High strength porous material for controlled release

Abstract

To provide a high-strength biomedical material and a method for producing the same.SOLUTION: Included in the present disclosure are nanoporous hydrophilic solids that can be extruded with high aspect ratios to create high strength medical catheters and other devices with lubricious and biocompatible surfaces. A biologically active agent can be encapsulated in the pores of the material to provide controlled release of the biologically active agent.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] (Related Applications) This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application No. 62 / 782,186, filed December 19, 2018, the contents of which are incorporated herein by reference in their entirety.

[0002] The technical field of the present invention relates generally to porous biomaterials, including high strength hydrophilic nanoporous biomaterials, for example, for the controlled release of biologically active agents. [Background technology]

[0003] Biomaterials with high strength, low thrombogenicity, and lubricious surface properties, including biologically active agents, are useful in medical technology. Their porous nature allows for both high-strength bulk materials for medical devices and channels for controlled dissolution of biologically active agents. These biologically active properties can prevent or reduce biofilms, microbial colonization, infection, fibrin sheath formation, inflammation, pain, and / or tumor growth, and / or treat biological conditions such as tumor reduction, fungal and bacterial infections, inflammation, and pain. Complications seen with such devices can increase hospital stays and patient morbidity and mortality. Therefore, improved devices and methods are needed. Summary of the Invention

[0004] Disclosed herein are biomaterials useful for the manufacture of medical devices. In some embodiments, materials and methods are provided herein for producing tough, lubricious, biocompatible biomaterials for various medical device applications. Processing techniques are disclosed for creating materials with superior properties, such as strength, hemocompatibility, and sustained release, compared to polyurethanes and silicones. Included herein are methods for extruding hydrophilic polymers to create high-strength, hemocompatible, nanoporous biomaterials. Porous materials may also contain polymers or biologically active agents within the pores of the material. These processes can be performed without the use of chemical crosslinkers or radiation-induced crosslinking. Incorporating polymers into the pores of a material in bulk contrasts with coating or adhesive processes that cover the pores or processes that rely solely on adhering a surface treatment material to the surface of the bulk material.

[0005] In one aspect, a device is provided. In some embodiments, the device includes a body portion formed from a polymeric material comprising a first water-soluble polymer and a biologically active agent associated with the polymeric material, the biologically active agent being substantially homogeneously distributed within the polymeric material, the device having an elongation at break of 50% or greater, and / or the device having an increase in overall length at equilibrium moisture content of 1% or greater compared to its overall length in a dehydrated state.

[0006] In some embodiments, the device comprises a body portion formed from a polymeric material comprising a first water-soluble polymer, the body portion comprising a plurality of pores, a second water-soluble polymer disposed within at least a portion of the plurality of pores of the body portion, and a biologically active agent associated with the first water-soluble polymer and / or the second water-soluble polymer, wherein the biologically active agent is substantially homogeneously distributed within the first water-soluble polymer.

[0007] In some embodiments, the device comprises a body portion formed from a polymeric material comprising a first water-soluble polymer and comprising a biologically active agent associated with the polymeric material, the biologically active agent being substantially homogeneously distributed within the polymeric material, and the polymeric material having a Young's modulus of 500 MPa or greater in a dehydrated state and a Young's modulus of 300 MPa or less and 5 MPa or greater in an equilibrium water content state.

[0008] In some embodiments, the device comprises a body portion formed from a polymeric material comprising a first water-soluble polymer and a biologically active agent associated with the polymeric material, the biologically active agent being substantially homogeneously distributed within the polymeric material, the polymeric material being less than 5 wt.% and greater than or equal to 0.1 wt.% in a dehydrated state, and the polymeric material being configured to swell from the dehydrated state to an equilibrium moisture content state by an amount greater than or equal to 50 wt.% inclusive within 60 minutes at 25°C.

[0009] In some embodiments, the device comprises a body portion, the body portion being formed from a polymeric material, the polymeric material comprising a water soluble polymer and a biologically active agent associated with the polymeric material, the biologically active agent being present in the device in an amount of 0.01 w / w% or greater, the polymeric material being characterized by having a Young's modulus of 500 MPa or greater in a dehydrated state and a Young's modulus of 5-300 MPa at equilibrium water content.

[0010] In some embodiments, the device is formed from a polymeric material comprising a first water-soluble polymer and a biologically active agent associated with the polymeric material, the biologically active agent being substantially homogeneously distributed within the polymeric material, and the biologically active agent being configured to be released from the polymeric material at a first average rate determined 24 hours after release, and to be released at a second average rate after 30 days that is at least about 1% of the first average rate.

[0011] In some embodiments, the device includes a body portion, the body portion being formed from a polymeric material comprising: a first water-soluble polymer; and a humectant, wherein the polymeric material has a water content of 6% w / w or more and 40% w / w or less, the water content being less than the equilibrium moisture content state, and the polymeric material is configured to swell by an amount of 2% w / w or more relative to the equilibrium moisture content state.

[0012] In some embodiments, the device includes a body portion, the body portion being formed from a polymeric material comprising a first water-soluble polymer, the polymeric material having a water content of 6% w / w or more and 40% w / w or less, the water content being less than an equilibrium water content state, and the polymeric material being configured to swell by 2% w / w or more to an equilibrium water content state in 60 minutes or less at 25°C.

[0013] In some embodiments, a device comprises a body portion formed from a polymeric material comprising a first water-soluble polymer, the body portion having an inner diameter, an outer diameter, and a length, the polymeric material having a water content of 6% w / w or more and 40% w / w or less, the water content being less than an equilibrium water content state, the polymeric material being configured to swell by an amount of 2% w / w or more relative to the equilibrium water content state, and the polymeric material being configured to swell such that the inner and / or outer diameter increases at a rate greater than the rate at which the length increases.

[0014] In another aspect, a catheter is provided, in some embodiments, the catheter includes a body portion formed from a polymeric material configured for administration to a subject, the body portion comprising the polymeric material and a biologically active agent substantially homogeneously dispersed within the polymeric material.

[0015] In some embodiments, the catheter includes a body portion formed from a polymeric material configured for administration to a subject, the body portion comprising the polymeric material and a biologically active agent dispersed within the bulk of the polymeric material, the biologically active agent being present in the catheter in an amount of 0.01 w / w% based on the total weight of the catheter in a dehydrated state.

[0016] In yet another aspect, a kit is provided. In some embodiments, the kit provides a device comprising a body portion, the body portion comprising a polymeric material including a first water-soluble polymer and a humectant, the polymeric material having a water content less than an equilibrium water content state, and the polymeric material configured to swell by 2 wt% or more relative to the equilibrium water content state.

[0017] In some embodiments, the kit is a device comprising a body portion, the body portion comprising a polymeric material comprising a first water-soluble polymer; and The polymer material has a water content that is less than the equilibrium water content state, and is configured to swell by 2 wt% or more relative to the equilibrium water content state within 60 minutes or less at 25°C.

[0018] In some embodiments, the kit includes a body portion, the body portion comprising a polymeric material including a first water-soluble polymer, the body portion having an inner diameter, an outer diameter, and a length, the polymeric material having a water content that is less than an equilibrium water content state, the polymeric material configured to swell by an amount of 2 wt% or more relative to the equilibrium water content state, and the polymeric material configured to swell such that the inner and / or outer diameter increases at a rate that is greater than the rate at which the length increases.

[0019] In yet another aspect, methods, such as methods for treating an object, are provided. In some embodiments, the method includes the steps of: extruding a mixture comprising a first water-soluble polymer and a salt, wherein the first water-soluble polymer is present in the mixture in an amount of 13 wt% or more, based on the total weight of the mixture, onto a core at a temperature of 65°C or higher to form a polymeric material disposed on the core; and exposing the polymeric material to a non-solvent for the polymeric material at a temperature of 28°C or lower for 15 minutes or longer. Also included are the steps of: introducing a solution containing a biologically active agent into the polymeric material; heating the polymeric material and the solution to a temperature of 30°C or higher; flowing the solution adjacent to the polymeric material; and drying the polymeric material, wherein the biologically active agent is substantially uniformly distributed within the polymeric material and within 50% or less of the average loading of the biologically active agent within the polymeric material.

[0020] In some embodiments, a method of treating a subject includes administering into an orifice of the subject a device comprising: a body portion, the body portion comprising a polymeric material comprising a first water-soluble polymer; and a humectant, the polymeric material having a water content that is less than the equilibrium water content state; and swelling the polymeric material by an amount of 2 wt% or more relative to the equilibrium water content state.

[0021] In some embodiments, a method of treating a subject includes administering into a cavity of the subject a device comprising: a body portion, the body portion comprising a polymeric material comprising a first water-soluble polymer; the polymeric material having a water content that is less than an equilibrium water content state; and swelling the polymeric material to an equilibrium water content state by an amount of 2 wt% or more at 25°C within a time period of 60 minutes or less.

[0022] In some embodiments, a method of treating a subject comprises administering to a cavity of the subject a device comprising: a body portion; the body portion made of a polymeric material comprising a first water-soluble polymer, the body portion having an inner diameter, an outer diameter, and a length; the polymeric material having a water content that is less than an equilibrium water content state; and swelling the polymeric material by an amount of 2 wt% or more relative to the equilibrium water content state, such that the inner diameter and / or the outer diameter increases at a rate greater than the rate at which the length increases.

[0023] In some embodiments, the method includes administering into an external orifice of a subject a device including a body portion, the body portion comprising a polymeric material including a water-soluble polymer and a biologically active agent associated with the polymeric material, the device having an aspect ratio of 3:1 or greater, and the biologically active agent being substantially homogeneously distributed within the polymeric material.

[0024] 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 figures. 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]

