High strength porous materials incorporating water soluble polymers

Abstract

To provide high strength biomedical materials and processes for making the same.SOLUTION: There are provided nanoporous hydrophilic solids that can be extruded with a high aspect ratio to make high strength medical catheters and other devices with lubricious and biocompatible surfaces. Polymers may be entrapped in pores of materials to provide a durable modification of the materials. The articles provided are substantially non-thrombogenic.SELECTED DRAWING: Figure 1A

Description

Related Applications

[0001] This application claims priority under 35 U.S.C. § 119(e) to co-pending U.S. Provisional Application No. 62 / 523,100, entitled "High Strength Porous Materials Incorporating Water-Soluble Polymers," filed June 21, 2017, which is incorporated herein by reference in its entirety for all purposes. [Technical Field]

[0002] The technical field generally relates to porous biomaterials, such as high strength hydrophilic nanoporous biomaterials, for example for medical devices. [Background technology]

[0003] Biomaterials with high strength, low thrombogenicity, and smooth surface properties are useful in medical technology. Surface treatments generally improve the properties of materials so that the bulk material's properties are preserved and the surface has favorable properties compared to those of the bulk material. However, despite such treatments, thrombus formation on medical devices can restrict flow through and around the device, which can adversely affect infusion and aspiration and often necessitates the use of expensive antithrombotic drugs or even device replacement to resolve the blockage. For example, within seconds of placing a catheter in the bloodstream, blood proteins (fibrinogen and collagen) and host cells (e.g., platelets) begin to deposit on the device surface. Thrombus formation can restrict flow through and around the device or become brittle and become liberated into the bloodstream, causing deep vein thrombosis and pulmonary embolism in several large-scale clinical trials. Complications seen with such devices can prolong hospital stays and increase patient morbidity and mortality.

[0004] Therefore, there is a need for improved devices and methods. Summary of the Invention

[0005] Disclosed herein are biomaterials that may be useful for manufacturing medical devices. In some embodiments, provided herein are materials and methods for the fabrication of strong, smooth, biocompatible biomaterials for various medical device applications. Disclosed herein are processing techniques for producing materials 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. Porous materials may also be fabricated with polymers in the pores of the material. These processes can be performed without the use of chemical crosslinkers or radiation crosslinking. Bulk incorporation of polymers into the pores of a material is in contrast to coating or adhesive processes that rely solely on the adhesion of a surface treatment to cover the pores or to the surface of the bulk material.

[0006] In one aspect, an article is provided. In some embodiments, the article comprises a polymeric material comprising a first water-soluble polymer having a plurality of pores and a second water-soluble polymer, the same or different from the first water-soluble polymer, disposed within at least a portion of the plurality of pores, wherein the article is substantially non-thrombogenic.

[0007] In some embodiments, an article comprises a polymeric material comprising a first water-soluble polymer having a plurality of pores, a second water-soluble polymer, the same or different from the first water-soluble polymer, disposed within at least a portion of the plurality of pores, and an osmotic agent present in the polymeric material, wherein the polymeric material has a Young's modulus of 500 MPa or more in a dehydrated state and a Young's modulus of 300 MPa or less and 5 MPa or more at an equilibrium water content state.

[0008] In another aspect, a dehydrated article is provided. In some embodiments, the dehydrated article comprises a polymeric material including a first water-soluble polymer having a plurality of pores and a second water-soluble polymer, different from the first water-soluble polymer, disposed within at least some of the plurality of pores, the polymeric material having a water content in a dehydrated state of less than 5 wt. % and greater than or equal to 0.1 wt. %, and the polymeric material is configured to swell from the dehydrated state to an equilibrium water content state by an amount greater than or equal to 5 wt. % and less than or equal to 50 wt. % within 60 minutes at 25°C.

[0009] In some embodiments described above and herein, the plurality of pores has an average pore size (or average pore diameter) of 500 nm or less and 10 nm or more. In some embodiments, at least 50% of the plurality of pores have a diameter of 1 μm or less. In some embodiments described above and herein, the article has a porosity of 5% or more and 50% or less in a dehydrated state.

[0010] In some embodiments described above and herein, the article is configured to swell from a dehydrated state to an equilibrium moisture content state by an amount of 5% w / w or more and 50% w / w or less. In some embodiments described above and herein, swelling occurs in water within 60 minutes. In some embodiments, swelling occurs in standard normal saline within 60 minutes.

[0011] In some embodiments described above and herein, the article has a Young's modulus of 1 GPa or greater in a dehydrated state. In some embodiments described above and herein, the article has a Young's modulus of 100 MPa or less and 5 MPa or greater in an equilibrium moisture content state.

[0012] In some embodiments described above and herein, the article is substantially smooth at equilibrium moisture content. In some embodiments described above and herein, the article has a surface roughness of 500 nm (Ra) or less at equilibrium moisture content. In some embodiments described above and herein, the article has a coefficient of friction of 0.10 or less at equilibrium moisture content.

[0013] In some embodiments described above and herein, the article includes an osmotic agent present in the polymeric material in an amount of 0.05% w / w or more and 2% w / w or less, based on the total article weight. In some embodiments described above and herein, the osmotic agent is selected from the group consisting of phosphate, borate, sodium chloride, citrate, ethylenediaminetetraacetate, sulfite, sulfate, hyposulfite, metal oxides, selenium dioxide, selenium trioxide, selenious acid, selenic acid, nitrate, silicate, and botanic acid.

[0014] In some embodiments described above and herein, the polymeric material has a water contact angle of 45 degrees or less at equilibrium water content.

[0015] In some embodiments described above and herein, the first water-soluble polymer is present in the article in an amount of 20% w / w or more and 95% w / w or less at equilibrium moisture content. In some embodiments described above and herein, the first water-soluble polymer does not contain a covalently bound crosslinker. In some embodiments described above and herein, the first water-soluble polymer is selected from the group consisting of poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylsulfobetaine), poly(acrylsulfobetaine), poly(methacrylcarboxybetaine), poly(acrylcarboxybetaine), povidone, polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof.

[0016] In some embodiments described above and herein, the polymeric material comprises a mixture comprising a first water-soluble polymer and a third water-soluble polymer, wherein the third water-soluble polymer is selected from the group consisting of poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylsulfobetaine), poly(acrylsulfobetaine), poly(methacrylcarboxybetaine), poly(acrylcarboxybetaine), povidone, polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof.

[0017] In some embodiments described above and herein, the second water-soluble polymer is selected from the group consisting of poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylsulfobetaine), poly(acrylsulfobetaine), poly(methacrylcarboxybetaine), poly(acrylcarboxybetaine), povidone, polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof.

[0018] In some embodiments described above and herein, the article is, or is designed for use with, a medical device such as a catheter, a balloon, a shunt, a wound drain, an infusion port, a drug delivery device, a tube, a guidewire, a contraceptive device, a feminine hygiene device, an endoscope, a graft, a pacemaker, an implantable cardioverter-defibrillator, a cardiac resynchronization device, a cardiovascular device lead, a ventricular assist device, an endotracheal tube, a tracheostomy tube, an implantable sensor, a ventilator pump, and an ophthalmic device. In some embodiments described above and herein, the catheter is selected from the group consisting of central venous catheters, peripheral central catheters, midline catheters, peripheral catheters, tunneled catheters, dialysis access catheters, urinary catheters, neurological catheters, percutaneous transluminal angioplasty catheters, and peritoneal catheters.

[0019] In some embodiments described above and herein, the second water-soluble polymer is disposed within the bulk of the first water-soluble polymer.

[0020] In some embodiments described above and herein, sorption of less than 0.5 wt / wt% of the therapeutic agent into the bulk of the first water-soluble polymer occurs at equilibrium water content after rinsing with 5 times the volume of the article with water or normal saline.

[0021] In some embodiments described above and herein, an article comprises a first component comprising a water-soluble polymer; a second component adjacent to the first component, the second component comprising a plurality of surface features configured to mechanically retain the second component within the first component; a first thermoplastic layer disposed between the first and second components; and a second thermoplastic layer in contact with an exterior surface of the first component.

[0022] In some embodiments described above and herein, an article comprises a first component comprising a water-soluble polymer and a second component adjacent to the first component, the second component comprising a plurality of surface features configured to mechanically retain the second component within the first component, wherein the article has a bond strength of 10 N or greater at the interface (or boundary) between the first component and the second component.

[0023] In some embodiments described above and herein, the article comprises a polymeric material comprising a water-soluble polymer and a component mechanically coupled to the polymeric material, wherein the polymeric material has a water content in a dehydrated state of less than 5 wt. % and greater than or equal to 0.1 wt. %; the polymeric material is configured to swell from the dehydrated state to an equilibrium water content state by an amount greater than or equal to 5 wt. % and less than or equal to 50 wt. % within 60 minutes; and the polymeric material is substantially non-thrombogenic.

[0024] In some embodiments described above and herein, the second component is thermally bonded to the first component, and in some embodiments described above and herein, the second component has a Young's modulus greater than the Young's modulus of the first component.

[0025] In some embodiments described above and herein, the interface between the first and second components is fluidly sealed. In some embodiments described above and herein, the interface between the first and second components is configured to withstand injection pressures of 100 PSI or greater.

[0026] In some embodiments described above and herein, the article includes at least a first thermoplastic layer disposed between a first component and a second component. In some embodiments described above and herein, the second component is disposed adjacent to the first component prior to sorption of the second water-soluble polymer. In some embodiments described above and herein, the second component is disposed adjacent to the first component after sorption of the second water-soluble polymer and re-extraction of the second water-soluble polymer with a solvent.

[0027] In some embodiments described above and herein, the first component has a porosity of 5% or greater. In some embodiments described above and herein, the first component comprises a plurality of pores having an average pore size of 500 nm or less and 10 nm or greater.

[0028] In some embodiments described above and herein, the first component is configured to swell from a dehydrated state to an equilibrium water content state by an amount greater than or equal to 5% w / w and less than or equal to 50% w / w. In some embodiments described above and herein, the first component has a Young's modulus of greater than or equal to 1 GPa in the dehydrated state.

[0029] In some embodiments described above and herein, the first component comprises a second material disposed within the pores of the water-soluble polymer.

[0030] In some embodiments described above and herein, the first component is substantially non-thrombogenic.

[0031] In some embodiments described above and herein, the article includes an osmotic agent present in the polymeric material in an amount of 0.05 wt% or greater based on the total article weight in a dehydrated state. In some embodiments described above and herein, the osmotic agent is selected from the group consisting of phosphate, borate, sodium chloride, citrate, ethylenediaminetetraacetate, sulfite, sulfate, hyposulfite, metal oxides, selenium dioxide, selenium trioxide, selenious acid, selenic acid, nitrate, silicate, and botanic acid.

[0032] In some embodiments described above and herein, the first component does not include covalent crosslinks.

[0033] In some embodiments described above and herein, the article further comprises a polyurethane dipping layer between the first component and the second component.

[0034] In some embodiments described above and herein, the article comprises a first component comprising a water-soluble polymer and a plurality of pores, a second component comprising a first thermoplastic material disposed within at least some of the plurality of pores, and a third component comprising a second thermoplastic material associated with the second component, and in some embodiments described above and herein, the third component is thermally bonded to the second component.

[0035] In some embodiments described above and herein, the first thermoplastic material is at least partially swellable in water at 25°C.

[0036] In some embodiments described above and herein, the third component is solvent bonded to the first thermoplastic material.

[0037] In some embodiments described above and herein, the first thermoplastic and / or the second thermoplastic may be selected from the group consisting of polyurethane elastomers, silicone elastomers, silicone-polyurethane copolymers, polyethylene, polypropylene, styrene-isoprene-butadiene copolymers, vinyl acetate homopolymers and copolymers such as ethylene-vinyl acetate copolymers, polyvinyl chloride, acrylate and methacrylate homopolymers and copolymers, polyvinylpyrrolidone, 2-pyrrolidone, polyacrylonitrile butadiene, polycarbonate, polyamide, polyether block amide, fluoropoly The polymers are selected from the group consisting of homopolymers and copolymers of ethylenediaminetetraacetic acid (e.g., homopolymers and copolymers of polytetrafluoroethylene and polyvinyl fluoride), fluorinated ethylene propylene, polystyrene, homopolymers and copolymers of styrene acrylonitrile, homopolymers and copolymers of styrene butadiene, cellulose acetate, homopolymers and copolymers of acrylonitrile butadiene styrene, polymethylpentene, polysulfone, polyester, polyimide, polyisobutylene, polymethylstyrene, polyoxymethylene, and homopolymers and copolymers of poly(lactic acid), poly(glycolic acid), and poly(caprolactone).

[0038] In another aspect, compositions are provided, in some embodiments, the compositions include an aqueous solution, an osmotic agent present in the solution at a concentration of 0.1 M or more and 8 M or less, a radio-opacifying agent present in the solution in an amount of 0 wt. % or more and 40 wt. % or less, and a water-soluble polymer having a molecular weight of 40 kDa or more and 5000 kDa or less and present in the solution in an amount of 10 wt. % or more and 50 wt. % or less.

[0039] In some embodiments described above and herein, the water-soluble polymer is present in the solution in an amount of 13% w / w or greater.

[0040] In some embodiments described above and herein, the water-soluble polymer includes poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylsulfobetaine), poly(acrylsulfobetaine), poly(methacrylcarboxybetaine), poly(acrylcarboxybetaine), povidone polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof.

[0041] In some embodiments described above and herein, the composition is extruded to form a swellable polymeric material.

[0042] In yet another aspect, a method is provided, which in some embodiments includes the steps of extruding a mixture onto a core material at a temperature of 65° C. or greater to form a polymeric material disposed on the core material, the mixture comprising a first water-soluble polymer and a salt, the first water-soluble polymer being present in the mixture in an amount of 13 wt % or greater based on the total weight of the mixture, exposing the polymeric material to a non-solvent for the polymeric material at a temperature of 28° C. or less for one hour or greater, introducing a solution comprising a second water-soluble polymer different from the first water-soluble polymer and a salt into the polymeric material, heating the polymeric material and the solution to a temperature of 30° C. or greater, flowing the solution adjacent to the polymeric material for three hours or greater, and drying the polymeric material; A second water-soluble polymer is disposed in at least one pore of the first water-soluble polymer.

[0043] In some embodiments described above and herein, the non-solvent comprises an alcohol.

[0044] In some embodiments, the non-solvent is ethanol.

[0045] In some embodiments described above and herein, exposing the polymeric material to the non-solvent for the polymeric material is for 10 hours or more.

[0046] In some embodiments described above and herein, the method includes annealing the polymeric material to a temperature of 100° C. or greater for 60 minutes or greater.

[0047] In some embodiments described above and herein, the core material may be air, water, a non-solvent liquid, a solid, or a gas.

[0048] In some embodiments described above and herein, the method comprises the steps of: heating the mixture to a temperature of 65°C or greater; cooling the mixture to a temperature at least 20°C below the melting point of the mixture and mechanically shaping the mixture after heating; extruding the mixture at a temperature of 65°C or greater onto a core material to form a polymeric material disposed on the core material after cooling the mixture; exposing the polymeric material to a non-solvent for the polymeric material at a temperature at or below room temperature for at least four hours; and removing at least a portion of the core material from the polymeric material.

[0049] In some embodiments described above and herein, the method includes mixing the mixture at an agitation speed of 200 RPM or greater.

[0050] In some embodiments described above and herein, the method includes mixing the mixture at an agitation speed of 1000 RPM or greater and at a temperature of 80° C. or greater.

[0051] In some embodiments described above and herein, the method includes annealing the polymeric material at a temperature of 100° C. or greater for 1.0 hour or greater.

[0052] In some embodiments described above and herein, the method includes sorption of a second water-soluble polymer into the polymeric material.

[0053] In some embodiments described above and herein, the second water-soluble polymer is PAA.

[0054] In some embodiments described above and herein, the method includes mechanical agitation of the mixture.

[0055] In some embodiments described above and herein, the non-solvent comprises an alcohol, hi some embodiments, the non-solvent is ethanol.

[0056] In some embodiments described above and herein, the method includes administering into an external orifice of a subject a polymeric material comprising a water soluble polymer and having an aspect ratio of 3:1 or greater, wherein administering the article does not include the use of a sheath introducer, wherein the polymeric material is substantially non-thrombogenic, and wherein the polymeric material has a water content in a non-dehydrated state of less than 5 wt.% and greater than or equal to 0.1 wt.%, and wherein the polymeric material is configured to swell from a dehydrated state to an equilibrium water content state by an amount greater than or equal to 5 wt.% and less than or equal to 50 wt.% within 60 minutes.

[0057] In some embodiments, the method includes providing a mixture comprising at least one water-soluble polymer, a salt, and water, wherein the at least one water-soluble polymer is present in the mixture in an amount of 13 wt% or more based on the total weight of the mixture; extruding the mixture onto a core material at a temperature of 65°C or more to form a polymeric material disposed on a core tube; exposing the polymeric material to ethanol at a temperature of room temperature or less; exposing the polymeric material to a humectant; and dehydrating the polymeric material, wherein the dehydrated polymeric material has a water content of less than 5 wt% and greater than or equal to 0.1 wt% in the dehydrated state.

[0058] Another embodiment is a method for making 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, molding the mixture, and passing the mixture through a solvent-removing environment. Extrusion may be used to mold the mixture, which forms into a continuous porous solid as it passes through a die. Nanoporous solids may be produced that have a Young's modulus of at least 5 MPa at the equilibrium water content (EWC) of the porous solid. Extrusion may also be used to mold high-strength materials with high aspect ratios, such as tubing useful as catheters.

[0059] Another 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 molded with a high aspect ratio, for example greater than 10:1, such as a material molded as a catheter.

[0060] Another embodiment is a method comprising solvating a previously desolvated hydrophilic structural matrix comprising one or more physically crosslinked hydrophilic polymers forming a porous matrix in a mixture with one or more water-soluble polymers that resolvate the porous hydrophilic matrix, the mixture optionally being further annealed.

[0061] Another embodiment is a material comprising a porous matrix of physically crosslinked hydrophilic polymers that are crosslinked to form a porous matrix and define the pores of the matrix, the matrix comprising a water-soluble polymer incorporated into the surface without covalent crosslinking to the surface. The water-soluble polymer may be incorporated, for example, as a monolayer, or may be present in the pores of the matrix at and below the surface.

[0062] Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying drawings. In cases where the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control. [Brief explanation of the drawings]

[0063] Non-limiting embodiments of the present invention are described, by way of example, with reference to the accompanying drawings, which are schematic and are not intended to be drawn to scale. In the drawings, each identical or nearly identical component illustrated is typically represented by a single numeral. For clarity, not every component is labeled in every drawing, and not every component of every embodiment of the present invention is shown, unless explanation is necessary for those skilled in the art to understand the invention. In the following figures: [Figure 1A] FIG. 1A is a cross-sectional schematic diagram of an exemplary article comprising a plurality of pores, according to one set of embodiments. [Figure 1B] FIG. 1B is a cross-sectional schematic diagram of an exemplary article comprising a plurality of pores, according to one set of embodiments. [Figure 1C] FIG. 1C is a schematic diagram of an extrusion apparatus for forming a continuous molded article, shown with a cross-sectional side view of a bus. [Figure 1D] FIG. 1D is an enlarged view of a portion of the apparatus of FIG. 1C, illustrating the die head from a perspective looking from outside the bath. [Figure 1E] FIG. 1E is an enlarged view of a portion of the apparatus of FIG. 1C, illustrating the die head positioned within the bath. [Figure 2] FIG. 2 is a longitudinal cross-section of a portion of a continuous porous solid formed with the apparatus of FIGS. 1C-1E. [Figure 3A] FIG. 3A is a schematic diagram of the process for bulk incorporation of polymers into porous solids. [Figure 3B] FIG. 3B is a cross-sectional view of a portion of the tube taken along line 3B-3B of FIG. 3A. [Figure 4] FIG. 4 is a process flow diagram of one embodiment of bulk incorporation of a surface polymer into a porous solid, which includes an extrusion process to create the porous solid. [Figure 5] FIG. 5 is a plot illustrating the stress-strain curve of a polymeric material. [Figure 6] FIG. 6 is a plot of tensile test data for a porous solid prepared using the apparatus of FIGS. 1C-1E. [Figure 7] FIG. 7 is a scanning electron micrograph (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 relating to 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 made according to Example 4, showing that the higher molecular weight polymer (PVA 67-99) provides a higher modulus and tensile strength than the lower molecular weight polymer (PVA 28-99). [Figure 11] FIG. 11 is a plot of tensile test data for porous solids made according to Example 4, showing that the highest concentration of polymer (26%) gives materials with the highest modulus and tensile strength compared to lower polymer concentrations (22% or 18%). [Figure 12] 12A-12F are photographs of porous solids incorporating radiopaque agents: 12A, control (Bard POWERPICC); 12B, 5.7 wt% bismuth subcarbonate, no annealing; 12C, 12.1 wt% bismuth subcarbonate, no annealing; 12D, 12.1 wt% bismuth subcarbonate, annealed; 12E, 5.7 wt% bismuth subcarbonate, annealed; and 12F, 4.2 wt% bismuth subcarbonate. [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 a second set of test samples described in Example 7. [Figure 15] 15A-15B are scanning electron micrographs (SEM) of transverse (15A) or longitudinal (15B) cross sections of the porous solid extruded as described in Example 8. FIG. [Figure 16] 16A-16D are SEMs of hydrophilic nanoporous materials prepared as described in Example 9, provided at various magnifications indicated by the scale bars. [Figure 17] 17A-17B are plots of tensile test data for samples produced as described in Example 10. [Figure 18] 18A-18B are plots of tensile data for various blends of polymers described in Example 11, with the data shown in N / mm 2 . [Figure 19] FIG. 19 is a plot of tensile data for various blends of polymers described in Example 12, with the data shown in N / mm 2 . [Figure 20] 20A-20C are photographs of the PEG / PVA copolymer extrusions described in Example 12, showing surfaces with PEG molecular weights of 8k (20A), 20k (20B), or 35K (20C). [Figure 21] 21A-21B provide the results of the blood contact experiment described in Example 15 as a plot of relative thrombus accumulation (21A) or a photograph of the samples examined (21B). [Figure 22] 22A-22C are photographs showing the results of the sixth experiment of the thrombogenicity test of Example 14, showing the control (22A), porous solid without (22B) or with (22C) bulk-loaded water-soluble polymer. [Figure 23] FIG. 23 is a scanning electron microscope (SEM) photograph of the surface of the PVA porous solid with RO agent of FIG. 7 at a magnification of 2000 times. [Figure 24]24A-24B are SEM micrographs of representative samples containing PVA porous solids with RO agents, where the solids contain bulk-loaded and surface-bound water-soluble polymers, at 300x magnification (24A) or 2500x magnification (24B). [Figure 25A] FIG. 25A is a plot of the results of Example 17 showing thrombus accumulation on samples of porous tubing compared to conventional catheter controls, where the porous solid had water-soluble polymers of various molecular weights bulk-incorporated and surface-bound. [Figure 25B] FIG. 25B is a plot of the results of Example 18 showing thrombus accumulation on a sample of a porous solid having a bulk-loaded and surface-bound water-soluble polymer, with accumulation shown over time. [Figure 25C] FIG. 25C is a plot of the results of Example 19 showing thrombus accumulation on samples of porous solids having bulk-loaded and surface-bound water-soluble polymers of various molecular weights and scaffold compositions compared to conventional catheter controls. [Figure 26] 26A-26B are SEM micrographs of the surface of a porous solid with bulk-loaded water-soluble PVA polymer (28-99) prepared according to Example 20, at 200x magnification (26A) or 2500x magnification (26B). [Figure 27] 27A-27B are SEM micrographs of porous solids with bulk-loaded water-soluble PVA polymer (67-99) prepared according to Example 20 at 200x magnification (32A, surface photograph) or 2500x magnification (surface photograph, 27B). [Figure 28] FIG. 28 is an SEM micrograph taken at 2200x magnification of the surface of a porous solid with bulk-loaded water-soluble polymer (PAA, 100 kMW) prepared according to Example 20. [Figure 29]FIG. 29 is an SEM micrograph taken at 4500x magnification of the surface of a porous solid with bulk-loaded water-soluble polymer (PAA, 250 kMW) prepared according to Example 20. [Figure 30] FIG. 30 is an SEM micrograph taken at 5000x magnification of a cross section of a CARBOPOL 907 conditioned porous solid prepared according to Example 20. [Figure 31] FIG. 31 is an SEM micrograph taken at 2500x magnification of the surface of a CARBOPOL 907 conditioned porous solid prepared according to Example 20. [Figure 32] FIG. 32 is an SEM micrograph taken at 2500x magnification of the surface of a CARBOPOL 907 conditioned porous solid prepared according to Example 20. [Figure 33] 33A-33C are plots of FTIR data generated according to Example 21. [Figure 34] 34A-34C are plots of FTIR data generated according to Example 22, showing a control and test sample (34A), a spectral overlay (34B), and an expansion of the region 1500-1600 cm of FIG. 34B (34C). [Figure 35] 35A-35B are SEM micrographs of cross-sections of porous solids with (35A) or without (35B) bulk-loaded water-soluble polymer according to Example 23. [Figure 36] FIG. 36 is a photograph of an exemplary thrombogenicity test. [Figure 37A] FIG. 37A is a schematic cross-sectional view of an exemplary article having a first component and a second component, according to one set of embodiments. [Figure 37B] FIG. 37B is a schematic side view of an exemplary article having a first component and a second component, according to one set of embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0064] Generally, high-strength porous materials incorporating water-soluble polymers are provided. For example, materials, methods, and uses for biomaterials, including medically acceptable porous solids, are described herein. The disclosed compositions and articles may be useful for administration to a subject (e.g., a patient). Advantageously, the compositions and / or articles described herein may be substantially non-thrombogenic, lubricious, and / or biocompatible. In some embodiments, the compositions and / or articles described herein may be suitable for administration to a subject for a relatively long period of time, e.g., without forming thrombi, without fouling, and / or without absorbing (or adsorbing) one or more substances present within the subject (e.g., therapeutic agents, proteins, blood, plasma). Methods of forming such compositions and / or articles are also provided.

[0065] In some embodiments, the compositions and articles described herein (e.g., article 10 of FIG. 1A , article 12 of FIG. 1B ) comprise a polymeric material including a first water-soluble polymer having a plurality of pores and a second water-soluble polymer, the same or different from the first water-soluble polymer, disposed within at least a portion of the plurality of pores. While not wishing to be bound by theory, in some embodiments, the presence of the second water-soluble polymer disposed within at least a portion of the first water-soluble plurality of pores may reduce the thrombogenicity of the article (e.g., article 10 of FIG. 1A , article 12 of FIG. 1B ) and / or increase the lubricity of the article (e.g., article 10 of FIG. 1A , article 12 of FIG. 1B ) compared to an article (e.g., article 10 of FIG. 1A , article 12 of FIG. 1B ) without the second water-soluble polymer disposed within the pores (all other factors being equal). In one exemplary set of embodiments, the first water-soluble polymer is polyvinyl alcohol. In another exemplary set of embodiments, the second water-soluble polymer is polyacrylic acid. As described herein, other water-soluble polymers are possible.

[0066] In some embodiments, the articles (e.g., article 10 of FIG. 1A, article 12 of FIG. 1B) and compositions described herein are administered to a subject. In some embodiments, the articles may be administered orally, rectally, vaginally, nasally, intravenously, subcutaneously, or uretherally. In some cases, the articles may be administered into a cavity, epidural space, and / or abscess of a subject.

[0067] As described herein, in some embodiments, the compositions and articles described herein comprise a polymeric material comprising a first water-soluble polymer having a plurality of pores. For example, as illustrated in FIG. 1A, article 10 comprises a polymeric material comprising a first water-soluble polymer 20 and having a plurality of pores 30. In some embodiments, second water-soluble polymer 40 is disposed within at least a portion of the plurality of pores (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.99%). In some embodiments, second water-soluble polymer 40 is disposed within no more than 100%, no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, or no more than 10% of the plurality of pores 30. Combinations of the above-listed ranges are also possible.

[0068] In some embodiments, the second water-soluble polymer is disposed within the bulk of the first water-soluble polymer (e.g., within the pores and / or interstices of the first water-soluble polymer). In some embodiments, as illustrated in Figure 1B, the second water-soluble polymer 40 may be present as a coating 45 on at least a portion of the surface of the polymeric material 20. While Figure 1B shows the second water-soluble polymer as a coating on the first water-soluble polymer and in the pores of the first water-soluble polymer, it should be understood that in some embodiments, only the coating 45 is present and the pores 30 are not substantially filled with the second water-soluble polymer 40. Other configurations are possible.

[0069] In some embodiments, article 10 and / or article 12 may be hollow (e.g., include a hollow core 25). However, while Figures 1A and 1B are depicted as having a hollow core, one skilled in the art will understand, based on the teachings herein, that such a hollow core may not be present. That is, in some cases, core 25 of an article (e.g., article 10 of Figure 1A, article 12 of Figure 1B) may be a bulk material without a hollow core 25.

