA solution extruded using the method of Example 1A, except as otherwise specified. The sample was hydrated in distilled water at 37°C for 24 hours and then rapidly frozen using liquid nitrogen to preserve the pore structure. The sample was then freeze-dried for 48 hours to remove the water and subjected to SEM analysis. Figure 15A shows a cross-section of the extruded PVA tube, showing no macroporosity in the gel structure. Figure 15B shows a longitudinal cross-section of the extruded tube at higher magnification, showing no macroporosity in the structure. This material has a higher water content and is more porous, with pore sizes less than approximately 10 nm.

[0107] A PVA extrudate sample was prepared by heating 200 g of distilled water in a jacketed reactor at 95°C. To this, 40 g of PVA (Sigma, 146k-186k) was added over 5 minutes while mixing at 200 RPM. The polymer was mixed at 300 RPM for 1.5 hours. The polymer was degassed at 90°C for less than 2 hours. The polymer was then extruded into ethanol at -23°C using the apparatus shown in Figures 1-3. It was then stored in ethanol at -25°C in a freezer for 24 hours. The sample was allowed to dry for 6 hours. After drying, the sample was immersed in glycerol at 120°C for 17 hours. After annealing, the sample was removed, cooled, and rinsed with ethanol. After rinsing, the core was removed. The sample was then dried at 50°C for 12 hours. Two SEM images (Figures 16A-16D) illustrate the results. Additionally, Figures 16C-16D were taken at higher magnification, showing nano-porosity.

[0108] Example 10: Salt Additive Various salts were used in the batch process, which refers to the process of driving the polymer into solution in a polymer-solvent mixture, to vary the maximum tensile stress and Young's modulus. Multifunctional salts such as phosphoric acid, boric acid, and citric acid were used. These salts were added as sodium and / or potassium salts with various degrees of neutralization.

[0109] PBS (phosphate-buffered saline) contains sodium chloride, potassium chloride, and phosphate as its major components. Three neutralization points are analyzed in comparison with PBS. Mixtures of 18% PVA (MW 146k-186k, Sigma-Aldrich #363065), 6% bismuth carbonate (Foster) (20 wt% based on solids), and a fixed molar ratio of these phosphate solutions at 51.7 mM were tested with phosphoric acid (Sigma-Aldrich), monosodium (Sigma-Aldrich), and disodium phosphate (Sigma-Aldrich) in water. Monosodium phosphate yielded the highest Young's modulus, and phosphoric acid yielded the highest tensile strength. Figure 17A is a plot of the tensile strength of 18% PVA samples formulated with PBS, monosodium phosphate, disodium phosphate, and phosphoric acid. The effect of other multifunctional (two or more neutralization sites) salts was also evaluated, and the results are plotted in Figure 17B. Boric acid (Sigma-Aldrich), citric acid (Sigma-Aldrich), and phosphoric acid (Sigma-Aldrich) were compared in a 51.7 mM solution of each acid, 18% PVA (Sigma-Aldrich), and 6% bismuth carbonate (Foster's) (20 wt% solids). Boric acid increased both the Young's modulus and the maximum tensile stress, while citric and phosphoric acids remained relatively similar.

[0110] Example 11: Blended Batch of PVA and PAA and Copolymer Extrusion PVA-PAA blend solutions were batched using the following method (see Table 8 for formulation composition). 100 g of water and PVA were added to a high-viscosity jacketed vessel heated to 90 °C and mixed at 600 RPM. The bismuth subcarbonate concentrate was homogenized with the remaining water for 15 minutes, and then 32 g of the concentrate was added to the jacketed reactor at 90 °C, unless otherwise noted. The PVA was then added to the vessel while mixing at 600 RPM. After 1 hour of mixing, the PAA was added to the solution, and mixing was continued for 0.5 hours until the solution was completely homogenous. The polymer was then aliquoted into 20 mL syringes. [Table 8]

[0111] The polymer was reheated to 90°C and degassed at 90°C for 1 hour. The polymer was then extruded into ethanol at about 10°C to about 21°C. The extrudate was left in the ethanol on the monofilament for about 0.5 hours. The extrudate was then transferred to room temperature ethanol, the monofilament was removed, and the extrudate was allowed to dehydrate for 24 hours.

[0112] The extrudates were transferred to a vacuum oven and dried at 50°C for 48 hours. After drying, the samples were poured into USP-grade mineral oil at 120°C and then immersed in the mineral oil at 120°C in a convection oven for 2 hours. The samples were then removed from the mineral and allowed to cool to room temperature. Rinsing / washing was performed once with ethanol and twice with distilled water. The samples were transferred to PBS at 37°C to hydrate before tensile testing and surface evaluation. Tensile testing was performed according to ISO-10555 protocols. Tensile values ​​were not normalized to the cross-sectional area of ​​the sample.