[0025] Non-limiting embodiments of the present invention are illustratively described 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 shown is typically represented by a single numeral. For clarity, not every component is labeled in every drawing, and not every component of each embodiment of the present invention is shown unless illustration is necessary for those skilled in the art to understand the invention. [Figure 1A] 1A-1C are cross-sectional schematic diagrams of exemplary devices according to one set of embodiments. [Figure 1B]1A-1C are cross-sectional schematic diagrams of exemplary devices including multiple holes, according to one set of embodiments. [Figure 1C] 1A-1C are cross-sectional schematic diagrams of exemplary devices including multiple holes, according to one set of embodiments. [Figure 1D] 1A-1C are schematic diagrams of an exemplary extrusion device for forming a continuous form in a cutaway view of a bathtub, according to one set of embodiments. [Figure 1E] 1E is an enlarged view of a portion of the device of FIG. 1D, showing a perspective of the die head as seen from outside the bath, according to one set of embodiments. [Figure 1F] 1E is an enlarged view of a portion of the device of FIG. 1D, depicting the die head positioned in the bath, according to one set of embodiments. [Figure 1G] 1A-1C are cross-sectional schematic diagrams of exemplary devices according to one set of embodiments. [Figure 2] 1A-1C are side views of a catheter depicting dimensional changes before and after swelling according to one set of embodiments. [Figure 3A] FIG. 1 is a schematic diagram of a process for bulk incorporation of a polymer into a porous solid, according to one set of embodiments. [Figure 3B] 3B is a cross-section of a portion of a tube taken along line 3B-3B of FIG. 3A, according to one set of embodiments. [Figure 4A] 1 is a process flow diagram of an embodiment for bulk incorporation of a surface polymer into a porous solid, according to one set of embodiments, including an extrusion step to create the porous solid. [Figure 4B] 1 is a process flow chart for an embodiment of incorporating a biologically active agent and a polymer into a porous solid, according to one set of embodiments. [Figure 5] The results of the blood contact experiment described in Example 1 are provided as a plot of relative thrombus accumulation (FIG. 5A) or as a photograph of the tested samples (FIG. 5B). [Figure 6] 1 is a plot of the cumulative release profile of a 2.5 w / w% chlorhexidine load according to one set of embodiments. [Figure 7]1 is a plot of the 6.0 w / w% chlorhexidine loading cumulative release profile according to one set of embodiments. [Figure 8] 1 is a plot of a standard curve for chlorhexidine free radical according to one set of embodiments. [Figure 9] 1 is a plot of the total release of chlorhexidine in 2.21 mL of 0.9% saline per squeeze according to one set of embodiments. [Figure 10] 1 is a plot of chlorhexidine release versus number of squeezes according to one set of embodiments. [Figure 11] 1 is a plot of chlorhexidine release over time according to one set of embodiments. [Figure 12] 1 is a plot of Bupivacaine release over time according to one set of embodiments. [Figure 13A] 1 is a schematic diagram of an exemplary extrusion device for forming a device including two or more layers of polymeric material, according to one set of embodiments. [Figure 13B] 1A-1C are schematic diagrams of an exemplary extrusion device for forming a device including two or more layers of polymeric material, according to one set of embodiments. [Figure 14] 1 is a plot of the inner diameter in millimeters of 24 samples in the dry state according to one set of embodiments. [Figure 15] 15 shows a plot of the inner diameter in millimeters of the 24 samples of FIG. 14 in the swollen state, according to one set of embodiments. [Figure 16] 15 shows a plot of the outer diameter in millimeters of the 24 samples of FIG. 14 in the dry state, according to one set of embodiments. [Figure 17] 15 shows a plot of the outer diameter in millimeters of the 24 samples of FIG. 14 in the swollen state, according to one set of embodiments. [Figure 18] 1 is a plot of a representative stress-strain curve of a heat-treated composite PVA / PAA hydrogel, according to one set of embodiments. [Figure 19]1 is a plot of the measured average Young's modulus versus the calculated crosslink density for each heat treatment group, according to one set of embodiments. [Figure 20] 1 is a plot of representative stress-strain curves of an untreated composite PVA / PAA hydrogel, a 150° C. heat-treated PVA / PAA composite hydrogel, and two conventional TPUs, according to one set of embodiments. [Figure 21] 1 is a box plot of the mean ± standard deviation of maximum injection pressure for TPU control samples compared to composite hydrogel devices, according to one set of embodiments. [Figure 22A] 1 is a photograph of a 2 microliter (μL) water droplet on a dehydrated PVA / PAA composite hydrogel tube according to one set of embodiments. Scale bar is 1 mm. [Figure 22B] 1 is a photograph of a 2 microliter (μL) water droplet on a dehydrated PVA / PAA composite hydrogel tube according to one set of embodiments. Scale bar is 1 mm. [Figure 22C] Photograph of a 2 microliter (μL) water droplet on a TPU tube of hydrated Control 1. Scale bar is 1 mm. [Figure 22D] Photograph of a 2 microliter (μL) water droplet on a TPU tube of hydrated Control 2. Scale bar is 1 mm. [Figure 23] 1 is a bar graph showing the percent length change over time for the 30% glycerol group compared to the 10% poloxamer 407 group, according to one set of embodiments. [Figure 24] 1 is a bar graph showing that the addition of a humidity control sponge in packaging, according to one set of embodiments, improved thermal stability by eliminating curl and pigtails upon 5 minutes of hydration after exposure to extreme temperature changes. DETAILED DESCRIPTION OF THE INVENTION

[0026] High-strength porous materials incorporating water-soluble polymers are generally provided. For example, materials, methods, and uses are described herein for biomaterials including medically acceptable porous solids. The disclosed compositions and devices are useful for administration to a subject (e.g., a patient). Advantageously, the compositions and / or devices described herein may be substantially non-thrombogenic, lubricious, and / or biocompatible. In some embodiments, the devices described herein are useful for delivering biologically active agents (e.g., therapeutic agents such as drugs) to a subject. In some embodiments, the compositions and / or devices described herein are believed to be suitable for administration to a subject and / or delivery of biologically active agents over a relatively long period of time, for example, without forming thrombus, without fouling, and / or without absorbing (or adsorbing) one or more substances (e.g., therapeutic agents, proteins, blood, plasma) within the subject. Methods for forming such compositions and / or devices are also provided.

[0027] The devices described herein are useful for a wide variety of applications, including, for example, the administration of biologically active agents. In some embodiments, therapeutic, antimicrobial, or antiseptic active agents may be incorporated into the bulk material (e.g., polymeric material) of the device such that the agent is released from the bulk material. In some such embodiments, the biologically active agent can advantageously prevent or reduce biofilm, microbial colonization, infection, fibrin sheath formation, inflammation, pain, and / or tumor growth, and / or treat physiological conditions such as tumor shrinkage, fungal and bacterial infection, inflammation, and pain. The devices described herein can, in some cases, be used to create blood-contacting or bodily fluid-contacting devices, including ex vivo and / or in vivo devices such as blood-contacting implants. Examples of drug delivery devices into which the devices described herein may be embodied or incorporated include medical tubing, wound dressings, contraceptives, feminine hygiene products, endoscopes, implants (e.g., including diameters as small as 6 mm or less), pacemakers, implantable cardioverter defibrillators, cardiac resynchronization devices, cardiovascular device leads, ventricular assist devices, catheters (including, e.g., cochlear implants, endotracheal tubes, tracheostomy tubes, ports, shunts), implantable sensors (e.g., intravascular, percutaneous, intracranial), ventilator pumps, and ophthalmic devices, including drug delivery systems.

[0028] In some embodiments, the devices described herein comprise a body portion. For example, as illustratively shown in FIG. 1A, device 10 includes body portion 20. In some embodiments, body portion 20 is formed from and / or includes a polymeric material. The polymeric material may include a first water-soluble polymer. In some embodiments, a biologically active agent 50 is associated with the polymeric material.

[0029] In some embodiments, one or more biologically active agents are present throughout the bulk of the polymeric material (e.g., distributed throughout the polymeric material matrix). For example, in some embodiments, a first optional section 52 within the cross-section of body portion 20 comprises a non-zero concentration of biologically active agent. In some embodiments, a second optional section 54 within the cross-section of body portion 20, different from first optional section 52, comprises a non-zero concentration of biologically active agent. Based on the teachings herein, one of ordinary skill in the art will understand that the presence of a biologically active agent within the bulk of the polymeric material (e.g., embedded in the polymer matrix of the polymeric material) is not intended to refer to a coating of biologically active agent on the polymeric material, but rather to a biologically active agent dispersed throughout the bulk of the polymeric material. However, in some embodiments, a coating including a biologically active agent may optionally be present. Example sections are described in more detail below.

[0030] 1A are depicted as circular, those skilled in the art will understand, based on the teachings herein, that the body portion and other sections in the embodiments disclosed herein need not be circular, and that other cross-sectional shapes are possible (e.g., flat, rectangular, square, oval, elliptical, S-shaped, etc.). For example, in some embodiments, the body portion is S-shaped, which in some cases can provide ease of implantation into a subject, achieve a lower infiltration rate, and reduce the likelihood of dislodgement within the subject.

[0031] In some embodiments, the biologically active agent is present in a bulk polymeric material formed as a layer within the device. For example, in some embodiments, the polymeric material includes a first surface and a second surface, and the first surface and / or the second surface may be coated. In some embodiments, the first surface and / or the second surface is coated with a polymer, a second biologically active agent (the same or different from the biologically active agent present in the polymeric material), or a combination thereof. In some embodiments, the device comprises two or more layers of polymeric material in the body portion. In some embodiments, each layer of polymeric material is composed of the same, different, or no biologically active agent. In an exemplary embodiment, the body portion of the device comprises a first polymeric material layer containing a first biologically active agent and a second polymeric material layer disposed on the first polymeric material layer and containing a second biologically active agent. Other layer combinations are possible.

[0032] In some embodiments, the biologically active agent is substantially homogeneously distributed within the polymeric material (of the body portion) and / or the first water-soluble polymer, e.g., in some embodiments, the amount of biologically active agent does not vary by more than 50% at any given cross-section across the cross-sectional area of ​​the body portion and / or first water-soluble polymer (e.g., cross-sections 52, 54 in FIG. 1A ) compared to the average amount of biologically active agent within the body portion and / or first water-soluble polymer.

[0033] In some embodiments, the biologically active agent is distributed non-homogeneously within the polymeric material (i.e., on one or more surfaces of the polymeric material). For example, in some embodiments, the amount of biologically active agent varies by 50% or more at any given cross-section across the cross-sectional area of ​​the body portion and / or first water-soluble polymer (e.g., cross-sections 52, 54 in FIG. 1A) compared to the average amount of biologically active agent within the body portion and / or first water-soluble polymer.

[0034] In some embodiments, the biologically active agent is distributed within the body portion (or polymeric material of the body portion) and / or first water-soluble polymer in a range of at least 0.1%, at least 1%, at least 1%, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% of the average loading of the biologically active agent in the body portion (or polymeric material) and / or first water-soluble polymer. In some embodiments, the biologically active agent is distributed within the body portion (or polymeric material of the body portion) and / or first water-soluble polymer in a range of 99% or less, 98% or less, 95% or less, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 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 of the average loading of the biologically active agent in the body portion (or polymeric material) and / or first water-soluble polymer. Combinations of the above ranges are possible (e.g., 0.1%-99%, 1%-50%). Other ranges are also possible.

[0035] The loading of a biologically active agent can be determined at locations within the body portion (or polymeric material) by dissecting the body portion followed by extraction and liquid chromatography. For example, an article formed from the body portion (e.g., article 10 of FIG. 1A) may be cut along a cross-sectional dimension through its central axis and flattened. Three or more sections (e.g., a top section, a middle section, and a bottom section) of the flattened body portion may be sliced ​​across the length and / or width of the body portion, and the biologically active agent is extracted from each section. The amount of biologically active agent present in each section may be determined by liquid chromatography. The highest loading variability (relative to the average loading) among the measured sections constitutes the variability of the article or device. For example, if the biologically active agent is distributed within the body portion with variability levels of 5% of the average loading from the top section, 15% of the average loading from the middle section, and 10% of the average loading from the bottom section, the article / device including the body portion will have a 15% average loading variability. Such articles / devices are said to have a biologically active agent dispersed within the body portion (or polymeric material of the body portion) that is 15% or less of the average loading of the biologically active agent within the body portion (or polymeric material), and the biologically active agent is considered to be substantially uniformly dispersed within the body portion. In contrast, by way of example, an article (e.g., a coated catheter) having a biologically active agent coated on the exterior surface of the body portion, but without the biologically active agent present in the bulk polymeric material of the body portion, would not be considered to have a biologically active agent dispersed within the body portion that is 15% or less of the average loading as the loading in the first section (e.g., the upper section comprising the coating). The loading in the first section of the body portion (e.g., the upper section comprising the coating) would vary by 15% or more from the average loading of the biologically active agent in the body portion (or polymeric material).Thus, based on the teachings herein, one of ordinary skill in the art will understand that an article or device comprising a coating of a biologically active agent, where the biologically active agent is not present in the bulk polymeric material of the body portion, does not have the biologically active agent substantially homogeneously distributed (e.g., within 50% of the average loading) within the polymeric material (of the body portion).

[0036] In embodiments in which there is more than one layer of polymeric material in the device, each layer of polymeric material may contain a biologically active agent in one or more of the aforementioned ranges, homogeneously or non-homogeneously distributed throughout each polymeric material.

[0037] In some embodiments, the amount of biologically active agent does not vary by more than 50% (or any combination of the aforementioned percentages) in any of at least 2, 4, 6, 8, 10, 20, or 30 sections of the body portion, hi some embodiments, the sections are randomly selected across the length and / or width of the polymeric material forming the body portion.

[0038] It should be understood that when multiple biologically active agents are present (e.g., first and second biologically active agents present in the polymeric material forming the majority of the body portion), each biologically active agent may be independently distributed within the polymeric material in one or more of the ranges described above. In some embodiments, as described in more detail below, the body portion (e.g., polymeric material) may comprise a plurality of pores. The polymeric material of the body portion may comprise a first water-soluble polymer as described herein. In some embodiments, the biologically active agent is homogeneously or non-homogeneously distributed within any of the above ranges within the polymeric material (e.g., the first water-soluble polymer), but is not distributed within the plurality of pores. That is, in some embodiments, the plurality of pores may be substantially free of a biologically active agent. In some embodiments, the plurality of pores may comprise a second biologically active agent, which may be the same as or different from the (first) biologically active agent present within the polymeric material (e.g., the polymeric material comprising the first water-soluble polymer) forming the bulk of the device. In still other embodiments, the biologically active agent is present only within the plurality of pores.