[0070] In some embodiments, the plurality of pores (e.g., of an article (e.g., article 10 of FIG. 1A , article 12 of FIG. 1B ) or of a first water-soluble material, which may optionally have a second water-soluble polymer disposed within at least some of the pores) have a particular average pore size. In some embodiments, the average pore size of the plurality of pores is 500 nm or less, 450 nm or less, 400 nm or less, 350 nm or less, 300 nm or less, 250 nm or less, 200 nm or less, 150 nm or less, 100 nm or less, 75 nm or less, 50 nm or less, 25 nm or less, 20 nm or less, or 15 nm or less. In some embodiments, the plurality of pores have an average pore size of 10 nm or more, 15 nm or more, 20 nm or more, 25 nm or more, 50 nm or more, 75 nm or more, 100 nm or more, 150 nm or more, 200 nm or more, 250 nm or more, 300 nm or more, 350 nm or more, 400 nm or more, or 450 nm or more. Combinations of the above-listed ranges are also possible (e.g., less than or equal to 500 nm and more than or equal to 10 nm). Other ranges are also possible. As described herein, the average pore size may be measured by mercury intrusion porosimetry of the material in a dehydrated state (i.e., having less than 5 w / w% water).

[0071] In some embodiments, at least a portion of the plurality of pores may be characterized as nanopores, e.g., pores having an average cross-sectional dimension of less than 1 micron. In some embodiments, at least a portion of the plurality of pores may be characterized as micropores, e.g., pores having an average cross-sectional dimension of less than 1 mm and equal to or greater than 1 micron. In some embodiments, at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.9%) of the plurality of pores have a diameter that is less than 1 micron, 800 nm or less, 600 nm or less, 500 nm or less, 450 nm or less, 400 nm or less, 350 nm or less, 300 nm or less, 250 nm or less, 200 nm or less, 150 nm or less, 100 nm or less, 75 nm or less, 50 nm or less, 25 nm or less, 20 nm or less, or 15 nm or less. In some cases, at least 50% of the plurality of pores have a diameter that is 10 nm or more, 15 nm or more, 20 nm or more, 25 nm or more, 50 nm or more, 75 nm or more, 100 nm or more, 150 nm or more, 200 nm or more, 250 nm or more, 300 nm or more, 350 nm or more, 400 nm or more, 450 nm or more, 500 nm or more, 600 nm or more, or 800 nm or more. Combinations of the above-listed ranges are also possible (e.g., 1000 nm or less and 10 nm or more). Other ranges are also possible.

[0072] Compositions and articles described herein (e.g., article 10 of FIG. 1A and article 12 of FIG. 1B) may have a particular porosity, for example, in a dehydrated state. In some embodiments, the article (or polymeric material) has a porosity of 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, or 45% or more in a dehydrated state. In some embodiments, the article (or polymeric material) has a porosity of 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, or 10% or less in a dehydrated state. Combinations of the above-listed ranges are also possible (e.g., 5% or more and 50% or less in a dehydrated state). Other ranges are also possible.

[0073] As described herein, in some embodiments, the article (or polymeric material) is substantially non-thrombogenic. Non-thrombogenicity may be measured as described in Example 13.

[0074] In some embodiments, an article (e.g., article 10 of FIG. 1A, article 12 of FIG. 1B) (or polymeric material (e.g., polymeric material 20 of FIGS. 1A-1B)) is hydrophilic. As used herein, the term "hydrophilic" is given its ordinary meaning in the art and refers to a material surface having a water contact angle of less than 90° as measured by goniometry. In some embodiments, the polymeric material surface of the article has a water contact angle of 45° or less, 40° or less, 35° or less, 30° or less, 25° or less, 20° or less, 15° or less, 10° or less, 5° or less, or 2° or less at equilibrium water content. In some embodiments, the polymeric material surface has a water contact angle of 1° or more, 2° or more, 5° or more, 10° or more, 15° or more, 20° or more, 25° or more, 30° or more, 35° or more, or 40° or more at equilibrium water content. Combinations of the above-listed ranges are also possible (e.g., 1° or more and 45° or less). Other ranges are possible.

[0075] As used herein, an equilibrium moisture content state refers to the steady state of an article (or material) that does not gain (e.g., absorb) or lose bulk water content, as measured when submerged in water at 25° C. without externally applied mechanical stress. Those skilled in the art will appreciate that a steady state (or equilibrium moisture content state) should be understood not to require absolute conformance to a strict thermodynamic definition of such terms, but rather to refer to conformance to the thermodynamic definition of such terms to the extent possible for the subject matter characterized as understood by one of ordinary skill in the art most closely related to such subject matter (e.g., taking into account factors such as passive diffusion and / or Brownian motion).

[0076] In some embodiments, the article (e.g., article 10 of FIG. 1A, article 12 of FIG. 1B) is substantially smooth at equilibrium moisture content. For example, in some embodiments, the article (or the polymeric material of the article) has a surface roughness (Ra) of 1000 nm or less at equilibrium moisture content. In some embodiments, the article (or the polymeric material of the article) has a surface roughness (Ra) of 500 nm or less, 400 nm or less, 300 nm or less, 250 nm or less, 200 nm or less, 150 nm or less, 100 nm or less, 50 nm or less, 25 nm or less, 10 nm or less, or 5 nm or less at equilibrium moisture content. In some embodiments, the article (or polymeric material of the article) has a surface roughness (Ra) at equilibrium moisture content of 5 nm or more, 10 nm or more, 25 nm or more, 50 nm or more, 100 nm or more, 150 nm or more, 200 nm, 250 nm or more, 300 nm or more, 400 nm or more, or 500 nm or more. Combinations of the above-listed ranges are also possible (e.g., 5 nm or more and 1000 nm or less). Other ranges are also possible.

[0077] In some embodiments, an article (e.g., article 10 of FIG. 1A or article 12 of FIG. 1B) has a surface with a coefficient of friction of 0.10 or less at equilibrium moisture content. For example, the coefficient of friction of the surface of the article (or polymeric material of the article) is 0.1 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, or 0.02 or less. In some embodiments, the coefficient of friction of the surface of the article (or polymeric material of the article) is 0.01 or more, 0.02 or more, 0.03 or more, 0.04 or more, 0.05 or more, 0.06 or more, 0.07 or more, 0.08 or more, or 0.09 or more. Combinations of the above-listed ranges are also possible (e.g., 0.1 or less and 0.01 or more). Other ranges are also possible.

[0078] Advantageously, the compositions and articles described herein may have low sorption of substances such as therapeutic agents (and / or, e.g., proteins) in the presence of a dynamic fluid containing such substances. For example, such articles and compositions may be useful for use in a subject where the presence of the article should not substantially reduce the availability and / or concentration of a therapeutic agent delivered to the subject (e.g., via the article). In some embodiments, administration of a therapeutic agent via a fluid flowed through an article described herein does not substantially reduce the concentration of the therapeutic agent in the fluid. In some cases, the article may not absorb and / or adsorb a therapeutic agent, for example, during flow or use.

[0079] In some embodiments, sorption of 0.5 wt.% or less of the therapeutic agent onto the surface and / or bulk of the first water-soluble polymer occurs when measured at equilibrium water content after exposing the polymer to the therapeutic agent and rinsing with 5 times the article's volume of water or an aqueous solution, such as normal saline. In some embodiments, sorption of 0.5 wt.% or less, 0.4 wt.% or less, 0.3 wt.% or less, 0.2 wt.% or less, or 0.1 wt.% or less of the therapeutic agent onto the surface and / or bulk of the first water-soluble polymer occurs. In some embodiments, sorption of 0.05 wt.% or more, 0.1 wt.% or more, 0.2 wt.% or more, 0.3 wt.% or more, or 0.4 wt.% or more of the therapeutic agent onto the surface and / or bulk of the first water-soluble polymer occurs. Combinations of the above-listed ranges are possible (e.g., 0.5 wt.% or less and 0.05 wt.% or more). Other ranges are also possible.

[0080] Advantageously, the articles and compositions described herein may have desirable swelling properties (eg, in water, saline, in the fluid environment of the subject).

[0081] In some embodiments, an article described herein (e.g., article 10 of FIG. 1A or article 12 of FIG. 1B) is in a dehydrated state. For example, in some embodiments, an article (or polymeric material) described herein has a water content of 5 wt.% or less, 4 wt.% or less, 3 wt.% or less, 2 wt.% or less, 1 wt.% or less, 0.8 wt.% or less, 0.6 wt.% or less, 0.4 wt.% or less, or 0.2 wt.% or less in a dehydrated state. In some embodiments, an article (or polymeric material) described herein has a water content of 0.1 wt.% or more, 0.2 wt.% or more, 0.4 wt.% or more, 0.6 wt.% or more, 0.8 wt.% or more, 1 wt.% or more, 2 wt.% or more, 3 wt.% or more, or 4 wt.% or more. Combinations of the above-listed ranges are also possible (e.g., less than 5 wt.% and 0.1 wt.% or more). Other ranges are possible. As described herein, a dehydrated state generally refers to a steady state measured under ambient conditions in which the article (or polymeric material) has no appreciable decrease in water content of less than 5 w / w% over a 24-hour period. In some embodiments, the articles described herein may include a coating, such as a water-retentive coating, or unbound porogen, as described in further detail below.

[0082] Advantageously, the articles and compositions described herein may be configured to rapidly swell in the presence of water and / or an aqueous solution, such as saline. In some embodiments, the article (e.g., article 10 of FIG. 1A, article 12 of FIG. 1B) (or polymeric material (e.g., polymeric material 20 of FIGS. 1A-1B)) is configured to swell from a dehydrated state to an equilibrium moisture content state by an amount of 5 wt. % or more, 10 wt. % or more, 15 wt. % or more, 20 wt. % or more, 25 wt. % or more, 30 wt. % or more, 35 wt. % or more, 40 wt. % or more, or 45 wt. % or more at 25° C. in a specified time (e.g., within 60 minutes), as described in further detail below. In some embodiments, the article (or polymeric material) is configured to swell from a dehydrated state to an equilibrium moisture content state by 50 w / w% or less, 45 w / w% or less, 40 w / w% or less, 35 w / w% or less, 30 w / w% or less, 25 w / w% or less, 20 w / w% or less, 15 w / w% or less, or 10 w / w% or less in a specified amount of time (e.g., within 60 minutes), as described in further detail below. Combinations of the above-listed ranges are also possible (e.g., 5 w / w% or more and 50 w / w% or less). Other ranges are also possible.

[0083] In some embodiments, the article (e.g., article 10 of FIG. 1A, article 12 of FIG. 1B) (or polymeric material (e.g., polymeric material 20 of FIGS. 1A-1B)) is configured to swell by 5% w / w or more from a dehydrated state to an equilibrium moisture content state in 60 minutes, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 2 minutes at 25° C. In some embodiments, the article (or polymeric material) is configured to swell by 5% w / w or more from a dehydrated state to an equilibrium moisture content state in 1 minute or more, 2 minutes or more, 5 minutes or more, 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, or 50 minutes or more at 25° C. Combinations of the above-listed ranges are also possible (e.g., 60 minutes or less and 1 minute or more). Other ranges are also possible.

[0084] In exemplary embodiments, the article (e.g., article 10 of FIG. 1A or article 12 of FIG. 1B) (or polymeric material (e.g., polymeric material 20 of FIGS. 1A-1B)) is configured to swell in water from a dehydrated state (e.g., less than 5% w / w) to an equilibrium water content (e.g., 5% w / w or more) within 60 minutes. In some embodiments, the article (or polymeric material) is configured to swell in standard normal saline from a dehydrated state (e.g., less than 5% w / w) to an equilibrium water content (e.g., 5% w / w or more) within 60 minutes. In another exemplary embodiment, the article (or polymeric material) is configured to swell in normal saline from a dehydrated state (e.g., less than 5% w / w) to an equilibrium water content (e.g., 5% w / w or more) within 60 minutes.

[0085] In some embodiments, an article (e.g., article 10 of FIG. 1A, article 12 of FIG. 1B) (or polymeric material (e.g., polymeric material 20 of FIGS. 1A-1B)) has a particular length in a dehydrated state. In some embodiments, the article (or polymeric material) has an increase in overall length of 0.1% or more, 0.5% or more, 1% or more, 2% or more, 4% or more, 6% or more, 8% or more, 10% or more, 12% or more, 14% or more, 16% or more, or 18% or more at equilibrium moisture content compared to its length in a dehydrated state. In some cases, the article (or polymeric material) has an increase in overall length of 20% or less, 18% or less, 16% or less, 14% or less, 12% or less, 10% or less, 8% or less, 6% or less, 4% or less, 2% or less, 1% or less, or 0.5% or less at equilibrium moisture content compared to its length in a dehydrated state. Combinations of the above-noted ranges are possible (eg, greater than or equal to 0.1% and less than or equal to 20%). Other ranges are also possible.

[0086] In some embodiments, an article (e.g., article 10 of FIG. 1A, article 12 of FIG. 1B) (or polymeric material (e.g., polymeric material 20 of FIGS. 1A-1B)) has a particular outer maximum cross-sectional dimension, such as an outer diameter, in a dehydrated state. In some embodiments, the article (or polymeric material) has an increase in outer maximum cross-sectional dimension (e.g., outer diameter) at equilibrium moisture content of 0.1% or more, 0.5% or more, 1% or more, 2% or more, 4% or more, 6% or more, 8% or more, 10% or more, 12% or more, 14% or more, 16% or more, or 18% or more compared to the outer maximum cross-sectional dimension (e.g., outer diameter) in a dehydrated state. In some cases, the article (or polymeric material) has an increase in its maximum cross-sectional dimension (e.g., outer diameter) at equilibrium moisture content of 20% or less, 18% or less, 16% or less, 14% or less, 12% or less, 10% or less, 8% or less, 6% or less, 4% or less, 2% or less, 1% or less, or 0.5% or less compared to the maximum cross-sectional dimension (e.g., outer diameter) at equilibrium moisture content. Combinations of the above-listed ranges are also possible (e.g., 0.1% or more and 20% or less, 0.1% or more and 10% or less). Other ranges are also possible.

[0087] In some embodiments, the article (or polymeric material) has a particular inner diameter in a dehydrated state (e.g., in embodiments in which the article includes a hollow core). In some embodiments, the article (or polymeric material) has an increase in inner diameter at equilibrium moisture content relative to the inner diameter in the dehydrated state of 0.1% or more, 0.5% or more, 1% or more, 2% or more, 4% or more, 6% or more, 8% or more, 10% or more, 12% or more, 14% or more, 16% or more, or 18% or more. In some cases, the article (or polymeric material) has an increase in inner diameter at equilibrium moisture content relative to the inner diameter in the dehydrated state of 20% or less, 18% or less, 16% or less, 14% or less, 12% or less, 10% or less, 8% or less, 6% or less, 4% or less, 2% or less, 1% or less, or 0.5% or less. Combinations of the above-listed ranges are also possible (e.g., 0.1% or more and 20% or less). Other ranges are also possible.

[0088] In some embodiments, an article (e.g., article 10 of FIG. 1A, article 12 of FIG. 1B) comprises a polymeric material having desirable mechanical properties. For example, in some embodiments, the polymeric material has a Young's modulus in a dehydrated state (e.g., a water content of less than 5 wt%) of 500 MPa or more, 600 MPa or more, 750 MPa or more, 800 MPa or more, 900 MPa or more, 1000 MPa or more, 1250 MPa or more, 1500 MPa or more, 1750 MPa or more, 2000 MPa or more, 2500 MPa or more, 3000 MPa or more, 3500 MPa or more, or 4000 MPa or more. In some embodiments, the polymeric material has a Young's modulus in a dehydrated state (e.g., less than 5% w / w water content) of 5000 MPa or less, 4000 MPa or less, 3500 MPa or less, 3000 MPa or less, 2500 MPa or less, 2000 MPa or less, 1750 MPa or less, 1500 MPa or less, 1250 MPa or less, 1000 MPa or less, 900 MPa or less, 800 MPa or less, 750 MPa or less, or 600 MPa or less. Combinations of the above-listed ranges are also possible (e.g., 500 MPa or more and 5000 MPa or less). Other ranges are also possible.

[0089] In some embodiments, the polymeric material has a Young's modulus at equilibrium water content of 300 MPa or less, 250 MPa or less, 200 MPa or less, 150 MPa or less, 100 MPa or less, 75 MPa or less, 50 MPa or less, 25 MPa or less, 20 MPa or less, or 10 MPa or less. In some embodiments, the polymeric material has a Young's modulus at equilibrium water content of 5 MPa or more, 10 MPa or more, 20 MPa or more, 25 MPa or more, 50 MPa or more, 75 MPa or more, 100 MPa or more, 150 MPa or more, 200 MPa or more, or 250 MPa or more. Combinations of the above-listed ranges are also possible (e.g., 300 MPa or less and 5 MPa or more). Other ranges are also possible.

[0090] In some embodiments, an article (e.g., article 10 of FIG. 1A, article 12 of FIG. 1B) includes an osmotic agent. For example, in some embodiments, the osmotic agent may be added during formation of the article (e.g., to a prepolymer). In some embodiments, the osmotic agent is present in the polymeric material (e.g., after formation of the polymeric material) in an amount of 0.05 w / w% or more, 0.1 w / w% or more, 0.2 w / w% or more, 0.4 w / w% or more, 0.6 w / w% or more, 0.8 w / w% or more, 1 w / w% or more, 1.2 w / w% or more, 1.4 w / w% or more, 1.6 w / w% or more, or 1.8 w / w% or more. In some cases, the osmotic agent may be present in the polymeric material (e.g., after formation of the polymeric material) in an amount of 2 w / w% or less, 1.8 w / w% or less, 1.6 w / w% or less, 1.4 w / w% or less, 1.2 w / w% or less, 1 w / w% or less, 0.8 w / w% or less, 0.6 w / w% or less, 0.4 w / w% or less, 0.2 w / w% or less, or 0.01 w / w% or less.

[0091] Combinations of the above-noted ranges are possible (e.g., greater than or equal to 0.05% w / w and less than or equal to 2% w / w). Other ranges are also possible.

[0092] Non-limiting examples of suitable osmotic agents include phosphate, borate, sodium chloride, citrate, ethylenediaminetetraacetate, sulfite, sulfate, hyposulfite, metal oxides, selenium dioxide, selenium trioxide, selenious acid, selenic acid, nitrate, silicates, and botanic acids.

[0093] In some embodiments, the composition (e.g., including the polymeric material) does not include covalent crosslinks, as described in further detail below. However, in other embodiments, the composition includes physical crosslinks (e.g., interpenetrating networks, chain entanglements, and / or one or more bonds, such as covalent, ionic, and / or hydrogen bonds). In one particular set of embodiments, no covalent crosslinking agents are used to form the polymeric material, the first water-soluble polymer, and / or the second water-soluble polymer of the polymeric material.

[0094] The first water-soluble polymer can be present in the article (e.g., article 10 of FIG. 1A, article 12 of FIG. 1B) in any suitable amount. For example, in some embodiments, the first water-soluble polymer is present in the article in an amount at equilibrium moisture content of 20 w / w% or more, 25 w / w% or more, 30 w / w% or more, 35 w / w% or more, 40 w / w% or more, 45 w / w% or more, 50 w / w% or more, 55 w / w% or more, 60 w / w% or more, 65 w / w% or more, 70 w / w% or more, 75 w / w% or more, 80 w / w% or more, 85 w / w% or more, or 90 w / w% or more. In some embodiments, the first water-soluble polymer is present in the article in an amount of 95 w / w% or less, 90 w / w% or less, 85 w / w% or less, 80 w / w% or less, 75 w / w% or less, 70 w / w% or less, 65 w / w% or less, 60 w / w% or less, 55 w / w% or less, 50 w / w% or less, 45 w / w% or less, 40 w / w% or less, 35 w / w% or less, 30 w / w% or less, or 25 w / w% or less at equilibrium water content. Combinations of the above-listed ranges are also possible (e.g., 20 w / w% or more and 95 w / w% or less). Other ranges are also possible.

[0095] In some embodiments, the first water-soluble polymer comprises or is selected from the group consisting of poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylsulfobetaine), poly(acrylsulfobetaine), poly(methacrylcarboxybetaine), poly(acrylcarboxybetaine), povidone, polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof. In one exemplary set of embodiments, the first water-soluble polymer is poly(vinyl alcohol).

[0096] In some embodiments, the polymeric material comprises a mixture comprising a first water-soluble polymer and another (e.g., third) water-soluble polymer. In some embodiments, the third water-soluble polymer comprises or is selected from the group consisting of poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylsulfobetaine), poly(acrylsulfobetaine), poly(methacrylcarboxybetaine), poly(acrylcarboxybetaine), povidone, polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof. The first water-soluble polymer and the other (e.g., third) water-soluble polymer may have different chemical compositions.

[0097] In some embodiments, the total weight of the first water-soluble polymer and another (e.g., third) water-soluble polymer in the article at equilibrium moisture content is 20 w / w% or more, 25 w / w% or more, 30 w / w% or more, 35 w / w% or more, 40 w / w% or more, 45 w / w% or more, 50 w / w% or more, 55 w / w% or more, 60 w / w% or more, 65 w / w% or more, 70 w / w% or more, 75 w / w% or more, 80 w / w% or more, 85 w / w% or more, 90 w / w% or more, 95 w / w% or more, 98 w / w% or more, or 99 w / w% or more. In some embodiments, the total weight of the first water-soluble polymer and another (e.g., third) water-soluble polymer in the article, at equilibrium moisture content, is in an amount of 100 w / w% or less, 90 w / w% or less, 98 w / w% or less, 95 w / w% or less, 90 w / w% or less, 85 w / w% or less, 80 w / w% or less, 75 w / w% or less, 70 w / w% or less, 65 w / w% or less, 60 w / w% or less, 55 w / w% or less, 50 w / w% or less, 45 w / w% or less, 40 w / w% or less, 35 w / w% or less, 30 w / w% or less, or 25 w / w% or less.

[0098] Combinations of the above-listed ranges are possible (e.g., greater than or equal to 20% w / w and less than or equal to 100% w / w). Other ranges are also possible.

[0099] In some embodiments, the ratio of the first water-soluble polymer to the third water-soluble polymer present in the article is 100:0 or less, 99:1 or less, 95:5 or less, 90:10 or less, 80:20 or less, 70:30 or less, 60:40 or less, or 55:45 or less. In some embodiments, the ratio of the first water-soluble polymer to the third water-soluble polymer present in the article is 50:50 or more, 60:40 or more, 70:30 or more, 80:20 or more, 90:10 or more, 95:5 or more, or 99:1 or more. Combinations of the above-listed ranges are also possible (e.g., 100:0 or less and 50:50 or more). Other ranges are also possible.

[0100] As described above and herein, in some embodiments, an article (e.g., article 10 of FIG. 1A , article 12 of FIG. 1B ) comprises a second water-soluble polymer (e.g., second water-soluble polymer 40) disposed within at least a portion of a plurality of pores (e.g., plurality of pores 30) of a polymeric material (e.g., polymeric material 20). In some embodiments, the second water-soluble polymer comprises or is selected from the group consisting of poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylsulfobetaine), poly(acrylsulfobetaine), poly(methacrylcarboxybetaine), poly(acrylcarboxybetaine), povidone-polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof. In some embodiments, the second water-soluble polymer is poly(acrylic acid). The second water-soluble polymer may have a chemical composition that is different from the chemical composition of the first (eg, and optionally, third) water-soluble polymer.

[0101] The second water-soluble polymer (e.g., second water-soluble polymer 40) may be present in the article in any suitable amount. For example, in some embodiments, the second water-soluble polymer is present in the article in an amount at equilibrium moisture content of 0.05 w / w% or more, 0.1 w / w% or more, 0.2 w / w% or more, 0.5 w / w% or more, 1.0 w / w% or more, 2.0 w / w% or more, 3.0 w / w% or more, 4.0 w / w% or more, 5.0 w / w% or more, 10 w / w% or more, 20 w / w% or more, 30 w / w% or more, 40 w / w% or more, 50 w / w% or more, 60 w / w% or more, 70 w / w% or more, 80 w / w% or more, or 90 w / w% or more. In some embodiments, the second water-soluble polymer 40 is present in the article in an amount of 95 w / w% or less, 90 w / w% or less, 80 w / w% or less, 70 w / w% or less, 60 w / w% or less, 50 w / w% or less, 40 w / w% or less, 30 w / w% or less, 20 w / w% or less, 10 w / w% or less, 5.0 w / w% or less, 4.0 w / w% or less, 3.0 w / w% or less, 2.0 w / w% or less, 1.0 w / w% or less, less than 0.5 w / w%, less than 0.2 w / w%, or less than 0.1 w / w% at equilibrium moisture content. In some embodiments, 0 w / w% of the second water-soluble polymer is present. Combinations of the above-listed ranges are also possible (e.g., 0.05 w / w% or more and 95 w / w% or less). Other ranges are also possible.

[0102] In some embodiments, the water-soluble polymer (eg, the first water-soluble polymer, the second water-soluble polymer, the third water-soluble polymer) has a particular molecular weight. In some embodiments, the molecular weight of the water-soluble polymer (e.g., each independently the first water-soluble polymer, the second water-soluble polymer, or the third water-soluble polymer) can be 40 kDa or more, 50 kDa or more, 75 kDa or more, 100 kDa or more, 125 kDa or more, 150 kDa or more, 175 kDa or more, 200 kDa or more, 250 kDa or more, 300 kDa or more, 350 kDa or more, 400 kDa or more, 450 kDa or more, 500 kDa or more, 600 kDa or more, 700 kDa or more, 800 kDa or more, 900 kDa or more, 1000 kDa or more, 1500 kDa or more, 2000 kDa or more, 3000 kDa or more, or 4000 kDa or more. In some embodiments, the molecular weight of the water-soluble polymer (e.g., each independently the first water-soluble polymer, the second water-soluble polymer, or the third water-soluble polymer) can be 5000 kDa or less, 4000 kDa or less, 3000 kDa or less, 2000 kDa or less, 1500 kDa or less, 1000 kDa or less, 900 kDa or less, 800 kDa or less, 700 kDa or less, 600 kDa or less, 500 kDa or less, 450 kDa or less, 400 kDa or less, 350 kDa or less, 300 kDa or less, 250 kDa or less, 200 kDa or less, 175 kDa or less, 150 kDa or less, 125 kDa or less, 100 kDa or less, 75 kDa or less, or 50 kDa or less. Combinations of the above-listed ranges are also possible (e.g., molecular weights of 40 kDa or greater and 5000 kDa or less). Other ranges are also possible.

[0103] In some embodiments, the article (e.g., article 10 of FIG. 1A , article 12 of FIG. 1B ) (and / or polymeric material) described herein is or is designed for use with a medical device, such as a catheter, a balloon, a shunt, a wound drain, an infusion port, a drug delivery device, a tubing, a contraceptive device, a feminine hygiene product, an endoscope, an implant, a pacemaker, an implantable cardioverter-defibrillator, a cardiac resynchronization device, a cardiovascular device lead, a ventricular assist device, an endotracheal tube, a tracheostomy tube, an implantable sensor, a ventilator pump, and an ophthalmic device. In some embodiments, the catheter is selected from the group consisting of a central venous catheter, a peripheral central catheter, a midline catheter, a peripheral catheter, a tunneled catheter, a dialysis access catheter, a urinary catheter, a neurocatheter, a percutaneous transluminal angioplasty catheter, and a peritoneal catheter. Other suitable applications are described in further detail below. Other suitable applications are described in further detail below.

[0104] In some embodiments, an article (e.g., article 10 of FIG. 1A , article 12 of FIG. 1B ) comprises a first component comprising a polymeric material (e.g., comprising a water-soluble polymer) and a second component adjacent to the first component. For example, in some cases, the second component is mechanically coupled to the first component. In some such embodiments, the second component may comprise a plurality of surface features designed to mechanically retain the second component within or on the first component. In some embodiments, as illustrated in FIGS. 37A-37B , an article 300 comprises a first component 310 (e.g., article 10 of FIG. 1A , article 12 of FIG. 1B , etc.) and a second component 320 (e.g., an extension, connector, luer lock, suture wing, second component such as article 10 of FIG. 1A or article 12 of FIG. 1B ) adjacent to first component 310. In some embodiments, a first thermoplastic layer 330 is disposed between first component 310 and second component 320. In some embodiments, the optional second thermoplastic layer 340 is adjacent to the first component 310 (e.g., in contact with the outer surface of the first component 310). In some cases, the second component 320 may include a plurality of surface features 350 associated with the first component 310 such that the second component 320 is mechanically held to (e.g., within, on, adjacent to) the first component 310.

[0105] In some embodiments, the second component can be a connector (e.g., to a medical component and / or medical device). In some embodiments, the second component can be selected from the group consisting of an extender, a connector, a luer lock, and a suture wing. In some embodiments, the second component can be another article comprising a polymeric material, such as an article described herein.