[0113] Figure 18A compares PVA-PAA blends with 450k molecular weight PAA. The 0.1% and 0.4% (w / w) PAA blends in water extruded with 11-13% PVA concentrations exhibited higher tensile strength than the 4.0% blend. Higher water content correlates with the increased proportion of PAA, which may reduce the strength between PVA bonds and therefore tensile strength. Furthermore, the 4.0% 450k PAA blend exhibited a spongy surface. Figure 18B compares PVA-PAA blends with 3m molecular weight PAA. The 3m molecular weight PAA blends at 0.3% and 0.4% (w / w relative to the solvent) exhibited higher tensile strength than the 0.2% blend. The 3m molecular weight PAA-containing blends exhibited approximately half the tensile strength of the 450k PAA-containing blends, except for the 4.0% blend.

[0114] Example 12: Blended batch of PVA and PEG and copolymer extrusion PVA-PEG blend solutions were batched using the following method (see Table 9). The formulation consisted of PVA (Sigma, 146k-186k), bismuth subcarbonate (Foster), 100g distilled water, and PEG 8k (Sigma), PEG 20k (Sigma), or PEG 35k (Sigma). The bismuth subcarbonate was homogenized with water for 15 minutes and then added to a jacketed reactor at 90°C. PVA was then added to the reactor with mixing at 600 RPM for 2 hours. PEG was then added to the solution, and mixing continued for 2 hours until the solution was completely homogenous. The polymer was then aliquoted into 20mL syringes. [Table 9]

[0115] The polymer was reheated to 90°C and extruded into ethanol at approximately 3°C to 21°C. The extrudate was left in the ethanol on the monofilament for approximately 1 hour. The extrudate was then transferred to room temperature ethanol, the monofilament removed, and allowed to dehydrate for 24 hours.

[0116] The extrudates were transferred to a vacuum oven and dried at 50°C for 48 hours. After drying, the samples were poured into USP-grade mineral oil at 120°C and then immersed in the mineral oil at 120°C in a convection oven for 2 hours. The samples were then removed from the oven and cooled to room temperature. Rinsing / washing was performed once with ethanol and twice with distilled water. Prior to tensile testing and surface evaluation, the samples were transferred to distilled water for hydration. Tensile testing was performed according to ISO-10555 protocols. Figure 19 shows the results, comparing PVA-1% PEG blends with various MW PEGs (tensile values ​​were not normalized to the cross-sectional area of ​​the sample). PEG blend extrudates produced smooth surfaces, with the exception of PEG 35k, which developed a scale pattern along the outside of the extrudate. Due to the large standard deviations for all 1% PEG blends, no significant differences were observed in the tensile strength of the 8k, 20k, and 35k PEG co-extrudates. Figures 20A-20C are images of 8k, 20k, and 35k PEG co-extrudates, respectively.

[0117] Example 13: Evaluation of thrombus formation of PVA gel A PVA extrudate sample was prepared by heating 200 g of distilled water to a temperature of 95°C in a jacketed reactor. To this, 40 g of PVA (Sigma, 146k-186k) was added over 5 minutes while mixing at 200 RPM. The polymer was mixed at 300 RPM for 1.5 hours. The polymer was degassed at 90°C for less than 2 hours. The polymer was then extruded into ethanol at -23°C and then stored in ethanol in a -25°C freezer for 24 hours. The sample was allowed to dry for 6 hours.

[0118] After drying, the samples were immersed in glycerol at 120°C for 17 hours. After annealing, the samples were removed, cooled, and rinsed with ethanol. After rinsing, the cores were removed. The samples were then dried at 50°C for 12 hours.

[0119] A sample of PVA with barium sulfate was made by heating 50g of water in a jacketed reaction vessel at 90°C. In a side vessel, 4g of barium sulfate and 50g of water were homogenized at 11k RPM for 15 minutes and then added to the jacketed vessel. This was mixed and heated for 10 minutes. After heating, 16g of PVA (Sigma, 146k-186k) was added and mixed at 360 RPM for approximately 2 hours.

[0120] The PVA-RO polymer mixture was heated to 90°C and extruded into -16°C ethanol. The extrudates were dehydrated at -25°C for 24 hours. The cores were removed and the samples were dried in an incubator at 50°C for approximately 6 hours. After drying, the samples were immersed in glycerol (Sigma) at 120°C for 17 hours. After annealing, the samples were removed, cooled, and rinsed with distilled water. The samples were dried at 50°C for 12 hours and packaged for testing.

[0121] Samples were evaluated for antithrombotic durability testing at Thrombodyne, Inc. (Salt Lake City, UT). Each sample was cut into 15 cm lengths with N=5 per sample group. Prior to testing, samples were sterilized using 12 hours of ethylene oxide exposure. To represent clinical use, samples were hydrated in distilled water for approximately 48 hours prior to evaluation.