[0039] In one exemplary set of embodiments, the device is a catheter. In some embodiments, the catheter is configured for administration to a subject. For example, in some embodiments, the catheter is formed from a polymeric material and configured for administration to a subject, and the catheter includes a biologically active agent dispersed (e.g., homogeneously dispersed) within the polymeric material. In some embodiments, the catheter includes a body portion, and the body portion is formed from a polymeric material including a first water-soluble polymer as described herein.

[0040] Suitable biologically active agents are described in more detail below and include, for example, pharmaceutical agents (e.g., drugs), calcium salts (e.g., calcium chloride), iron salts (e.g., ferrous sulfate), starch, modified silica, cellulose, etc. As used herein, the term "biologically active agent" generally refers to an agent that, when administered to a subject, has a biologically significant effect on at least a portion of the subject's body.

[0041] In some embodiments, the compositions and devices described herein (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, and device 14 of FIG. 1C) comprise a body portion having a plurality of pores. The body portion may be formed from a polymeric material comprising a first water-soluble polymer. In some embodiments, the body portion further comprises a second water-soluble polymer, the same as or different from the first water-soluble polymer. For example, in some embodiments, the second water-soluble polymer, the same as or different from the first water-soluble polymer, may be disposed within at least a portion of the plurality of pores. In some embodiments, the second water-soluble polymer is disposed within the bulk of the first water-soluble polymer. In some embodiments, the second water-soluble polymer is substantially uniformly dispersed within the bulk of the first water-soluble polymer. In some embodiments, the second water-soluble polymer is substantially non-homogeneously dispersed within the bulk of the first water-soluble polymer. While the following embodiments generally refer to devices comprising a second water-soluble polymer disposed within a plurality of pores, one of skill in the art will understand, based on the teachings herein, that the second water-soluble polymer need not always be present. Without wishing to be bound by theory, in some embodiments, the presence of a second water-soluble polymer disposed within at least a portion of the plurality of pores of the body portion or the first water-soluble polymer can reduce the thrombogenicity and / or increase the lubricity of a device (e.g., device 12 of FIG. 1B, device 14 of FIG. 1C) compared to a device without a 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.

[0042] In some embodiments, a second water-soluble polymer can be considered the same as a first water-soluble polymer if they are both polymers of the same monomers but differ in other properties, such as the number of monomers and / or molecular weight.

[0043] In some embodiments, the devices (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, device 14 of FIG. 1C) and compositions described herein are administered to a subject. In some embodiments, the device may be administered orally, rectally, vaginally, nasally, intravenously, subcutaneously, or urethrally. In some cases, the device may be administered to a cavity, epidural space, vein, artery, orifice, external orifice, and / or abscess of a subject. Non-limiting examples of openings include wounds. Non-limiting examples of wounds include wound openings created through the skin for venous access (e.g., created as an insertion site).

[0044] As described herein, in some embodiments, the compositions, devices, and devices described herein are comprised of or formed of a polymeric material comprising a first water-soluble polymer having a plurality of pores. For example, as shown in FIG. 1B, device 12 includes a body portion 20 comprised of a first water-soluble polymer and comprised of or formed of a polymeric material having a plurality of pores 30. In some embodiments, a second water-soluble polymer 40 is disposed within at least a portion (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%) of the plurality of pores. In some embodiments, the 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 (e.g., between 10% and 100% of the plurality of pores). Combinations of the above ranges are also possible.

[0045] In some embodiments, the second water-soluble polymer is disposed (e.g., dispersed) 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 shown in FIG. 1C, the second water-soluble polymer 40 may be present as a coating 45 on at least a portion of the surface of the body portion 20. While FIG. 1C depicts the second water-soluble polymer as a coating on the first water-soluble polymer and within 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.

[0046] In some embodiments, the devices and / or devices described herein may be hollow (e.g., have a hollow core). For example, device 10 and / or device 12 may be hollow (e.g., include a hollow core 25). However, while FIGS. 1A-1C are depicted as having a hollow core, one of ordinary skill in the art will understand based on the teachings herein that such a hollow core need not be present. That is, in some cases, core 25 of a device (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, device 14 of FIG. 1C) may be a bulk material (e.g., a solid core) without a hollow core 25.

[0047] As previously mentioned, in some embodiments, one or more biologically active agents may be distributed within body portion 20 and / or plurality of holes 30 (FIGS. 1B-1C). In some embodiments, the biologically active agent is a therapeutic agent. As used herein, the term "therapeutic agent" or "drug" as used herein refers to an agent that is administered to a subject to treat, alleviate, delay, ameliorate, and / or prevent a disease, disorder, or other clinically recognized condition, or for prophylactic purposes, and in some embodiments has a clinically significant effect on the subject's body to treat, alleviate, delay, ameliorate, and / or prevent a disease, disorder, or condition. Therapeutic agents include, but are not limited to, those agents described in the United States Pharmacopeia (USP), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, McGraw Hill, 2001; Katzung, B. (publisher) Basic and Clinical Pharmacology, McGraw-Hill / Appleton & Lange; 8th Edition (September 21, 2000); Physician's Desk Reference (Thomson Publishing), and / or The Merck Manual of Diagnosis and Therapy, 17th Edition (1999), or its subsequent 18th Edition (2006), Mark H. Beers and Robert Berkow (publisher), Merck Publishing Group, or for animals, The Merck Veterinary Manual, 9th Edition, Kahn, CA (publisher), Merck Publishing Group, 2005. In some embodiments, the therapeutic agent may be selected from the "Approved Drug Products with Therapeutic Equivalence and Evaluations" ("Orange Book") published by the United States Food and Drug Administration (FDA).In some cases, therapeutic agents may be used that have already been determined to be safe and effective in humans or animals by the appropriate governmental or regulatory agency. For example, drugs approved for human use are listed by the FDA in 21 C.F.R. §§ 330.5, 331-361, and 440-460, which are incorporated herein by reference. Veterinary drugs are listed by the FDA in 21 C.F.R. §§ 500-589, which are incorporated herein by reference. All of the listed drugs are contemplated as being suitable for use in accordance with the present invention. In some embodiments, the therapeutic agent is a small molecule. Exemplary classes of drugs include analgesics, anti-analgesics, anti-inflammatory agents, antipyretics, antidepressants, antiepileptics, antipsychotics, neuroprotective agents, antiproliferative agents, e.g., anti-cancer agents (e.g., antineoplastic agents (e.g., taxanes such as paclitaxel, docetaxel, cisplatin, doxorubicin, methotrexate, etc.), antihistamines, anti-neoplastic agents, antihistamines, anti-migraine drugs, hormonal agents, prostaglandins, antibacterial agents (e.g., antibiotics, antifungals, antivirals, antiparasitics, etc.), antimuscarinics, anxiolytics, bacteriostatics, immunosuppressants, sedatives, hypnotics, antipsychotics, bronchodilators, antiasthmatics, cardiovascular drugs, These include anesthetics, anticoagulants, enzyme inhibitors, steroids, steroidal or nonsteroidal anti-inflammatory drugs, corticosteroids, dopaminergic agents, electrolytes, gastrointestinal drugs, muscle relaxants, nutrients, vitamins, parasympathomimetics, stimulants, anorectics, antinarcoleptics, etc. Nutritional supplements can also be incorporated, including vitamins, calcium and biotin supplements, and natural ingredients such as plant extracts and plant hormones.

[0048] In some embodiments, the biologically active agent is an anti-inflammatory agent. Non-limiting examples of suitable anti-inflammatory agents include betamethasone, beclomethasone, budesonide, ciclesonide, dexamethasone, desoximethasone, fluocinolone acetonide, fluocinonide, flunisolide, fluticasone, icomethasone, and rofleponide. Triamcinolone acetonide, fluocortin butyl, hydrocortisone acebonate, hydrocortisone buterate, hydroxycortisone 17-butyrate, prednicarbate, 6-methylprednisolone acebonate, mometasone furoate, elastin, prostaglandins, leukotrienes, and bradykinin antagonists.

[0049] In some embodiments, the biologically active agent is an anesthetic. Non-limiting examples of suitable anesthetics include bupivacaine, lidocaine, procaine, and tetracaine.

[0050] In some embodiments, the biologically active agent is an antiplatelet agent. Non-limiting examples of suitable antiplatelet agents include clopidogrel, prasugrel, ticagrelor, ticlopidine, cilostazol, vorapaxar, abciximab, eptifatide, tirofiban, dipyridamole, and terutroban.

[0051] In some embodiments, the biologically active agent is an analgesic. Non-limiting examples of suitable analgesics include paclitaxel, clopidogrel, prasugrel, ticagrelor, aspirin, ibuprofen, naproxen (and other NSAIDs), warfarin, heparin, apixaban, dabigatran, rivaroxaban, and statins.

[0052] In some embodiments, the biologically active agent is an anti-neoplastic agent. Non-limiting examples of suitable anti-neoplastic agents include paclitaxel, oxaliplatin, fluorouracil (5-FU), docetaxel, methotrexate, doxorubicin, mitoxantrone, teniposide, etoposide, novobiocin, mervalone, and aclarubicin.

[0053] In some embodiments, the biologically active agent is an antiseptic. Non-limiting examples of suitable antiseptics include chlorhexidine, alexidine, iodine, povidone, octenidine, polybiguanide, cetrimide, biphenol, chlorophene, triclosan, copper, silver, nanosilver, gold, selenium, gallium, taurolidine, cyclotaurolidine, N-chlorotaurine, alcohol, ethyl lauroylarginine, myristamidopropyl dimethylamine (MAPD), and oleamidopropyl dimethylamine (OAPD).

[0054] In some embodiments, the biologically active agent is an antibacterial agent. Non-limiting examples of suitable antibacterial agents include penicillins: benzylpenicillins (e.g., penicillin-G-sodium, clemizole penicillin, benzathine penicillin G); phenoxypenicillins (e.g., penicillin V, propicillin, etc.); aminobenzylpenicillins (ampicillin, amoxicillin, bacampicillin, etc.), acylaminopenicillins (azlocillin, mezlocillin, piperacillin, apalcillin, etc.), kale, ... Ruboxypenicillins (e.g., carbenicillin, ticarcillin, temocillin, etc.), isoxazolylpenicillins (e.g., oxacillin, cloxacillin, dicloxacillin, flucloxacillin, etc.), amidine penicillins (e.g., mecillinam), cephalosporins such as cefazolins (e.g., cefazolin, cefazolin, etc.); cefuroximes (e.g., celfoxime, cefamandole, cefotiam); cefoxitins (e.g., : Cefoxitin, cefotetan, latamoxif, flomoxif; Cefotaximes (e.g., cefotaxime, ceftriaxone, ceftizoxime, cefmenoxime); Ceftazidimes (e.g., ceftazidime, cefpirome, cefpime); Cephalexins (e.g., cephalexin, cefaclor, cefadroxil, cephradine, loracarbef, cefprozil); Cefiximes (e.g., cefixime, cefpodoxime proxetil) cefotiam hexetil), carbapenems; imipenem; cilastatin; meropenem; biapenem monobactam; gyrase inhibitors: ciprofloxacin, gatifloxacin, norfloxacin, ofloxacin, levofloxacin, pefloxacin, lomefloxacin, fleroxacin, clinafloxacin, sitafloxacin, gemifloxacin, balofloxacin, trovafloxacin, moxifloxacin, rifampicin, minocycline, tetracycline, erythromycin, roxithromycin, azithromycin, clarithromycin, sulfonamides, aminoglycosides; and combinations thereof.