[0106] In some embodiments, an article (e.g., article 10 of FIG. 1A , article 12 of FIG. 1B ) includes a first thermoplastic layer disposed between a first component and a second component (e.g., to aid in mechanical retention between the first and second components). In some cases, the second thermoplastic layer may be in contact with an exterior surface of the first component. For example, the second thermoplastic layer may cover both a portion of the second component and a portion of the first component. Each thermoplastic layer may comprise a suitable thermoplastic material. In some embodiments, the first thermoplastic material and / or the second thermoplastic material may each independently be selected from the group consisting of polyurethane elastomers, silicone elastomers, silicone-polyurethane copolymers, polyethylene, polypropylene, styrene-isoprene-butadiene copolymers, ethylene-vinyl acetate copolymers, vinyl acetate homopolymers and copolymers such as polyvinyl chloride, acrylate and methacrylate homopolymers and copolymers, polyvinylpyrrolidone, 2-pyrrolidone, polyacrylonitrile butadiene, polycarbonate, polyamides, polyether block amides, fluoropolymers (polytetrafluoroethylene), and the like. The thermoplastic may include, or be selected from the group consisting of, poly(vinyl fluoride) fluorinated ethylene propylene, polystyrene, styrene-acrylonitrile homopolymers and copolymers, styrene-butadiene homopolymers and copolymers, cellulose acetate, acrylonitrile-butadiene styrene homopolymers and copolymers, polymethylpentene, polysulfone, polyester, polyimide, polyisobutylene, polymethylstyrene, polyoxymethylene, and homopolymers and copolymers of poly(lactic acid), poly(glycolic acid), and poly(caprolactone). In some embodiments, the first thermoplastic and / or the second thermoplastic is at least partially swellable in water at 25°C.

[0107] In some embodiments, the second component is thermally bonded to the first component. In some embodiments, the second component is solvent bonded to the first thermoplastic. In some embodiments, the solvent can be selected based on its ability to solvate both the first component and / or the second component. Non-limiting examples of suitable solvents include tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, chloroform, dichloromethane, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, nitromethane, propylene carbonate, diethyl ether, 1,4-doxane, benzene, cyclohexane, hexane, cyclopentane, pentane, formic acid, n-butanol, isopropyl alcohol, ethanol, methanol, acetic acid, hexafluoroisopropanol, trifluoroacetic acid, water, and combinations thereof. In an exemplary embodiment, the water-swellable polyurethane is solvent bonded to the hydrophobic polyurethane using tetrahydrofuran.

[0108] In some embodiments, the second component has a Young's modulus greater than the Young's modulus of the first component in a dehydrated state and / or at an equilibrium moisture content state, hi some embodiments, the second component has a Young's modulus greater than the Young's modulus of the first component at an equilibrium moisture content state, but less than the Young's modulus of the first component in a dehydrated state.

[0109] In some embodiments, the second component includes a plurality of surface features, such as protrusions or spikes. The surface features may be present at the interface between the first component and the second component to mechanically maintain the connection between the two components. In some embodiments, the plurality of surface features comprises rounded edges. In some embodiments, the plurality of surface features comprises rounded edges, sharp edges, blunt edges, flares, bulges, and / or raised features. In some embodiments, the plurality of surface features comprises a plurality of barbs and / or bulges. Other surface features are possible.

[0110] In some embodiments, the plurality of surface features can have a particular radius of curvature (e.g., on a surface adjacent to the first component). For example, in some cases, at least some of the plurality of surface features have a radius of curvature that is 0.1 times or more, 0.2 times or more, 0.3 times or more, 0.5 times or more, 0.7 times or more, 0.9 times or more, 1 time or more, 1.1 times or more, 1.2 times or more, 1.5 times or more, 2 times or more, 2.5 times or more, 3 times or more, 3.5 times or more, 4 times or more, or 4.5 times or more the radius of curvature of the interior surface of the article (e.g., a hollow portion of the article). In some embodiments, at least a portion of the plurality of surface features have a radius of curvature that is 5 times or less, 4.5 times or less, 4 times or less, 3.5 times or less, 3 times or less, 2.5 times or less, 2 times or less, 1.5 times or less, 1.2 times or less, 1.1 times or less, 1 times or less, 0.9 times or less, 0.7 times or less, 0.5 times or less, 0.3 times or less, or 0.2 times or less the radius of curvature of the interior surface of the article (e.g., a hollow portion of the article). Combinations of the above-listed ranges are also possible (e.g., 0.1 times or more and 5 times or less). Other ranges are also possible.

[0111] In some embodiments, the bond strength between a first component and a second component (e.g., at the interface between the first component and the second component) is 10 N or more, 15 N or more, 20 N or more, 25 N or more, 30 N or more, 40 N or more, 50 N or more, 60 N or more, 70 N, or 75 N or more. In some embodiments, the bond strength is 100 N or less, 75 N or less, 70 N or less, 60 N or less, 50 N or less, 40 N or less, 30 N or less, 25 N or less, 20 N or less, or 15 N or less. Combinations of the above-listed ranges are also possible (e.g., 10 N or more and 100 N or less). Other ranges are also possible. Bond strength may be measured as described in Example 26.

[0112] In some embodiments, the interface between the first component and the second component is fluidly sealed. For example, in some embodiments, the interface between the first component and the second component is configured to withstand an injection pressure (injection of fluid through the first component into a second component fluidly connected to the first component) of 50 PSI or more, 75 PSI or more, 100 PSI or more, 125 PSI or more, 150 PSI or more, 175 PSI or more, 200 PSI or more, 225 PSI or more, 250 PSI or more, 300 PSI or more, or 350 PSI or more. In some embodiments, the interface between the first component and the second component is configured to withstand an injection pressure of 500 PSI or less, 400 PSI or less, 350 PSI or less, 300 PSI or less, 250 PSI or less, 225 PSI or less, 200 PSI or less, 175 PSI or less, 150 PSI or less, 125 PSI or less, 100 PSI or less, or 75 PSI or less. Combinations of the above-listed ranges are also possible (e.g., above 50 PSI and below 500 PSI). Other ranges are also possible.

[0113] As described herein, in some embodiments, an article (e.g., article 10 of FIG. 1A , article 12 of FIG. 1B ) comprises at least one first thermoplastic layer disposed between a first component and a second component. In some embodiments, the second component is disposed on or adjacent to the first component prior to sorption of the second water-soluble polymer. In some embodiments, the second component is disposed on or adjacent to the first component after sorption of the second water-soluble polymer and re-extraction of the second water-soluble polymer with a solvent. In some embodiments, the article comprises a first component comprising a water-soluble polymer and a plurality of pores, a second component comprising a first thermoplastic material disposed in at least some of the plurality of pores, and a third component comprising a second thermoplastic material associated with the second component (e.g., adjacent to the second component, directly adjacent to the second component, or on the second component).

[0114] These materials can be fabricated as durable, 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 up to 100 nm in diameter. Methods for producing hydrogels are also described. Hydrophilic polymers may be used to create these various porous solids, resulting in hydrophilic solids. The water content of nanoporous or microporous solids can be high (e.g., 50% w / w in EWC). The water content of hydrogels can be even higher, e.g., in principle, up to 90% w / w. Porous solid materials can be used to fabricate various devices, such as medical catheters and implants, with significantly reduced adsorption and / or adhesion of biological components to their surfaces.

[0115] These and other porous materials may be processed to include a polymer bulk-incorporated within the pores of the solid. One embodiment of the material is a porous material comprising a water-soluble polymer encapsulated within the pores of the material. The polymer encapsulated by this method resides within the pores and has been observed to remain in the pores after repeated hydration and dehydration. The encapsulated polymer provides a virtually permanent surface that is scratch-resistant, and the incorporated polymer imparts desirable properties beyond the outer surface of the material. In aqueous media, the encapsulated hydrophilic polymer hydrates and extends beyond the surface, enhancing biocompatibility and lubricity. Methods of fabricating the material can include extrusion, so that devices with high aspect ratios may be fabricated. One embodiment of a method of fabricating the material includes heating a mixture comprising at least one water-soluble polymer and a solvent in a solvent-removing environment to a temperature above the melting point of the polymer solution forming the mixture, resulting in a crosslinked matrix, and continuing to remove the solvent until the crosslinked matrix is a microporous or nanoporous solid material. Crosslinking can occur during cooling of the mixture and / or in the solvent-removing environment. Additional polymers may be incorporated into the pores of the material.

[0116] Disclosed herein are molding processes, such as extrusion, for producing high-strength porous solids. Guidance on methods and parameters for producing porous solids and porous solids are disclosed. Guidance on bulk-incorporation of polymers into porous solids is disclosed. Porous solids are disclosed with good properties, and the inclusion of bulk-incorporated polymers provides further improvements.

[0117] Various techniques for producing solid plastic materials are known. 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. The plastic may undergo some changes after passing through the opening, such as shrinkage, solvent removal, or crosslinking, but upon solidification, its shape is fixed. Thermoplastics can be remelted. Some thermoplastics form strong inter- and / or intra-chain bonds that are non-covalent crosslinks, referred to as physical crosslinks to distinguish them from covalent bonds. Thermosets are formed irreversibly by covalent crosslinks.

[0118] Examples of forming processes are thermoforming, molding processes, and extrusion processes. Extrusion processes typically involve forcing a polymeric material under pressure through a shaped die. Typically, 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 rapidly cools and solidifies into a solid shape. Extrusion can also include drawing processes. Many complex shapes can be formed using extrusion processes, such as tubes with one or more lumens, coatings, layered coatings, filaments, hollow-profiled objects, objects with round, square, or complex cross-sections, and copolymeric extrusions that combine multiple polymers in an 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, including mandrels, die combinations, port-hole dies, dies with multiple openings that cooperate to produce an extruded product, dies that cooperate with a core, core tubing, core wire, dies that cooperate with blown air or gas acting as a core, or dies containing one or more of slit dies. Cores are useful for providing a lumen for continuously extruded products and may be used temporarily for devices with hollow lumens or permanently for coated devices, such as coated wire. Almost any shape can be produced with a die, as long as the shape produced has a continuous profile. The term "continuous" refers to the theoretical production of infinitely long material, although semi-continuous, intermittent, or other processes can also be used.

[0119] The extrusion process typically involves heating a polymer and forcing it through a die while it is hot so that it can be rapidly cooled and solidify into 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 effects caused by solvents, if any. Tm indicates the transition between a crystalline or semi-crystalline phase and a 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 processing a polymer at high temperatures, typically above 150°C, while the polymer is in an extruder.

[0120] Disclosed herein is a novel process for extruding high-strength materials. Some embodiments of the process provide for one or more of removing solvent from a hydrophilic polymer-solvent mixture as the material is extruded, extruding at low temperatures, extruding into a solvent-removing environment, and further removing solvent for a period of time after extrusion. Additionally, annealing and / or bulk incorporation of additional polymers may also be included.

[0121] 1C-1E illustrate an embodiment of an apparatus for producing a porous solid 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 that optionally provides heating to the die head 106 and a power cable 109 for the heating element 108 (not shown in detail in FIG. 1C), a dispensing spool 110 for a core tube 112, an intake spool 114 and motor (not shown) for the core tube, and a bath 116 for extruded material 117, the bath 116 having temperature control for cooling or heating, illustrated as a heat exchanger 118 including heat exchange piping 120 in the bath 116. The die head 106 accepts the core tube 110 as it passes through the die head 106. A supply line 122 from the syringe to the die head 106 provides a 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 exiting the bath 116. The system may also include a heating station for thermally annealing the tubing or other extruded product, if desired. In addition to a PTFE core tube, wire, air, gas, non-solvent liquid, or other materials may be used for the core.

[0122] 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, e.g., 80-95°C or less, and degassed prior to extrusion. The syringe 104 is attached to a syringe pump 102 along with a wrap heater to maintain the temperature during extrusion. The core 112 loops through a die head 106, e.g., a heated external die head, into an extrusion bath 116, and then attached to a motor-driven intake spool 114. The bath temperature is controlled using a heat exchanger 118, such as a chiller; the extruded material may be 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 readily understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., −30° C., −25° C., −20° C., −15° C., −10° C., −5° C., 0° 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. can all be used as upper or lower limits. The motor speed of the intake (e.g., puller) spool 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 play a role in adjusting the final tubing gauge, e.g., in embodiments where a catheter is being manufactured. The polymer feed rate can be adjusted, for example, in this embodiment, by controlling the syringe pump 102. A connector 122 connects one or more syringes to the die head 106. Many pumps and other tools are known for controllably delivering polymer solutions, and the present apparatus and methods can be adapted for the drawing process, although other delivery processes are available.

[0123] In some embodiments, a composition (e.g., a prepolymer composition) may be provided prior to formation of the polymeric material (e.g., for extrusion). In some embodiments, the composition comprises an aqueous solution. The aqueous solution may include an osmotic agent at a concentration of 0.1 M or more and 8 M or less. The aqueous solution may include a radiopaque agent in an amount of 0 wt% or more and 40 wt% or less. The composition may further include a water-soluble polymer having a molecular weight of 40 kDa or more and 5000 kDa or less, present in the solution in an amount of 10 wt% or more and 50 wt% or less.

[0124] In some embodiments, the composition forms a swellable polymeric material upon extrusion.

[0125] In some embodiments, the osmotic agent is present in the solution at a concentration of 0.1 M or greater, 0.5 M or greater, 1 M or greater, 2 M or greater, 3 M or greater, 4 M or greater, 5 M or greater, or 6 M or greater. In some embodiments, the osmotic agent is present in the solution at a concentration of 8 M or less, 6 M or less, 4 M or less, 2 M or less, 1 M or less, or 0.5 M or less. Combinations of the above-listed ranges are also possible (e.g., 0.1 M or more and 8 M or less). Osmotic agents are described in further detail herein.

[0126] In some embodiments, the radiopaque agent is present in the solution in an amount of 0% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, or 35% or more (w / w). In some embodiments, the radiopaque agent is present in the solution in an amount of 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, or 5% or less (w / w). Combinations of the above-listed ranges are also possible (e.g., 0% or more and 40% or less). Other ranges are also possible. Radiopaque agents are described in further detail below.

[0127] In some embodiments, the water-soluble polymer is present in the solution in an amount of 10 w / w% or more, 13 w / w% or more, 15 w / w% or more, 20 w / w% or more, 25 w / w% or more, 30 w / w% or more, 35 w / w% or more, 40 w / w% or more, or 45 w / w% or more. In some embodiments, the water-soluble polymer is present in the solution in an amount of 50 w / w% or less, 45 w / w% or less, 40 w / w% or less, 35 w / w% or less, 30 w / w% or less, 25 w / w% or less, 20 w / w% or less, 15 w / w% or less, or 13 w / w% or less. Combinations of the above-listed ranges are also possible (e.g., 10 w / w% or more and 50 w / w% or less). In some embodiments, the water-soluble polymer is present in the solution in an amount of 13 w / w% or more.

[0128] In some embodiments, methods of forming polymeric materials and / or articles described herein include providing a mixture comprising a first water-soluble polymer as described above and an osmotic agent (e.g., a salt). In some embodiments, the mixture is extruded. In some embodiments, the extrusion mixture is extruded onto a core material to form a polymeric material disposed on the core material. In some embodiments, the formed polymeric material is exposed to a non-solvent for the polymeric material. In some embodiments, a solution comprising a second water-soluble polymer different from the first water-soluble polymer and an optional osmotic agent is introduced into the polymeric material. In some embodiments, the polymeric material is heated (e.g., after introducing the solution into the osmotic agent). In some embodiments, the solution is allowed to flow over the polymeric material. In some embodiments, the polymeric material may be dried.

[0129] In one exemplary set of embodiments, a method for forming a polymeric material and / or article described herein includes providing a mixture comprising a first water-soluble polymer and an osmotic agent, wherein the first water-soluble polymer is present in the mixture in an amount of 10 wt / w% or more (e.g., 13 wt / w% or more and 50 wt / w% or less) based on the total weight of the mixture; extruding the mixture onto a core material at a temperature of 65°C or more (e.g., 65°C or more and 100°C or less) at atmospheric pressure to form a polymeric material disposed on the core material; and extruding the mixture onto a core material at a temperature of 28°C or less (e.g., 28°C or more). the polymeric material to a non-solvent for the polymeric material at a temperature (below 25°C and above -20°C) for 1 hour or more (e.g., 1 hour or more and 240 hours or less); introducing a solution comprising a second water-soluble polymer different from the first water-soluble polymer and an osmotic agent (e.g., a salt) into the polymeric material; heating the polymeric material and the solution to a temperature of 25°C or more (e.g., 25°C or more and 65°C or less); flowing the solution adjacent to the polymeric material for 3 hours or more (e.g., 3 hours or more and 48 hours or less); and drying the polymeric material.

[0130] In some embodiments, the second water-soluble polymer is disposed in at least one pore (or pores) of the first water-soluble polymer, as described herein.

[0131] In some embodiments, the non-solvent comprises an alcohol. In some embodiments, the non-solvent is ethanol, methanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, decanol, dodecanol, dimethyl sulfoxide, ethyl acetate, acetate, propionate, ether, dimethylformamide, dimethylacetamide, acetone, acetonitrile, ethylene glycol, propylene glycol, glycerol air, vacuum, or a combination thereof. Other non-solvents are also possible (e.g., solvents that are highly soluble in water but have a lower solubility in the water-soluble polymer compared to their solubility in water).

[0132] In some embodiments, extruding the mixture is carried out at a temperature of 65° C. or more, 70° C. or more, 75° C. or more, 80° C. or more, 85° C. or more, 90° C. or more, or 95° C. or more under atmospheric pressure. In some embodiments, extruding the mixture is carried out at a temperature of 100° C. or less, 95° C. or less, 90° C. or less, 85° C. or less, 80° C. or less, 75° C. or less, or 70° C. or less under atmospheric pressure. Combinations of the above-listed ranges are also possible (e.g., 65° C. or more and 100° C. or less). Other ranges are also possible. One of ordinary skill in the art will understand, based on the teachings herein, that additional pressures (e.g., above atmospheric pressure, below atmospheric pressure) and / or temperatures are also possible.

[0133] In some embodiments, the step of exposing the polymeric material to a non-solvent for the polymeric material is carried out at a temperature of 28° C. or less, 25° C. or less, 20° C. or less, 15° C. or less, 10° C. or less, 5° C. or less, 0° C. or less, −5° C. or less, −10° C. or less, or −15° C. or less. In some embodiments, the step of exposing the polymeric material to a non-solvent for the polymeric material is carried out at a temperature of −20° C. or more, −15° C. or more, −10° C. or more, −5° C. or more, 0° C. or more, 5° C. or more, 10° C. or more, 15° C. or more, 20° C. or more, or 25° C. or more. Combinations of the above-noted ranges are also possible (e.g., 28° C. or less and −20° C. or more). Other ranges are also possible.

[0134] In some embodiments, the step of exposing the polymeric material to the non-solvent for the polymeric material is carried out for a period of 1 hour or more, 2 hours or more, 4 hours or more, 6 hours or more, 8 hours or more, 10 hours or more, 15 hours or more, 20 hours or more, 30 hours or more, 40 hours or more, 50 hours or more, 60 hours or more, 80 hours or more, 100 hours or more, 120 hours or more, 140 hours or more, 160 hours or more, 180 hours or more, 200 hours or more, or 220 hours or more (e.g., at a temperature of 28°C or less and -20°C or more). In some embodiments, the step of exposing the polymeric material to the non-solvent for the polymeric material is carried out for 240 hours or less, 220 hours or less, 200 hours or less, 180 hours or less, 160 hours or less, 140 hours or less, 120 hours or less, 100 hours or less, 80 hours or less, 60 hours or less, 50 hours or less, 40 hours or less, 30 hours or less, 20 hours or less, 15 hours or less, 10 hours or less, 8 hours or less, 6 hours or less, 4 hours or less, or 2 hours or less. Combinations of the above-listed ranges are also possible (e.g., 1 hour or more and 240 hours or less). Other ranges are also possible.

[0135] In some embodiments, the step of introducing a solution comprising a second water-soluble polymer, different from the first water-soluble polymer, and an optional osmotic agent (e.g., a salt), into the polymeric material comprises heating the polymeric material and solution to a temperature of 25° C. or more, 30° C. or more, 35° C. or more, 40° C. or more, 45° C. or more, 50° C. or more, 55° C. or more, or 60° C. or more. In some embodiments, the polymeric material and solution are heated to a temperature of 65° C. or less, 60° C. or less, 55° C. or less, 50° C. or less, 45° C. or less, 40° C. or less, 35° C. or less, or 30° C. Combinations of the above-listed ranges are also possible (e.g., 25° C. or more and 65° C. or less). Other ranges are also possible.

[0136] In some cases, the solution may be flowed adjacent (e.g., directly adjacent) to the polymeric material for a specified period of time. In some embodiments, the solution is flowed adjacent to the polymeric material for 3 hours or more, 5 hours or more, 6 hours or more, 8 hours or more, 10 hours or more, 12 hours or more, 16 hours or more, 20 hours or more, 24 hours or more, 28 hours or more, 32 hours or more, 36 hours or more, 40 hours or more, or 44 hours or more. In some embodiments, the solution is flowed adjacent to the polymeric material for 48 hours or less, 44 hours or less, 40 hours or less, 36 hours or less, 32 hours or less, 28 hours or less, 24 hours or less, 20 hours or less, 16 hours or less, 12 hours or less, 10 hours or less, 8 hours or less, 6 hours or less, or 5 hours or less. Combinations of the above-listed ranges are also possible (e.g., 3 hours or more and 48 hours or less). Other ranges are also possible. Combinations of the above-listed temperatures and times are also possible.

[0137] In some embodiments, the method includes annealing the polymeric material at a temperature of 80° C. or greater (e.g., 80° C. or greater and 250° C. or less) for 60 minutes or greater (e.g., 60 minutes or greater and 480 minutes or less). In some embodiments, the polymeric material is annealed at a temperature of 80° C. or greater, 90° C. or greater, 100° C. or greater, 120° C. or greater, 140° C. or greater, 160° C. or greater, 180° C. or greater, 200° C. or greater, 220° C. or greater, or 240° C. or greater. In some embodiments, the polymeric material is annealed at a temperature of 250° C. or less, 240° C. or less, 220° C. or less, 200° C. or less, 180° C. or less, 160° C. or less, 140° C. or less, 120° C. or less, 100° C. or less, or 90° C. Combinations of the above-listed ranges are also possible (e.g., 80° C. or greater and 250° C. or less). Other ranges are also possible.

[0138] In some embodiments, the polymeric material is annealed for 60 minutes or more, 80 minutes or more, 100 minutes or more, 120 minutes or more, 160 minutes or more, 200 minutes or more, 240 minutes or more, 280 minutes or more, 320 minutes or more, 360 minutes or more, 400 minutes or more, or 440 minutes or more. In some embodiments, the polymeric material is annealed for 480 minutes or less, 440 minutes or less, 400 minutes or less, 360 minutes or less, 320 minutes or less, 280 minutes or less, 240 minutes or less, 200 minutes or less, 160 minutes or less, 120 minutes or less, 100 minutes or less, or 80 minutes or less. Combinations of the above-listed ranges are also possible (e.g., 60 minutes or more and 480 minutes or less). Other ranges are also possible. Combinations of the above-listed temperatures and times are also possible.

[0139] In some embodiments, the core material may be air, water, a non-solvent liquid, a solid, or a gas. In some cases, the core material may be removed after the polymeric material is formed on the core material. In some cases, the core material may be physically removed and / or dissolved.

[0140] In exemplary embodiments, the method comprises heating the mixture (e.g., a solution described above and herein) to a temperature of 65°C or greater, the mixture comprising at least one water-soluble polymer, a salt, and water, the at least one water-soluble polymer being present in the mixture in an amount of 13% by weight or greater, based on the total weight of the mixture; cooling the mixture to a temperature at least 20°C below the melting point of the mixture after heating; and mechanically shaping the mixture. In some embodiments, after cooling the mixture, the mixture may be extruded onto a core material at a temperature of 65°C or greater to form a polymeric material disposed on the core material. The method may also include exposing the polymeric material to a non-solvent for the polymeric material at a temperature of 28°C or less for 4 hours or greater; and removing at least a portion of the core material from the polymeric material.

[0141] In some embodiments, the step of cooling the mixture comprises cooling to a temperature that is at least 20°C, at least 25°C, at least 30°C, at least 35°C, at least 40°C, at least 45°C, at least 50°C, at least 60°C, at least 70°C, at least 80°C, or at least 90°C below the melting point of the mixture. In some embodiments, the step of cooling the mixture comprises cooling to a temperature that is 100°C or less, 90°C or less, 80°C or less, 70°C or less, 60°C or less, 50°C or less, 45°C or less, 40°C or less, 35°C or less, 30°C or less, or 25°C or less below the melting point of the mixture. Combinations of the above-noted ranges are also possible (e.g., at least 20°C and no more than 100°C below). Other ranges are also possible. The mixture may be cooled for any suitable period of time.

[0142] In some embodiments, the mixture may be mechanically shaped. In some embodiments, the composition (e.g., prior to extrusion, i.e., the mixture) may be mechanically shaped by kneading, rolling, cutting, and combinations thereof.

[0143] In some embodiments, the method includes mixing the mixture at an agitation rate of 200 RPM or more (e.g., 200 RPM or more and 5000 RPM or less). In some embodiments, the agitation rate is 200 RPM or more, 400 RPM or more, 600 RPM or more, 800 RPM or more, 1000 RPM or more, 1500 RPM or more, 2000 RPM or more, 2500 RPM or more, 3000 RPM or more, 3500 RPM or more, 4000 RPM or more, or 4500 RPM or more. In some embodiments, the agitation rate is 5000 RPM or less, 4500 RPM or less, 4000 RPM or less, 3500 RPM or less, 3000 RPM or less, 2500 RPM or less, 2000 RPM or less, 1500 RPM or less, 1000 RPM or less, 800 RPM or less, 600 RPM or less, or 400 RPM or less. Combinations of the above-listed ranges are possible (e.g., ≧200 RPM and ≦5000 RPM, ≧1000 RPM and ≦5000 RPM). Other ranges are also possible.

[0144] In some embodiments, the method includes mixing the mixture at an agitation speed of 200 RPM or greater (eg, 1000 RPM or greater) and at a temperature of 80° C. or greater.

[0145] In some embodiments, the mixture is mixed at a temperature of 80° C. or higher, 90° C. or higher, 100° C. or higher, 120° C. or higher, 140° C. or higher, 160° C. or higher, 180° C. or higher, 200° C. or higher, 220° C. or higher, or 240° C. or higher. In some embodiments, the mixture is mixed at a temperature of 250° C. or lower, 240° C. or lower, 220° C. or lower, 200° C. or lower, 180° C. or lower, 160° C. or lower, 140° C. or lower, 120° C. or lower, 100° C. or lower, or 90° C. Combinations of the above-listed ranges are also possible (e.g., 80° C. or higher and 250° C. or lower). Other ranges are also possible.

[0146] In some embodiments, the method includes sorption of a second water-soluble polymer into the polymeric material, as described above and herein.

[0147] In some embodiments, the polymeric materials and / or articles described herein may be exposed to a humectant. In some embodiments, the humectant is a nonionic surfactant (i.e., a surfactant having a net uncharged hydrophilic head and a hydrophobic tail comprising a carbon chain) or a zwitterionic surfactant. In some embodiments, the humectant is a nonionic surfactant selected from the group consisting of poloxamer, triacetin, alpha-hydroxy acid, polyethylene glycol, polypropylene glycol, ethylene glycol, propylene glycol, hexylene glycol, butylene glycol, glycerol, sorbitol, mannitol, xylitol, maltitol, and combinations thereof.

[0148] Porous solids (e.g., produced by the apparatus of Figures 1C-1E) may be annealed. Furthermore, with or without prior annealing, porous solids may be further processed to include bulk-incorporated polymers. In Figure 3A, material 210 including a porous solid matrix 212 is desolvated, exposed to a mixture including a polymer in a resolvating solvent, and resolvated into the mixture to form material 212 having bulk-incorporated polymer 214. A cross-section of matrix 212 (Figure 3B) shows an outermost zone 216 where the pores of matrix 212 are filled, a middle zone 218 where the density of polymer in the pores is lower, filling is lower, and / or fewer pores are occupied, and an inner zone 220 where the polymer is not permeated. The matrix can be solvated and / or desolvated prior to exposure to the mixture, provided that the desolvation allows the water-soluble polymer to migrate into the matrix upon exposure to the mixture.

[0149] An exemplary flow chart of a process for making a porous solid containing bulk-incorporated polymer is shown in Figure 4. In this process, a radiopaque (RO) agent is included in the extrusion process. The heated hydrophilic polymer solution presents the bulk-incorporated polymer into the pores of the extruded porous solid.

[0150] Those skilled in the art, having read this disclosure, will be able to adapt the principles in light of what is known about extrusion or other molding techniques to create alternative processes and devices that achieve the same end product as described herein. Scaled-up embodiments of this process may be adapted for use with, for example, a multi-zone screw extruder, where the solvent mixture is provided via appropriate injectors or hoppers and the zones are controlled to provide a cold extrudate. Syringe pumps and other mechanisms can be replaced with appropriately metered and controlled liquid or solid polymer delivery systems.