[0122] Fresh heparinized bovine blood with autologous 111-labeled platelets was divided into a test sample and a control portion. The sample was inserted into an extracorporeal blood flow loop of 0.25-inch ID polyvinyl chloride tubing for approximately 120 minutes. The blood was maintained at 98°C and pumped through the blood loop using a peristaltic pump for the duration of the study. After 45 minutes in the blood flow loop, the sample was first checked for thrombus and removed after 120 minutes. At the end of the study, the device was explanted from the tubing, rinsed with saline, and placed in a gamma counter for thrombus quantification. Test parameters are shown in Table 10. To allow for simultaneous comparisons without crossover effects, each study consisted of a separate flow system for each test sample and / or control circulating blood from the same animal.

[0123] Samples were assayed for radioactivity and qualitatively evaluated for specific types of thrombus deposition (i.e., adhesion or fibrin deposition). Counting results are shown in Table 10. Percent thrombosis was calculated relative to the average total thrombus formation observed in all test and control groups per animal's blood circulation. Thrombus deposition results are shown in Tables 11-12 and Figure 21A. Visual assessment of thrombus formation is shown in Figure 21B for the commercial control catheter, the 17% PVA extrudate, and the 17% PVA-barium sulfate extrudate. [Table 10] [Table 11] [Table 12]

[0124] Results show a reduction in thrombus formation with the PVA formulation compared with commercially available PICCs. The PVA-RO (barium as the RO agent) formulation was not superior to the control group. Possible reasons include a lack of barium micronization and evidence of larger barium particles on the surface of the extrudate.