[0055] In some embodiments, the biologically active agent is a clotting agent. Non-limiting examples of suitable clotting agents include cellulose, oxidized cellulose, tranexamic acid, aprotinin, epsilon-aminocaproic acid, aminomethylbenzoic acid, fibrinogen, and calcium salts.

[0056] In some embodiments, the biologically active agent is a biological entity. Non-limiting examples of suitable biological entities include peptides and peptide oligomers: insulin, adrenocorticotropic hormone, calcitonin, oxytocin, vasopressin, octreotide, leuprorelin, exenatide, carfilzomib, bortezomib, lixisenatide, voclosporin, daptomycin, glatiramer, rindopepimut, dulaglutide. Trebananib, lutetium, romiplostim, liraglutide, peginesatide, zoptarelin, tesamorelin, lucinactant, pasireotide, linaclotide, teduglutide, albiglutide, dulaglutide, afamelanotide, etelcalcetide, plecanatide; checkpoint inhibitors: PD-1, CTLA-4, PD-L1; immune cell therapy: tumor infiltrating lymphocytes (TILs), chimeric antigen receptor (CAR), tisagenlukul therapeutic antibodies: trastuzumab, rituximab, ofatumumab, alemtuzumab, ado-trastuzumab emtansine, brentuximab vedotin, blinatumomab; therapeutic vaccines: sipuleucel-T, talimogene laherpepbec; and immunomodulatory agents: cytokines, bacillus Calmette-Guerin (BCG), thalidomide, lenalidomide, pomalidomide, imiquimod.

[0057] In some embodiments, the biologically active agent comprises a natural and / or synthetic cannabinoid or derivative thereof.

[0058] It should be understood that when multiple biologically active agents are present (e.g., a first biologically active agent present in the polymeric material forming the bulk of the body portion or a second biologically active agent present in the pores of the body portion), each biologically active agent may independently be one of the aforementioned active agents.

[0059] The biologically active agent (e.g., first biologically active agent, second biologically active agent) may be distributed within the body portion and / or polymeric material and present in any suitable amount in the device. In some embodiments, the biologically active agent is present in the body portion or polymeric material of the device in an amount of about 0.01% to about 50% by weight, based on the total weight of the device, when the device is in a first configuration (e.g., a water content less than the equilibrium water content, such as a dehydrated state). In some embodiments, the biologically active agent is present in the body portion of the device in an amount of at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.5%, at least about 1%, at least about 2%, at least about 3%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, or at least about 40% by weight, based on the total weight of the device when the device is in a first configuration (e.g., a water content less than the equilibrium water content, such as a dehydrated state). In some embodiments, the biologically active agent is present in the body portion or polymeric material of the device in an amount of about 50% by weight or less, about 40% by weight or less, about 30% by weight or less, about 20% by weight or less, about 10% by weight or less, about 5% by weight or less, about 3% by weight or less, about 2% by weight or less, about 1% by weight or less, about 0.5% by weight or less, about 0.1% by weight or less, or about 0.05% by weight or less. Combinations of the above ranges are possible (e.g., about 0.01% by weight to about 50% by weight). Other ranges are also possible. It should be understood that when multiple biologically active agents are present (e.g., a first biologically active agent present in the polymeric material forming the bulk of the body portion or a second biologically active agent present in the pores of the body portion), each biologically active agent may independently be present in an amount within one or more of the above ranges.

[0060] The devices, catheters, kits, and methods described herein may be administered to any suitable subject. The term "subject," as used herein, refers to an individual organism, such as a human or an animal. In some embodiments, the subject is a mammal (e.g., a human, a non-human primate, or a non-human mammal), a vertebrate, a laboratory animal, a livestock animal, an agricultural animal, or a companion animal. Non-limiting examples of subjects include humans, non-human primates, cows, horses, pigs, sheep, goats, dogs, cats, birds, fish, or rodents, such as mice, rats, hamsters, and guinea pigs. Generally, the present invention is intended for use in humans. In some embodiments, the subject may exhibit health benefits, for example, upon administration of the device.

[0061] Advantageously, the devices described herein can incorporate higher concentrations (weight percent) of active agents, such as biologically active agents, into the device compared to certain other devices (e.g., certain devices that include only a coating of a biologically active agent). In some embodiments, the biologically active agent is associated with the first water-soluble polymer and / or the second water-soluble polymer. In some embodiments, the biologically active agent is dispersed within the first water-soluble polymer and / or the second water-soluble polymer. Additionally, or alternatively, the devices described herein can allow for extended release of one or more biologically active agents compared to certain other devices (e.g., certain devices that include only a coating of a biologically active agent).

[0062] In some embodiments, the biologically active agent may be released from the body portion of the device by any suitable means. In some embodiments, the biologically active agent is released by diffusion from the body portion (e.g., the polymeric material of the body portion). In some embodiments, the biologically active agent is released by degradation of at least a portion of the body portion (e.g., biodegradation, enzymatic degradation, hydrolysis of the polymeric material forming the body portion, or hydrolysis of the polymeric material within the pores of the body portion). In some embodiments, the active agent is released from the device at a specific rate. Those skilled in the art will appreciate that the release rate may, in some embodiments, depend on the solubility of the biologically active agent in the medium to which the device is exposed, such as physiological fluids such as blood. In some embodiments, the release rate may depend on the crosslink density, porosity, pore size distribution, pore interconnectivity (e.g., tortuosity), crystallinity, and / or the number of biologically active agent-containing layers in the device (e.g., the body portion of the device).

[0063] In some embodiments, 0.05% to 99% by weight of the biologically active agent is released between 24 hours and 1000 days after administration to a subject (e.g., immediately after administration, after the first 24 hours after administration). That is, in some embodiments, the devices described above and herein are configured to release a biologically active agent (e.g., a therapeutically significant amount of a biologically active agent) for 24 hours or more, 36 hours or more, 72 hours or more, 96 hours or more, 192 hours or more, 15 days or more, 30 days or more, 40 days or more, 50 days or more, 60 days or more, 70 days or more, 80 days or more, 90 days or more, 100 days or more, 120 days or more, 150 days or more, 200 days or more, 300 days or more, 365 days or more, or 600 days or more. In some embodiments, the devices described above and herein are configured to release a biologically active agent in 1000 days or less, 600 days or less, 365 days or less, 300 days or less, 200 days or less, 150 days or less, 120 days or less, 100 days or less, or 90 days or less after administration to a subject. They are configured to release a biologically active agent in 80 days or less, 70 days or less, 60 days or less, 50 days or less, 40 days or less, 30 days or less, 15 days or less, 192 hours or less, 96 hours or less, 72 hours or less, or 36 hours or less. Combinations of the above ranges are also possible.

[0064] In some embodiments, about 0.05% to about 99% by weight of the biologically active agent is released from the device after a period of time. In some embodiments, after about 24 hours, about 32 hours, about 72 hours, about 96 hours, or about 192 hours, at least about 0.05%, at least about 0.1%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 98%, and / or no more than about 99%, no more than about 98%, no more than about 95%, no more than about 90%, no more than about 75%, no more than about 50%, no more than about 20%, no more than about 10%, no more than about 5%, no more than about 1%, no more than about 0.5%, or no more than about 0.1% by weight of the biologically active agent associated with the device is released from the device. In some embodiments, at least about 0.05% by weight, at least about 0.1% by weight, at least about 0.5% by weight, at least about 1% by weight, at least about 5% by weight, at least about 10% by weight, at least about 20% by weight, at least about 50% by weight, at least about 75% by weight, at least about 90% by weight, at least about 95% by weight, or at least about 98% by weight, and / or 99% by weight or less, about 98% by weight or less. About 95% by weight or less, about 90% by weight or less, about 75% by weight or less, about 50% by weight or less, about 20% by weight or less, about 10% by weight or less, about 5% by weight or less, about 1% by weight or less, about 0.5% by weight or less, or about 0.1% by weight or less of the biologically active agent associated with the polymeric component is released from the device (e.g., after about 1 day, about 3 days, about 5 days, about 7 days, about 15 days, about 30 days, about 40 days, about 50 days, about 60 days, about 70 days, about 80 days, about 90 days, about 100 days, about 120 days, about 150 days, about 200 days, about 300 days, about 365 days, about 600 days, or 1000 days). For example, in some cases, at least about 70% by weight of the biologically active agent associated with the polymeric component is released from the component after the first 24 hours and after about 120 days following administration to a subject.It should be understood that when multiple biologically active agents are present (e.g., a first biologically active agent present in the polymeric material forming the bulk of the body portion, or a second biologically active agent present in the pores of the body portion), each biologically active agent may be independently released at a rate within one or more of the aforementioned ranges.

[0065] In some embodiments, the biologically active agent is released from the device at a particular initial average rate (hereinafter "initial average release rate") determined by the first 24 hours of release. In some embodiments, the biologically active agent is released at an average rate after the first 24 hours of release that is at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, or at least about 98% of the initial average release rate. In some embodiments, the biologically active agent is released at an average release rate that is no more than about 99%, no more than about 98%, no more than about 95%, no more than about 90%, no more than about 80%, no more than about 75%, no more than about 50%, no more than about 30%, no more than about 20%, no more than about 10%, no more than about 5%, or no more than about 2% of the initial average release rate. Combinations of the above ranges are possible (e.g., about 1% to about 99%, about 1% to about 98%, about 2% to about 95%, about 10% to about 30%, about 20% to about 50%, about 30% to about 80%, about 50% to about 99%). Other ranges are also possible. It should be understood that when multiple biologically active agents are present (e.g., a first biologically active agent present in the polymeric material forming the bulk of the body portion or a second biologically active agent present in the pores of the body portion), each biologically active agent may be independently released at a rate within one or more of the foregoing ranges.

[0066] The biologically active agent may be released at an average rate over a given 24-hour period after the initial 24-hour release period. The average release rate may be about 1% to about 99% of the initial average release rate, determined between 48 hours and about 1000 days (e.g., between 48 hours and 1 week, 3 days and 1 month, 1 week and 1 month, 1 month and 6 months, 3 months and 1 year, 6 months and 2 years) after the initial release. That is, in some embodiments, the devices described above and herein may have a relatively long, non-zero release rate of the biologically active agent (e.g., after hydration when administered to a subject) after the initial 24-hour release period. In an exemplary embodiment, the biologically active agent is configured to be released from the polymeric material at a first average rate determined over the 24 hours of release and at a second average rate after 30 days that is at least about 1% of the first average rate.

[0067] In some embodiments, the biologically active agent is not released from the device as a burst release. In exemplary embodiments in which at least about 0.05% by weight of the biologically active agent is released from the device after about 24 hours, about 0.05% to about 10% by weight (e.g., at least about 0.05%, at least about 0.1%, at least about 0.5%, at least about 1%, or at least about 5%) is released on the first day of release, and about 0.05% to about 10% by weight is released on the second day of release. Those skilled in the art will appreciate that similar amounts of biologically active agent may be released during the third, fourth, fifth, etc. days, depending on the characteristics of the device and / or the biologically active agent.

[0068] In some embodiments, at least a portion of the biologically active agent is released in a burst release (e.g., a single burst release, two or more burst releases, multiple burst releases). For example, in exemplary embodiments, based on the total weight percent of the biologically active agent present in the device, 0.05% by weight or more, 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, 2% by weight or more, 5% by weight or more, 10% by weight or more, 15% by weight or more, 20% by weight or more, 25% by weight or more, 30% by weight or more, 40% by weight or more, 50% by weight or more, 60% by weight or more, 70% by weight or more, 80% by weight or more, 90% by weight or more, 95% by weight or more, 98% by weight or more, 99% by weight or more, 99.5% by weight or more, or 99.8% by weight or more of the biologically active agent is released in a burst release. In some embodiments, up to 100%, up to 99.9%, up to 99.8%, up to 99.8%, up to 99.5%, up to 99%, up to 98%, up to 95%, up to 90%, up to 80%, up to 70%, up to 60%, up to 50%, up to 40%, up to 30%, up to 25%, up to 20%, up to 15%, up to 10%, up to 5%, up to 2%, up to 1%, up to 0.5%, or up to 0.1% by weight of the biologically active agent is released in a burst release. Combinations of the above ranges are also possible (e.g., 0.05% to 100%, 0.1% to 50%, 10% to 90%, 40% to 100% by weight). Other ranges are also possible.