[0151] The porous material manufacturing system has been used to produce a variety of porous solid products, including 6F catheters with the properties shown in Table 1. Samples were fabricated using 13% w / w 85kDa PVA and 0.1% w / w 450kDa PAA or 1% w / w 20kDa PVP-iodine. In each case, the samples were extruded into chilled ethanol at 0-15°C, soaked in the ethanol overnight, and then dried. The chilled ethanol never reached a temperature that allowed the samples to freeze. The samples were then annealed in glycerol at 120°C for 6-17 hours and then rehydrated before testing. After several days of hydration in aqueous solution, samples were fabricated with an average outer diameter of 1.59 mm (5F), and 1.86 mm and 2.01 mm for PVA-PAA and PVP-iodine, respectively. These 6F catheters were fabricated using PVA. At equilibrium moisture content (EWC), the tensile strength of some of the formulations was evaluated, showing that even higher strengths than the ISO-10555 standard requirements could be readily achieved. These samples not only met but exceeded the ISO standard (see Table 1). The samples were flexible; for example, a 30 cm long sample could be easily bent 90 degrees by hand without twisting.

[0152] JPEG2025114716000002.jpg65170

[0153] 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 an OD between 1.14 and 1.82 mm and 3.37 lbs (15 N) for catheters larger than 1.82 mm. The average strength of samples (approximately 12 F) produced using the final casting process resulted in samples with a tensile strength 164% greater than the required minimum. Catheters can be graded using the French nomenclature, where F denotes the inner diameter. Fukumori et al. (2013) Open J. Organic Polymer Materials 3:110-116 reported a freeze-thaw process to produce a poly(vinyl alcohol) (PVA) material with a Young's modulus of 181 MPa. For the samples tested by Fukumori et al., a Young's modulus of approximately 5 MPa or greater required at least approximately three cycles. The process to produce these gels required multiple freeze-thaw cycles. The resulting materials were tested in dry conditions and are not comparable to the strength measured by EWC. reported that the crystalline content of the material increases with the number of freeze-thaw cycles, and that the strength of the material is due to larger crystals that form as the freeze-thaw cycles progress, with larger crystals forming better cross-links that increase the Tg of the material. By their very nature, these processes produce dry materials. Furthermore, as discussed below, the freeze-thaw process produces macropores.

[0154] In contrast, the methods herein are free of freeze-thaw and / or freezing and / or thawing steps. Furthermore, the methods herein can be used to create solid porous materials that exhibit little or no swelling, e.g., swelling of 0% to 100% w / w at EWC, even in the absence of a covalent crosslinker. Those skilled in the art will readily appreciate that all ranges and values between the explicitly stated boundaries are contemplated, e.g., any of the following can be used as upper or lower limits: 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 95, 100% w / w, and the swelling ratio is measured as % swelling ratio = 100 times (total weight at EWC - dry weight) / dry weight, where dry weight is the weight of the material without water.

[0155] Figure 5 shows the different zones of a polymeric material's stress-strain curve. There are three main zones: Young's modulus, strain hardening, and failure. Young's modulus is defined as the slope of a material's linear elasticity (change in stress / change in strain). Strain hardening is defined as the strengthening of a material due to deformation. The failure point is the point of maximum elongation. Tensile load versus displacement was plotted for a PVA (5F) sample, as shown in Figure 6. The shape of the load curve was representative of other samples subjected to tensile testing. The steep initial slope and eventual leveling off as elongation occurred may indicate the viscoelastic properties of extruded PVA, where the material strain hardens and eventually strain softens until failure. This sample exhibited a maximum tensile load of 14.9 N and a displacement of 115 mm (454% elongation). Another sample fabricated using the same method with an average diameter of 2.03 mm (6.4 F) had an average maximum tensile strength of 24.6 N (5.52 lbs). This large increase in tensile strength with such a small increase in cross-sectional area indicates that catheters made from these materials will significantly exceed the minimum standards of ISO 10555.

[0156] As evidenced by the SEM of the nanoporous material shown in Figure 7, the extruded sample possesses horizontal chain orientation and alignment along the length of the sample (in the direction of extrusion). This polymer chain orientation is 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 below 100 nm. For example, in Figure 8, it can be seen that the 1 μm scale bar is subdivided into 10 segments of 100 nm each. At this resolution, pores larger than 10 nm would be visible, but none are visible. The micrograph has various large strands of polymer that exhibit some roughness on the microscopic scale, but the surface below the strands is smooth and lacks open areas indicative of pores.

[0157] Qualitative observations regarding strength, radiopacity, and surface finish and symmetry of the samples yielded very good results. The sample surfaces, while not perfect, were substantially defect-free. No significant lines, ridges, or other defects were observed, and extrusion produced superior results to the same components when used to produce cast samples that contained significant parting lines. The extrusion process was observed to be efficient and useful for producing strong, flexible, high tensile strength tubing with high aspect ratios that are not possible using conventional molds. A drawing process, similar to extrusion, may also be used.

[0158] Example 1A describes a general method for extruding porous solids. Surprisingly, this method was effective. A cold extrusion process was performed, maintaining the die on 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 an extremely strong material with other excellent properties, such as flexibility, smoothness, lack of defects, and consistent pore size. To achieve this extrusion, a mixture of the polymer in a solvent with PVA in water, as used in Example 1A, was used. Extrusion into a solvent-removing environment, which in this example was an alcohol bath, contributed to the desirable properties. In general, it is useful to have one or more combinations of extrusion of hydrophilic polymers in a solvent; cold extrusion; and extrusion into a bath that rapidly removes the solvent from the extrudate. Furthermore, additional solvent-removal and / or annealing steps provide further utility for producing desirable porous solids.

[0159] The method of Example 1A produced a nanoporous solid. Requirements for nanoporous materials include a high level of crosslinking as well as a high polymer concentration of greater than about 10% w / w in the polymer-solvent mixture. Those skilled in the art will readily understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 10, 12, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 95, or 99 w / w% polymer in the total weight of the polymer-solvent mixture can be used as upper or lower limits. 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. Solvation of the polymer contributes to polymer chain alignment and crosslinking between polymers during extrusion. Without being bound by theory, it is possible that a high concentration of the starting polymer-solvent mixture can aid in the solvation of the polymer. Additionally, chain alignment of the material, which may occur as the material passes through the die, is believed to promote intrapolymer crosslinking compared to interpolymer crosslinking. It is believed that the extrudate or otherwise formed mixture entering a desolvation environment, whether gas or liquid, further collapses the pore structure before the densely concentrated polymers are fully crosslinked, thereby improving chain proximity and promoting further crosslink density. It is useful to deposit the extruded or otherwise formed material directly into the solvent removal environment. Further solvent removal can be continued to collapse the material until the desired end point in structure and / or properties is reached. An annealing process can further contribute to strength.

[0160] On the other hand, freezing also achieves chain proximity and improves crosslink density, but increases strength by forcing superconcentrated microregions to 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 research has shown that such nanoporous solids possess greater strength than macroporous materials.

[0161] 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 readily understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 2, 5, 7, 8, 9, 10% w / w of polymer in the total weight of the polymer-solvent mixture can all be used as upper or lower limits. Additionally or alternatively, the polymer-solvent mixture is not extruded into a solvent removal environment.

[0162] Microporous materials may be produced using process conditions intermediate between those of nanoporous solids and hydrogels. One embodiment 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.

[0163] Extrusion of hydrophilic polymers, such as the PVA of Example 1A, in a solvent is useful for producing high-strength materials. The use of solvents in the starting material for extrusion is, at least, uncommon. Typically, extrusion involves a solid material that is heated to a flowable temperature, extruded, and then cooled by various methods. For example, extrusion of pure PVA is believed possible. However, such extrusion lacks the polymer structure required to produce a porous solid and instead behaves like a conventional plastic. According to theory of operation, extrusion of pure PVA 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 extruded PVA and use them in extrusion processes. The high viscosity of PVA and other hydrophilic polymers makes them difficult to penetrate into solution. A narrow working band of temperatures, e.g., 85-95°C, has been observed to be particularly useful. Below about 85°C, the PVA was unable to truly melt and therefore not become completely amorphous for extrusion. Above about 95°C, the process became ineffective due to reduced boiling and evaporation. These temperature ranges can be offset by increasing the pressure above atmospheric, but pressurized systems are difficult to use and scale. The method is usefully carried out at temperatures below the boiling point of the polymer-solvent material.

[0164] The flowing polymer-solvent mixture had low cohesion upon exiting the die. The use of a core to support the mixture in the die helps maintain its shape in the die. This condition contrasts with typical core extrusion, used as a coating process, for example, to coat cell phone charger wires. Typical processes that avoid the use of solvents or significant solvent concentrations have relatively higher cohesion exiting the die that can easily hold the tube, and do not rely on active bonds, such as hydrogen bonds in hydrophilic polymers, to form the solid material into a coherent shape upon exiting the die.

[0165] 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 atypical compared to conventional processes; the bath or other solvent-removal environment helps to sufficiently solidify the extruded material and stabilize it on the core, which would otherwise result in a teardrop-like melt. Attempting to recover the extruded material at the end of extrusion while it is still molten would destroy it. Conventional baths containing water cause PVA or similar hydrophilic polymeric materials to lose their shape by swelling, dissolving, or both. Example 1B is directed to 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.

[0166] Example 2 demonstrates the effectiveness of this method when incorporating a radiopaque additive; 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), yet retained its desired properties and can be effectively transported / stored in a sealed package or solution, or kept in the ambient environment for a reasonable shelf life, or after opening by the user for final use as needed. Example 4 demonstrates that strength (modulus and ultimate break) increased as the molecular weight of the hydrophilic polymer (PVA) increased 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).

[0167] Porous solids are very smooth, can be used in a hydrated state, and can be conveniently bonded to other materials. For catheters, 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 was tested). SEM images (Figures 15A-15B, Example 8) are of nanoporous solids. Example 9 focuses on nanoporous solids (Figures 16A-16D).

[0168] Without being limited to a particular theory, observation of test samples indicated 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 may be due to the ability to incorporate higher molecular weight species of the second polymer (PAA or PEG), which provides additional material strength. The results generally indicate that extrusion of copolymers is useful in the range of 0.1% to 10% w / w of the second polymer or up to 10% w / w of the first polymer, with up to 5% w / w also being useful. Those skilled in the art will readily understand 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 are all useful as upper or lower limits.

[0169] 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, essentially 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.

[0170] Further tensile tests were performed on coextrudates of a concentration of a first hydrophilic polymer and a relatively lower concentration of a second hydrophilic partner (Example 11). Figure 18A shows tensile tests on 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 are the w / w concentrations of polymers in solvent). PAA concentrations of 0.1 to 0.4% w / w had higher strengths, supporting the conclusions stated for Examples 9 and 10 above. Higher molecular weight (MW) PAA (3 million Da) was tested (Figure 18B), but 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 the longer 3 million MW chains. 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-20C, 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-12B).

[0171] An embodiment of the polymer blend includes 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, polyalkylene glycols, hydrophilic polymers, and combinations thereof. Example concentrations include at least one second hydrophilic polymer present in an amount ranging from 1 part to 10,000 parts of the first hydrophilic polymer. Those skilled in the art will readily understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 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, and 10,000 parts are all usable as upper or lower limits. Examples of concentrations of polymers in a polymer-solvent mixture 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 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.

[0172] Example 14 describes the bulk incorporation of a water-soluble polymer into a porous solid. A porous solid containing an RO agent was extruded as in Example 1A, desolvated by drying, immersed in an aqueous solution of polyacrylic acid (PAA), and allowed to rehydrate for 24 hours, at which point it was an EWC in the aqueous solution. The sample was annealed, rinsed, and placed in deionized water. Samples conditioned to incorporate the water-soluble polymer were observed to undergo multiple cycles of hydration and dehydration without any observable effect (data not shown).

[0173] Samples made using this process were tested for thrombogenicity, as described, for example, in Example 15. The porous solid tubing (PVA) with bulk-incorporated water-soluble polymer (PAA) showed an 89% reduction in platelet adhesion compared to the standard polyurethane control. Also noteworthy was the lower standard deviation assessed for the overall results, indicating improved consistency and demonstrating the durability of the bulk-incorporated polymer. Without being bound by any particular theory, the porous solid tubing without bulk-incorporated PAA (Sample 153-A) likely had higher gamma counts due to the radiopaque agent. The significant reduction in thrombogenicity of the RO agent-containing porous solid PVA tubing prepared with bulk-incorporated surface polymer (PAA) (Sample 153-C) supports the modification of surface durability via the bulk-incorporated process described in Example 14. Figure 22 shows an example photograph of the test sample from Example 15.

[0174] Figures 23 and 24 (Example 16) are SEM images of the surface of a porous solid (PVA) prepared with added RO agent without (Figure 24) or with (Figures 24A-24B) bulk-incorporated polymer. Figure 23 is a higher magnification image of the sample shown in Figure 7. Conditioning with a water-soluble polymer resulted in surfaces with different morphologies.

[0175] Example 17 (Figure 25A) describes testing the nonthrombogenicity of porous solids (PVA) with bulk-incorporated water-soluble polymers (PAA) of various molecular weights (100-710 kDa). No significant differences were observed. The improved nonthrombogenic properties of porous solids with bulk-incorporated water-soluble polymers were measured at several time points, as in Example 18. As the length of the test increased, an increasing improvement was observed compared to the control (Figure 25B). In Example 19, various bulk-incorporated water-soluble polymers were tested. All of the incorporated water-soluble polymers were observed to be effective in reducing thrombogenicity (Figure 25C).

[0176] For example, porous solids incorporating various water-soluble polymers in bulk were prepared and visualized (Figures 26-32) as described in Example 20. SEM evaluation demonstrated successful surface modification through the presence of various water-soluble hydrophilic polymers using the bulk incorporation technique.

[0177] Example 21 describes the bulk incorporation of another water-soluble polymer, poly(sulfobetaine methacrylate) (pSBMA), into porous solid tubes. Successful incorporation of pSBMA was demonstrated by Fourier transform infrared spectroscopy (FTIR) measurements.

[0178] Example 22 describes a test to demonstrate that a water-soluble polymer was incorporated into a porous solid such that there was little loss of the water-soluble polymer upon exposure to physiological solutions. Flowing saline across a sample for 24 hours while directly exposing the sample to a mechanical pump head equivalent to 500,000 compressions at a flow rate of 11 mL / sec resulted in a loss of approximately 24% w / w of the bulk incorporated polymer. Embodiments include porous matrices conditioned with water-soluble polymers that lose no more than 20-90% w / w of the water-soluble polymer under equivalent conditions; those skilled in the art will readily understand that all ranges and values between the explicitly stated boundaries, e.g., 20, 25, 30, 33, 40, 50, 60, 70, 80, and 90% w / w, are contemplated. This test is an indicator of durable incorporation of the bulk polymer. It is clear that a water-soluble polymer that is merely adsorbed would not exhibit such a high degree of durability. The porous matrix was hydrophilic and the incorporated polymer was not treated under conditions that would promote the formation of a coating with covalent or other crosslinks.

[0179] Samples were exposed to water-soluble polymers that were either desolvated (Figure 35A) or not (Figure 35B) prior to exposure to the mixture with the polymer (Example 23). The morphology is different; in contrast to the many features seen in the conditioned samples, the samples made without bulk-incorporated polymer are smooth, consistent with other images taken of bulk-incorporated samples. Figure 35A shows a cross-section of the surface of a sample that was a PVA tube exposed to a PAA solution after desolvation. Similar to the results shown in Example 20, thin threads along the surface indicate bulk-incorporated PAA in the solid, porous PVA tube. In Figure 35A, an outer zone is visible extending from the surface into the porous matrix for a distance of approximately 10–30 μm; this zone appears solid in the micrograph, a region where the bulk-incorporated polymer apparently completely fills the pores. Figure 35B shows that PAA cannot be bulk-incorporated after the PVA tube is annealed but not desolvated when exposed to the conditioning mixture; as is evident in Figure 35B, no thin lines are observed on the surface. This test confirms the presence of the water-soluble polymer (PAA) on the surface using the described bulk incorporation technique. A set of samples (Figure 35B) was created as porous hydrophilic matrices that were annealed, exposed to the water-soluble polymer, and then annealed again, but these samples did not have the morphology typical of that seen in bulk incorporation, such as in Figure 35A. Therefore, to create a material with bulk-incorporated polymer, it is not sufficient to simply coat or otherwise expose the sample to the water-soluble polymer and then have an annealing step, etc.

[0180] Example 24 shows the physical properties of samples with and without bulk-incorporated polymer. Compared to unconditioned samples, the maximum load, Young's modulus, tensile strength, and elongation were significantly different in samples with bulk-incorporated water-soluble polymer compared to unconditioned samples. Without being bound by theory, it appears that the bulk-incorporated polymer penetrated the pores of the porous solid matrix, preventing collapse during subsequent annealing. As a result, materials with bulk-incorporated polymer exhibited lower tensile strength, lower modulus, and greater elongation. Embodiments include materials whose physical properties were altered as a result of conditioning with a water-soluble polymer. In fact, these physical properties were observed to decrease, which is the opposite of typical coating or other surface modification processes, where the changes have minimal impact on or are intended to improve such physical properties.

[0181] Bulk-incorporated materials may exhibit a monolayer on the surface. The term "monolayer" refers to a layer that is a single molecule thick. A monolayer does not rely on cohesive forces between the molecules of the monolayer to remain stable on the surface. At least one water-soluble polymer forms a monolayer. In contrast, even a thin polymer coating that is crosslinked to itself has a thickness comparable to the thickness of the network formed by the crosslinked polymer. For example, it may be possible to create a crosslinked PVA coating on a surface, but such a coating relies on the interconnections between PVA molecules to necessarily form a crosslinked network. Thus, embodiments include a water-soluble polymer present on the surface of a porous solid that does not have a covalent bond to the surface and the polymer is not part of a network.

[0182] Bulk-incorporated polymers are durably incorporated. In contrast, a layer of water-soluble material that is simply adsorbed onto the underlying material, e.g., applied by dip coating or spraying, can be essentially removed from the hydrophilic substrate in most or all circumstances, i.e., at least 90% w / w of the material can be separated from the underlying material in an aqueous solution, e.g., saline, at 90°C for 24 hours. Covalently bonded materials are not expected to be removed under these conditions, and although some of the physically crosslinked network of the water-soluble polymer may not be removed, such a network may be less favorable than bulk-incorporated polymers; for example, it may be more thrombogenic or less durable. Covalent bonding utilizes chemically reactive moieties that can be avoided by the bulk-incorporation process.

[0183] Processing systems and parameters for producing porous materials Provided herein are processes for producing biocompatible porous solids, such as microporous or nanoporous solid materials, that have low protein adsorption characteristics and provide the basis for non-biofouling devices. Modifications of starting polymer concentration, molecular weight, solvent removal, molding processes, and curing / annealing processes may be used to provide surface properties with reduced protein adsorption and other properties. Some embodiments include the production of various continuous shapes through the extrusion of polymer mixtures. The mixtures may be further cured and annealed. These processes may be used to produce strong, highly smooth materials. Embodiments include polymer mixtures extruded into single- or multi-lumen shapes of various diameters and wall thicknesses.

[0184] An embodiment of a process for producing a nanoporous solid material comprises heating a mixture containing 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 material is formed. Depending on the process, one or more of these operations may be combined. Additionally, it may be useful to cool the mixture as it exits the die. Without being bound by a particular theory of operation, it appears that crosslinking the polymer while passing through the die initially forms a porous matrix that has spaces between the polymer strands but lacks a pore structure and is therefore not a true nanoporous solid material. As the solvent is removed under appropriate conditions, the crosslinked structure becomes a nanoporous solid. Crosslinking begins as the polymer mixture is extruded through the die and the mixture cools. Crosslinking may continue while the solvent is being removed. As the solvent is removed, a transition to form the nanoporous material occurs and is generally considered to be complete or essentially (meaning 90% or greater) complete at this stage. The resulting material may be further processed by annealing in the presence or absence of additional solvents or plasticizers. This process, as well as other extrusion or other forming processes and / or materials described herein, such as bulk incorporation processes, 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, more than one freeze-thaw cycle, ice crystal formation, blowing agents, surfactants, hydrophobic polymers, hydrophobic polymer segments, reinforcements, wires, braids, non-porous solids, and fibers.

[0185] Porous materials may be made by an extrusion process comprising passing a polymer mixture through a die into a cooling environment. The cooling environment may also be a solvent removal environment. If the solvent is water, the solvent removal environment is a dehydrating environment. The die may have a core extending therethrough such that the polymer mixture may form around the core. Additional solvent removal and / or annealing environments may be used.

[0186] The extrusion process for 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, and does not require heating 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 noted above.

[0187] 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 polymeric mixture may include 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. Aqueous solutions contain water, e.g., 10-100% (w / w or v / v) of the liquid is water; one of skill in the art will readily recognize that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 10, 20, 30, 40, 50, 60, 70, 80, or 90%, or at least one of these.

[0188] Extrusion is a useful process for forming the material. Other forming processes, such as molding, casting, or thermoforming of a polymer-solvent mixture, may also be used. Generally, the polymer-solvent mixture is prepared without boiling and formed into a shape that is subjected to solvent removal conditions that are controlled to produce nanoporous or microporous materials using the guidelines provided herein. An annealing process may also be included. Hydrogels that are not microporous or nanoporous may also be produced.

[0189] The heated polymer mixture may be molded or otherwise formed as it cools, or molded / formed and immediately cooled. "Formed" is a broad term that refers to the transformation of a material from an amorphous molten state into a final product or an intermediate shape for further processing. Forming encompasses casting, lamination, coating, injection molding, stretching, and extrusion. Forming can be accomplished using an injection molding setup, where the mold is made of a material with thermal conductivity properties that allow it to be easily heated to enhance the flow of the injected polymer mixture and then rapidly cooled in a cooling environment. In other embodiments, the molding process can be accomplished by extruding the polymer mixture through a die to form a continuous material.

[0190] Cooling the polymer mixture may include cooling an 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. below the boiling point or Tm of the polymer, or a bath or other environment at a temperature between −50° C. and 30° C. Those skilled in the art will readily appreciate that all ranges and values between the explicitly stated boundaries are contemplated, e.g., −50, −45, −25, −20, −10, −5, −4, 0, 15, 20, 25, and 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 intermolecular hydrogen bonding and locks chain mobility. This may occur at a temperature of 30°C, or higher if time permits. The bath may be aqueous, or may be adjusted with salts or other osmotic agents to provide an osmotic pressure value to effect solvent removal through osmotic pressure and diffusion for aqueous materials at relatively lower osmotic pressure values. The bath may also be other solvents that freeze at a lower temperature than water, so that temperatures below 0°C may be used without freezing the solvent or material. When hydrophilic copolymers are used in combination with PVA, for example, temperatures above 20°C may be used for crosslinking, with chain immobilization occurring at much higher temperatures.

[0191] 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 the temperature 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 in the polymer mixture. For example, an aqueous polymer mixture may be introduced into an ethanol bath in which ethanol is replaced with water. The ethanol may then be removed. The salt bath may be, for example, a high-concentration salt bath (1M to 6M). The treatment time in the solvent-removing environment and / or the cooling process may be independently selected to be 1 to 240 hours. One skilled in the art will readily understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 1, 2, 5, 10, 24 hours, 1, 2, 5, 7, or 10 days may be used as upper or lower limits. The salt may dissociate to form monovalent, divalent, or triply charged ions.

[0192] 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. A cleaning step may be performed before or after cooling or solvent removal, for example, by immersion in a series of solvents at different concentrations, various salt solutions, various proportions of ethanol or other solvents.

[0193] One embodiment is an extruded material that has undergone a solvent removal process involving exposure to a salt bath, where 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 using temperatures ranging from 20-60°C, for example. Dehydration is typically performed at 37°C for greater than 24 hours.

[0194] One embodiment is a polymer mixture that is extruded or otherwise formed and 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, the polymer mixture is soaked in a 6M solution of NaCl for 16-24 hours. After soaking, the material is rinsed to remove the 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 may be performed at 37°C for more than 4 hours, more than 24 hours, or for a range of 4 hours to 150 hours. Those skilled in the art will readily appreciate 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 an upper or lower limit. For example, dehydration at 40°C for 6 to 24 hours has been observed to be useful.

[0195] 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. With stirring, the polymer is dissolved in a heated solution, which is then heated above the polymer's melting point. Dry NaCl is slowly added to the 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 drawing. 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.

[0196] The term "annealing," as used in the context of semicrystalline polymers or solid porous materials, refers to heat treatment at an annealing temperature corresponding to the melting temperature of one or more polymers in the material. This temperature is usually below the melting temperature, within about 0-15% of the melting temperature on the absolute temperature scale. Plasticizers or other additive materials may affect the melting temperature, usually by lowering it. For example, for pure PVA, the annealing temperature will be within about 10% of the melting point of PVA; if other materials are present, the annealing temperature will typically be lower. The theory of operation is that annealing is a process of stress relief coupled 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 or gas, or in the absence of oxygen or water, such as one or more of nitrogen, vacuum nitrogen, argon, oxygen scavengers, etc. For example, tests have been conducted while annealing dehydrated PVA nanoporous materials. Annealing is used to increase the crystallinity of the PVA network, further reduce the pore size of the PVA network, and reduce the adsorption properties of the final gel surface. Annealing can be performed, for example, at temperatures ranging from 100-200°C; in a preferred embodiment, this step is performed by immersing the dehydrated gel in a mineral oil bath. Bulk incorporation of a polymer into a porous solid may also involve the annealing process already described above for porous solids. Annealing may be performed after exposing the desolvated porous solid to a mixture containing the polymer to be bulk-incorporated. The Tg of the material may be increased or decreased depending on the residual solvent content and / or the presence of a bulk-incorporated second hydrophilic polymer. Thus, as previously described, annealing process conditions may be adapted depending on the substrate temperature, time, ramp rate, and cooling rate.

[0197] Annealing can be carried out 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 silicone oil, glycerin, polyols, and polyethylene glycols less than 500 Da. 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 through interaction and neutralization of the free hydroxyl end groups of the PVA network. The annealed nanoporous material is cooled, removed from the annealing bath, and rinsed using a series of extended immersions to remove the bath medium. The product is then dehydrated and prepared for terminal sterilization.

[0198] Various types of dies may be used, including longitudinal, angular, transverse, and helical extrusion heads, as well as single-polymer extrusion heads used to extrude a single polymer and multilayer extrusion heads used for the coextrusion of multiple polymer layers or other layers. Cyclical heads may also be used, as well as continuous operation heads. Various materials, such as reinforcing materials, fibers, wires, braiding materials, braided wires, and braided plastic fibers, 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 solvent content, which are known and therefore measurable to the exclusion of various other materials. Thus, embodiments include materials disclosed herein that are described in terms of their properties independent of various other incorporated materials. For example, a nanoporous solid may have a known Young's modulus, even if the material contains reinforcing wires that contribute additional strength.

[0199] A core may be used with the extrusion die. The core may be air, water, a liquid, a solid, a non-solvent, or a gas. After reading this disclosure, one skilled in the art will understand that various extrusion processes may be useful using these various types of cores. Cores made of polytetrafluoroethylene tubing (PTFE) are useful. In some embodiments, the core is a wire.

[0200] Multi-lumen tubing has multiple channels running through its profile. These extrusions can be custom fabricated to fit device designs. Multi-lumen tubing has variable outer diameters (ODs), numerous custom inner diameters (IDs), and various wall thicknesses. This tubing is available 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 some embodiments, the OD can be as large as 0.5 inches, the ID can be 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 readily understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 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 all be used as upper or lower limits for OD and / or ID. Tolerances can be, for example, 0.0005 to 0.1 inches. Those skilled in the art will readily understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 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 all be used as upper or lower limits.

[0201] Braided tubing can be made in a variety of configurations. For example, it can be braided using round or flattened single-ended or double-ended wire as small 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 various 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 braiding 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 with walls as thin as 0.007 inches can be achieved, if desired.

[0202] Porous, microporous and nanoporous materials The term "porous solid" is used broadly herein to refer to a material having a solid phase containing open spaces, and is also used to describe true porous materials and to describe 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 definition here. The term "nanoporous material" or "nanoporous solid" is used herein specifically to refer to solids fabricated with interconnected pores having pore sizes up to about 100 nm in diameter. The term "diameter" is broad and, as is customary in these arts, encompasses pores of any shape. Similarly, the term "microporous solid" or "microporous material" is used herein specifically to refer to solids fabricated with interconnected pores having pore sizes up to about 10 μm in diameter. These nano- or microporous materials are characterized by an interconnected porous structure.

[0203] Some hydrogels, sometimes referred to by those skilled in the art as hydrogel sponges, are also 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 although they are generally referred to as porous materials or likened to pores when characterizing their diffusion or other properties, such hydrogels do not fall under the terms nanoporous or microporous solids as used herein. The spaces between the strands of an open matrix hydrogel and the matrix strands are not interconnected pores. Although hydrogels are crosslinked gels with solid-like properties that are not true solids, it is convenient herein, and in these technical fields generally, to refer to them as solids because they are crosslinked, insoluble in solvents, and have significant mechanical strength. Hydrogels may have high water contents, e.g., 25% w / w or more in EWC. Those skilled in the art of hydrogel technology sometimes use the term "porous" to characterize the net molecular weight cutoff or to refer to the spacing between strands of an open hydrogel matrix; however, in this case, the hydrogel does not have a true porous structure and does not fall under the terms nanoporous or microporous as used herein. The definitions of nanoporous and microporous materials used herein also contrast with the sometimes-followed convention that microporous materials are described as having pore diameters less than 2 nm, macroporous materials having pore diameters greater than 50 nm, and the mesoporous category lies in between.