[0125] (Further Disclosure) 1. A method for producing a porous solid material comprising heating a mixture comprising at least one water-soluble polymer and a solvent to a temperature above the melting point of at least one polymer in the polymer-solvent mixture, cooling the mixture in a solvent-removing environment to crosslink the polymers to form a crosslinked matrix, and continuing to remove the solvent until the crosslinked matrix becomes a microporous or nanoporous solid material. 2. A method for producing a porous solid material comprising heating a mixture comprising at least one water-soluble polymer and a solvent to a temperature above the melting point of the last polymer in the mixture, forming the mixture (e.g., by molding or extrusion through a die), and passing the formed mixture through a solvent-removing environment. The method may further comprise, for example, one or more of: cooling the mixture in the solvent-removing environment; and continuing to remove the solvent until the crosslinked matrix is ​​a nanoporous solid material or until it is a microporous solid material. 3. A method for producing a porous polymeric material and / or a hydrophilic porous solid, comprising heating a mixture comprising at least one water-soluble polymer and a solvent to a temperature above the melting point of the polymer, forming a mixture (e.g., by extrusion through a die), and passing the formed mixture through a solvent removal environment. In the case of extrusion, a continuous porous solid is formed as the polymer passes through the die. Embodiments include removing at least 50% w / w of the solvent in less than 60 minutes (or less than 1, 2, 5, or 10 minutes). Embodiments include removing at least 90% w / w of the solvent in less than 60 minutes (or less than 1, 2, 5, or 10 minutes). The resulting material may be, for example, a hydrogel, a microporous material, or a nanoporous material. The extrusion may be cold extrusion. 4. The method of any of 1-3, wherein a salt is present in the mixture or added during the process. The salt may be useful for aiding in the dissolution and / or crosslinking of the polymer. The salt may be, for example, anionic, cationic, divalent, or trivalent. Additionally, salts or other additives that may have two or more hydrogen bond acceptors and / or hydrogen bond donor sites may be added to the polymer. 5. The method according to any one of 1 to 4, wherein crosslinking occurs while the mixture is cooling and / or in a solvent-removing environment. 6. The method of any one of 1 to 5, wherein the porous solid is crosslinked with bonds that are covalent bonds or physical crosslinks. These embodiments include the absence of covalent bonds when physical crosslinks are included. 7. The method according to any one of 1 to 6, further comprising annealing the porous solid. 8. The method of any one of 1 to 7, further comprising aligning the polymer chains of the continuous porous solid substantially parallel to one another. 9. The method of claim 8, wherein aligning the polymer chains comprises passing the mixture through a die. 10. The method according to any one of 1 to 9, wherein the at least one water-soluble polymer comprises PVA, PAA, PEG, PVP-I or PVP. 11. The method of any of 1-10, wherein at least one water-soluble polymer contains a hydroxyl or carboxyl pendant group. 12. The method of any one of 1 to 11, wherein the mixture has at least one polymer in the mixture, the polymer being at a concentration of 5% to 50% w / w of the mixture. 13. The method of any one of 1 to 11, wherein the mixture has at least one polymer in the mixture at a concentration of 5% to 50% w / w of polymer to solvent. 14. The method according to claim 12, wherein at least 50% of the solid material forming the porous solid is PVA, PAA, PEG or PVP. 15. The method according to any one of 1 to 14, wherein the crosslinking is completed while the porous solid is in a solvent-removing environment. 16. The method of any one of 1 to 14, wherein the porous solid is prepared as a tube. 17. The method of any of 1-15, wherein exposure to the solvent removal environment removes at least half of the solvent in less than 60 minutes. 18. The method of any of 1-17, comprising exposure to a solvent-removing environment for at least 1 hour, e.g., exposure to a dehydrating environment for a period during which at least about 50% w / w of the total solvent is removed. 19. The method of any of 1 to 18, wherein the porous solid has a Young's modulus at EWC of at least 5 MPa. 20. The method of any of 1 to 18, wherein the porous solid has, at EWC, an elongation at break of at least 200%, a Young's modulus of at least 5 MPa, and a tensile strength of at least 20 MPa. 21. The method of any one of 1 to 20, wherein the polymeric material further comprises a second material in contact with the porous solid, for example a second material which is a reinforcing material, fiber, wire or plastic fiber. 22. The method of any one of 1 to 21, wherein the mixture comprises at least two polymers. 23A. The method of any of 1-22, wherein at least one polymer comprises a first hydrophilic polymer and a second hydrophilic polymer. For example, the first polymer and the second polymer are independently selected from PVA, PAA, PEG, PVP-I, and PVP. And / or, for example, the first polymer and the second polymer are present in a ratio of 1 part second polymer to 1 to 100,000 parts first polymer (w / w). 23B. The method of any of 1-22, wherein the at least one polymer comprises a first concentration of a first polymer and a second concentration of a second polymer, the first concentration being 10%-60% w / w and the second polymer being 1%-10% w / w, where w / w is the weight of the polymer relative to the sum of the total weights of the polymer and solvent in the mixture. 24. The method according to any one of 1 to 23, wherein the mixture further comprises a salt or other additive for cross-linking (23 refers to 23A and 23B). 25. The method of any one of 1 to 24, further comprising an additive capable of having two or more hydrogen bond acceptor and / or hydrogen bond donor sites. 26. The method according to any one of 22 to 25, wherein at least two polymers (e.g., two or more of polyvinylpyrrolidone, polyvinylpyrrolidone-iodine, polyethylene glycol, and polyacrylic acid) are co-extruded. 27. The method of claim 26, wherein the coextruded polymers are mixed in the die head. 28. The method of any one of 22 to 26, wherein the water-soluble polymer is a first polymer formed as a first layer, and further comprises a second polymer formed as a second layer. 29. The method of any of 22-28, wherein the first polymer and the second polymer are coextruded as separate layers. 30. The method of any of 28-29, wherein the first polymer layer is formed as a sheet and the second polymer layer is formed in contact with the sheet. 31. The method of any one of 1 to 31, further comprising adding a third polymer. 32. The method of claim 31, wherein the third polymer is polyvinylpyrrolidone, polyvinylpyrrolidone-iodine, PEG, or polyacrylic acid. 33. The method of any of 21 to 32, wherein the second material is at least part of a reinforcing material, fiber, wire, braid material, braided wire, braided plastic fiber, or connector. 34. The method of any of 21 to 32, comprising a second material or polymer provided as a layer on or in the material. 35. The method of any of 21 to 34, wherein the second polymer or second material comprises polyethylene glycol or a polyol (e.g., the polyol is a polymer having at least three hydroxyl groups or the polyol is glycerin). 36. The method of any one of 1 to 35, further comprising adding a brazing material in contact with the porous solid. 37. The method of any one of 1 to 36, wherein preparing the mixture comprises adding PVA to a solvent. 38. The method of any of 1-37, wherein the solvent comprises (or consists essentially of) water, alcohol, ethanol, a water-miscible organic solvent, or a combination thereof. 39. The method according to any one of 1 to 38, wherein the heated solvent is at a temperature of 70 to 120°C. 40. The method according to any one of 1 to 39, wherein the PVA concentration in the mixture is 15% to 25% w / w. 41. The method of any of 1 to 40, comprising cooling the mixture after or during formation, and passing the mixture through a cooling bath, a cooled mold, a frozen mold, or liquid nitrogen. 42. The method of any of 1-41, wherein the solvent removal environment is a chamber filled with a gas, such as dry air or nitrogen or a gas at a pressure below atmospheric pressure. 43. The method according to any one of 1 to 41, wherein the solvent removal environment is a solution comprising ethanol or a polyol. 44. The method of any of 1 to 41, wherein the solvent removal environment comprises a solution having an osmotic pressure that exceeds the osmotic pressure of the mixture. 