[0069] In some embodiments, at least a portion of the biologically active agent is released from the device in a single burst release within one or more of the above ranges. In some embodiments, at least a portion of the biologically active agent is released from the device in two or more (e.g., three or more, four or more, five or more, six or more) burst releases, each release occurring within one or more of the above ranges relative to the amount of biologically active agent present in the device after initial loading or relative to the amount of biologically active agent present in the device after the previous burst release. Each burst release may be separated by any suitable time, including, for example, 0.1 seconds or more, 1 second or more, 5 seconds or more, 10 seconds or more, 30 seconds or more, 1 minute or more, 5 minutes or more, 30 minutes or more, 1 hour or more, 4 hours or more, 12 hours or more, 24 hours or more, 3 days or more, 1 week or more, 1 month or more, or 1 year or more. In some embodiments, each burst release is separated by 2 years or less, 1 year or less, 1 month or less, 1 week or less, 3 days or less, 24 hours or less, 12 hours or less, 4 hours or less, or 5 hours or less. The ranges are divided into 4 hours or less, 1 hour or less, 30 minutes or less, 5 minutes or less, 1 minute or less, 30 seconds or less, 10 seconds or less, 5 seconds or less, or 1 second or less. Combinations of the above ranges are also possible (e.g., 0.1 seconds to 1 year). Other ranges are also possible.

[0070] As used herein, the term burst release is given its ordinary meaning in the art and generally refers to a substantial change in the release rate of a compound (e.g., a biologically active agent) from a device over a relatively short period of time. In some embodiments, the burst release of a particular weight percent of biologically active agent occurs over a period of 60 seconds or less, 30 seconds or less, 15 seconds or less, 10 seconds or less, 5 seconds or less, 2 seconds or less, 1 second or less, 0.5 seconds or less, or 0.1 seconds or less. In some embodiments, the burst release occurs over a period of 0.01 seconds or more, 0.1 seconds or more, 0.5 seconds or more, 1 second or more, 2 seconds or more, 5 seconds or more, 10 seconds or more, 15 seconds or more, or 30 seconds or more. Combinations of the above ranges are also possible (e.g., 0.01 seconds to 60 seconds). Other ranges are also possible.

[0071] In some embodiments, the device may be configured to release one or more biologically active agents using a combination of burst and controlled release. In an illustrative example, the biologically active agent may be released via an initial burst release followed by a controlled release at any of the amounts, average rates, and / or times described above. In another example, a first biologically active agent may be released via a burst release, and a second biologically active agent may be released at a particular average rate, as described above. In some embodiments, the first and second biologically active agents may begin to release at substantially the same time. In some embodiments, the first and second biologically active agents may be released at different times.

[0072] The biologically active agent may be released at a substantially constant average rate (e.g., a substantially zero-order average release rate) over a period of at least about 24 hours. In some embodiments, the biologically active agent is released at a first order release rate (e.g., the release rate of the biologically active agent is approximately proportional to the concentration of the biologically active agent) over a period of at least about 24 hours.

[0073] In some embodiments, the plurality of pores (e.g., device 12 of FIG. 1B , device 14 of FIG. 1C ) or the first water-soluble material, optionally having a second water-soluble polymer disposed within at least a portion 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 has 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 ranges are also possible (e.g., 10 nm to 500 nm). Other ranges are also possible. The average pore sizes described herein can be determined by mercury intrusion porosimetry of the material in the first configuration (e.g., at a moisture content below equilibrium moisture content, such as a dehydrated state).

[0074] 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 μm. 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 μm. 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 are 1 μm or less, 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, 250 nm or less, 300 nm or less, 250 nm or less, 250 nm or less. The pores have a diameter of 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 pores have a diameter 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, 450 nm or more, 500 nm or more, 600 nm or more, or 800 nm or more. Combinations of the above ranges are also possible (e.g., 10 nm to 1000 nm). Other ranges are also possible.

[0075] Compositions and devices described herein (e.g., device 10 of FIG. 1A , device 12 of FIG. 1B , device 14 of FIG. 1C ) may have a particular porosity, for example, in a first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state). In some embodiments, the device (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 the first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state). In some embodiments, the device (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 the first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state). Combinations of the above ranges are also possible (eg, 5% to 50% in the first configuration (eg, moisture content less than the equilibrium moisture content state, such as a dehydrated state)). Other ranges are also possible.

[0076] As described herein, in some embodiments, the devices, methods, catheters, or kits (or polymeric materials) described herein are substantially non-thrombogenic. Non-thrombogenicity may be determined as described in Example 1.

[0077] In some embodiments, a device (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, device 14 of FIG. 1C) (or body portion (e.g., body portion 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 degrees, as determined by goniometry. In some embodiments, a polymeric material (or surface thereof) (e.g., of a device) has a water contact angle of 45 degrees or less, 40 degrees or less, 35 degrees or less, 30 degrees or less, 25 degrees or less, 20 degrees or less, 15 degrees or less, 10 degrees or less, 5 degrees or less, or 2 degrees or less at equilibrium water content. In some embodiments, the polymeric material (or its surface) has a water contact angle at equilibrium water content of 1° or greater, 2° or greater, 5° or greater, 10° or greater, 15° or greater, 20° or greater, 25° or greater, 30° or greater, 35° or greater, or 40° or greater. Combinations of the above ranges are also possible (e.g., 1° to 45°). Other ranges are also possible.

[0078] As used herein, an equilibrium moisture content state refers to a steady state of a device (or material) that does not gain (e.g., absorb) or lose bulk moisture content as determined when submerged in water at 25° C. without the application of external mechanical stress. Those skilled in the art will understand that a steady state (or equilibrium moisture content state) does not require absolute conformance to the strict thermodynamic definition of such terms, but rather will be understood to indicate conformance to the thermodynamic definition of such terms to the extent possible for the requirements so characterized, as understood by those skilled in the art most closely related to such requirements (e.g., taking into account factors such as passive diffusion and / or Brownian motion).

[0079] In some embodiments, the device (or polymeric material) has an equilibrium moisture content of 10 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, 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, or 70 w / w% or more. In some embodiments, the device (or polymeric material) has an equilibrium moisture content of 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, 25 w / w% or less, or 20 w / w% or less. Combinations of these ranges are also possible (eg, 10 w / w % to 80 w / w %). Other ranges are also possible.

[0080] In some embodiments, a device (e.g., device 10 of FIG. 1A , device 12 of FIG. 1B , device 14 of FIG. 1C ) is substantially lubricious at equilibrium moisture content. For example, in some embodiments, the device (or the polymeric material of the device) has a surface roughness of 1000 nm (Ra) or less at equilibrium moisture content. In some embodiments, the device (or the polymeric material of the device) 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 device (or the polymeric material of the device) has a surface roughness (Ra) of 5 nm or more, 10 nm or more, 25 nm or more, or 50 nm or more at equilibrium moisture content. The range can be 100 nm or greater, 150 nm or greater, 200 nm or greater, 250 nm or greater, 300 nm or greater, 400 nm or greater, or 500 nm or greater. Combinations of the above ranges are also possible (e.g., 5 nm or greater, 1000 nm or less). Other ranges are also possible.

[0081] In some embodiments, a device (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, or device 14 of FIG. 1C) 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 device (or the polymeric material of the device) 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 device (or the polymeric material of the device) 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 ranges are also possible (e.g., 0.1 or less, 0.01 or more). Other ranges are also possible.

[0082] Advantageously, the compositions, devices, and devices described herein can have low sorption of substances such as therapeutic agents (and / or, e.g., proteins) in the presence of dynamic fluids containing such substances. Such devices and compositions can be useful, for example, for use in subjects where the presence of the device should not substantially reduce the availability and / or concentration of a therapeutic agent delivered to the subject (e.g., via the device). In some embodiments, administration of a therapeutic agent via a fluid flowing within a device described herein does not substantially reduce the concentration of the therapeutic agent within the fluid. In some cases, the device may not absorb and / or adsorb a therapeutic agent, for example, during flow or use.

[0083] In some embodiments, sorption of the therapeutic agent to the surface and / or bulk of the first water-soluble polymer is 0.5 wt% or less, as determined at equilibrium water content after exposing the polymer to the therapeutic agent and then rinsing the device 5 times its volume with an aqueous solution, such as water or saline. In some embodiments, sorption of the therapeutic agent to the surface and / or bulk of the first water-soluble polymer occurs at 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. In some embodiments, sorption of the therapeutic agent to the surface and / or bulk of the first water-soluble polymer occurs at 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. Combinations of the foregoing ranges are also possible (e.g., 0.5 wt% or less and 0.05 wt% or more). Other ranges are also possible.

[0084] Advantageously, the devices and compositions described herein can have desirable swelling properties (eg, in water, saline, in the fluid environment of a subject).

[0085] In some embodiments, a device (or polymeric material) described herein has a first configuration (e.g., a moisture content less than an equilibrium moisture content state, such as a dehydrated state) that has a moisture content of 40 w / w% or less, 30 w / w% or less, 20 w / w% or less, 10 w / w% or less, 5 w / w% or less, 4 w / w% or less, 3 w / w% or less, 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, or 0.2 w / w% or less. In some embodiments, a device (or polymeric material) described herein has a first configuration (e.g., a moisture content less than an equilibrium moisture content state, such as a dehydrated state) that has a moisture content of 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, 2 w / w% or more, 3 w / w% or more, 4 w / w% or more, 5 w / w% or more, 6 w / w% or more, 7 w / w% or more, 8 w / w% or more, 9 w / w% or more, 10 w / w% or more, 15 w / w% or more, 20 w / w% or more, 25 w / w% or more, 30 w / w% or more, or 35 w / w% or more. Combinations of the above ranges are also possible (e.g., 0.1 w / w% to 5 w / w% or more, 2 w / w% to 10 w / w% or more, 2 w / w% to 40 w / w% or more, or 6 w / w% to 40 w / w% or more). Other ranges are also possible.

[0086] In some embodiments, a device (or polymeric material) described herein has a first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state). In some embodiments, a device (or polymeric material) described herein swells from the first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state) to a second configuration (e.g., an equilibrium water content state) in 60 minutes or less (e.g., 10 minutes or less, 5 minutes or less, 1 minute or less, or 10 seconds or less). In some embodiments, a device (or polymeric material) described herein swells from the first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state) to a second configuration (e.g., an equilibrium water content state) at 25°C.

[0087] In some embodiments, a device (or polymeric material) described herein swells by 2 wt.% or more, 3 wt.% or more, 4 wt.% or more, 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, e.g., from a first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state) to a second configuration (e.g., an equilibrium water content state). In some embodiments, a device (or polymeric material) described herein swells by 50 wt.% or less, 45 wt.% or less, 40 wt.% or less, 35 wt.% or less, or 30 wt.% or less. 25 w / w% or less, 20 w / w% or less, 15 w / w% or less, 10 w / w% or less, 5 w / w% or less, 4 w / w% or less, or 3 w / w% or less, for example, from a first configuration (e.g., a moisture content less than the equilibrium moisture content state, such as a dehydrated state) to a second configuration (e.g., an equilibrium moisture content state). Combinations of these ranges are also possible (e.g., 5 w / w% to 40 w / w%).

[0088] In some embodiments, a device described herein (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, device 14 of FIG. 1C) is in a first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state). For example, in some embodiments, a device (or polymeric material) described herein has a first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state) of 40 wt.% or less, 30 wt.% or less, 20 wt.% or less, 10 wt.% or less, 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 some embodiments, the devices (or polymeric materials) described herein have a water content of 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, 2 w / w% or more, 3 w / w% or more, or 4 w / w% or more. Combinations of the above ranges are also possible (e.g., 0.1 w / w% to 5 w / w%, or 2 w / w% to 40 w / w%, etc.). Other ranges are also possible. As used herein, a dehydrated state generally refers to a steady state, determined at ambient conditions, in which the device (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 devices described herein may include a coating, such as a humectant coating, or unbound porogen, as described in more detail below.