[0204] 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 suppressed 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 and the placement of one or more lumens. The use of high concentrations of polymer above its melting point in a solvent has been useful to enable extrusion. Importantly, attempts by others to produce high-strength materials using similar polymers have used other techniques that do not allow extrusion and are less efficient and often not suitable for producing practical end products.

[0205] For example, poly(vinyl alcohol) (PVA) was used herein to fabricate nanoporous materials with superior properties, especially compared to traditionally used PVA medical materials. Indeed, PVA is widely used throughout the medical device industry and has a well-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. It is an attractive material for these applications due to its biocompatibility and low protein adsorption properties, resulting in low cell adhesion compared to other hydrogels.

[0206] Others have attempted to improve the properties of PVA for biomedical purposes. For example, others have experimented with freeze / thaw processes. 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 through the combination of two solutions to use PVA as an injectable in situ-forming gel for intervertebral disc repair (see U.S. Pat. Nos. 7,845,670, 8,637,063, and 7,619,009). In general, a conventional process for producing tough PVA materials was investigated in U.S. Pat. No. 8,541,484. Methods for producing tough PVA materials without the use of radiation or chemical crosslinkers have also been investigated, as shown in U.S. Pat. No. 6,231,605. None of this PVA-related research by others led to the inventions described herein. Some of these other materials were useful in terms of tensile strength, but were nevertheless macroporous in nature.

[0207] In contrast, the processes herein provide high-strength materials with true porous structures and other useful characteristics, such as a combination of unexpectedly good biocompatibility and mechanical properties. Embodiments of porous solid materials are provided with structural characteristics independently selected from pore size, tensile strength, Young's modulus, solids concentration, type and degree of crosslinking, internal alignment, hydrophilicity, and material composition, as well as end-user devices or intermediate materials with desired aspect ratios relative to the molded shape, tubing with a lumen, multiple lumens, concentrically arranged lumens, or a range of thickness tolerances, or specific medical devices; each of these is described in further detail herein.

[0208] Embodiments include nanoporous materials having pore diameters less than or equal to 100 nm or in the range of 10-100 nm; one of skill in the art will readily understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 1, 2, 3, 4, 5, 10, 20, 50, 60, 70, 80, 90, 100 nm can all be used as upper or lower limits.

[0209] 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 ordinary skill in the art will readily appreciate that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 10, 20, 30, 40, 50, 60, 70, 100, 200, 300 MPa can all be used as upper or lower limits.

[0210] Embodiments include nanoporous or microporous materials having a Young's modulus strength, as measured by EWC, of at least about 1 MPa or between 1 and 100 MPa. One of skill in the art will readily appreciate that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100 MPa, any of which may be used as an upper or lower limit.

[0211] Embodiments include nanoporous or microporous materials or hydrogels having an elongation at break, as measured by EWC, of at least about 100%, or 50-1500%.

[0212] Those of ordinary skill in the art will immediately understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 50, 60, 70, 80, 90, 100, 200, 300, 400, 450, or 500% can all be used as upper or lower limits.

[0213] Embodiments include nanoporous or microporous materials or hydrogels having a solids content of at least 20% or 20-90% w / w solids, as measured by EWC. One of skill in the art will readily understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 5, 10, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90% w / w solids, any of which can be used as an upper or lower limit. Percent solids are measured by comparing the total weight at EWC to the dry weight.

[0214] The tensile strength, modulus and elongation values may be combined in any suitable manner to fall within the ranges set forth as guidelines by this disclosure.

[0215] Embodiments include nanoporous or microporous materials or hydrogels, or combinations thereof, having physical or covalent crosslinks. The physical crosslinks are non-covalent, e.g., physical crosslinks are ionic, hydrogen, electrostatic, van der Waals, or hydrophobic packing. These materials may be free of covalent crosslinks, their covalent crosslinkers, and chemical products. Chemicals can be added during processing to create covalent crosslinks, as is known in the polymerization art. Alternatively, the process and materials may be free of chemicals 22.

[0216] Embodiments include nanoporous or microporous materials or hydrogels with internal alignment of the polymer structure. Alignment may be visualized using SEM images of cross sections taken 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).

[0217] Embodiments include nanoporous or microporous materials or hydrogels having 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 at 20°C. A water-soluble polymer is hydrophilic. 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 degrees. Those skilled in the art will readily understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 2, and 0 degrees can all be used as upper or lower limits. If the matrix is hydrophilic and a droplet of solvent on the surface is less than 90 degrees, the matrix of the material is hydrophilic to the solvent.

[0218] Materials for use in the process and / or biomaterial may include polymers. Hydrophilic polymers are useful, for example, one or more polymers may be selected from polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyacrylic acid (PAA), polyacrylamide, hydroxypropyl methacrylamide, polyoxazoline, polyphosphate, polyphosphazene, poly(vinyl acetate), polypropylene glycol, poly(N-isopropylacrylamide) (PNIPAM), polysaccharides, sulfonated hydrophilic polymers (e.g., sulfonated polyphenylene oxide, Nafion®, sulfobetaine methacrylate), and iodine-added variations thereof (e.g., PVA-I, PVP-I), or variations with additional pendant groups, copolymers thereof, and combinations thereof. Two or more hydrophilic polymers may be mixed together to form nanoporous materials. The molecular weight of the polymer can 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 having a molecular weight of 40k to 5000k Daltons. One of ordinary skill in the art will readily understand 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, 800, 900k, 1 million, 1.5 million, 2 million, 2.5 million, and 3 million.

[0219] 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, underivatized, 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 repeating units 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 the polymer and may be the same or different from the polymer repeating units. Thus, references to polymers also include highly derivatized polymers and polymers having 0.01-20% w / w or less of derivatized moieties, calculated as the total MW of the derivatized moieties compared to the total weight of the polymer. Those of skill in the art will immediately understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 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, any of which can be used as an upper or lower limit.

[0220] 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 nanoporous material or materials that include 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.

[0221] The process for producing the material can also affect material properties, such as 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 weight-volume percent (w / w) in water; about 10 to 30% (w / w) is generally preferred; one of skill in the art will readily recognize that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70% can all be used as upper or lower limits.

[0222] The processes described herein may be terminated before the polymers are crosslinked and processed to become true nanoporous materials, 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 contents. 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 have properties approaching those of nanoporous materials and have strength superior to that of hydrogels.

[0223] Those skilled in the art are familiar with quantifying pore size distribution in materials. Nanoporous, microporous, and nanoporous materials are disclosed herein, and control of pore size in such materials is demonstrated. Accordingly, embodiments include materials having a specific amount or distribution of pore sizes. These can be measured at the surface, at depth from the surface in a cross-sectional sample, or for the bulk of the material. For example, the pore size of a material on the surface, at depth from the surface, or in the bulk can be a percentage of pore diameters that fall within a range of 50-100%, or above or below a certain value, from 1 nm to 20 μm. Those of ordinary skill in the art will immediately understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 10, 20, 30, 40, 50, 60, 65, 70, 75, 80, 90, 95, 98, 99, 99.9 or 100 and 1, 10, 20, 30, 40, 50, 100, 200, 400, 500, 1000, 2000, 3000, 5000, 10000, 15000 or 20000 nm. An example of quantification for depth is, for example, quantification at a depth of at least 1 to 5000 μm or at a depth in the range of 1 to 5000 μm; one of skill in the art will immediately understand that all ranges and values between the explicitly stated boundaries are contemplated: 1, 2, 3, 4, 5, 10, 20, 50, 100, 250, 500, 750, 1000, 2000, 3000, 4000, or 5000 μm. For example, a surface may have a certain percentage of pores that do not exceed a certain diameter, or a depth or depth range may have a certain percentage of pores that do not exceed a certain diameter.

[0224] Embodiments include methods for producing a polymeric material comprising 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 cooling the mixture while the mixture crosslinks. When multiple polymers are present in a solvent, with or without other additives, the melting point of the combined polymers in the solvent can be readily determined by one skilled in the art, for example, by observing the mixture, as the mixture changes from a cloudy state to a significantly more translucent appearance upon heating. Additionally, some or all of the solvent may be removed from the mixture while cooling occurs 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).

[0225] Bulk incorporation of polymers into porous solids The porous material may be exposed to a mixture containing a solvated polymer (for bulk-incorporated polymers) to draw the polymer into the pores as the porous matrix is desolvated. The solvent of the mixture has an affinity for the matrix and is drawn in as the matrix absorbs the solvent. The solvent in the mixture containing the bulk-incorporated polymer can be selected to have an affinity for the matrix, so that the solvent is absorbed into the desolvated matrix, but need not be the same as the solvent in the matrix. Generally, the hydrophilic solvent in the mixture is drawn into the hydrophilic porous matrix that is at least partially desolvated and contains the hydrophilic solvent; one skilled in the art can adjust the various solvents as needed to create appropriate conditions if bulk incorporation is the intended end goal.

[0226] A hydrophilic solvent is a solvent that is freely miscible with water or is present in the mixture at a concentration that is freely miscible with water at 20°C.

[0227] By "desolvated," we mean that the matrix is solvent-free, e.g., completely dry, or below the matrix's EWC relative to the solvent it contains. If the solvent in the matrix is not water, the EWC can be calculated for the material based on measurements in the solvent; i.e., the term "EWC" can be used in appropriate circumstances for the non-water solvent. For example, a hydrophilic matrix may be solvated in an aqueous solution of an alcohol and have an EWC relative to that solvent. While embodiments include amounts of desolvation of porous solids from 1 to 100, those skilled in the art will readily understand that all ranges and values between the explicitly stated boundaries are contemplated: 1, 5, 10, 15, 20, 33, 40, 50, 60, 70, 80, 90, 95, 99, 100% w / w, based on the total weight of solvent that can be removed.

[0228] Without being bound by any particular theory, it is believed that a porous material can be desolvated (dehydrated if water is the solvent in the porous material) and exposed to a polymer in a solution that resolvates the porous material so that the polymer is drawn into the pores. The polymer then forms physical bonds with the matrix material that defines the pores and, for practical purposes, is permanently incorporated into the bulk of the material by at least partially filling the pores and through physical bonds with the matrix. Alternatively or additionally, the polymer has a hydrodynamic radius that causes it to exhibit a diameter that exceeds the opening diameter of the pores, so that the polymer is permanently incorporated into the pores of the material, particularly when the material is to be used in water or physiological solutions. Generally, if a bulk-incorporated polymer is solvated in a polymer that wets the pores of the porous solid, the polymer can be drawn into the pores of the matrix as it dissolves. If the hydrophilic porous matrix is below the EWC of the matrix, the mixture containing the polymer for bulk incorporation will be drawn in because the solvent for the polymer is compatible with the matrix material, e.g., wets the pores of the material. For example, a hydrophilic solvent will typically wet the pores of a hydrophilic matrix.

[0229] Materials comprising a porous matrix of non-covalently bound polymers are preferred embodiments because they can be made with a high degree of control over pore size and material properties, including the selection of nanoporous, microporous, or other characteristic pore sizes. The matrix may also include physically crosslinked water-soluble polymers that define the pores. The solids concentration of these water-soluble polymers may be at least 33% w / w of the matrix at the equilibrium water content (EWC) of the matrix, although other concentrations may also be used.

[0230] Thus, an embodiment of a method for incorporating a polymer into a porous material includes providing a material comprising a porous hydrophilic matrix including one or more water-soluble polymers (also referred to herein as matrix polymers) crosslinked to each other to form a matrix. The material with the matrix is exposed to a mixture comprising one or more polymers solvated in a solvent (also referred to as bulk-incorporated polymers, preferably the polymers are water-soluble, the mixture also referred to as a conditioning mixture or bulk-incorporated mixture), where prior to exposure to the mixture, the matrix is below its EWC and is hydrophilic relative to the solvent. The material is desolvated prior to exposure to the mixture comprising the bulk-incorporated polymers.

[0231] In general, the bulk incorporation process was observed to produce an outer zone of filled pores, a middle zone where the pores are largely or nearly filled, and an inner zone where there is little or no polymer penetration, see Figure 35A. Bulk incorporation not only modifies surface pores, but also modifies pores below the surface, e.g., in the range of at least 1-5000 μm or 1-5000 μm; one of skill in the art will immediately understand that all ranges and values between the explicitly stated boundaries, e.g., 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 75, 100, 250, 500, 750, 1000, 2000, 3000, 4000, or 5000 μm, are contemplated. The percentage of pores with polymer may be assayed as previously described, and the permeation is graded by percentage cutoffs, e.g., a first zone with 100% filling of pores, a second zone with 50% pores filled, and a third zone with 0% pores filled.

[0232] The bulk incorporation process is preferably carried out using a porous matrix made from a water-soluble polymer, which may be made without hydrophobic domains in the polymer, such as a matrix made solely from PVA. The polymer may form a matrix with physical crosslinks. Thus, embodiments include materials including matrices that do not contain hydrophobic domains, or matrices made using water-soluble polymers that do not contain hydrophobic domains, or matrices that do not contain any water-soluble polymers. However, some hydrophobic domains can be tolerated when creating a hydrophilic matrix using water-soluble polymers with physical crosslinks without disrupting the matrix formed by the water-soluble polymers with physical crosslinks. Embodiments of the present invention include porous matrix-forming polymers with a hydrophobic content of 0, 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, or 15% w / w.

[0233] A porous matrix consisting essentially of water-soluble polymers refers to a maximum 3% w / w content of polymers that are crosslinked to form the matrix. RO agents, such as salts, are not polymers that are crosslinked to form the matrix. A porous matrix consisting essentially of physically crosslinked polymers refers to a matrix that is free of agents that create covalent bonds between polymers, or a matrix that has a small amount of such agents, such that no more than about 6% of the polymers (by number) are crosslinked with such agents, e.g., a stoichiometric ratio of polymer number to bifunctional crosslinker of at least 100:3. Similarly, a matrix that is essentially free of covalent bonds is made using crosslinked polymers in which no more than about 6% of the polymers (by number) are covalently crosslinked. Similarly, the number of covalent bonds in the matrix may be limited to a stoichiometric ratio of 100:3 to 100:100, e.g., 100:3, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, or 100 by number. For example, hydrogels made by free radical polymerization typically have 100% of the polymers bonded to each other by covalent bonds, ie, a 100:100 stoichiometry of polymer:covalent bonds.

[0234] As noted elsewhere, porous solids can be fabricated to have a controlled range of pore diameters, or may be fabricated to provide a matrix with no pores larger than a particular diameter. Diameters may be measured, for example, by EWC in distilled water, in appropriate circumstances. Thus, embodiments include polymers entrapped in a porous matrix in which no pores larger than 1-5000 μm are present; those skilled in the art will readily recognize that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 50, 100, 200, 250, 300, 400, 500, 750, 1000, 2000, 3000, 4000, or 5000 μm.

[0235] The porous solid may contain other materials, such as radiopaque (RO) agents, as described elsewhere herein, that are added to the matrix but are not part of it. The RO agents typically contribute little to the crosslinking that gives the matrix its strength. Similarly, other materials, such as wires and reinforcing materials, may be present in the matrix without being part of it. A matrix formed by physical crosslinks may be formed by a material that defines pores having a diameter, and can be understood to be a type of matrix in contrast to hydrogels, which generally have polymer strands spaced apart and connected in a mesh network structure, such as those typically formed using free radical polymerization or by the reaction of a monomer / polymer in solution. Such mesh networks would generally not be expected to stably incorporate polymers into their pores without covalent bonding using a process of imbibing the polymer. Porous materials are described in detail herein, and may be freely selected for use with bulk-incorporated polymers, as guided by the disclosure herein. Porous materials may be selected for their bulk properties, as described herein.

[0236] The bulk-incorporated polymer may be any of the polymers described elsewhere herein with respect to the porous solid. Examples include water-soluble polymers. Examples of water-soluble polymers include polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyacrylic acid (PAA), polyacrylamide, hydroxypropyl methacrylamide, polyoxazoline, polyphosphate, polyphosphazene, poly(vinyl acetate), polypropylene glycol, poly(N-isopropylacrylamide) (PNIPAM), polysaccharides, sulfonated hydrophilic polymers (e.g., sulfonated polyphenylene oxide, Nafion®, sulfobetaine methacrylate), and iodine-added variations thereof (e.g., PVA-I, PVP-I), or variations with additional pendant groups, copolymers thereof, and combinations thereof. A blend may contain more than one polymer, i.e., polymers of different chemical compositions, such as PVA and PEG. The term "polymer" refers to one or more polymers.

[0237] The solubility of the water-soluble polymer for the porous matrix or for bulk incorporation may be selected, for example, as at least 1, 2, 5, or 10 g / 100 ml in water at 20° C. The polymer may be selected to be linear or branched. Embodiments include, for example, polymers or hydrophilic polymers having a molecular weight of 40 kDa to 5,000 kDa. Those skilled in the art will readily recognize that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 40 kDa, 50 kDa, 100 kDa, 125 kDa, 150 kDa, 250 kDa, 400 kDa, 500 kDa, 600 kDa, 750 kDa, 800 kDa, 900 kDa, 1 million, 1.5 million, 2 million, 2.5 million, and 3 million molecular weights may be used as upper or lower limits. The molecular weight of the polymer may be selected taking into account the available pore size in the porous solid. Nanoporous or microporous materials are preferred.

[0238] The bulk-incorporated polymer may be the same as that forming the porous matrix, may be selected to be the same as at least one of the polymers that make up the matrix, or may be different.

[0239] The concentration of bulk-incorporated polymer in the mixture refers to the mixture at the start of the process and can be any concentration that will cause the polymer to go into solution; note that polymer or other unsolvated materials not in solution are not destined to enter the pores. In some embodiments, the concentration is 1-50% w / w. Those skilled in the art will readily understand that all ranges and values between the explicitly stated boundaries are contemplated, e.g., 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 33, 35, 40, 50% w / w.

[0240] The solvent for the mixture is appropriately selected to solvate the polymer and provide a solvent that is absorbed by the porous solid. Generally, hydrophilic solvents are preferred for hydrophilic matrices. The solvent may be water, an organic solvent, an aqueous solvent, or a solvent that does not contain these, e.g., an organic solvent. In some embodiments, the concentration of water is 0-99, e.g., 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 95, or 99 w / w%.

[0241] The temperature of the conditioning mixture should not exceed the melting temperature of the porous solid matrix, and may range, for example, from 10 to 100°C, such as 10, 20, 30, 37, 40, 50, 60, 70, 80, or 90°C.

[0242] The exposure time is preferably the time required for the porous solid to reach the EWC in the mixture. Durations may include 2, 4, 6, 8, 10, 12, 16, 20, 24, and 48 hours in some embodiments. Stirring time and temperature may be manipulated to affect the exposure time, for example, to accelerate the attainment of the EWC or to adjust the viscosity of the mixture. Salt and / or osmolality content may be adjusted as useful, for example, with respect to solubility, viscosity, and / or EWC.

[0243] The examples provide guidance regarding salt concentrations for conditioning mixtures. An example salt concentration is 0.1-2% w / w. Generally, singly charged cations with smaller atomic radii penetrate deeper into porous solids, while larger cations decrease penetration. Examples of salts include salts with single cations, divalent cations, or other cations, such as sodium, potassium, lithium, copper, quaternary ammonium (NR4+, where R is hydrogen, alkyl, or aryl), magnesium, calcium, copper, iron, or zinc salts. Generally, physiological pH using buffers has been useful for the mixtures. The pH may be adjusted to increase or decrease penetration into the matrix, and the solvent may contain or omit buffer salts. An example pH is 4-10, e.g., 4, 5, 6, 7, 8, 9, or 10.

[0244] The viscosity of the conditioning mixture representing the water-soluble polymer and solvent is affected by pH (the higher the pH, the higher the viscosity), the concentration and / or molecular weight of the polymer, and the branching of the polymer, with increases in any of these generally resulting in higher viscosities. Generally, higher viscosity reduces the penetration of bulk-incorporated polymer into the porous solid. One embodiment is a porous material comprising a water-soluble polymer trapped within the pores of a porous matrix. The matrix may comprise physically crosslinked water-soluble polymers that crosslink with each other to form the matrix and define the pores. The matrix may have characteristics as disclosed herein, such as polymer content, weight percent of polymer, strength, Young's modulus, coverage, pore size, etc.

[0245] Surface coverage of the water-soluble polymer in the porous matrix may be complete. Complete coverage under SEM conditions, where no underlying surface pores are visible, indicates coverage in an EWC. The degree of coverage may be less than 100%, e.g., 50-100%; one skilled in the art will readily understand that all ranges and values between the explicitly stated boundaries, e.g., 50, 60, 70, 80, 90, 95, 98, 99, 99.9, or 100%, are contemplated.

[0246] As noted above in Example 24, bulk incorporation can decrease the physical properties of a porous solid. Accordingly, embodiments include porous solids, such as those disclosed herein, that have a 1-20% lower Young's modulus and / or tensile strength as a result of conditioning with a water-soluble polymer compared to the same material not conditioned with a water-soluble polymer. Those skilled in the art will readily appreciate that all ranges and values between the explicitly stated boundaries, e.g., 1, 2, 3, 4, 5, 7, 9, 10, 12, 15, or 20%, are contemplated. Example 22 provided a test for exposing materials for stable incorporation of a water-soluble polymer. The test for stable incorporation of a water-soluble polymer was to immerse a test article in a physiologically representative fluid (i.e., PBS) at body temperature conditions in a circulating peristaltic loop, with the test article placed directly in the head of the pump at 150 rpm and a flow rate of 10-12 mL / sec for 24 hours, and to measure the incorporation rate of 0.1225 cm. 3 *s -1 *cm -2 This approximates 500,000 mechanical sample compressions at a volumetric flux rate of 1000 psi. Testing has revealed a maximum reduction of 25%, but other test criteria may be used, e.g., 0-50% w / w, e.g., 1, 5, 10, 15, 20, 25, 30, 40, or 50% w / w. Or other tests may be used, e.g., 0-5% w / w, e.g., 1, 2, 3, 4, or 5% w / w, over 1-52 weeks of static exposure to excess PBS, e.g., 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, or 52 weeks.

[0247] product Using the materials described herein, including nanoporous materials, microporous materials, and hydrogels, products, such as final or intermediate products or 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 the width decreases. Those skilled in the art will readily understand that all ranges and values between the explicitly stated 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 all 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 length constraints. Such devices include, for example, tubes, rods, cylinders, and cross-sections with square, polygonal, or circular profiles. Any of the devices may be provided with one or more lumens. The device may be made of a single material, essentially a single material, or multiple materials including the various layers already described, or reinforcements, fibers, wires, braided materials, braided wires, braided plastic fibers.

[0248] In particular, the extrusion process provides concentric placement of the lumens; concentricity is in contrast to eccentricity, which means 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 lumens positioned without eccentricity or one lumen that is concentric with the longitudinal axis of the device and having an aspect ratio of at least 3:1.

[0249] Porous solids, such as nanoporous materials, microporous materials, and strong hydrogels, may be used to fabricate catheters or medical fibers. These may be made with bulk-incorporated polymers and may have various characteristics described for bulk-incorporated polymers. Examples of catheters include central venous, peripheral central, midline, peripheral, tunneled, dialysis access, urethral, neurological, celiac, intra-aortic balloon pump, diagnostic, interventional, drug delivery, shunts, wound drains (external, such as ventricular, ventriculoperitoneal, and lumboperitoneal), and infusion ports. Porous solids may be used to fabricate either permanent or temporary implantable devices, including fully implantable and percutaneously implanted devices. Porous solid materials may be used to fabricate devices that contact blood or bodily fluids, such as ex vivo and / or in vivo devices, as well as blood-contacting implants. Examples of such devices include drug delivery devices (e.g., insulin pumps), tubing, contraceptives, feminine hygiene products, endoscopes, implants (including those with diameters less than 6 mm), pacemakers, implantable cardioverter-defibrillators, cardiac resynchronization devices, cardiovascular device leads, ventricular assist devices, catheters (including 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 the materials, fibers, or devices.The term radiopacifier refers to agents commonly used in the medical device industry to impart radiopacity to materials, e.g., barium sulfate, bismuth, or tungsten. The RO agent may be incorporated, for example, at 5-50% w / w of the total solids weight, e.g., 5, 10, 20, 30, 40, or 50%.

[0250] Medical fibers made from porous solid materials include applications such as sutures, threads, medical textiles, 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.

[0251] In an exemplary embodiment, a method includes administering a polymeric material into an external orifice of a subject, the polymeric material including a water-soluble polymer and having an aspect ratio of 3:1 or greater, wherein administration of the article (e.g., article 10 of FIG. 1A, article 12 of FIG. 1B) does not include use of a sheath introducer. The polymeric material is substantially non-thrombogenic, the polymeric material has a water content in a dehydrated state of less than 5 wt.% and greater than or equal to 0.1 wt.% and the polymeric material is configured to swell from the dehydrated state to an equilibrium water content state by an amount greater than or equal to 5 wt.% and less than or equal to 50 wt.% within 60 minutes.

[0252] Further definitions The term "medically acceptable" refers to a material that is highly purified to be free of contaminants and is non-toxic. The term "consists essentially of," when used in the context of a biomaterial or medical device, refers to a material or device having 3% w / w or less of other materials or components, which does not render the device unsuitable for its intended medical use. Equilibrium water content (EWC) is a term that refers to the water content of a material when its wet weight becomes constant and before it begins to degrade. Materials with high solids contents are generally observed to reach equilibrium water content in 24 to 48 hours. Distilled water is used to measure EWC unless otherwise specified.

[0253] 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 include biomedically acceptable materials intended for use 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 the material is suitable for biomedical applications, it is not limited to biomedical applications and may be manufactured as a general-purpose material. "Saline" refers to a phosphate buffer solution having a pH of 7 to 7.4 and a human physiological osmolality at 37°C.

[0254] 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 it is crosslinked. 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, when used with polymers, also refers to the weight average.

[0255] The publications, journal articles, patents, and patent applications referenced herein are incorporated herein for all purposes, and in the event of a conflict, the present specification will control. Features of the embodiments described herein may be mixed and matched as needed to produce a workable process or product.

[0256] As used herein, the term "therapeutic agent," also referred to as "drug," refers to an agent that is administered to a subject to treat a disease, disorder, or other clinically recognized condition, or for prophylactic purposes, and that has a clinically significant effect on the subject's body to treat and / or prevent the disease, disorder, or condition.

[0257] As used herein, when an element is referred to as "adjacent" to another element, the element can be directly adjacent to (e.g., touching) the other element, or there may be one or more intervening elements. An element that is "directly adjacent" to another element means that there are no intervening elements.

[0258] "Subject" refers to any animal, such as a mammal (e.g., a human). Non-limiting examples of subjects include humans, non-human primates, cows, horses, pigs, sheep, goats, dogs, cats, or rodents, such as mice, rats, hamsters, birds, fish, or guinea pigs. Generally, the present invention is intended for use in humans. In some embodiments, a subject may exhibit a health benefit upon administration of, for example, a self-righting article.

[0259] As used herein, "fluid" is given its ordinary meaning, i.e., a liquid or a gas. A fluid cannot maintain a definite shape and flows over an observable time frame to fill a container in which it is placed. Thus, a fluid may have any suitable viscosity that allows it to flow. When more than one fluid is present, each fluid may be independently selected by one skilled in the art from among essentially any fluid (liquid, gas, etc.). [Example]

[0260] The following examples are intended to illustrate some of the embodiments described herein, including some aspects of the present invention, but do not exemplify the full scope of the invention.

[0261] 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 (MW = 85 kDa, Sigma-Aldrich). The water was heated (100 °C) until it began to boil. Then, with moderate mixing (mixer speed approximately 40), the dry PVA was slowly added (over approximately 5-10 minutes) to the water. To prevent boiling, the heating was stopped as soon as or before boiling began (i.e., a boil-free process). 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 high to ensure complete dissolution and thorough mixing of the polymer. 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 did not exceed 2 hours.

[0262] Polymer samples were extruded into a bath of 13°C ethanol (Fisher, 190 proof) using a PTFE monofilament (e.g., core) pull speed of 7 (ARDUINO specific motor movement software, 84 mm diameter puller wheel). After extrusion, the sample was allowed to stand in the cold ethanol for approximately 30 minutes before being moved. The sample was then transferred to another container of ethanol and placed in a -25°C freezer for 24 hours. The core (e.g., monofilament) was then removed from the sample by clamping the ends of the monofilament with tongs and slowly sliding the sample. A mandrel slightly smaller than the sample's inner diameter (0.033 inches) 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) at 120°C in a sealed container in an oven for 24 ± 4 hours. After annealing, the samples were removed from the glycerol and gently rinsed with deionized water. The samples were then transferred to a new container of deionized water and allowed to rehydrate for approximately 24 hours. The samples can be dehydrated and rehydrated without any adverse effects or changes to the porous solid observed. This process produced catheters containing nanoporous solid materials.