45. The method of any of 1-44, wherein the solvent removal environment or solution comprises a salt present in a concentration of at least 0.1 molar. 46. ​​The method of any of 44-41, wherein the solvent removal environment or solution comprises a salt present at a concentration in the range of 0.1 to 8 molar. 47. The method of any of 1-43, wherein the solvent removal environment or solution further comprises an osmotic agent, such environment having an osmotic pressure greater than the osmotic pressure of the formed mixture. 48. The method of any of 1 to 47, wherein the solvent removal process is carried out over a period of 3 to 48 hours. 49. The method of any of 1 to 48, wherein the solvent removal process is carried out while the polymer is crosslinking. 50. The method of claim 49, wherein crosslinking is completed before the solvent removal process is completed. 51. The method of any of 1 to 50, further comprising an annealing process comprising heating the porous solid material to an annealing temperature. 52. The method according to claim 51, wherein the annealing temperature is 90 to 250°C. 53. A method according to any one of 51 to 52, wherein the annealing is carried out in the absence of air and / or oxygen and / or water. 54. A method according to any one of 50 to 53, wherein the annealing is carried out at least partially in a liquid bath. 55. The method of claim 54, wherein the liquid bath comprises mineral oil and / or polyol and / or glycerin. 56. A method according to any one of 50 to 55, wherein annealing is carried out for a period of 3 hours to 1 week. 57. The method of any one of 1 to 56, wherein the mixture is passed through a die. 58. The method of 57, wherein the mixture is formed as a tube having at least one lumen. 59. The method of claim 57, wherein the tube is formed around the core. 60. The method according to claim 59, wherein the core is air, water, liquid, solid or gas. 61. The method of any of 57-60, further comprising a second material or polymer extruded as a layer onto or within the crosslinked matrix. 62. The method of any of 57-61, wherein the mixture is a first mixture and the method further comprises a second mixture comprising yet another material, and the second mixture is also passed through an extrusion die to form a second tubular layer. 63. The method of claim 61, wherein the second material is or comprises a reinforcement, fiber, wire, or plastic fiber. 64. Any of the methods 57-63, wherein the solid material surrounds the core and is confined within the tubular hydrogel layer or, if present, the second tubular layer. 65. The method of claim 64, wherein the solid material comprises wire, braid, metal wire, plastic wire, metal braid, plastic braid, mesh, fabric mesh, metal mesh, or plastic mesh. 66. The method of any of 1-65, wherein the porous solid is formed as a continuous form, a tube, a sheet, a solid cylinder, a tube with multiple lumens, or a ring. 67. The method of any of 1-66, wherein the porous material has an aspect ratio of at least 4:1 (length:diameter), alternatively an aspect ratio of 3:1 to 100:1. 68. A method according to any one of 1 to 67, wherein the porous material is hydrophilic. 69. A catheter comprising a biocompatible material, a polymeric material or a medically acceptable hydrophilic porous solid. 70. A catheter comprising a biocompatible material, polymeric material, or porous polymeric solid having a tensile strength of at least 20 MPa, a Young's modulus of at least 5 MPa, a solids content of 10% to 50% w / w at EWC, a solids content of at least 10% w / w or at least 33% w / w at EWC, or a solids content of 10, 20, 30, 33, 35, 40, 50, or 60% w / w at EWC, e.g., a polymeric material comprising a hydrophilic porous solid having a solids content of at least 33% w / w at EWC and a porous solid having a Young's modulus of at least 5 MPa, and formed with, e.g., an aspect ratio of at least 10:1. For example, a polymeric material wherein the porous solid comprises at least one polymer, the at least one polymer comprising a first hydrophilic polymer and a second hydrophilic polymer, the second hydrophilic polymer being present in an amount of 1 part to 1000 parts per 10,000 parts of the first polymer. 71. The biomaterial according to 69 or 70, wherein the porous polymer solid comprises a crosslinked hydrophilic polymer. 72. The biomaterial according to claim 70 or 71, having a porous polymer solid having a solids content of at least 33% w / w at equilibrium water content (EWC) in saline at 37°C, or alternatively, a solids content of at least 50% w / w or in the range of 40% to 99% w / w. 73. A biomaterial according to any one of 70 to 72, wherein the nanoporous material has a solids content of at least 50% w / w in the EWC and has a tensile strength of at least 20 MPa and / or a Young's modulus of at least 5 MPa. 74. A biomaterial according to any one of 70 to 73, having a pore diameter of 100 nm or less. 75. A biomaterial according to any one of 70 to 74, having internal alignment of the polymer structure. 76. A biomaterial according to any one of 70 to 75, having a porous material in which the PVA content of the hydrogel in the EWC is at least 50% w / w and which, when placed in excess saline and allowed to freely expand, swells by less than 50% w / w in the EWC. 77. A biomaterial according to any one of 70 to 76, which is a nanoporous or microporous material comprising or consisting essentially of at least one hydrophilic polymer, PVA, PAA, PEG or PVP or a combination thereof. 78. A biomaterial according to any one of 70 to 77, wherein the porous material comprises a matrix of a cross-linked hydrophilic polymer, the water-soluble polymer comprising hydroxyl and / or carboxyl pendant groups. 79. A biomaterial according to any one of 70 to 78, wherein the porous material comprises a crosslinked polymer having a molecular weight before crosslinking of at least 50 kg / mol, or a molecular weight (g / mol) of 50 kJ to 1000 kJ. 80. A biomaterial according to any one of 70 to 79, wherein at least 50% of the solid material forming the porous material is PVA, PAA, PEG or PVP. 81. A biomaterial according to any one of 70 to 80, wherein the porous material is crosslinked with covalent crosslinks or does not contain covalent crosslinks and / or does not contain a covalent crosslinking agent. 82. A biomaterial according to any one of 70 to 81, wherein the nanoporous material is crosslinked by physical crosslinking. 83. The biomaterial according to 82, wherein the physical crosslinks are ionic bonds, hydrogen bonds, electrostatic bonds, van der Waals forces or hydrophobic packing. 84. A biomaterial according to any one of 70 to 83, further comprising a layer of a second material or second polymer. 85. A biomaterial according to any one of 70 to 83, further comprising a second material encapsulated within the porous solid. 86. The biomaterial according to claim 85, wherein the second material is at least part of a reinforcement material, fiber, wire, braid material, braided wire, braided plastic fiber or connector. 87. A biomaterial according to any of 84 to 86, wherein the coating or layer of the second material or the second polymer comprises polyethylene glycol or a polyol (e.g., the polyol is a polymer having at least three hydroxyl groups, or the polyol is glycerin). 88. A biomaterial according to any one of 84 to 87, wherein the coating or layer of the second material or the second polymer comprises PVA, PAA, PEG or PVP. 89. A biomaterial according to any one of 70 to 88, further comprising a radiopaque (RO) agent, which may be, for example, a coating, a layer on or in the biomaterial. 90. The biomaterial according to any one of 70 to 83, which consists essentially of PVA or the porous material consists essentially of PVA. 91. The biomaterial according to any one of 70 to 91, which has a tubular shape. 92. A biomedical catheter comprising any one of the biological materials of 70 to 92. 93. The catheter according to 92, which is a central venous catheter, a peripherally inserted central venous catheter (PICC), a tunneled catheter, a dialysis catheter, a central venous catheter, a peripheral central venous catheter, a midline catheter, a peripheral catheter, a tunneled catheter, a dialysis access catheter, a urinary catheter, a neurocatheter, an intraperitoneal catheter, an intra-aortic balloon pump catheter, a diagnostic catheter, an interventional catheter or a drug delivery catheter. 94. A catheter described in any one of 92 to 93, comprising multiple lumens. 95. A biomedical catheter comprising a medically acceptable material, such as any of the materials of 1-94 (e.g., a hydrophilic nanoporous material, a hydrophilic microporous material, or a hydrogel).