[0089] Advantageously, the devices and compositions described herein may be configured to swell rapidly in the presence of water and / or aqueous solutions such as saline. In some embodiments, the device (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, device 14 of FIG. 1C) (or body portion (e.g., body portion 20 of FIGS. 1A-1C) or polymeric material) is configured to swell by an amount of 2 wt. % or more, 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, e.g., from a first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state) to a second configuration (e.g., an equilibrium water content state), e.g., at 25° C., e.g., in a specified time (e.g., 60 minutes or less, 10 minutes or less, 5 minutes or less, 1 minute or less, or 10 seconds or less), e.g., as described in more detail below. In some embodiments, the device or device (or body portion) is configured to swell by 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 10 w / w% or less, e.g., from a first configuration (e.g., a moisture content less than an equilibrium moisture content state, such as a dehydrated state, as described in more detail below) to a second configuration (e.g., an equilibrium moisture content state), e.g., at 25°C, e.g., for a specified time (e.g., 60 minutes or less, 10 minutes or less, 5 minutes or less, 1 minute or less, or 10 seconds or less). Combinations of the above ranges are also possible (e.g., 5 w / w% to 50 w / w%). Other ranges are also possible.

[0090] In some embodiments, the device (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, device 14 of FIG. 1C) (or body portion (e.g., body portion 20 of FIGS. 1A-1B)) is configured to swell from a first configuration (e.g., a moisture content less than an equilibrium moisture content state, such as a dehydrated state) to a second configuration (e.g., an equilibrium moisture content state) by an amount of 2 wt. % or more, 5 wt. % or more, in a time period of 60 minutes or less, 50 minutes or less, 40 minutes or less, 30 minutes or less, 20 minutes or less, 10 minutes or less, 5 minutes or less, 2 minutes or less, 1 minute or less, 30 seconds or less, or 10 seconds or less at 25°C. In some embodiments, the device (or polymeric material) is configured to swell from a first configuration (e.g., a water content less than the equilibrium water content state, such as a dehydrated state) to a second configuration (e.g., an equilibrium water content state) by an amount of 5 wt. % or more in 5 seconds or more, 15 seconds or more, 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 ranges are also possible (e.g., 1 minute to 60 minutes). Other ranges are also possible.

[0091] In exemplary embodiments, the device (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, device 14 of FIG. 1C) (or body portion (e.g., body portion 20 of FIGS. 1A-1B)) is configured to swell in water from a first configuration (e.g., a moisture content less than an equilibrium moisture content state, such as a dehydrated state) (e.g., less than 5 wt / w%, or 2 wt / w% to 40 wt / w%) to an equilibrium moisture content state (e.g., 5 wt / w% or more, or 20 wt / w% to 80 wt / w%) in 60 minutes or less (e.g., 10 minutes or less, 5 minutes or less, 1 minute or less, or 10 seconds or less). In some embodiments, the device (or polymeric material) is configured to swell from a first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state) (e.g., less than 5 w / w%) in, e.g., standard saline solution to an equilibrium water content state (e.g., 5 w / w% or more, or 20 w / w% to 80 w / w%) in 60 minutes or less (e.g., 10 minutes or less, 5 minutes or less, 1 minute or less, or 10 seconds or less). In another exemplary embodiment, the device (or polymeric material) is configured to swell from a first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state) (e.g., less than 5 w / w%) in, e.g., saline solution to an equilibrium water content state (e.g., 5 w / w% or more, or 20 w / w% to 80 w / w%) in 60 minutes or less (e.g., 10 minutes or less, 5 minutes or less, 1 minute or less, or 10 seconds or less).

[0092] In some embodiments, a device (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, device 14 of FIG. 1C) (or body portion (e.g., body portion 20 of FIGS. 1A-1B)) has a particular length in a first configuration (e.g., a water content less than the equilibrium water content state, such as a dehydrated state). In some embodiments, the device (or polymeric material) has an increase in overall length at the equilibrium water content state compared to the length in the first configuration (e.g., a water content less than the equilibrium water content state, such as a 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 device (or polymeric material) exhibits an increase in overall length in an equilibrium moisture content state compared to its length in a first configuration (e.g., a moisture content less than the equilibrium moisture content state, such as a dehydrated state) of no more than 20%, no more than 18%, no more than 16%, no more than 14%, no more than 12%, no more than 10%, no more than 8%, no more than 6%, no more than 4%, no more than 2%, no more than 1%, or no more than 0.5%. Combinations of the above ranges are also possible (e.g., 0.1% to 20%). Other ranges are also possible.

[0093] In some embodiments, a device (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, device 14 of FIG. 1C) (or body portion (e.g., body portion 20 of FIGS. 1A-1B)) has a particular outer largest cross-sectional dimension, such as the outer diameter of a cylindrical, elliptical, oblong, or rectangular tube. In embodiments where the device is comprised of multiple lumens, the outer diameter refers to the outer largest cross-sectional dimension of one or more of the lumens. For example, in some embodiments, only one lumen may have a recited outer diameter. In other embodiments, all lumens may independently have a recited outer diameter. In some embodiments, the device (or polymeric material) has an increase in outer maximum cross-sectional dimension (e.g., outer diameter) at equilibrium moisture content compared to the maximum cross-sectional dimension in the first configuration (e.g., outer diameter) 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 embodiments, the device (or polymeric material) has an increase in outer maximum cross-sectional dimension (e.g., outer diameter) at equilibrium moisture content compared to the maximum cross-sectional dimension in the first configuration (e.g., moisture content less than the equilibrium moisture content state, such as a dehydrated state) of 14% or more, 16% or more, or 18% or more. In some cases, the device (or polymeric material) has an increase in maximum cross-sectional dimension (e.g., outer diameter) at an equilibrium moisture content 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 compared to the maximum cross-sectional dimension (e.g., outer diameter) at a first configuration (e.g., a moisture content less than the equilibrium moisture content state, such as a dehydrated state). Combinations of the foregoing ranges are also possible (e.g., 0.1% to 20%, 0.1% to 10%). Other ranges are also possible.

[0094] In some embodiments, the device (or body portion) has a particular inner diameter (e.g., in embodiments where the device comprises a hollow core) that is the largest inner cross-sectional dimension, such as the inner diameter of a cylindrical or rectangular tube (or other non-circular device or body portion). In embodiments where the device (or body portion) comprises multiple lumens, the inner diameter refers to the largest inner cross-sectional dimension (i.e., the largest inner cross-sectional dimension of the largest lumen). In some embodiments, the device (or body portion) has a first configuration (e.g., a moisture content less than that of an equilibrium moisture content state, such as a dehydrated state) in which the increase in inner diameter at equilibrium moisture content is 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 device (or body portion) exhibits an increase in inner diameter at an equilibrium moisture content state compared to the inner diameter at a first configuration (e.g., a moisture content less than the equilibrium moisture content state, such as a dehydrated state) of no more than 20%, no more than 18%, no more than 16%, no more than 14%, no more than 12%, no more than 10%, no more than 8%, no more than 6%, no more than 4%, no more than 2%, no more than 1%, or no more than 0.5%. Combinations of the above ranges (e.g., 0.1% to 20%) are also possible. Other ranges are also possible.

[0095] In some embodiments, the device (or body portion) increases in overall length at a rate greater than the increase in inner and / or outer diameter when the device (or polymeric material) swells from a first configuration (e.g., a moisture content less than the equilibrium moisture content, such as a dehydrated state) to a second configuration (e.g., an equilibrium moisture content). For example, in some embodiments, the overall length may increase by 1-20% (e.g., 5-15%), while the inner and / or outer diameter may increase by 0.1-19% (e.g., 1-10%).

[0096] In some embodiments, when a device (or polymeric material) swells from a first configuration (e.g., a moisture content less than the equilibrium moisture content, such as a dehydrated state) to a second configuration (e.g., an equilibrium moisture content state), the ratio of the rate of increase in overall length to the rate of increase in inner and / or outer diameter is 1.1 or greater, 1.5 or greater, 2 or greater, 5 or greater, 7 or greater, or 10 or greater. In some embodiments, when a device (or polymeric material) swells from a first configuration (e.g., a moisture content less than the equilibrium moisture content, such as a dehydrated state) to a second configuration (e.g., an equilibrium moisture content state), the ratio of the rate of increase in overall length to the rate of increase in inner and / or outer diameter is 20 or less, 15 or less, 10 or less, 5 or less, or 2 or less. Combinations of these ranges are also possible (e.g., 1.1 to 20).

[0097] In some embodiments, a device (or body portion) increases its inner and / or outer diameter at a rate greater than its overall length when the device (or polymeric material) swells from a first configuration (e.g., a moisture content less than the equilibrium moisture content state, such as a dehydrated state). As a non-limiting example, in FIG. 2 , device 320-device 340 swells from a first configuration (e.g., a moisture content less than the equilibrium moisture content state, such as a dehydrated state) to a second configuration (e.g., an equilibrium moisture content state). According to some embodiments, in FIG. 2 , outer diameter 302 and inner diameter 301 of device 320 increase to outer diameter 305 and inner diameter 304 of device 340, respectively, while overall length 300 increases to overall length 303. According to some embodiments, in FIG. 2 , inner diameter 301 and outer diameter 302 increase at a rate greater than the increase in overall length 300 when device 320 swells to the equilibrium moisture content state—device 340. In some embodiments, the inner and / or outer diameter may increase by 1-20% (eg, 5-15%) while the overall length may increase by 0.1-19% (eg, 1-10%).

[0098] In some embodiments, the ratio of the rate of increase in inner and / or outer diameter to the rate of increase in overall length when the device (or polymeric material) swells from a first configuration (e.g., a water content lower than the equilibrium water content, such as a dehydrated state) to a second configuration (e.g., an equilibrium water content) is 1.1 or greater, 1.5 or greater, 2 or greater, 5 or greater, 7 or greater, or 10 or greater. In some embodiments, the ratio of the rate of increase in inner and / or outer diameter to the rate of increase in overall length when the device (or polymeric material) swells from a first configuration (e.g., a water content lower than the equilibrium water content, such as a dehydrated state) to a second configuration (e.g., an equilibrium water content) is 20 or less, 10 or less, 5 or less, or 2 or less. Combinations of these ranges (e.g., 1.1 to 20) are also possible.

[0099] In some embodiments, the device (e.g., device 10 of FIG. 1A , device 12 of FIG. 1B , device 14 of FIG. 1C ) (or body portion (e.g., body portion 20 of FIGS. 1A-1B )) comprises a polymeric material having desirable mechanical properties. For example, in some embodiments, the polymeric material has a Young's modulus (e.g., any of 100 MPa or more, 250 MPa or more, 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 the first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state). Young's modulus in the above configuration (for example, a water content lower than the equilibrium water content state, such as a dehydrated state) (for example, 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, 600 MPa or less, 500 MPa or less, or 250 MPa or less. Combinations of the above ranges are also possible (for example, 100 MPa to 5000 MPa). Other ranges are also possible.

[0100] In some embodiments, the polymeric material has a Young's modulus at equilibrium moisture 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 moisture 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 ranges are also possible (e.g., 5 MPa to 300 MPa, etc.). Other ranges are also possible.