[0263] Example 1B: Molded PVA PVA gel was 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 injected into a preheated mold at 60°C and then rapidly cooled using a refrigerated cooling source. The PVA gel was then removed from the mold intact on the mandrel.

[0264] 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 cured 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.

[0265] Some of these gels were then annealed by immersing them in mineral oil and heating them to 140°C for 1 hour. The gels were rinsed thoroughly 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 them in glycerin and heating them to 120-130°C for 3-24 hours. The gels were rinsed thoroughly 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.

[0266] Example 2: Extrusion of PVA-Barium A PVA-barium polymer solution was prepared using 100 ml of deionized water, 16 g of 85 kDa PVA (Sigma-Aldrich), and 4 g of barium sulfate (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 high to ensure complete dissolution and thorough mixing of the polymer. 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 did not exceed 2 hours.

[0267] The sample was extruded in a similar manner to that described in Example 1 and then allowed to rest in cold ethanol for approximately 30 minutes before moving. After exiting the extruder die and entering the ethanol bath, the sample measured approximately 3 mm in outer diameter and remained solid but pliable. To completely dehydrate the sample into a stable, opaque, smooth, white tube, the sample was transferred to another container of ethanol and placed in a freezer set at -25°C for 24 hours. The sample was not frozen. The monofilament (e.g., core) was then removed from the sample by clamping the ends with tongs and gently sliding the sample. A mandrel slightly smaller than the sample's inner diameter 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±4 hours in an oven. A rigid, opaque, smooth tube was produced.

[0268] After annealing, the samples were removed from the glycerol and gently rinsed with deionized water. The samples 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.

[0269] Example 3: Rehydration / dehydration rate of PVA porous material Over a 23-hour period, a percent weight 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.

[0270] JPEG2025114716000003.jpg136111

[0271] Example 4: Tensile Test Example PVA extrusion samples were prepared by heating a slurry of 17.6 g of bismuth subcarbonate and 100 g of 6.2 g / L monosodium phosphate solution in a jacketed reactor at 95°C. To this, 25.8 g of PVA (Mowiol 28-99, 145 kDa or Sekisui Selvol 165, also known as 67-99, Mw 186 kDa) was added over 5 minutes while mixing at a 70% run setting (DITC V2 mixer). The polymer was mixed at 70% run setting 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.

[0272] The polymers were dried at 55°C for 3 hours and annealed in a forced convection oven at 140°C for 1.5 hours. The samples were then rehydrated in 1x PBS at 37°C for 2 hours. After annealing and rehydration, the outer diameters of the extruded samples were 1.55 mm and 1.46 mm for PVA 28-99 and PVA 67-99, respectively, and the inner diameters were 0.69 mm and 0.76 mm for PVA 28-99 and PVA 67-99, respectively.

[0273] 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 areas were measured for samples using calipers (Mark 10 Model #500-474) to measure outer diameter and a pin gauge set to measure inner diameter. PVA 67-99 exhibits a nominal viscosity of 67 cPs (as a 4% solution in water) with greater than 99% hydrolysis. PVA 28-99 exhibits a nominal viscosity of 28 cPs (as a 4% solution in water) with greater than 99% 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.

[0274] JPEG2025114716000004.jpg76148 An 18% PVA extrusion sample was prepared by heating a slurry of 17.6 g of bismuth subcarbonate 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) was added over 5 minutes with mixing at 70% run setting (DIT CV2 mixer).

[0275] A 22% PVA extrusion sample was prepared by heating a slurry of 23.3 g of bismuth subcarbonate and 100 g of a 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 a 70% run setting (DIT CV2 mixer).

[0276] A 26% PVA extrusion sample was prepared by heating a slurry of 35.4 g of bismuth subcarbonate and 115.9 g of a 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 a 70% run setting (DIT CV2 mixer).

[0277] Each set of polymers was mixed for 1.5-2 hours at 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.

[0278] 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 Tables 4 and 5.

[0279] The PVA content in the mixtures in Table 4 was increased in the batch process relative to the monobasic salt solution. Increasing the PVA content provided higher ultimate tensile strength and a higher Young's modulus. As the ratio of PVA to monobasic sodium phosphate increased, stronger materials could be prepared. Figure 11 and Table 5 show that 26% PVA 28-99 had an increased Young's modulus and maximum tensile stress compared to 22% and 18% PVA 28-99. The samples showed an increase in OD as the PVA was aligned, as shown in Table 5. OD measurements were 1.32, 1.40, and 1.48 mm for the 18, 22, and 26% PVA concentrations, respectively; ID did not change significantly and ranged from 0.71 to 0.76 mm for the samples.

[0280] JPEG2025114716000006.jpg85164

[0281] 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, exposing the PU / PVA overlap 10 times at 0.5 second intervals, and the process was repeated until an infusion bond between the PU and PVA occurred. Tensile data was evaluated for multiple samples:

[0282] 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 - 0.065 inch) and 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 / tube assembly into the ID of the PVA tubing.

[0283] Three samples using PE hub and PVA tube butt welds were fabricated at 400°F. The joints were observed to be very strong.

[0284] The clear luer hub and tubing assembly was slid into approximately 0.75 inches of PVA extrusion, and a melt liner of ethyl vinyl acetate and polyolefin was added to the assembly. The melt was prepared and joined at 400°F. Once the PVA extrusion and melt liner were noticed to be melted, a more controlled shrinkage method was applied using gentle hand rolling of the melted joint to form a smooth seal and prevent melting of the PVA tubing.

[0285] 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 and used for hydration and testing. After conditioning in PBS at 37°C for 2 hours, the samples were tensile tested and the results are shown in Table 7.

[0286] JPEG2025114716000008.jpg54170

[0287] The suture wing overmold was also successfully attached. EVA (Ateva 2803G with 20% bismuth subcarbonate) was used to injection mold the suture wings. A tension line (HTP Meds#2006-0335 Rev A) and PVA tubing were attached. A maximum break force (Wagner Instruments# FDK 30) of 27 N (6.1 lbf) 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).

[0288] Example 6: Radiopacity Samples were prepared according to the method of Example 2, except that bismuth subcarbonate was used as the radiopaque agent. The samples are shown in Figures 12A-12F: control (12A, BARD PowerPICC), 5.7 wt.% bismuth subcarbonate, no annealing (12B), 12.1 wt.% bismuth subcarbonate, no annealing (12C), 12.1 wt.% bismuth subcarbonate, annealed (12D), 5.7 wt.% bismuth subcarbonate, annealed (12E), and 4.2 wt.% bismuth subcarbonate (12F). After alcohol exposure, the extruded samples had an OD range of 2.71-2.84 mm and a constant ID of 1.397 mm. After annealing, the samples had an OD range of 1.63-1.93 mm and an ID of 0.97-1.04 mm. Hydration of the material after annealing in glycerol resulted in a hydrated OD ranging from 1.89 to 2.44 mm, with an ID range of 1.19 to 1.25 mm.

[0289] All samples B-E exceeded the radiopacity of the control sample. The 4.2% bismuth subcarbonate sample (12F) exhibited approximately the same level of radiopacity or less, which is considered minimal for the sample. Radiopacity testing was performed at Mount Auburn Hospital in Cambridge, Massachusetts.

[0290] 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.

[0291] Water was injected at 5 mL / sec for 1 second, but did not clog the sample (it was free flowing) and passed through without breaking the sample. Another identical sample of the same PVA-RO formulation was then 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.

[0292] Another set of samples, shown in Figure 13, was then attached to barbed fittings with Loctite 4902 and heat-shrunk onto silicone tubing using the method described in Example 5; 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 thermal exposure (failure locations shown in Figure 14).

[0293] Sample 3 was tested with decreasing injection rates and volumes and passed two of three cycles: Cycle 1 used a flow rate of 0.4 mL / s with a maximum pressure of 100 PSI and a total volume of 1 mL, while Cycle 2 used the same parameters with a maximum pressure of 200 PSI; both cycles were completed. Cycle 3 used a flow rate of 5.0 mL / s with a total volume of 1 mL and a maximum pressure of 350 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 was able to withstand power injection when using the appropriate mounting method (i.e., overmolding).

[0294] Example 8: Contact angle Contact angles were measured for PVA-RO-incorporated hydrogels prepared according to Example 2. A 1 cm section of the extruded material was cut from the main strand using a new blade; 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 lightly applied along the edge of the sample, and forceps were used to gently press the sample wall onto the glass slide until a flat shape was achieved. A small droplet of colored water was placed on the surface of the material using a 20 μL pipettor. To measure the contact angle of the droplet, the droplet was immediately photographed and captured in an image viewer. All surfaces and the camera were leveled before testing. The sample had a contact angle of 60° (obtained through the droplet) as measured by the drop test.

[0295] Example 9: SEM Results Figures 15A-15B are SEM images of a 17% PVA solution extruded using the method of Example 1A, unless otherwise noted. Samples were hydrated in distilled water at 37°C for 24 hours and then rapidly frozen using liquid nitrogen to preserve the pore structure. The samples were then freeze-dried for 48 hours to remove water and subjected to SEM analysis. Figure 15A shows a cross-section of an extruded PVA tube, demonstrating no macroporosity in the gel structure. Figure 15B shows a longitudinal cross-section of the extruded tube at a higher magnification, demonstrating the absence of macroporosity in the structure. This material has a high water content and is highly porous, with pores approximately 10 nm or smaller in diameter.

[0296] A PVA extrudate sample was also 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 and then stored in ethanol at -25°C in a freezer for 24 hours. The sample was dried 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; the core was removed after rinsing. The sample was then dried at 50°C for 12 hours. Two SEM images (Figures 16A-16D) illustrate the results. Figures 16C-16D are taken at higher magnification demonstrating nano-porosity.

[0297] Example 10: Salt Additive To change the maximum tensile stress and Young's modulus, Various salts were used in a batch process that represents the process of driving the polymer into solution in the polymer-solvent mixture. Multifunctional salts such as phosphate, borate, and citric acid were used. These salts were added as sodium and / or potassium salts with various degrees of neutralization.

[0298] PBS (phosphate-buffered saline) contains sodium chloride, potassium chloride, and phosphate as its main components. Three neutralization points were analyzed in comparison with PBS. Mixtures of 18% PVA (MW 146kJ-186kJ, Sigma-Aldrich #363065) with 6% bismuth subcarbonate (Foster) (20% w / w on a solids basis) and these phosphate solutions at a fixed molar ratio of 51.7 mM were tested using 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 18% PVA (Sigma-Aldrich), 6% bismuth subcarbonate (Foster's) (20 w / w% solids) solutions with 51.7 mM of each acid. Boric acid increased both Young's modulus and maximum tensile stress, while citric and phosphoric acids were relatively identical.

[0299] The sample dimensions after hydration in PBS at 37°C for the various salt additives were as follows:

[0300] JPEG2025114716000009.jpg86170

[0301] Example 11: Blend Batching 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 remaining water was used to homogenize the bismuth subcarbonate concentrate 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 dispensed into 20 mL syringes.

[0302] JPEG2025114716000010.jpg91170

[0303] 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 with the monofilament for about 0.5 hours. The extrudate was then transferred to room temperature ethanol, the monofilament was removed, and the extrudate was dehydrated for 24 hours.

[0304] The extrudates were transferred to a vacuum oven and dried at 50°C for 48 hours. After drying, the samples were poured with 120°C USP-grade mineral oil 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 allowed to cool to room temperature. Rinsing / washing was performed once with ethanol and twice with distilled water. The samples were then transferred to 37°C PBS to hydrate before tensile testing and surface evaluation. After hydration, the sample surfaces were smooth, with ODs ranging from 1.8 to 2.4 mm and IDs ranging from 1.5 to 1.6 mm. Tensile testing was performed according to ISO-10555 protocols. Tensile values were not normalized to the cross-sectional area of the samples.

[0305] 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 showed higher tensile strength than the 4.0% blend. Higher water content correlates with increased PAA percentage, decreasing the strength between PVA bonds and therefore lowering 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 0.3% and 0.4% (w / w relative to the solvent) 3m molecular weight PAA blends showed higher tensile strength than the 0.2% blend. The 3m molecular weight PAA-containing blends, with the exception of the 4.0% blend, exhibited approximately half the tensile strength of the 450k PAA-containing blend.

[0306] Example 12: Blend batch of PVA and PEG and copolymer extrusion The PVA-PEG blend solution was batch processed using the following method; see Table 9: PVA (Sigma, 146k-186k), bismuth subcarbonate (Foster), 100 g 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. The PVA was then added to the reactor with mixing at 600 RPM for 2 hours; the PEG was then added to the solution, and mixing continued for 2 hours until the solution was completely homogenous. The polymer was then dispensed into 20 mL syringes.

[0307] JPEG2025114716000011.jpg48165

[0308] The polymer was reheated to 90°C and extruded to an OD of approximately 2.3-2.4 mm into ethanol at approximately 3-21°C. The extrudate was allowed to stand in the ethanol on the monofilament for approximately 1 hour. The extrudate was then transferred to room temperature ethanol, and the monofilament was removed and allowed to dehydrate for 24 hours.

[0309] The extrudates were transferred to a vacuum oven and dried at 50°C for 48 hours. After drying, the samples were poured with 120°C USP-grade mineral oil 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 before being measured for OD and wall thickness. Sample diameters were approximately 1.9-2.3 mm, with wall thicknesses of 0.48 mm. 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 protocol. Figure 19 shows the results, comparing PVA-1% PEG blends with various MW PEGs; note that tensile values were not normalized to the cross-sectional area of the samples. PEG blend extrudates yielded smooth surfaces, with the exception of PEG35k, which formed a scale pattern along the exterior of the extrudate. Due to the wide standard deviations for all 1% PEG blends, no significant differences were observed in the tensile strength of the 8k, 20k, and 35k PEG coextrusions. Figures 20A-20C show photographs of the 8k, 20k, and 35k PEG coextrusions, respectively.

[0310] Example 13: Evaluation of thrombogenicity of PVA gel A PVA extrudate sample was prepared by heating 200 g of distilled water to 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 the ethanol in a -25°C freezer for 24 hours. The sample was allowed to dry for 6 hours.

[0311] 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; the core was removed after rinsing. The samples were then dried at 50°C for 12 hours.

[0312] A sample of PVA with barium sulfate was prepared by heating 50 g of water to 90°C in a jacketed reactor. 4 g of barium sulfate and 50 g of water were homogenized in a side vessel at 11 k RPM for 15 minutes and then added to the jacketed reactor. This was mixed for 10 minutes to heat. After heating, 16 g of PVA (Sigma, 146k-186k) was added and mixed at 360 RPM for approximately 2 hours.

[0313] 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.

[0314] Samples were evaluated for non-thrombogenic durability testing at Thrombodyne, Inc. (Salt Lake City, UT). Each sample was cut to a length of 15 cm with N=5 per sample group. Prior to testing, samples were sterilized using 12 hours of ethylene oxide exposure. Samples were hydrated in distilled water for approximately 48 hours prior to evaluation to represent clinical use.

[0315] Fresh heparinized bovine blood containing IuIn-labeled autologous platelets was divided into a portion for test samples and a portion for control evaluation. Samples were inserted into an in vitro 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 test. After 45 minutes in the blood flow loop, samples were first checked for thrombus and removed at 120 minutes. At the end of the experiment, the devices were explanted from the tubing, rinsed with saline, and placed in a gamma counter for thrombus quantification. Experimental parameters are shown in Table 10. To allow for simultaneous comparisons without crossover effects, each experiment consisted of a separate flow system for test samples and / or control circulating blood from the same animal.

[0316] Samples were measured for radioactivity and also qualitatively evaluated for the specific type of thrombus accumulation (i.e., adhesion or fibrin accumulation). Counting results are shown in Table 10. Percent thrombosis was calculated relative to the average total thrombus formation observed across all test and control groups per animal's blood cycle. Thrombus accumulation results are shown in Tables 11-12 and Figure 21A. Visual assessment of thrombus formation is shown in Figure 21B for the commercially available control catheters, 17% PVA extrudate, and 17% PVA-barium sulfate extrudate.

[0317] JPEG2025114716000012.jpg53169

[0318] JPEG2025114716000013.jpg97154

[0319] JPEG2025114716000014.jpg95146

[0320] The results show a reduction in thrombus formation for the PVA formulation compared to the commercially available PICC. The PVA-RO (barium as agent) formulation was not superior to the control. Possible reasons include a lack of barium micronization and evidence of larger barium particles on the surface of the extrudate.

[0321] Example 14: Incorporation of polyacrylic acid (PAA) into extruded PVA Porous solids were prepared according to the process of Example 1A, further including polyacrylic acid (PAA) and other modifications described below. A PVA-PAA solution was prepared by first preparing a 13 wt. % PVA polymer solution in physiological phosphate buffered saline (PBS) using 200 g of PBS (Lot SLBH9016, Sigma-Aldrich), 32 g of PVA (Lot MKBR1224V, Sigma-Aldrich, Mw 146-186 kDa), and 14 g of bismuth subcarbonate (Foster's). The PBS was heated to 90°C, and then the dry PVA was slowly added with moderate mixing. Once all the PVA had been added and the solution began to thicken, the stirring speed was increased to high to ensure complete dissolution and thorough mixing. The bismuth subcarbonate was then added to form the final suspension. The PVA solution was stirred for approximately 2 hours. Upon completion, the solution was highly viscous and opaque. The suspension was poured into a 20 cc syringe and degassed in a 90° C. oven; heating during degassing was approximately 4 hours.

[0322] The PVA-containing mixture was extruded into a bath of ethanol (lot SHBF8329V, Sigma-Aldrich) at 3 °C using a monofilament puller speed of 7 (Arduino-specific motor movement software, 84 mm diameter puller wheel) to achieve a gauge size of 6 French.

[0323] After extrusion, the sample was placed in cold ethanol for approximately 30 minutes before being transferred. The sample was then transferred to another container of ethanol for 24 hours. The monofilament was then removed from the sample by holding the end of the monofilament with tongs and slowly removing the sample. A mandrel slightly smaller than the sample's inner diameter (0.033 inches) was inserted into the sample, and the sample was allowed to dry flat in an incubator at 40°C for approximately 24 hours. After complete drying, the sample was immersed in a 5% PAA solution prepared using 2.5 g of PAA (lot MKBT4716V, Mw 450 kDa) and 50 ml of deionized water (lot BCBP9977V, Sigma-Aldrich) at 45°C for 24 hours. The sample was then hung to air dry for approximately 3 hours, after which it was dried again in an incubator at 40°C. After drying, the samples were annealed by immersion in anhydrous glycerol (lot BCBM4755V, Sigma-Aldrich) at 120 °C in a sealed container for 17 h in an oven.

[0324] After annealing, the samples were removed from the glycerol, gently rinsed with deionized water, and placed back into the incubator to dehydrate. The samples were transferred to a new container of deionized water and allowed to rehydrate for approximately 24 hours. Samples can be dehydrated and rehydrated without any observed adverse effects or changes.

[0325] Example 15: Absence of fouling in the blood loop Nonthrombogenic durability testing was performed at Thrombodyne, Inc. (Salt Lake City, UT). Porous solid PVA tubing containing a radiopaque agent was prepared with (153-C) or without (153-A) a bulk-incorporated surface polymer (PAA) according to the process of Example 14. A 6F polyurethane catheter (Bard POWER PICC, 6F Dual-Lumen) was used as a control. Each sample was cut to a 10 cm length, with N = 6 per sample group. Prior to testing, samples were sterilized with ethylene oxide using a 12-hour cycle; samples were also hydrated in deionized water (Lot BCBP7797V, Sigma-Aldrich) for approximately 12 hours. Platelets were radiolabeled using indium-111. Samples were inserted into an in vitro blood flow loop of 1 / 8-inch polyvinyl chloride tubing for approximately 60 minutes. The blood was kept at 98°F and a constant pressure was maintained using a peristaltic pump during the test. Samples were qualitatively evaluated for thrombus (see Table 13 and Figure 22, which shows the results of Experiments (EXP) 1-6, with Figure 22 showing the results of Experiment 6). Samples were quantitatively evaluated for platelet levels via gamma counting (Table 14). Based on irradiated platelet count, the porous solid PVA tubing with bulk incorporated PAA agent showed an 89% reduction compared to the standard polyurethane control.

[0326] JPEG2025114716000015.jpg236170

[0327] JPEG2025114716000016.jpg138150

[0328] Example 16: Surface morphology Scanning electron microscopy (SEM) of samples described in Example 14 containing PVA with RO agent (Figure 23A at 500x and Figure 23B at 2000x) and PVA with RO agent soaked in PAA (Figure 24A at 300x and Figure 24B at 2500x). The surface of the PVA with RO agent extrudates shown in Figure 23 exhibits a non-porous surface with large ridges across the surface; the ridges are an artifact of the initial extrusion process used to produce these samples. The surface of the PVA with RO agent soaked in PAA shown in Figures 24A-B exhibits a distinctly different surface, with significantly more porosity on the surface, demonstrating that bulk incorporation has altered the surface properties of the PVA with RO agent extrudates.

[0329] Example 17: Role of molecular weight of bulk-incorporated and surface-bound polymers on thrombus reduction Batch processing and extrusion of PVA-bismuth subcarbonate polymer solutions A PVA-bismuth subcarbonate polymer solution was prepared using 42 g of bismuth subcarbonate (Lot: Foster, FEI5577), 179 g of 0.6 wt% monobasic sodium phosphate solution, and poly(vinyl alcohol) 28-99 (Lot: EMD, K45556756). In a sealed polypropylene jar, the substitutes were heated to 67°C and mixed in a Flaktech SPEEDMIXER double asymmetric centrifuge (DAC) until visually uniform. The polymer was immediately placed on a roller at approximately 70 RPM for 4 hours.

[0330] Once the polymer cooled to room temperature, it was cut into 1 cm x 1 cm x 1 cm cubes. The cubed polymer was extruded using a Brabender 3 / 4-inch uniaxial Advance Torque Rheometer (ATR). The heated polymer was extruded onto a 0.031-inch acetal core filament in an ethanol bath at approximately 10°C to form a tube. The 1.75 mm extruded material (extrudate) on the die exit was cut into 24-30 inch segments. After dehydration in ethanol for approximately 3 hours, the monofilament was removed. The extrudate was then dehydrated in ethanol at room temperature (21°C) for 24 hours to a moisture content of less than 5%, resulting in an outer diameter of 1.4 mm and an inner diameter of 0.79 mm.

[0331] The extruded 4 Fr single-lumen PVA tubing was then cut into 10 cm pieces and loaded with 1% poly(acrylic acid) in 5x PBS solution of various molecular weights at 37°C for 16 hours. Molecular weights included 100 kDa (Sigma-Aldrich: 523925), 250 kDa (Sigma-Aldrich: 416002), and 710 kDa (Lubrizol: CARBOPOL 907, 710 kDa). The tubing was heat-treated: dried at 55°C for 3 hours and annealed at 140°C for 90 minutes. After 24 hours of hydration in 1x PBS, tubing with an outer diameter of 1.2–1.25 mm and an inner diameter of approximately 0.78 mm was tested in an in vitro blood flow loop as described in Example 15, and the output was a platelet count (Thrombone). Figure 25A shows that there was no significant difference in thrombus accumulation as a function of increasing molecular weight of poly(acrylic acid) when compared to the control (100%) (CR Bard: POWERPICC 4Fr, Single Lumen). At least a 70% thrombus reduction was obtained.

[0332] Example 18: Effect of bulk-incorporated and surface-bound polymer over time in a blood loop thrombogenicity test The extruded 4F single lumen PVA tubing described in Example 17 was cut into 10 cm pieces and filled with 1% poly(acrylic acid) (Lubrizol: CARBOPOL 907, Mw 710 kDa) in 5x PBS solution at 37°C. The tubing was heat-treated: dried at 55°C for 3 hours and annealed at 140°C for 90 minutes. After hydration in 1x PBS for 24 hours, the tubing was tested in an in vitro blood flow loop as described in Example 17, with the output being platelet count (Thrombone). Exposure times were 3, 16, and 40 hours. Figure 26B shows that thrombus accumulation decreased with increasing exposure time of the extruded 4F single lumen PVA tubing to poly(acrylic acid) when compared to the control (100%) (CR Bard: POWERPICC 4Fr, Single Lumen). A maximum 93% thrombus reduction was obtained.

[0333] Example 19: Effect of varying the molecular weight and type of polymer of water-soluble polymers used as surface-bound polymers bulk-incorporated in porous tubes The extruded 4F single lumen PVA tubing described in Example 17 was cut into 10 cm pieces and immersed in 1% w / w of various polymers of varying molecular weights in 5x PBS solution at 37°C for 3 hours. The polymers used were 200 kDa poly(ethylene oxide) (PEO) (Sigma-Aldrich: 181994), 360 kDa poly(vinylpyrrolidone) (PVP) (Sigma-Aldrich: PVP360), and 710 kDa poly(acrylic acid) (PAA) (Lubrizol: CARBOPOL 907). The tubing was heat-treated: dried at 55°C for 3 hours and annealed at 140°C for 90 minutes. After 24 hours of hydration in 1x PBS, the tubing was tested in an in vitro blood flow loop according to the procedure in Example 17, and the output was a platelet count (Thrombone). Figure 26C shows a reduction in thrombus accumulation with each bulk-incorporated polymer compared to the control (100%) (CR Bard: POWERPICC 4Fr, Single Lumen). At least a 30% reduction was achieved.

[0334] Example 20: Batching and Extrusion of PVA-Bismuth Subcarbonate Polymer Solutions Extruded 4F single lumen PVA tubing, produced under conditions similar to those in Example 17 except that a 0.039-inch acetal core filament was used, was cut into 24- to 30-inch segments. After dehydration in ethanol for approximately 3 hours, the monofilament was removed and a PTFE-covered stainless steel mandrel was inserted into the lumen. The extrudate was then dehydrated in room temperature (21°C) ethanol for 24 hours.

[0335] A 1% PVA 28-99 solution was prepared using 2.5 g of PVA 28-99 (Lot: EMD, K4555675628, Mw 145 kDa) and 247.5 g of 1x PBS. The solution was heated to 90°C and mixed until the solids were completely dissolved. A 1% PVA 67-99 solution was prepared using 2.5 g of PVA 67-99 (Lot: SEKISUI, 02812328S1, Mw 180 kDa) and 247.5 g of 1x PBS. The solution was heated to 90°C and mixed until the solids were completely dissolved. A 1% PVA 100k solution was prepared using 1.905g of PAA 100k (Lot: Sigma, STBF3673V, Mw=100kDa), 31.76g of distilled water, and 33g of 10x PBS. The solution was heated to 90°C and mixed until the solids were completely dissolved. A 1% PAA 250k solution was prepared using 1.905g of PAA 250k (Lot: Sigma, STBF3186V, Mw=250kDa), 31.76g of distilled water, and 33g of 10x PBS. The solution was heated to 90°C and mixed until the solids were completely dissolved. A 1% CARBOPO 907 solution was prepared using 2.5 g of PAA (CARBOPOL 907, Lot: Lubrizol, 010164597, Mw=710 kDa), 495.0 g of USP water (Lot: Fisher, 1607174), and 495.0 g of 10x PBS. The solution was heated to 90°C and mixed until the solids were completely dissolved.

[0336] As shown in Table 15, the extruded material was immersed in each of the listed solutions for 16 or 40 hours at 37° C. with or without circulation.

[0337] JPEG2025114716000017.jpg103169

[0338] After the indicated time period, the samples were removed from immersion and mounted on a stainless steel mandrel. The samples were then placed in an oven heated to 55°C and heated at 55°C for 3 hours. The dried samples were then annealed in air on the mandrel in a forced air oven at 140°C for 1.5 hours. The samples were then hydrated in PBS at room temperature (approximately 21°C for 3 hours).

[0339] SEM preparation After annealing, all samples were hydrated in 1x PBS at 37°C for 3 hours. The samples were gently rinsed with distilled water and then lyophilized. Before SEM analysis, the lyophilized samples were coated with 5 nm of platinum.

[0340] analysis FM012-151-1. The PVA 28-99-soaked samples were uniformly coated along the outside of the tube body, with a spherical coating of PVA on the surface; no porosity was observed (see Figures 26A and 26B). The outer surface of the PVA 28-99-conditioned samples is shown. At 200x magnification (26A) or 2500x magnification (31B), the outer surface appears spherical and irregular in appearance (compare Figures 16-17 or 20), demonstrating bulk incorporation at the surface, compared to the PVA extruded porous solid without bulk incorporation.

[0341] FM012-151-2. The PVA 67-99 conditioned sample shown in Figure 27A exhibits a highly porous cross section near the outer surface with web-like strands, forming a boundary layer of pores toward the outer surface of the tube body. The web-like chains decrease toward the inner wall, where the PVA apparently could not penetrate. The surface also exhibits a spherical appearance compared to non-bulk-incorporated PVA extruded porous solids (see prior patent art). Figure 27B is an SEM micrograph of the outer surface, showing complete coverage of the porous surface by the bulk-incorporated water-soluble PVA polymer.