[0126] This application claims priority to U.S. Provisional Application No. 62 / 271,150, filed December 22, 2015, which is incorporated herein by reference in its entirety.

Claims

1. A method for producing a hydrophilic porous solid tube comprising a polymer mixture containing at least one water-soluble polymer and a solvent, wherein the polymer mixture contains the at least one water-soluble polymer at a concentration of at least 10% w / w, A step of heating the polymer mixture to a temperature higher than the melting point of the polymer mixture. A step of extruding the polymer mixture as a tube, The process of removing the solvent from the tube at a temperature above the freezing point of the solvent until the tube becomes a porous solid. It consists of, The tube is a porous solid containing at least one water-soluble polymer, The porous solid tube contains interconnected pores with a diameter of up to 100 nm. A method wherein the porous solid tube has a Young's modulus of 5 to 100 MPa at equilibrium water content (EWC).

2. The method according to claim 1, wherein the hydrophilic porous solid tube is chemically crosslinked.

3. The method according to claim 1, wherein the hydrophilic porous solid tube comprises chemically crosslinked poly(acrylic acid) (PAA), chemically crosslinked poly(vinyl alcohol) (PVA), chemically crosslinked poly(vinylpyrrolidone) (PVP), and / or chemically crosslinked polyethylene glycol (PEG).

4. The method according to claim 3, wherein the hydrophilic porous solid tube comprises two or more selected from the group consisting of chemically crosslinked PAA, chemically crosslinked PVA, chemically crosslinked PVP, and / or chemically crosslinked PEG.

5. The method according to any one of claims 1 to 4, wherein the extrusion step includes extruding a polymer mixture through a die.