[0101] In some embodiments, a device (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, device 14 of FIG. 1C) (or body portion (e.g., body portion 20 of FIGS. 1A-1B)) includes an osmotic agent. For example, in some embodiments, the osmotic agent may be added during formation of the device (e.g., to a prepolymer). In some embodiments, the osmotic agent is present in the polymeric material in an amount (e.g., 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, 0.6 w / w% or more, 0.8 w / w% or more, 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, and 0.2 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, based on the total weight of the device in the first configuration (e.g., dehydrated state) and / or the second configuration. 1.6 w / w% or more, based on the total weight of the device in the first configuration (e.g., dehydrated state) and / or the second configuration (e.g., equilibrium moisture content state). or greater than 1.8 w / w%. In some cases, the osmotic agent may be present in the polymeric material in an amount (e.g., 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, 1.6 w / w% or less, 1.4 w / w% or less, 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, based on the total weight of the device in the first configuration (e.g., dehydrated state) and / or second configuration (e.g., equilibrium moisture content state). Combinations of the foregoing ranges are also possible (e.g., 0.05 w / w% to 2 w / w%). Other ranges are also possible.

[0102] Non-limiting examples of suitable osmotic agents include phosphates, borates, sodium chloride, citrates, ethylenediaminetetraacetates, sulfites, hyposulfites, metal oxides, selenium dioxide, selenium trioxide, selenic acid, selenic acid, nitrates, silicates, and peony acid.

[0103] In some embodiments, as described in more detail below, the composition (e.g., comprising or formed from a polymeric material) and / or the first water-soluble polymer does not contain covalent crosslinks. However, in other embodiments, the composition and / or the first water-soluble polymer contains physical crosslinks (e.g., interpenetrating networks, chain entanglements, and / or one or more bonds, such as covalent, ionic, and / or hydrogen bonds). In a particular set of embodiments, no covalent crosslinkers are used to form the polymeric material, the first water-soluble polymer of the polymeric material, and / or the second water-soluble polymer.

[0104] The first water-soluble polymer may be present in a device (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, or device 14 of FIG. 1C) (or body portion (e.g., body portion 20 of FIGS. 1A-1B)) in any suitable amount. For example, in some embodiments, the first water-soluble polymer is present in the device and / or body portion in an amount 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, or at an equilibrium water content of 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 device and / or body portion 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, at an equilibrium moisture content of 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. Combinations of the above ranges are also possible (e.g., 20 w / w% or more, 95 w / w% or less, etc.). Other ranges are also possible.

[0105] In some embodiments, 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. In an exemplary set of embodiments, the first water-soluble polymer is poly(vinyl alcohol).

[0106] In some embodiments, the polymeric material comprises a mixture of a first water-soluble polymer and another (e.g., third) water-soluble polymer. In some embodiments, the third water-soluble polymer is selected from or consists of the group including poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylsulfobetaine), poly(acrylsulfobetaine), poly(methacrylcarboxybetaine). Examples include 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.

[0107] In some embodiments, the combined weight of the first water-soluble polymer and another (e.g., third) water-soluble polymer in the device is at an equilibrium water content of at least 20 w / w%, at least 25 w / w%, at least 30 w / w%, at least 35 w / w%, at least 40 w / w%, at least 45 w / w%, at least 50 w / w%, at least 55 w / w%, at least 60 w / w%, at least 65 w / w%, at least 70 w / w%, at least 75 w / w%, at least 80 w / w%, at least 85 w / w%, at least 90 w / w%, at least 95 w / w%, at least 98 w / w%, or at least 99 w / w%. In some embodiments, the total weight of the first water-soluble polymer and another (e.g., third) water-soluble polymer in the device is 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, at an equilibrium water content of 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. Combinations of the above ranges are also possible (e.g., 20 w / w% or more, 100 w / w% or less, etc.). Other ranges are also possible.

[0108] In some embodiments, the ratio of the first water-soluble polymer to the third water-soluble polymer present in the device 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 device 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 ranges are also possible (e.g., 50:50 to 100:0). Other ranges are also possible.

[0109] As discussed above and herein, in some embodiments, a device (e.g., device 12 of FIG. 1B , device 14 of FIG. 1C ) comprises a second water-soluble polymer (e.g., second water-soluble polymer 40) disposed within at least some of the plurality of pores (e.g., plurality of pores 30) of a body portion (e.g., body portion 20 constructed or formed from a polymeric material). In some embodiments, the second water-soluble polymer is selected from or consists of a group including 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 (e.g., optionally the third) water-soluble polymer.

[0110] The second water-soluble polymer (e.g., second water-soluble polymer 40) may be present in the device in any suitable amount. For example, in some embodiments, the second water-soluble polymer is present in the device in an amount 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 at equilibrium moisture content. In some embodiments, the second water-soluble polymer 40 is present in the device at an equilibrium moisture content 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, 0.5 w / w% or less, 0.2 w / w% or less, or 0.1 w / w% or less. In some embodiments, 0 w / w% of the second water-soluble polymer is present. Combinations of the foregoing ranges are also possible (e.g., 0.05 w / w% or more and 95 w / w% or less). Other ranges are also possible.

[0111] In some embodiments, the water-soluble polymer (e.g., the first water-soluble polymer, the second water-soluble polymer, or the third water-soluble polymer) has a specific molecular weight. In some embodiments, the molecular weight of the water-soluble polymer (e.g., the first water-soluble polymer, the second water-soluble polymer, or the third water-soluble polymer, each independently) may 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, or 800 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) may 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, 600 kDa or less, 500 kDa or less, 450 kDa or less, 400 kDa or less, 350 kDa or less, 300 kDa or less, or 250 kDa or less. The molecular weight can be 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 ranges are also possible (e.g., a molecular weight of 40 kDa or more and 5000 kDa or less). Other ranges are also possible.

[0112] In some embodiments, the devices (e.g., device 10 of FIG. 1A , device 12 of FIG. 1B , device 14 of FIG. 1C ) are configured for use with medical devices such as catheters, balloons, shunts, wound drains, infusions, etc. The devices (e.g., device 10 of FIG. 1A , device 12 of FIG. 1B , device 14 of FIG. 1C ) described herein are or are configured for use with medical devices such as catheters, balloons, shunts, wound drains, injection ports, drug delivery devices, tubing, contraceptives, feminine hygiene products, endoscopes, grafts, pacemakers, implantable cardioverter-defibrillators, cardiac resynchronization devices, leads for cardiovascular devices, ventricular assist devices, endotracheal tubes, tracheostomy tubes, implantable sensors, ventilator pumps, ophthalmic devices, etc. In some embodiments, the catheter is selected from the group comprising 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 neurological catheter, a percutaneous transluminal angioplasty catheter, and / or a peritoneal catheter. Other suitable applications are described in more detail below.

[0113] These materials can be made into tough, high-strength materials with lubricious, 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. A process for producing hydrogels is also described. Hydrophilic polymers can 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., up to 90 w / w% in principle. Porous solid materials can be used to make various devices, including medical catheters and implants, with significantly reduced adsorption and / or adhesion of biological components to their surfaces.

[0114] These or other porous materials may be engineered to contain a polymer bulk-entrapped within the pores of the solid. One embodiment of the material of the present invention is a porous material containing a water-soluble polymer entrapped within the pores of the material. The polymer encapsulated in this manner resides within the pores and has been observed to remain within the pores even after repeated hydration and dehydration. The entrapped polymer provides a scratch-resistant, effectively permanent surface, and the incorporated polymer provides desirable properties beyond the outer surface of the material. In aqueous media, the hydrophilic polymer encapsulated in this manner hydrates and extends beyond the surface, enhancing biocompatibility and lubricity.

[0115] Processes for making the material are described in International Patent Application Publication Nos. WO 2018 / 237166 and WO 2017 / 112878, which are incorporated herein by reference in their entireties. The process for producing the material can include extrusion, so that devices with high aspect ratios can be created. One embodiment of the process for producing the material includes heating a mixture containing at least one water-soluble polymer and a solvent to a temperature above the melting point of the polymer solution in a solvent-removing environment to form a crosslinked matrix, and continuing to remove the solvent until the crosslinked matrix becomes a microporous or nanoporous solid material. Crosslinking can occur while the mixture is cooling or in the solvent-removing environment. Additional polymers can be incorporated into the pores of the material.

[0116] Disclosed herein are molding processes, including extrusion, for making high strength porous solids. Guidance regarding the processes and parameters for making the porous solids is disclosed as well as the porous solids. Guidance regarding the bulk incorporation of polymers into the porous solids is disclosed. Porous solids with good properties are disclosed, with further improvements obtained by further including bulk-incorporated polymers.

[0117] Disclosed herein is a new process that provides for the extrusion of high-strength materials. Some embodiments of this process provide one or more of the following: removing solvent from the 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 steps for additional polymers may also be included.

[0118] Figures 1D-1F show one embodiment of a device for making porous solid materials. The depicted device 100 includes a syringe pump 102 for receiving at least one syringe 104, an optional heating jacket (not shown) for heating the syringe, a die head 106, a heating element 108, and a power cable 109 for the same to provide heating to the die head 106 as needed (details not shown in Figure 1D). The die head 106 (details in Figure 1D) includes a dispensing spool 110 for a core tube 112, a take-up spool 114 and motor (not shown) for the core tube, a bath 116 for extrusion material 117, the bath having temperature control for cooling or heating, and a heat exchanger 118 including a heat exchange pipe 120 within the bath 116. The die head 106 receives the core tube 110 passing therethrough. A supply line 122 from the syringe to the die head 106 provides supply to the device 100. This system may further include a metering station, a jacketed vessel for heating and mixing the solution for filling the syringes, and a solvent removal environment for further drying the tubing after it is removed from 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 PTFE core tubes, materials such as wire, air, gas, and non-solvent liquids may also be used for the core.

[0119] In use, for example, a polymer is heated in a suitable solvent in a jacketed vessel and placed in a syringe 104. One or more polymers may be present, and radiopaque agents or other additives may be added. One or more syringes may be used with the same or different mixtures. The polymer syringe is heated to a predetermined temperature, for example, 80-95°C or less, and degassed prior to extrusion. The syringe 104 is attached to a syringe pump 102 equipped with a wrap heater to maintain temperature during extrusion. The core 112 is looped through a die head 106, for example, a heated out-well die head, and fed into an extrusion bath 116, which is then attached to a motor-driven take-up 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, although other temperatures may be used; 0°C is a commonly useful temperature setting for extrusion. Those skilled in the art will readily understand that all ranges and values ​​between the stated boundaries are contemplated, for example, any of the following could be used as upper or lower limits: -30, -25, -20, -15, -10.5, 0.5, 10, 15, 20, 25, 30, 35, 40, 45, 50.55, 60, 65, 70, 75°C. The motor speed of the take-up (e.g., puller) spool 114 can be controlled to adjust the outer diameter gauge size around the core 112. Adjusting the die size, material feed rate, tubing core diameter, and puller speed can serve to adjust the final tubing gauge, for example, in an embodiment producing a catheter. The polymer feed rate can be adjusted, for example, in this embodiment, by controlling the syringe pump 102. A connector 122 couples one or more syringes to the die head 106. Many pumps and other tools are known for controllably feeding polymer solutions. The present device and method can be adapted to a drawing process, although alternative feeding processes are available.

[0120] In some embodiments, a composition (e.g., a prepolymer composition) may be provided prior to forming the polymeric material (e.g., for extrusion). In some embodiments, the composition comprises an aqueous solution. The aqueous solution can include an osmotic agent at a concentration of 0.01 M or more and 8 M or less, and the aqueous solution can include a radiopaque agent in an amount of 0 wt% or more and 50 wt% or less (e.g., 40 wt% or less). The composition can further include 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.

[0121] In some embodiments, the composition forms a swellable polymeric material upon extrusion.

[0122] In some embodiments, the osmotic agent is present in the solution at a concentration of 0.01 M or more, 0.1 M or more, 0.5 M or more, 1 M or more, 2 M or more, 3 M or more, 4 M or more, 5 M or more, or 6 M or more. 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, 0.5 M or less, or 0.1 M or less. Combinations of the above ranges are also possible (e.g., 0.01 M or more and 8 M or less). Osmotic agents are described in further detail herein.

[0123] In some embodiments, the radiopaque agent is present in the solution in an amount of 0% w / w or more, 5% w / w or more, 10% 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 radiopaque agent 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, 10% w / w or less, or 5% w / w or less. Combinations of the above ranges are also possible (e.g., 0% w / w or more, 50% w / w or less). Other ranges are also possible. Radiopaque agents are described in more detail below.