[0342] FM012-151-3. The sample with bulk-incorporated water-soluble polymer (PAA 100k) showed complete coverage of the underlying porous solid, with no discernible pores. The coverage was spherical in some areas, confirming bulk incorporation into the surface, compared to the PVA extruded porous solid not exposed to bulk incorporation. In other areas, the coverage was smooth and continuous, although a few particles of bismuth subcarbonate were visible beneath the thin layer of PAA 100k (see Figure 28).

[0343] FM012-151-4. The sample bulk-incorporated with high molecular weight PAA (250k) exhibited a rougher surface than the sample conditioned with 100k PAA. The entire outer surface of the tube showed continuous coating, with visible "thread-like" features, indicating bulk incorporation of PAA compared to the unincorporated PVA extruded porous solid (see prior patent art). Figure 29 shows that a thicker level of poly(acrylic acid) was coated on FM151-4 (250k PAA) than on FM151-3 (100k PAA).

[0344] DD010-121-A. The sample conditioned in CARBOPOL 907 for 40 hours (see Figure 30) still showed some levels of bismuth subcarbonate visible on the cross section, but was quite dense and less porous compared to the bulk-incorporated PVA extruded porous solid. The outer surface of DD010-121-A shows a high concentration of "thread-like" strands that completely cover the surface. The surface morphology of DD010-121-A immersed for 40 hours (see Figure 31) is similar to that observed in the CARBOPOL 907 sample immersed for 16 hours, with the "thread-like" surface Shows bulk incorporation of CARBOPOL 907 compared to a PVA extruded porous solid that was not exposed to bulk incorporation of PAA. There may be more "threads" present on the 40 hour immersion sample, but no testing was done to support that conclusion.

[0345] DD010-128-2. Samples conditioned in CARBOPOL 907 for 16 hours showed little to no difference compared to the 40 hour samples (see Figure 32).

[0346] Example 21: Bulk integrated pSBMA Extruded 4F Single Lumen PVA tubing, produced under the conditions in Example 17 except that a 0.039 inch acetal core filament was used, was cut into 24-30 inch segments. The extrudate was then dehydrated in room temperature (21°C) ethanol for 24 hours. The cut segments were removed from the ethanol and then decorated to remove the filament.

[0347] Poly(sulfobetaine methacrylate) (pSBMA) was prepared via free-radical aqueous polymerization. 0.4121 g of sulfobetaine methacrylate (Sigma-Aldrich: 537284) was polymerized with 0.2316 μg of potassium persulfate (Sigma-Aldrich: MKBW9558V) in 19.9693 g of USP water (RICCA: 9190). The mixture was dissolved with the aid of a vortex mixer. The solution was sparged with nitrogen (Airgas: NI-150) for 5 minutes and then sealed. This was heated to 70°C for 16 hours. 19.7784 g of the polymerized solution was then added to 28.021 g of 1x phosphate-buffered saline (FM012-173) in a 50 mL conical tube.

[0348] Dehydrated 4 Fr extruded polyvinyl alcohol (PVA)-bismuth subcarbonate porous solid tubes were cut into 10 cm long segments and placed in pSBMA solution for 16 h at 37 °C. The tubes were removed from the solution, dried at 55 °C for 3 h, and then annealed at 150 °C for 90 min. The tubes were placed in 1x phosphate-buffered saline for 1 h and dried again at 55 °C for 3 h.

[0349] FTIR was performed on the samples as shown in Figure 32. The top spectrum shows the annealed bulk-loaded p(SBMA) PVA porous solid tubes. The middle spectrum shows the control reference spectrum for SBMA, and the bottom spectrum is the control spectrum for the annealed bulk-unloaded PVA porous solid tube control. Comparing the FTIR spectrum of the annealed p(SBMA) bulk-loaded tubes (Figure 33A) with the FTIR spectrum of the control PVA-bismuth subcarbonate (Figure 33B) reveals a distinct peak at 1040 cm associated with the sulfite group of SBMA. -1 (Figure 33C), which indicates that p(SBMA) was bulk-incorporated into the porous PVA-bismuth subcarbonate solid. The control sample, PVA-bismuth subcarbonate (Figure 33B), exhibited a peak at 1080 cm -1Although there is a strong PVA-related peak at 1040 cm -1 The results for bulk-incorporated pSBMA PVA porous solid tubes show no peak at 1080 cm, as can be seen in Figure 33A. -1 The decrease in peaks indicates that pSBMA was successfully bulk-incorporated into the PVA matrix.

[0350] Example 22: Durability of PAA A 1% w / w solution of poly(acrylic acid) (PAA) (Lubrizol: CARBOPOL 907) was prepared in a 50:50 solution of 10x phosphate-buffered saline (DD010-148) and USP water (RICCA:9190). Extruded 4F single-lumen PVA tubing was fabricated using the conditions of Example 17, except a 0.039-inch acetal core filament was used. The tubing was cut into 24-30 inch segments. The extrudates were then dehydrated in ethanol at room temperature (21°C) for 24 hours. The cut segments were removed from the ethanol and then decorated to remove the filament. The segments were then cut into 10 cm lengths and placed in the PAA solution at 37°C for 16 hours. The segments were removed from the solution, dried at 55°C for 3 hours, annealed at 150°C for 90 minutes, hydrated in 1x PBS for 1 hour, and dried again at 55°C for 3 hours. Samples were set aside as controls or for further treatment by use in a peristaltic pump; the treated samples are referred to as injured-treated tubing. 40 cm of the completed tubing was placed into a 40 cm neoprene tubing connected in a loop with a double-barbed connection. The 0.25 inch ID tubing was filled with 1x PBS, and the PAA-treated PVA tubing was allowed to hydrate for 2 hours at 37°C. The PAA-treated PVA and neoprene tubing were placed in the peristaltic pump for 24 hours at ambient conditions. The pump was set at 120 rpm to circulate PBS through the loop, placing the sample directly into the peristaltic pump head to equally expose the sample to flow, rubbing, and compression, approximating 500,000 compressions at a flow rate of approximately 1.1 mL / sec (66 mL / min) or a total of 95 L. The tubing had an internal diameter (ID) of 0.25 inches and was 45 cm long, resulting in a total volume of 89.8 cm. 2 and an inner surface area of 0.12 cm 3 s -1 cm -2 The FTIR in FIG. 34A of the undamaged surface catheter (control, not exposed to compression) compared to the outer and inner surfaces of the damaged section shows a peak at 1650 cm corresponding to the acid group of PAA. -1There was no significant difference in the peak at 1600 cm -1 and 780cm -1 There were no significant differences in the other peaks between 1500 and 1600 cm, indicating that the PVA:bismuth subcarbonate ratio did not change. An overlay of the FTIR spectra is shown in Figure 34B. -1 An enlarged view of the region of 1558 cm associated with sodium acrylate is shown in Figure 34C. -1 The amount of PAA was measured before and after exposure to durability tests using the peak of . The signal intensity before rubbing and rinsing was 0.05183, while the signal intensity after rubbing and rinsing was 0.04484. Considering the baseline signal intensity of 0.02299 in the control sample, only a 25% decrease was observed after exposure to these conditions. This demonstrated that the bulk incorporation of a second hydrophilic polymer into the solid porous PVA extrusion was durable.

[0351] Example 23: Role of Desolvation in Bulk Incorporation of Polymers Extruded 4F Single Lumen PVA tubing, produced under conditions similar to those in Example 17 except that a 0.039-inch acetal core filament was used, was cut into 24-30 inch segments. The extrudates were then dehydrated in ethanol at room temperature (21°C) for 24 hours. The cut segments were removed from the ethanol and then decorated to remove the filament. The samples were divided into two groups.

[0352] A sample of extruded and dehydrated PVA tubing was immersed in a 1% solution of PAA (Lubrizol: CARBOPOL 907, Mw=710 kDa) in 5x PBS for 16 hours at 37°C. The tubing was then dried at 55°C for 3 hours and annealed at 150°C for 90 minutes. Figure 35A shows an SEM image. The arrow indicates the outer surface of the tubing.

[0353] A sample of the extruded, dehydrated PVA tubing was dried at 55°C for 3 hours and annealed at 150°C for 90 minutes. The sample was then immersed in a 1% solution of PAA (Lubrizol: CARBOPOL 907) in 5x PBS for 16 hours at 37°C. After the PAA immersion, the exposed tubing was dried again at 55°C for 3 hours and annealed again at 150°C for 90 minutes. An SEM image is shown in Figure 35B.

[0354] Example 24: Bulk incorporation effects demonstrated by changes in physical properties Extruded 4F Single Lumen PVA tubing, produced under conditions similar to those in Example 17 except that a 0.039-inch acetal core filament was used, was cut into 24-30 inch segments. The extrudates were then dehydrated in ethanol at room temperature (21°C) for 24 hours. The cut segments were removed from the ethanol and then decorated to remove the filament. The samples were divided into two groups.

[0355] Samples of extruded, dehydrated PVA tubing were immersed in a 1% solution of PAA (Lubrizol: Carbopol 907, Mw = 710 kDa) in 5x PBS for 16 hours at 37°C. The tubing was then dried at 55°C for 3 hours and annealed at 150°C for 90 minutes. They were tested for maximum load at break using an Instron tensile tester (Model 3343, 500 N load cell) with pneumatic grips at 40 psi and a grip strength of 1 kN. Starting from a gap distance of 20 mm, the samples were pulled at 400 mm / min, and the tensile strength and modulus of the samples were calculated. Bulk-loaded hydrophilic PVA tubing samples were compared to unloaded controls that underwent identical drying and annealing conditions.

[0356] Table 16 shows the results for maximum load, Young's modulus, and normalized tensile at break. Table 17 shows the calculated area per sample based on the measured ID and OD of the tubes. The p-values for significant differences between the PAA bulk-incorporated samples and the control samples were calculated. While the area was significant, it is clear that there was no significant difference between OD and ID. The maximum load, modulus, elongation, and normalized tensile at break were all significant. This indicates that the detailed method results in the bulk incorporation of a second hydrophilic material into the existing porous PVA matrix, occupying the pores of the matrix prior to annealing and altering the overall mechanical properties of the matrix. A true surface coating would not alter the mechanical strength of the underlying porous PVA solid.

[0357] JPEG2025114716000018.jpg70170

[0358] JPEG2025114716000019.jpg101170

[0359] Example 25: Hydration rate of extrudates The following example shows the hydration rate of an exemplary extruded PVA tube using a 0.039 inch acetal core filament.

[0360] A PVA-bismuth subcarbonate polymer solution (e.g., first water-soluble polymer) was prepared using 42.0 g of bismuth subcarbonate (Lot: Foster, FEI5577), 179.25 g of 6.2 wt / wt% monobasic sodium phosphate solution, and poly(vinyl alcohol) 28-99 (Lot: EMD, K45556756). The substitutes were heated and mixed in a Flaktech Speedmixer in a sealed polypropylene jar.

[0361] The polymer was immediately placed on a roller at approximately 70 RPM for 4 hours. Once the polymer had cooled to room temperature, it was cut into 1 cm x 1 cm x 1 cm cubes.

[0362] The cubed polymer was extruded using a Brabender 3 / 4-inch single-screw ATR. The heated polymer was extruded onto a 0.039-inch acetal core filament in an ethanol bath at approximately 10°C. The extruded PVA tubing (extrudate) was cut into 24-inch to 30-inch segments. After dehydration in ethanol for approximately 3 hours, the core filament was removed and a PTFE-covered stainless steel mandrel was inserted into the lumen.

[0363] A hydrophilic solution was prepared using Carbopol 907 (Lot: Lubrizol, 010164597), USP water (Lot: Fisher, 1607174), and PBS. The solution was heated and mixed until the solids were completely dissolved.

[0364] All samples were immersed in Carbopol 907 solution in a stainless steel circulating bath at 37°C for 16 hours.

[0365] After the indicated time periods, the samples were removed from immersion and mounted on a stainless steel mandrel. The dried samples were then annealed in air on the mandrel in a forced air oven at 140°C for 1.5 hours. The samples were then hydrated in PBS at room temperature (approximately 21°C for 3 hours). After hydration, the samples were dried at 37°C for 5 hours.

[0366] The dried samples were cut into pieces approximately 20 mm long. The length, inner diameter, outer diameter, and mass of each sample were recorded. The samples were then immersed in 1x PBS at room temperature (approximately 21-22°C). A syringe was used to ensure all air was expelled from the lumen.

[0367] At various time intervals, samples were removed from the PBS and gently tapped on a lint-free lab wipe to remove excess PBS from the lumen and surface; length and mass were recorded, and the samples were quickly placed back into PBS. Samples were allowed to hydrate for a total of 22 hours. The inner and outer diameters were measured again after 1 hour and 22 hours of hydration.

[0368] The following formulas were used to calculate the percent change in length, mass and inner diameter (ID) / outer diameter (OD): JPEG2025114716000020.jpg2788

[0369] The percent change for each variable was averaged for each time point (see Table 18).

[0370] JPEG2025114716000021.jpg88170

[0371] During hydration, the percent increase in mass varied slightly between 22.9% and 33.3% over the 22-hour hydration period, but did not show significant differences in mass gain between any of the time points.

[0372] The percent increase in sample length, compared to the mass increase, exhibited a narrow standard deviation and served as a representative indicator of the level of sample hydration. After 2.5 and 5 minutes of hydration, the length increased by 2.9% and 4.5%, respectively; the length increase then plateaued at approximately 10 minutes of hydration, with no significant increase in length after that point (see Table 18).

[0373] The inner and outer diameters showed increases of 4.9% and 18.8% at 60 and 1320 minutes, respectively. Without wishing to be bound by theory, the significant difference between the ID and OD may be due to the fact that the shrinkage of the ID is constrained by the size of the core diameter during ethanol dehydration, drying, and annealing, causing the ID to retain more of its initial size, whereas the OD is not constrained during post-extrusion processing and therefore is able to swell more when hydrated. The OD showed no significant change between 1 and 22 hours of hydration.

[0374] A 4F catheter extruded on a 0.039 inch core filament showed no further increase in length after hydration in 1×PBS at 21° C. for 10 minutes.

[0375] Example 26: Strength testing of dehydrated articles The following examples demonstrate the properties of articles according to some embodiments described herein.

[0376] Twenty-two articles / catheters (e.g., first components as described above) with integrated suture wings (e.g., second components as described above) were used during the study. Length was first measured using a graduated tape measure, measuring from the distal tip to the proximal suture wing.

[0377] Catheter tubing (e.g., an article comprising a first water-soluble polymer as described above) was cut 5 cm distal to the suture wings. They were tested for maximum load at break using an Instron tensile tester (Model 3343, 500 N load cell) with 40 psi pneumatic grips and a grip strength of 1 kN. Starting at a gap distance of 20 mm, the samples were pulled at 400 mm / min, and the tensile strength and modulus of elasticity of the samples were calculated. Separately, the bond strength of the suture wings and extension leg joint was tested. A 1-2 mm cross-section of the distal tip from the catheter body was measured. Modulus of elasticity, strain, and absolute tensile force were measured. Stress is generally defined as tensile force relative to the cross-sectional area according to the following: JPEG2025114716000022.jpg2173

[0378] The modulus of elasticity is generally defined as the maximum slope of stress versus % elongation (strain) according to the following: JPEG2025114716000023.jpg2091

[0379] Slope is generally defined as the ratio of the change in stress to the change in strain. Young's modulus was measured between 0% and 10% elongation. Typical breakage of a dehydrated PVA tube would occur at less than 50% elongation. Breakage was measured as a 40% drop in tensile force from the maximum.

[0380] Attaching the suture wings to the tube In many cases, fracture was detected before 50% elongation (40% drop in tension from maximum load). If fracture was not detected, stable necking of the dried PVA tube occurred. The ultimate tensile strength of 22 samples was 53 N (Table 19). All fractures were observed within the PVA tubing. Some of the fractures occurred within the suture wings, but continued to hold the dehydrated PVA tubing segments together, rather than complete slip outs, mechanical bonds from the heat shrinkage and hypotubes along with the aliphatic polyether-based thermoplastic polyurethane dip coating.

[0381] JPEG2025114716000024.jpg87100

[0382] The tensile strength of the catheter body was also evaluated, and the results are summarized in Table 20. The samples used for this test were post-sterilization.

[0383] JPEG2025114716000025.jpg114170

[0384] Example 27: Hydration Test The following examples illustrate the hydration profiles of exemplary articles / catheters described herein.

[0385] Twenty articles / catheters (e.g., articles comprising a first water-soluble polymer as described herein) were prepared as described in Example 24. The final products were packaged in a protective sheath within a 12 x 18 inch Tyvek / mylar pouch and sterilized with ethylene oxide.

[0386] The samples were removed from the protective sheath and a mass measurement was taken before any preparation or further conditioning. The samples were then hydrated by flushing 5 mL of normal saline at 22±2°C through the catheter. After 10 minutes, a mass measurement was taken. The catheter was then transferred to a 1×PBS bath at 37±2°C. Further mass measurements were taken at 30, 60, 90, 120 minutes, 3 hours, 4 hours, and 24 hours immersed in 1×PBS at 37±2°C. The mass results were used to define the range of observations for the inner lumen diameter.

[0387] Samples were evaluated for inner lumen diameter at four data points: a) dry, b) 10 minutes at 22±2°C, c) 20 minutes at 37±2°C, and d) 37±2°C when the sample reached steady state.

[0388] mass The percent mass gain from the dry state and the percent mass gain after hydration and exposure to in situ conditions (37°C, PBS) for 10 minutes at 22±2°C are summarized in Table 21.

[0389] JPEG2025114716000026.jpg85170

[0390] During the 10-minute initial hydration at 22°C, the sample mass increased by 4.5% with a standard deviation of 0.9%. Between 10 minutes and steady state, the sample mass increased by an average of 3.1% with a standard deviation of 0.9%, for an average total mass increase of 7.7% with an overall standard deviation of 1.0%.

[0391] Note that at some time points, the mass appears to have decreased compared to previous time points, which may be due to measurement error. During this study, a standard process was used to remove excess water before weighing, but water in the lumen or on the surface of the catheter may have varied between time points.

[0392] To determine what was considered steady state, t-tests were performed between consecutive time points, assuming two-tailed and unequal variances. The results can be seen in Table 22.

[0393] JPEG2025114716000027.jpg6393

[0394] As shown in Table 22, the first time point where the populations are not statistically different between successive time points (p-value > 0.05) is 60 minutes, which generally indicates the time at which the catheter reaches a steady state of hydration.

[0395] Based on the results of the mass study, the steady-state time point used for this study was 60 minutes. The mean internal diameters by time point are reported in Table 23.

[0396] JPEG2025114716000028.jpg54108

[0397] The measured hydrated internal diameter is 0.90±0.10 mm. Based on these results, after 10 minutes of hydration at 22±2°C, all catheters average 0.87 mm, which is within specification. A t-test was performed between the internal diameters at 20 and 60 minutes, assuming two-tailed and unequal variances, with a p-value of 0.58, indicating no significant difference between the internal diameter at 20 minutes (the earliest possible point used to infuse infusate) and the internal diameter at steady state.

[0398] This study shows that at 10 minutes, the catheter assembly was at 93% of its full mass and had an ID of 0.87 mm, within the desired range for a 4Fr catheter. This is further supported by the ID measurement taken at 20 minutes, which revealed an ID of 0.89 mm, resulting in an acceptable ID for injection of infusate at the time of insertion. Based on the results of the mass study, the samples reached full hydration in 60 minutes, resulting in an average mass gain of 3% from the mass after 10 minutes of hydration.

[0399] Example 28: Blood Loop Analysis The following examples compare the effectiveness of extruded PICCs compared to existing commercially available standard non-thrombogenic devices (BioFlo PICC, AngioDynamics, and PowerPICC®, Bard).

[0400] 1 shows the quantitative thrombogenicity of PVA tubing (eg, an article comprising a first water-soluble polymer described herein).

[0401] A PVA-bismuth subcarbonate polymer solution (e.g., first water-soluble polymer) was prepared using 42.0 g of bismuth subcarbonate (Lot: Foster, FEI5577), 179.25 g of 6.2 wt % monobasic sodium phosphate solution, and poly(vinyl alcohol) 28-99 (Lot: EMD, K45556756). The substitutes were heated and mixed in a Flacktek Speedmixer in a sealed polypropylene jar.

[0402] After mixing, the polymer was immediately placed on a roller at approximately 70 RPM for 4 hours. Once the polymer had cooled to room temperature, it was cut into 1 cm x 1 cm x 1 cm cubes.

[0403] The cubed polymer was extruded using a Brabender 3 / 4-inch single-screw ATR. The heated polymer was extruded onto a 0.039-inch acetal core filament in an ethanol bath at 10±2°C. The extruded PVA tubing was cut into approximately 60-75 mm segments. After 3 hours of dehydration in ethanol, the core filament was removed.

[0404] All samples were immersed in a 1% Carbopol 907 solution in a stainless steel circulating bath for 16 hours at 37°C to ensure a steady flow of solution through the lumen.

[0405] After the indicated time periods, the samples were removed from immersion and mounted on PTFE-coated stainless steel mandrels. The dried samples were air annealed at 140°C for 1.5 hours in a forced air oven.

[0406] A 20% poloxamer 407 solution was prepared using 401.27 g of poloxamer 407 (lot: Spectrum, 1FK0656), 160.97 g of 10x PBS (lot: Sigma, SLBQ7746V), and 1641.00 g of USP water (lot: RICCA, 1607174). After annealing, the samples were conditioned in 20% poloxamer 407 for 3 hours at room temperature (approximately 21°C). After conditioning, the samples were rinsed with USP water and immediately placed in Tyvek pouches; samples were double-bagged.

[0407] Samples were sterilized in an Anprolene Sterilizer with 18.2 g of ethylene oxide for a 24 hour exposure cycle.

[0408] These samples were designated DD010-132-A. Four separate comparative catheters were obtained: a 4F PowerPICC® and a 4F BioFlo PICC.

[0409] DD010-132-1 samples were measured to determine their outer diameter after full hydration. Samples were hydrated in PBS at 37°C for approximately 16 hours and then cut into 15 cm lengths. The outer diameter was measured at four points along the length of each 15 cm sample. The outer diameter measurements were spaced approximately 3-4 cm apart.

[0410] Non-thrombogenic durability testing was performed by hydrating samples in sterile saline for approximately 24 hours prior to testing; once fully hydrated, all samples longer than 15 cm were trimmed to length before placement in the blood loop. Full-length PowerPICC and BioFlo devices were cut to 15 cm in length; the tapered portions of these devices were not used in blood loop testing.

[0411] Fresh bovine blood was drawn and heparinized to achieve a concentration of 0.75 U / ml. Platelets were labeled with Indium-111. Samples were inserted into in vitro blood flow loops of 1 / 4 inch (6.4 mm) polyvinyl chloride tubing for approximately 120 minutes. Blood was maintained at 37°C and pumped through the loop at 200 ml / min using a peristaltic pump for the duration of the study. Samples were first checked for thrombus after 45 minutes in the blood flow loop and removed approximately 60-120 minutes later. A total of six replicates (N=6) were performed, using two samples of each catheter type per experiment.

[0412] First, samples were qualitatively evaluated for the specific type of thrombus accumulation (i.e., platelet adhesion and / or fibrin accumulation). Radioactive counts per minute (CPM) were measured for each sample and are summarized in Table 24.

[0413] JPEG2025114716000029.jpg115170

[0414] The outer diameter of DD010-132-A after hydration averaged 1.47 ± 0.04 mm for N = 24 time points (a total of three measurements were performed on each of six storage samples obtained from the same lot as the tested device).

[0415] Taken together, the expanded blood loop analysis of the PowerPICC® (control device) and BioFlo® devices demonstrated a significant reduction in thrombus accumulation on the DD0101-132-A compared to both comparison catheters. Visually, all six experiments demonstrated reduced thrombus accumulation on the DD0101-132-A sample, which showed little to no visible platelet adhesion (see Figure 36), while both the PowerPICC® control and BioFlo® devices showed clear signs of moderate to severe platelet accumulation.

[0416] In experiments where fibrin accumulation was observed, the comparative devices showed moderate (BioFlo) to severe (PowerPICC®) platelet accumulation that the DD010-132-A sample did not exhibit (see Figure 36).

[0417] Radioactive counts showed similarly large differences between both comparative devices and the DD010-132-A device. In general, unlike the DD010-132-A device, which maintained a relatively low average CPM and had narrow tolerances, both the PowerPICC® and Bioflo showed high levels of CPM variability, even between samples within the same experiment (see Table 24).

[0418] Using the PowerPICC® as a baseline of 100% thrombus accumulation, the BioFlo demonstrated a mean platelet accumulation of 19.2% ± 10.2%, representing a relative reduction of 80.8% compared to the PowerPICC. The PICC-141 demonstrated a platelet accumulation of 3.2% ± 1.2%, representing a 96.8% reduction in relative thrombus accumulation compared to the PowerPICC® (see Table 24 and Figure 36).

[0419] Using BioFlo as a baseline of 100% clot accumulation, DD010-132-A demonstrates a mean reduction in relative clots of 69.8% (see Tables 24-25).

[0420] JPEG2025114716000030.jpg71168

[0421] The DD010-132-A outperformed comparative devices during in vitro blood loop testing, demonstrating reduced clot accumulation on the device body as well as reduced variability across N=6 replicates. The DD010-132-A device demonstrated a 96.8% reduction in clot formation compared to the PowerPICC® and a 69.8% reduction compared to the BioFlo. Illustrative Embodiments

[0422] 1. A method for producing a porous solid material comprising heating a mixture (also referred to as a matrix-forming mixture) comprising at least one water-soluble polymer (also referred to as a matrix polymer or matrix-forming polymer) and a solvent (also referred to as a polymer-forming 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 physically crosslink the polymers to form a crosslinked matrix, and continuing to remove the solvent until the crosslinked matrix is a microporous solid material or until the crosslinked matrix is a nanoporous solid material.

[0423] 2A. A method for producing a porous solid material comprising heating a (matrix-forming) mixture comprising at least one water-soluble (matrix-forming) polymer and a (matrix-forming) solvent to a temperature above the melting point of at least one polymer in the (matrix-forming) mixture, for example, by molding or extruding the mixture through a die, to form a mixture, and passing the formed mixture through a solvent-removing environment. The method may further comprise one or more of, for example, cooling the formed mixture in the solvent-removing environment and continuing to remove the solvent until the crosslinked matrix becomes a nanoporous solid material or until the crosslinked matrix becomes a microporous solid material.

[0424] 2B. A method of resolvating a porous hydrophilic matrix comprising solvating a previously desolvated hydrophilic structural matrix containing one or more hydrophilic polymers in a mixture, the method comprising resolvating a porous hydrophilic matrix comprising one or more hydrophilic polymers in a mixture, the method optionally being further annealed.

[0425] 3. A method for producing a porous polymeric material and / or a hydrophilic porous solid material, comprising heating a (matrix-forming) mixture comprising at least one (matrix-forming) water-soluble polymer and a (matrix-forming) solvent to a temperature above the melting point of the (matrix-forming) polymer, forming a mixture, e.g., extruding the mixture through a die, and passing the formed mixture through a solvent removal environment. In the case of extrusion, as the (matrix-forming) polymer passes through the die, the (matrix-forming) polymer forms a continuous, porous, solid material. 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.

[0426] 4. The method of any of paragraphs 1-3, wherein a salt is present in the mixture or added during the process. The salt can be useful in aiding in the dissolution and / or crosslinking of the polymer. The salt can be, for example, anionic, cationic, divalent, or trivalent. Additionally, salts or other additives can be added to the polymer that can have two or more hydrogen-bond acceptor and / or hydrogen bond donor sites.

[0427] 5. The method of any of paragraphs 1 to 4, wherein crosslinking occurs while the mixture is cooling and / or in a solvent-removing environment.

[0428] 6. The method of any of paragraphs 1-5, wherein the porous solid is crosslinked with bonds that are covalent crosslinks or physical crosslinks. These embodiments include the absence of covalent bonds when physical crosslinks are included.

[0429] 7. The method of any of paragraphs 1 to 6, further comprising annealing the porous solid.

[0430] 8. The method of any of paragraphs 1-7, further comprising aligning the polymer chains of the continuous porous solid substantially parallel to one another.

[0431] 9. The method of paragraph 8, wherein aligning the polymer chains comprises passing the mixture through a die.

[0432] 10. The method of any of paragraphs 1 to 9, wherein the at least one water-soluble polymer comprises PVA, PAA, PEG, PVP-I, or PVP.

[0433] 11. The method of any of paragraphs 1-10, wherein at least one water-soluble polymer contains hydroxyl or carboxyl pendant groups.

[0434] 12. The method of any of paragraphs 1 to 11, wherein the mixture has a concentration of at least one polymer in the mixture that is between 5% and 50% w / w of polymer relative to the mixture.

[0435] 13. The method of any of paragraphs 1 to 11, wherein the mixture has a concentration of at least one polymer in the mixture that is between 5% and 50% w / w of polymer to solvent.

[0436] 14. The method of paragraph 12, wherein at least 50% of the solid material forming the porous solid is PVA, PAA, PEG or PVP.

[0437] 15. The method of any of paragraphs 1 to 14, wherein the crosslinking is completed while the porous solid is in a solvent-removing environment.