6. The method according to any one of claims 1 to 5, wherein the at least one water-soluble polymer comprises poly(vinyl alcohol) (PVA), and the PVA accounts for at least 50% w / w of the solid content of the porous solid.

7. The method according to any one of claims 1 to 6, wherein the hydrophilic porous solid tube has a solid content of 30 to 90% w / w at the equilibrium water content (EWC) of the hydrophilic porous solid tube.

8. The method according to any one of claims 1 to 7, wherein the polymer mixture is not heated above its boiling point, and the mixture is formed at a temperature lower than the melting point of the polymer mixture.

9. The method according to claim 5, wherein the polymer mixture exits the die and passes through a bath at a temperature of 25°C or lower to remove the solvent from the mixture.

10. The method according to any one of claims 1 to 9, wherein the hydrophilic porous solid tube comprises at least one lumen.

11. The method according to any one of claims 1 to 10, wherein the at least one water-soluble polymer comprises a first polymer at a first concentration and a second polymer at a second concentration, the first concentration being 10 to 60% w / w, the second polymer being 1 to 10% w / w, and the w / w being the weight of the polymer relative to the total weight of the polymer and the solvent in the mixture.

12. The method according to any one of claims 1 to 11, wherein the polymer mixture further comprises an additive that can have two or more hydrogen bond acceptors and / or hydrogen bond donors.

13. The method according to any one of claims 1 to 12, wherein the polymer mixture is extruded through a die and further comprises a core that passes through the die, and the hydrophilic porous solid tube is formed around the core.

14. The method according to claim 13, wherein the core is tubular, liquid, or gas.

15. The method according to any one of claims 1 to 14, further comprising a radiopaque agent in the polymer mixture.

16. The method according to any one of claims 1 to 15, further comprising removing the solvent by exposing the hydrophilic porous solid tube to a solvent removal environment for at least one hour.

17. The method according to any one of claims 1 to 16, further comprising annealing the hydrophilic porous solid tube at a temperature below the melting point of a polymer mixture of at least one water-soluble polymer in the solvent.

18. The method according to any one of claims 1 to 17, wherein the hydrophilic porous solid tube has lumens and an aspect ratio of at least 10:

1.

19. A hydrophilic porous solid tube formed by the method described in any one of claims 1 to 18.

20. A catheter comprising a hydrophilic porous solid tube having a lumen, comprising a central venous catheter, a peripheral to central vein catheter (PICC), a tunnel catheter, a dialysis catheter, a central venous catheter, a peripheral central venous catheter, a midline catheter, a peripheral catheter, a tunnel catheter, a dialysis access catheter, a urinary catheter, a nerve catheter, an intraperitoneal catheter, an intra-aortic balloon pump catheter, a diagnostic catheter, an interventional catheter, or a drug delivery catheter, comprising a hydrophilic porous solid tube formed by the method of any one of claims 1 to 17.

21. The hydrophilic porous solid tube comprises at least one crosslinked water-soluble polymer that forms the hydrophilic porous solid tube. An article comprising a hydrophilic porous solid tube having interconnected pores up to 100 nm in diameter, having a solid content of 33 to 90% w / w at equilibrium water content (EWC), and having a Young's modulus of 5 to 100 MPa at equilibrium water content (EWC).

22. The article according to claim 21, wherein the hydrophilic porous solid tube is chemically crosslinked.

23. The article according to claim 21, wherein the hydrophilic porous solid tube comprises chemically crosslinked PAA, chemically crosslinked PVA, chemically crosslinked PVP, and / or chemically crosslinked PEG.

24. The article according to claim 23, wherein the hydrophilic porous solid tube comprises two or more selected from the group consisting of chemically crosslinked PAA, chemically crosslinked PVA, chemically crosslinked PVP, and / or chemically crosslinked PEG.

25. An article according to any one of claims 21 to 24, wherein the aspect ratio is at least 10:

1.

26. The article according to any one of claims 21 to 25, wherein the hydrophilic porous solid tube comprises at least one polymer, and at least 50% w / w of the at least one polymer is poly(vinyl alcohol) (PVA).

27. The article according to any one of claims 21 to 26, wherein the hydrophilic porous solid tube has a solid content of 50 to 90% w / w at the equilibrium water content (EWC) of the hydrophilic porous solid tube.

28. The article according to any one of claims 21 to 27, wherein the at least one polymer comprises a first hydrophilic polymer and a second hydrophilic polymer, and the second hydrophilic polymer is present in an amount of 1 to 1,000 parts per 10,000 parts of the first hydrophilic polymer.

29. The article according to any one of claims 21 to 28, further comprising a layer of a second material in contact with the hydrophilic porous solid tube.

30. The article according to any one of claims 21 to 29, further comprising a second material in the hydrophilic porous solid tube or a coating of a hydrophobic material in the hydrophilic porous solid tube.

31. The article according to claim 30, wherein the second material is at least a portion of a reinforcing material, fiber, wire, braiding material, braiding wire, braiding plastic fiber, or connector.

32. The article according to any one of claims 21 to 31, further comprising a radiopaque agent.

33. Use of the article according to any one of claims 21 to 32 as a biomedical material or a catheter material.

34. A catheter comprising a hydrophilic porous solid tube comprising at least one crosslinked water-soluble polymer that forms a hydrophilic porous solid tube, The hydrophilic porous solid tube comprises interconnected pores up to 100 nm in diameter, has a solid content of 33-90% w / w at the equilibrium water content (EWC) of the hydrophilic porous solid tube, and has a Young's modulus of 5-100 MPa at the EWC of the hydrophilic porous solid tube, and is a catheter.

35. The catheter according to claim 34, wherein the hydrophilic porous solid tube is chemically crosslinked.

36. The catheter according to claim 34, wherein the hydrophilic porous solid tube comprises chemically crosslinked PAA, chemically crosslinked PVA, chemically crosslinked PVP, and / or chemically crosslinked PEG.

37. The catheter according to claim 36, wherein the hydrophilic porous solid tube comprises two or more selected from the group consisting of chemically crosslinked PAA, chemically crosslinked PVA, chemically crosslinked PVP, and / or chemically crosslinked PEG.

38. A hydrophilic porous solid tube comprising a polymer material formed by chemically crosslinking at least one water-soluble polymer to form a hydrophilic porous solid tube, Each of the hydrophilic porous solid tubes has a pore with a diameter of 1 μm or less. The hydrophilic porous solid tube has a solid content of 33 to 90% w / w at equilibrium water content (EWC) and a Young's modulus of 5 to 100 MPa at equilibrium water content (EWC).

39. The hydrophilic porous solid tube according to claim 38, wherein the polymer material comprises chemically crosslinked PAA, chemically crosslinked PVA, chemically crosslinked PVP, and / or chemically crosslinked PEG.

40. The hydrophilic porous solid tube according to claim 39, wherein the polymer material comprises two or more selected from the group consisting of chemically crosslinked PAA, chemically crosslinked PVA, chemically crosslinked PVP, and / or chemically crosslinked PEG.

41. The hydrophilic porous solid tube according to any one of claims 38 to 40, wherein the hydrophilic porous solid tube comprises at least one crosslinked polymer, and at least 50% w / w of the at least one polymer is poly(vinyl alcohol) (PVA).

42. A hydrophilic porous solid tube according to any one of claims 38 to 41, comprising a lumen, and being a central venous catheter, a peripheral to central vein catheter (PICC), a tunnel catheter, a dialysis catheter, a peripheral central venous catheter, a midline catheter, a peripheral catheter, a dialysis access catheter, a urinary catheter, a nerve catheter, an intraperitoneal catheter, an intra-aortic balloon pump catheter, a diagnostic catheter, an interventional catheter, or a drug delivery catheter.

43. A hydrophilic porous solid tube according to any one of claims 38 to 42, further comprising a connector or extension attached to a catheter.

44. A hydrophilic porous solid tube according to any one of claims 38 to 43, wherein at least one polymer comprises a first hydrophilic polymer and a second hydrophilic polymer, and the second hydrophilic polymer is present in an amount of 1 to 1,000 parts per 10,000 parts of the first hydrophilic polymer.

45. A hydrophilic porous solid tube according to any one of claims 38 to 44, wherein, at equilibrium water content (EWC), the outer diameter of the hydrophilic porous solid tube is 0.5 mm to 12.7 mm (0.02 to 0.50 inches), the inner diameter of the hydrophilic porous solid tube is 0.25 mm to 10.16 mm (0.01 to 0.40 inches), and the outer diameter is at least 0.0254 mm (0.001 inches) larger than the inner diameter.

46. A catheter comprising a polymer material formed by chemically crosslinking at least one water-soluble polymer to form a hydrophilic porous solid tube, Each of the hydrophilic porous solid tubes has a pore with a diameter of 1 μm or less. The hydrophilic porous solid tube is a catheter having a solid content of 33 to 90% w / w at equilibrium water content (EWC) and a Young's modulus of 5 to 100 MPa at EWC.

47. The catheter according to claim 46, wherein the hydrophilic porous solid tube comprises chemically crosslinked PAA, chemically crosslinked PVA, chemically crosslinked PVP, and / or chemically crosslinked PEG.

48. The catheter according to claim 47, wherein the hydrophilic porous solid tube comprises two or more selected from the group consisting of chemically crosslinked PAA, chemically crosslinked PVA, chemically crosslinked PVP, and / or chemically crosslinked PEG.

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