[0438] 16. The method of any of paragraphs 1 to 14, wherein the porous solid is prepared as a tube.

[0439] 17. The method of any of paragraphs 1-15, wherein exposure to the solvent removal environment removes at least half of the solvent in less than 60 minutes.

[0440] 18. The method of any of paragraphs 1-17, comprising exposure to a solvent-removing environment for at least 1 hour, e.g., exposure to a dehydrating environment during which at least about 50% w / w of the total solvent is removed.

[0441] 19. The method of any of paragraphs 1 to 18, wherein the porous solid has a Young's modulus at EWC of at least 5 MPa.

[0442] 20. The method of any of paragraphs 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.

[0443] 21. The method of any of paragraphs 1 to 20, wherein the polymeric material further comprises a second material in contact with the porous solid, for example, the second material is a reinforcement, fiber, wire, or plastic fiber.

[0444] 22. The method of any of paragraphs 1 to 21, wherein the mixture comprises at least two polymers.

[0445] 23A. The method of any of paragraphs 1-22, wherein the at least one polymer comprises a first hydrophilic polymer and a second hydrophilic polymer. For example, the first and second polymers are independently selected from PVA, PAA, PEG, PVP-I, and PVP.

[0446] And / or, for example, the first and second polymers are present in a ratio of 1 part second polymer to 1 to 100,000 parts first polymer (w / w).

[0447] 23B. The method of any of paragraphs 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 total weight of all of the polymers and solvent in the mixture.

[0448] 24. The method of any of paragraphs 1 to 23, wherein the mixture further comprises a salt or other additive for cross-linking (23 refers to 23A and 23B).

[0449] 25. The method of any of paragraphs 1 to 24, further comprising an additive capable of providing two or more hydrogen bond acceptors and / or hydrogen bond donor sites.

[0450] 26. The method of any of paragraphs 22 to 25, wherein at least two polymers, for example, two or more of polyvinylpyrrolidone, polyvinylpyrrolidone-iodine, polyethylene glycol, and polyacrylic acid, are coextruded.

[0451] 27. The method of paragraph 26, wherein the polymers to be coextruded are mixed in the die head.

[0452] 28. The method of any of paragraphs 22-26, wherein the water-soluble polymer is a first polymer formed in a first layer and further comprises a second polymer formed as a second layer.

[0453] 29. The method of any of paragraphs 22-28, wherein the first polymer and the second polymer are coextruded as separate layers.

[0454] 30. The method of any of paragraphs 28-29, wherein the first polymer layer is formed as a sheet and the second polymer layer is formed in contact with the sheet.

[0455] 31. The method of any of paragraphs 1-31, further comprising adding a third polymer.

[0456] 32. The method of paragraph 31, wherein the third polymer is polyvinylpyrrolidone, polyvinylpyrrolidone-iodine, PEG, or polyacrylic acid.

[0457] 33. The method of any of paragraphs 21 to 32, wherein the second material is at least part of a reinforcement material, fiber, wire, braid material, braided wire, braided plastic fiber, or connector.

[0458] 34. The method of any of paragraphs 21-32, further comprising a second material or second polymer disposed as a layer on or in the material.

[0459] 35. The method of any of paragraphs 21 to 34, wherein the second polymer or second material comprises polyethylene glycol or a polyol, for example, the polyol is a polymer having at least three hydroxyl groups, or the polyol is glycerin.

[0460] 36. The process of any of paragraphs 1 to 35, further comprising adding a brazing material in contact with the porous solid.

[0461] 37. The method of any of paragraphs 1 to 36, wherein preparing the mixture comprises adding PVA to a solvent.

[0462] 38. The method of any of paragraphs 1-37, wherein the solvent comprises (or consists essentially of) water, an alcohol, ethanol, a water-miscible organic solvent, or a combination thereof.

[0463] 39. The method of any of paragraphs 1 to 38, wherein the heated solvent is at a temperature of 70 to 120°C.

[0464] 40. The method of any of paragraphs 1 to 39, wherein the concentration of PVA in the mixture is 15% to 25% w / w.

[0465] 41. The method of any of paragraphs 1 to 40, wherein the mixture is cooled after or during formation, and comprises passing the mixture through a cooling bath, a cooled mold, a frozen mold, or liquid nitrogen.

[0466] 42. The method of any of paragraphs 1-41, wherein the solvent removal environment is a chamber filled with a gas, such as dry air, or nitrogen, or a gas, such as at sub-atmospheric pressure.

[0467] 43. The method of any of paragraphs 1 to 41, wherein the solvent removal environment is a solution comprising ethanol, methanol, isopropanol, or a polyol.

[0468] 44. The method of any of paragraphs 1-41, wherein the solvent removal environment comprises a solution having an osmotic pressure that exceeds the osmotic pressure of the mixture.

[0469] 45. The method of any of paragraphs 1 to 44, wherein the solvent removal environment or solution comprises a salt present in a concentration of at least 0.1 molar.

[0470] 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.

[0471] 47. The method of any of paragraphs 1-43, wherein the solvent removal environment or solution further comprises an osmotic agent, such environment having an osmotic pressure value greater than the osmotic pressure value of the formed mixture.

[0472] 48. The method of any of paragraphs 1 to 47, wherein the solvent removal process is carried out over a period of 3 to 48 hours.

[0473] 49. The method of any of paragraphs 1 to 48, wherein the solvent removal process is carried out while the polymer is crosslinking.

[0474] 50. The method of claim 49, wherein crosslinking is completed before the solvent removal process is completed.

[0475] 51. The method of any of paragraphs 1 to 50, further comprising an annealing process comprising heating the porous solid material to an annealing temperature.

[0476] 52. The method of paragraph 51, wherein the annealing temperature is 80 to 250°C.

[0477] 53. The method of any of paragraphs 51 to 52, wherein the annealing is carried out in the absence of air and / or oxygen and / or water.

[0478] 54. The method of any of paragraphs 50-53, wherein the annealing is carried out at least partially in a liquid bath.

[0479] 55. The method of paragraph 54, wherein the liquid bath comprises mineral oil and / or polyol and / or glycerin.

[0480] 56. The method of any of paragraphs 50-55, wherein annealing is carried out for a period of from 3 hours to 1 week.

[0481] 57. The method of any of paragraphs 1 to 56, wherein the mixture is forced through a die.

[0482] 58. The method of paragraph 57, wherein the mixture is formed as a tube having at least one lumen.

[0483] 59. The process of paragraph 57, wherein the tube is formed around the core.

[0484] 60. The method of paragraph 59, wherein the core is air, water, a liquid, a solid, or a gas.

[0485] 61. The method of any of paragraphs 57-60, further comprising a second material or second polymer extruded as a layer onto or within the crosslinked matrix.

[0486] 62. The method of any of paragraphs 57-61, wherein the mixture is a first mixture, the method further comprises forming a second mixture comprising a further material, and the second mixture is also forced through the extrusion die to form a second tubular layer.

[0487] 63. The method of paragraph 61, wherein the second material is or comprises a reinforcement, fiber, wire, or plastic fiber.

[0488] 64. The method of any of paragraphs 57 to 63, wherein the solid material surrounds the core and is entrapped within the tubular hydrogel layer or, if present, within the second tubular layer.

[0489] 65. The method of paragraph 64, wherein the solid material comprises wire, braid, metal wire, plastic wire, metal braid, plastic braid, mesh, fabric mesh, metal mesh, plastic mesh.

[0490] 66. The method of any of paragraphs 1 to 65, wherein the porous solid is formed as a continuous molding, a tube, a sheet, a solid cylinder, a tube with multiple lumens, or a ring.

[0491] 67. The method of any of paragraphs 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 1000:1. 68. The method of any of paragraphs 1 to 67, wherein the porous material is hydrophilic.

[0492] 69A. The method of any of paragraphs 1-68, wherein the porous material has been treated to further comprise at least one bulk-incorporated polymer.

[0493] 69B. A biomaterial, polymeric material, or catheter comprising a medically acceptable hydrophilic porous solid. The solid may further comprise at least one bulk-incorporated polymer.

[0494] 70. A biomaterial, polymeric material, or catheter comprising a porous polymeric solid having one or more of the following: 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. For example, a polymeric material comprising a hydrophilic porous solid having a solids content of at least 33% w / w at EWC and a Young's modulus of at least 5 MPa. The porous solid may be formed, for example, with an aspect ratio of at least 10:1. For example, the porous solid may comprise 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 1,000 parts per 10,000 parts of the first polymer.

[0495] 71. The biomaterial according to paragraph 69 or 70, wherein the porous polymer solid comprises a crosslinked hydrophilic polymer.

[0496] 72. The biomaterial according to paragraph 70 or 71, wherein the porous polymer solid has a solids content of at least 33% w / w at equilibrium water content (EWC) in saline at 37°C. Alternatively, the solids content is at least 50% w / w or in the range of 40% to 99% w / w.

[0497] 73. A biomaterial according to any of paragraphs 70 to 72, wherein the nanoporous material in the EWC has a solids content of at least 50% w / w and is a nanoporous material having a tensile strength of at least 20 MPa and / or a Young's modulus of at least 5 MPa.

[0498] 74. A biomaterial according to any one of paragraphs 70 to 73, having a pore diameter of 100 nm or less.

[0499] 75. A biomaterial according to any of paragraphs 70 to 74, having internal alignment of polymer structures.

[0500] 76. A biomaterial according to any of paragraphs 70 to 75, wherein when placed in excess saline and allowed to swell freely, the porous material swells to no more than 50% w / w in EWC and the PVA content of the hydrogel is at least 50% w / w.

[0501] 77. The biomaterial according to any of paragraphs 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 combinations thereof.

[0502] 78. A biomaterial according to any of paragraphs 70 to 77, wherein the porous material comprises a matrix of a crosslinked hydrophilic polymer, the water-soluble polymer comprising hydroxyl and / or carboxyl pendant groups.

[0503] 79. The biomaterial of any of paragraphs 70 to 78, wherein the porous material comprises a cross-linked polymer having a molecular weight before cross-linking of at least 50 kg / mol. Alternatively, a molecular weight of 50,000 to 1,000,000 g / mol.

[0504] 80. A biomaterial according to any of paragraphs 70 to 79, wherein at least 50% of the solid material forming the porous material is PVA, PAA, PEG or PVP.

[0505] 81. A biomaterial according to any of paragraphs 70 to 80, wherein the porous material is crosslinked with covalent crosslinks or does not comprise covalent crosslinks and / or does not comprise a covalent crosslinking agent.

[0506] 82. The biomaterial according to any of paragraphs 70 to 81, wherein the nanoporous material is crosslinked by physical crosslinks.

[0507] 83. The biomaterial according to 82, wherein the physical crosslinks are ionic bonds, hydrogen bonds, electrostatic bonds, van der Waals or hydrophobic packing.

[0508] 84. The biomaterial according to any of paragraphs 70 to 83, further comprising a layer of a second material or second polymer.

[0509] 85. A biomaterial according to any of paragraphs 70 to 83, further comprising a second material encapsulated within the porous solid.

[0510] 86. The biomaterial of paragraph 85, wherein the second material is at least part of a reinforcement material, fiber, wire, braid material, braided wire, braided plastic fiber, or connector.

[0511] 87. A biomaterial described in any of paragraphs 84 to 86, wherein the second polymer of the coating or layer or second material comprises polyethylene glycol or a polyol, for example, the polyol is a polymer having at least three hydroxyl groups, or the polyol is glycerin.

[0512] 88. A biomaterial according to any of paragraphs 84 to 87, wherein the second polymer of the coating or layer or second material comprises PVA, PAA, PEG or PVP.

[0513] 89A. The biomaterial of any of paragraphs 70-88, further comprising a radiopaque (RO) agent. The RO agent may be, for example, a coating, a layer on or in the biomaterial.

[0514] 90. A biomaterial according to any one of 70 to 83, which consists essentially of PVA or in which the porous material consists essentially of PVA.

[0515] 91. The biomaterial according to any one of paragraphs 70 to 91, having a shape that is a tube.

[0516] 92. A method for incorporating a polymer into a porous material, comprising providing a desolvated porous matrix and exposing the desolvated porous matrix to a mixture comprising one or more water-soluble polymers solvated in a solvent.

[0517] 93. A method for incorporating a polymer into a porous material, comprising a porous hydrophilic matrix comprising one or more water-soluble polymers physically crosslinked to each other to form a matrix, the method comprising providing a material in which the matrix has been desolvated, resolvating the porous hydrophilic matrix and exposing the matrix to a mixture comprising one or more water-soluble polymers solvated in a solvent of the mixture, and resolvating in the mixture.

[0518] 94. A method for incorporating a polymer into a porous material, comprising: providing a material comprising a porous hydrophilic matrix comprising one or more water-soluble polymers (also referred to as matrix polymers) physically crosslinked to each other to form a matrix, the material being desolvated; exposing the desolvated porous hydrophilic matrix to a mixture (also referred to as a conditioning mixture) comprising one or more water-soluble polymers (also referred to as bulk-incorporated polymers or conditioning polymers) solvated in a solvent (also referred to as a bulk-forming solvent or conditioning solvent), wherein exposing the hydrophilic matrix to the mixture draws the one or more water-soluble polymers into the pores. The porous hydrophilic matrix may be hydrophilic relative to the solvent.

[0519] 95. The method of any of paragraphs 92-94, wherein the matrix comprises a solvent and is desolvated to 0-90% of the EWC of the matrix in the solvent prior to exposure to the mixture.

[0520] 96. The method of any of paragraphs 92-95, wherein the matrix is resolvated in the mixture to EWC in the mixture.

[0521] 97. The method of any of paragraphs 92-96, wherein the matrix is annealed after exposure to the mixture.

[0522] 98. The method of any of paragraphs 92-97, wherein the desolvated matrix comprises a first composition of solvents and the mixture comprises a second composition of solvents. The first and second compositions may be the same or different and may be independently selected to be water, aqueous, organic, or a mixture thereof, wherein the water content for the first and second compositions is independently selected to be 0-100% of the total solvent weight.

[0523] 99. The method of paragraph 98, wherein the first composition and the second composition are independently selected to have 0-100% solvent that is methanol, ethanol, alcohol, dimethyl sulfone, or water.

[0524] 100. The method of any of paragraphs 92-99, wherein the polymers of the porous matrix and the polymers of the blend are independently selected to be one or more polymers selected from the group consisting of polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyacrylic acid (PAA), polyacrylamide, hydroxypropyl methacrylamide, polyoxazoline, polyphosphate, polyphosphazene, poly(vinyl acetate), polypropylene glycol, poly(N-isopropylacrylamide) (PNIPAM), polysaccharides, sulfonated hydrophilic polymers (e.g., sulfonated polyphenylene oxide, Nafion®, sulfobetaine methacrylate), and iodinated variations thereof (e.g., PVA-I, PVP-I), or variations with additional pendant groups, copolymers with one or more of these, and combinations of these. An RO agent or other material may be present in the matrix.

[0525] 101. The method of any of paragraphs 92-100, wherein exposure to the mixture causes a decrease in a physical property of the matrix, e.g., a decrease in Young's modulus and / or tensile strength independently selected from 1-20%, e.g., 1, 5, 10, or 15%. Obviously, the decrease is compared to the same process carried out without exposure to the mixture or when exposure to the mixture is carried out but bulk incorporation does not proceed, e.g., when the matrix is not properly desolvated before exposure.

[0526] 102. The method of any of paragraphs 92 to 101, wherein the coverage with the water-soluble polymer is at least 70, 80, 90, or 100%.

[0527] 103. A material comprising a porous matrix of physically crosslinked hydrophilic polymers crosslinked to form the matrix and defining the pores of the matrix, the matrix comprising a water-soluble polymer incorporated into the surface without covalent crosslinking to the surface. The water-soluble polymer may be incorporated, for example, as a monolayer, or may be present at and below the surface in the pores of the matrix.

[0528] 104. A water-soluble polymer conditioned material comprising a porous matrix comprising a water-soluble polymer incorporated into a surface portion of the porous matrix without covalent bonding to the material, the porous matrix having a thickness of 0.12 cm -3 s -1 cm -2 wherein no more than 25% w / w of the water-soluble polymer is removable from the surface when subjected to 500,000 compressions in a peristaltic pump flowing saline across the surface at a flow rate of 0.1% for 24 hours.

[0529] 105. A material comprising a porous matrix of physically crosslinked hydrophilic polymers crosslinked to form the matrix and defining the pores of the matrix, wherein the matrix comprises at least one water-soluble polymer incorporated into the surface of the matrix without covalent crosslinking of the water-soluble polymer to the surface, and wherein the incorporated water-soluble polymer confers at least a 10% decrease in Young's modulus of the porous matrix compared to the porous matrix in the absence of the incorporated polymer.

[0530] 106. A water-soluble polymer conditioned material, comprising a porous hydrophilic matrix comprising a water-soluble polymer entrapped in the pores of the porous matrix without covalent bonding to the material, the porous matrix comprising a hydrophilic polymer that has been physically crosslinked to form the hydrophilic matrix and the pores.

[0531] 107. A material having a bulk-incorporated polymer, comprising a water-soluble polymer entrapped in the pores of a hydrophilic porous matrix, the matrix comprising a physically crosslinked hydrophilic polymer.

[0532] 108. A material having a bulk-incorporated polymer, comprising a water-soluble polymer entrapped in the pores of a hydrophilic porous matrix, the matrix consisting essentially of a physically crosslinked hydrophilic polymer.

[0533] 109. The material of any of paragraphs 103-108, wherein the water-soluble polymer coats at least a portion of the surface of the matrix.

[0534] 110. The material of any of paragraphs 103-109, wherein the Young's modulus of the material is reduced by at least 10% (or 20%) by the water-soluble (bulk-incorporated) polymer.

[0535] 111. A material according to any of paragraphs 103 to 110, wherein the water-soluble polymer (bulk-incorporated polymer) is present on the surface without providing a network.

[0536] 112. The material of any of paragraphs 103-111, wherein the water-soluble polymers are essentially free of covalent bonds with each other and / or the EWC, water-soluble polymers are essentially free of hydrogen bonds with each other.

[0537] 113. The material of any of paragraphs 103-112, wherein the matrix is free or essentially free of covalent crosslinks and / or covalent crosslinkers.

[0538] 114. The material of any of paragraphs 103 to 113, wherein the matrix has pores at the surface of the material with openings at the surface having a diameter of 1 μm or less at the EWC, or a diameter of 2000, 1000, 500, 250, 100, or 10 nm or less. The percentage of pores below the stated diameter may be, for example, 50, 60, 70, 80, 90, 95, 99, or 100% of all pores at the surface.

[0539] 115. The material of any of paragraphs 100-114, wherein the water-soluble polymer is present in at least some pores of the porous solid within 10 μm of the surface of the matrix, or at any depth selected from 1 to 500 μm. Alternatively, the porous matrix comprises bulk-incorporated polymer to a depth of 1 to 500 μm.

[0540] 116. The material of any of paragraphs 103 to 115, wherein the molecular weight of the water-soluble polymer is 40k to 5000k or a range or value therein.

[0541] 117. A biomedical catheter comprising a material according to any one of paragraphs 70 to 116.

[0542] 118. The catheter of paragraph 117, wherein the catheter is a central venous catheter, a peripherally inserted central catheter (PICC), a tunneled catheter, a dialysis catheter, central venous, peripheral central, midline, peripheral, tunneled, dialysis access, urethral, neuro, celiac, intra-arterial balloon pump, diagnostic, percutaneous transluminal angioplasty, interventional, or drug delivery catheter.

[0543] 119. A catheter according to any of paragraphs 117-118, comprising multiple lumens.

[0544] 120. A biomedical catheter comprising a medically acceptable material, such as a material according to any of paragraphs 1 to 118, such as a hydrophilic nanoporous material, a hydrophilic microporous material or a hydrogel, further comprising, for example, a bulk-incorporated polymer.

[0545] While several embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily conceive of various other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each such variation and / or modification is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are intended to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the specific application or applications for which the teachings of the present invention are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is therefore to be understood that the foregoing embodiments are presented by way of example only, and that, within the scope of the appended claims and equivalents thereof, the invention may be practiced other than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. Furthermore, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present invention.

[0546] The indefinite articles "a" and "an" as used in this specification an...

Claims

1. An article, a first water-soluble polymer having a plurality of pores; a polymeric material disposed within at least a portion of the plurality of pores, the polymeric material comprising a first water-soluble polymer and a second water-soluble polymer, the same or different; and the article is substantially non-thrombogenic; the polymeric material has a Young's modulus of elasticity of 500 MPa or more in a dehydrated state and a Young's modulus of elasticity of 300 MPa or less and 5 MPa or more at equilibrium water content; The article, wherein the polymeric material is adapted to swell from a dehydrated state to an equilibrium moisture content state by an amount of not less than 5 wt / wt% and not more than 50 wt / wt% within 60 minutes at 25°C.

2. An article, a first water-soluble polymer having a plurality of pores; a polymeric material comprising a second water-soluble polymer, the second water-soluble polymer being the same as or different from the first water-soluble polymer, and disposed within at least a portion of the plurality of pores; The osmotic agent present in the polymer material and the polymeric material has a Young's modulus of elasticity of 500 MPa or more in a dehydrated state and a Young's modulus of elasticity of 300 MPa or less and 5 MPa or more at equilibrium water content; The article, wherein the polymeric material is adapted to swell from a dehydrated state to an equilibrium moisture content state by an amount of not less than 5 wt / wt% and not more than 50 wt / wt% within 60 minutes at 25°C.

3. A dehydrated article comprising: a first water-soluble polymer having a plurality of pores; a second water-soluble polymer different from the first water-soluble polymer and disposed within at least a portion of the plurality of pores. and the polymeric material has, in a dehydrated state, a water content of less than 5 wt. % and greater than or equal to 0.1 wt. %; the polymeric material has a Young's modulus of elasticity of 500 MPa or more in a dehydrated state and a Young's modulus of elasticity of 300 MPa or less and 5 MPa or more at equilibrium water content; A dehydrated article wherein the polymeric material is adapted to swell from a dehydrated state to an equilibrium moisture content state by an amount of not less than 5% w / w and not more than 50% w / w within 60 minutes at 25°C.

4. The article of any one of claims 1 to 3, wherein the plurality of pores has an average pore size of 500 nm or less and 10 nm or more.

5. The article of any one of claims 1 to 4, wherein at least 50% of the plurality of pores have a diameter of 1 µm or less.

6. The article of any one of claims 1 to 5, wherein in a dehydrated state the article has a porosity of greater than or equal to 5% and less than or equal to 50%.

7. 6. An article according to any one of claims 1 to 5, adapted to swell from a dehydrated state to an equilibrium moisture content state by an amount of at least 5% w / w and at most 50% w / w.

8. 8. The article of claim 7, wherein swelling occurs in water within 60 minutes.

9. 8. The article of claim 7, wherein swelling occurs in standard normal saline within 60 minutes.

10. 10. The article according to claim 1, wherein the article has a Young's modulus of elasticity of 1 GPa or more in a dehydrated state.

11. The article of any one of claims 1 to 10, wherein the article has a Young's modulus of elasticity of 100 MPa or less and 5 MPa or more at equilibrium moisture content.

12. The article of any preceding claim, wherein the article is substantially smooth at equilibrium moisture content.

13. The article of any one of claims 1 to 12, wherein the article has an average surface roughness of 500 nm (Ra) or less at equilibrium moisture content.

14. The article of any preceding claim, wherein the article has a coefficient of friction of 0.10 or less at equilibrium moisture content.

15. 15. The article of any one of claims 1 to 14, wherein the article comprises an osmotic agent present in the polymeric material in an amount of at least 0.05 w / w% and at most 2 w / w% based on the total article weight.

16. 16. The article of any of claims 1 to 15, wherein the osmotic agent is selected from the group consisting of phosphate, borate, sodium chloride, citrate, ethylenediaminetetraacetate, sulfite, sulfate, hyposulfite, metal oxides, selenium dioxide, selenium trioxide, selenious acid, selenic acid, nitrate, silicate, and vegetable acids.

17. 17. The article of any preceding claim, wherein the first water-soluble polymer is present in the article in an amount of at least 20 w / w% and at most 95 w / w% at equilibrium moisture content.

18. The article of any one of claims 1 to 17, wherein the polymeric material has a water contact angle of 45 degrees or less at equilibrium water content.

19. The article of any of claims 1 to 18, wherein the first water-soluble polymer does not include a covalently bonded crosslinker.

20. 20. The article of any of claims 1-19, wherein the first water-soluble polymer is selected from the group consisting of poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylsulfobetaine), poly(acrylsulfobetaine), poly(methacrylcarboxybetaine), poly(acrylcarboxybetaine), povidone, polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof.

21. The article of any preceding claim, wherein the polymeric material comprises a blend comprising a first water-soluble polymer and a third water-soluble polymer.

22. 22. The article of any of claims 1-21, wherein the third water-soluble polymer is selected from the group consisting of poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylsulfobetaine), poly(acrylsulfobetaine), poly(methacrylcarboxybetaine), poly(acrylcarboxybetaine), povidone, polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof.

23. 23. The article of any of claims 1-22, wherein the second water-soluble polymer is selected from the group consisting of poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylsulfobetaine), poly(acrylsulfobetaine), poly(methacrylcarboxybetaine), poly(acrylcarboxybetaine), povidone, polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof.

24. 24. The article of any one of claims 1 to 23, wherein the article is adapted for use with a medical device that is at least one selected from a catheter, a balloon, a shunt, a wound drain, an infusion port, a drug delivery device, a tubing, a contraceptive device, a feminine hygiene product, an endoscope, an implant, a pacemaker, an implantable cardiovascular defibrillator, a cardiac resynchronization device, a cardiovascular device lead, a ventricular assist device, an endotracheal tube, a tracheostomy tube, an implantable sensor, a ventilator pump, and an ophthalmic device.

25. 25. The article of claim 24, wherein the catheter is selected from the group consisting of a central venous catheter, a peripheral central catheter, a midline catheter, a peripheral catheter, a tunneled catheter, a dialysis access catheter, a urinary catheter, a neurocatheter, a percutaneous transluminal angioplasty catheter, and a peritoneal catheter.

26. The article of any preceding claim, wherein the second water-soluble polymer is located within the bulk of the first water-soluble polymer.

27. 27. The article of any one of claims 1 to 26, wherein sorption of less than 0.5 w / w% of the therapeutic agent into the bulk of the first water-soluble polymer occurs at equilibrium water content after rinsing with 5 times the volume of the article with water or normal saline.

28. An article according to any preceding claim, comprising a humectant associated with the polymeric material.

29. 29. The article of claim 28, wherein the humectant is a non-ionic surfactant selected from the group consisting of poloxamer, triacetin, alpha-hydroxy acid, polyethylene glycol, polypropylene glycol, ethylene glycol, propylene glycol, hexylene glycol, butylene glycol, glycerol, sorbitol, mannitol, xylitol, maltitol, and combinations thereof.

30. A method of forming the polymeric material of the article of any one of claims 1 to 29, comprising the steps of: the mixture comprises a first water-soluble polymer and a salt, the first water-soluble polymer being present in the mixture in an amount of 13 wt% or more based on the total weight of the mixture; extruding the mixture onto a core material at a temperature of at least 65°C to form a polymeric material disposed on the core material; exposing the polymeric material to a non-solvent for the polymeric material at a temperature of 28°C or less for a period of 1 hour or more; introducing into the polymeric material a solution comprising a second water-soluble polymer different from the first water-soluble polymer and a salt; heating the polymeric material and the solution to a temperature of 30°C or greater; flowing the solution adjacent to the polymeric material for at least 3 hours; drying the polymer material; performing A method of forming a polymeric material, wherein a second water-soluble polymer is disposed in at least one pore of a first water-soluble polymer.

31. A method of forming the polymeric material of the article of any one of claims 1 to 29, comprising the steps of: the mixture comprises at least one water-soluble polymer, a salt, and water, the at least one water-soluble polymer being present in the mixture in an amount of 13 wt. % or more based on the total weight of the mixture; heating the mixture to a temperature of at least 65°C; After heating the mixture, cooling the mixture to a temperature at least 20°C below the melting point of the mixture and mechanically shaping the mixture; after cooling the mixture, extruding the mixture onto a core material at a temperature of 65°C or greater to form a polymeric material disposed on the core material; exposing the polymeric material to a non-solvent for the polymeric material at a temperature below room temperature for at least four hours; removing at least a portion of the core material from the polymeric material; A method of forming a polymeric material comprising:

32. A method of forming the article of any one of claims 1 to 29, comprising the steps of: providing a mixture comprising at least one water-soluble polymer, a salt, and water, wherein the at least one water-soluble polymer is present in the mixture in an amount of 13 wt. % or more based on the total weight of the mixture; extruding the mixture onto a core material at a temperature of at least 65°C to form a polymeric material disposed on the core tube; exposing the polymeric material to ethanol at a temperature below room temperature; exposing the polymeric material to a humectant; and dehydrating the polymeric material, wherein the dehydrated polymeric material has a water content of less than 5 wt. % and greater than or equal to 0.1 wt. % in the dehydrated state; A method of forming an article comprising:

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