[0124] 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 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.

[0125] In some embodiments, methods of forming polymeric materials and / or devices described herein include providing a mixture comprising a first water-soluble polymer and an osmotic agent (e.g., a salt), as described above. In some embodiments, the mixture is extruded. In some embodiments, the extruded mixture is extruded onto a core to form a polymeric material disposed on the core. 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, optionally, an osmotic agent is introduced into the polymeric material. In some embodiments, the polymeric material (e.g., after introducing the solution into the osmotic agent) is heated. In some embodiments, the solution is allowed to flow over the polymeric material. In some embodiments, the polymeric material may be dried.

[0126] In an exemplary set of embodiments, a method of forming the polymeric materials and / or devices described herein includes providing a mixture comprising a first water-soluble polymer and an osmotic agent (e.g., a salt), wherein the first water-soluble polymer is present in the mixture in an amount of 10 wt% or more (e.g., 13 wt% or more, 50 wt% or less) based on the total weight of the mixture. is present in the mixture in an amount of 10 w / w% or more (e.g., 13 w / w% or more and 50 w / w% or less) based on the total weight of the mixture, and performing the following steps: extruding the mixture at a temperature of 65°C or more (e.g., 65°C or more; extruding at atmospheric pressure onto a core at a temperature of 65°C or more (e.g., 65°C or more and 100°C or less) to form a polymeric material (e.g., a solid rod or a gas) disposed on the core; exposing the polymeric material to a non-solvent for the polymeric material at a temperature of 28°C or less (e.g., 28°C or less and -20°C or more) for 15 minutes or more (e.g., 1 hour or more and 240 hours or less); dipping the polymeric material into a solution (e.g., a solution) comprising a biologically active agent and / or a second water-soluble polymer different from the first water-soluble polymer and / or an osmotic agent ... The polymeric material and solution are heated to a temperature of 25°C or higher (e.g., 30°C or higher, or 30°C or higher and 65°C or lower), the solution adjacent to the polymeric material is allowed to flow for, for example, 1 hour or longer (e.g., 1 hour or longer and 48 hours or longer, or 3 hours or longer and 48 hours or shorter), and the polymeric material is dried. In some embodiments, the biologically active agent is substantially uniformly distributed within the polymeric material within 50% or less of the average loading of the biologically active agent in the polymeric material. In some embodiments, the biologically active agent is non-homogeneously distributed within the polymeric material (i.e., on one or more surfaces of the polymeric material).

[0127] 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.

[0128] 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 for the water-soluble polymer compared to its solubility in water).

[0129] In some embodiments, the extruding step is carried out at atmospheric pressure 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, 95°C or more, 100°C or more, or 10.5°C or more. In some embodiments, the extruding step is carried out at atmospheric pressure at a temperature of 110°C or less, 10.5°C or less, 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. Combinations of the above ranges are also possible (e.g., 65°C or more, 110°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., greater than atmospheric pressure, less than atmospheric pressure) and / or temperatures are also possible.

[0130] In some embodiments, exposing the polymeric material to a non-solvent for the polymeric material occurs 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, exposing the polymeric material to a non-solvent for the polymeric material occurs 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 ranges are also possible (e.g., 28° C. or less, −20° C. or more). Other ranges are also possible.

[0131] In some embodiments, the step of exposing the polymeric material to the non-solvent for the polymeric material is for 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 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, or 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 ranges are also possible (e.g., 1 hour or more to 240 hours or less). Other ranges are also possible.

[0132] In some embodiments, the step of introducing to the polymeric material a second water-soluble polymer different from the first water-soluble polymer and an optional osmotic agent (e.g., a salt) comprises heating the polymeric material and solution to a temperature of 25° C. or higher, 30° C. or higher, 35° C. or higher, 40° C. or higher, 45° C. or higher, 50° C. or higher, 55° C. or higher, or 60° C. or higher. In some embodiments, the polymeric material and solution are heated to a temperature of 65° C. or lower, 60° C. or lower, 55° C. or lower, 50° C. or lower, 45° C. or lower, 40° C. or lower, 35° C. or lower, or 30° C. Combinations of the above ranges are also possible (e.g., 25° C. or higher and 65° C. or lower). Other ranges are also possible.

[0133] 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 ranges are also possible (e.g., 3 hours or more to 48 hours or less). Other ranges are also possible. Combinations of the above temperatures and times are also possible.

[0134] In some embodiments, the method includes annealing the polymeric material to a temperature of 80° C. or higher (e.g., 80° C. or higher and 250° C. or lower) for 60 minutes or longer (e.g., 60 minutes or longer and 480 minutes or shorter). In some embodiments, the polymeric material is annealed 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 polymeric material is annealed 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. or lower. Combinations of the above ranges are also possible (e.g., 80° C. or higher and 250° C. or lower). Other ranges are also possible.

[0135] In some embodiments, the polymeric material is annealed for 30 minutes or more, 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 ranges are also possible (e.g., 60 minutes or more and 480 minutes or less). Other ranges are also possible. Combinations of the above temperatures and times are also possible.

[0136] In some embodiments, the core material may be air, water, a non-solvent liquid, a solid, or a gas. In some embodiments, the core material may be removed after the polymeric material is formed on the core material. The core material may optionally be physically removed and / or dissolved.

[0137] In exemplary embodiments, the method includes performing the following steps with a mixture (e.g., a solution described above and herein) 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 greater, based on the total weight of the mixture: heating the mixture to a temperature of 65°C or greater; 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. In some embodiments, after cooling the mixture, the mixture may be extruded onto a core at a temperature of 65°C or greater to form a polymeric material disposed on the core. 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 more to remove at least a portion of the core from the polymeric material.

[0138] In some embodiments, 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, 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 ranges are also possible (e.g., 20°C or more, 100°C or less). Other ranges are also possible. The mixture may be cooled for any suitable period of time.

[0139] In some embodiments, the mixture may be mechanically shaped. In some embodiments, the composition (e.g., pre-extrusion or mixture) may be mechanically shaped by kneading, rolling, cutting, and combinations thereof.

[0140] 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 ranges are also possible (e.g., 80° C. to 250° C.). Other ranges are also possible.

[0141] In some embodiments, the method comprises sorbing a second water-soluble polymer onto the polymeric material, as described above and herein.

[0142] In some embodiments, the polymeric materials and / or devices described herein may be exposed to and / or include a humectant. For example, in some embodiments, device 10 includes humectant 70, as illustratively shown in FIG. 1G. In some embodiments, at least a portion of the humectant is disposed on the surface (e.g., the luminal and / or abluminal surfaces) of the polymeric material and / or device (e.g., the body portion). For example, in some embodiments, a portion of humectant 70 is disposed on the surface of device 10. In some embodiments, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or all of the humectant is disposed on the surface of the polymeric material and / or device (e.g., the body portion). In some embodiments, 100% or less, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, or 40% or less of the humectant is disposed on the surface of the polymeric material and / or device (e.g., the body portion). Combinations of these ranges are also possible (e.g., 40-100%).

[0143] In some embodiments, at least a portion of the humectant is present within the polymeric material and / or device (e.g., body portion). In some embodiments, at least a portion of the humectant is present within the polymeric material and / or device (e.g., body portion). For example, in some embodiments, some of the humectant 70 is present within the device 10 (e.g., absorbed into the bulk of the device). In some embodiments, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or all of the humectant is present within the polymeric material and / or device (e.g., body portion). In some embodiments, 100% or less, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, or 40% or less of the humectant is present within the polymeric material and / or device (e.g., body portion). Combinations of these ranges are also possible (e.g., 30-100%).

[0144] In some embodiments, the moisturizing agent is a nonionic surfactant (i.e., a surfactant with a hydrophilic head and a hydrophobic tail, with no net charge) or a zwitterionic surfactant (i.e., a surfactant with a hydrophilic head and a hydrophobic tail, with no net charge). In some embodiments, the moisturizing agent is a nonionic surfactant selected from the group consisting of sugar alcohols, poloxamers, triacetin, hydroxy acids, polyethylene glycols, polypropylene glycols, ethylene glycols, propylene glycols, hexylene glycols, butylene glycols, glycerol, sorbitol, mannitol, xylitol, maltitol, erythritol, threitol, arabitol, ribitol, galactitol, fuchitol, iditol, inositol, volemitol, malitol, lactitol, maltotriitol, maltotetriitol, polyglycitols, and combinations thereof. In some embodiments, the moisturizing agent comprises an oil such as vitamin E. In some embodiments, the moisturizing agent comprises a salt such as sodium chloride, potassium chloride, and / or phosphocholine.

[0145] In some embodiments, the polymeric materials and / or devices described herein are exposed to and / or contain 0.1 wt% or more humectant, 0.5 wt% or more humectant, 1 wt% or more humectant, 5 wt% or more humectant, 10 wt% or more humectant, or 20 wt% or more humectant. In some embodiments, the polymeric materials and / or devices described herein are exposed to and / or contain 30 wt% or less humectant, and contain 25 wt% or less humectant, 20 wt% or less humectant, 15 wt% or less humectant, 10 wt% or less humectant, 5 wt% or less humectant, or 1 wt% or less humectant. Combinations of these ranges are also possible (e.g., 0.1-30 wt% humectant or 1-10 wt% humectant).

[0146] Porous solids (e.g., those produced by the device of Figures 1D-1F) may be annealed. Furthermore, porous solids may be processed to further include bulk-incorporated polymer, with or without prior annealing. In Figure 3A, material 210 comprising porous solid matrix 212 is desolvated, exposed to a mixture containing polymer in a redissolution solvent, and redissolved in the mixture to form material 212 having bulk-incorporated polymer 214. A cross-section of matrix 212 (Figure 3B) reveals an outermost zone 216 where the pores of matrix 212 are filled, an intermediate zone 218 where the pores are less densely packed, less heavily loaded, and / or where fewer pores are occupied, and an inner zone 220 where the polymer is not permeated. The matrix may be solvated and / or desolvated prior to exposure to the mixture, provided that the matrix is ​​desolvated upon exposure to the mixture to allow the water-soluble polymer to migrate into the matrix.

[0147] In some embodiments, a method for wetting a device and / or polymeric material includes placing an extruded segment in a solution containing a humectant (e.g., glycerol or poloxamer). In some embodiments, the solution contains 1% or more, 5% or more, 10% or more, 15% or more, 20% or more, or 25% or more of the humectant (w / w). In some embodiments, the solution contains 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, or 5% or less of the humectant (w / w). Combinations of these ranges are also possible (e.g., 1-35% w / w). In some embodiments, the solution includes a surfactant. In some embodiments, the solution includes PBS.

[0148] In some embodiments, the extruded segments are allowed to sit in the solution for a period of time. In some embodiments, the period is 1 hour or more, 2 hours or more, or 3 hours or more. In some embodiments, the period of time is 4 hours or less, 3 hours or less, or 2 hours or less. Combinations of these ranges are also possible (e.g., 3 hours, or 1-4 hours).

[0149] In some embodiments, the solution is maintained at a temperature while the extruded segment is exposed to the solution. In some embodiments, the temperature is 20°C or higher, 30°C or higher, 37°C or higher, 40°C or higher, 50°C or higher, or 60°C or higher. In some embodiments, the temperature is 70°C or lower, 60°C or lower, 55°C or lower, 50°C or lower, 40°C or lower, 37°C or lower, or 30°C or lower. Combinations of these ranges are also possible (e.g., 20-70°C, 37-55°C, or 45°C).

[0150] In some embodiments, after the extruded segments are removed from the solution, they can be dried (e.g., in a convection oven). In some embodiments, the extruded segments are dried at a temperature. In some embodiments, the temperature is 20°C or higher, 30°C or higher, or 40°C or higher. In some embodiments, the temperature is 50°C or lower, 40°C or lower, or 30°C or lower. Combinations of these ranges are also possible (e.g., 30°C or 20-50°C). In some embodiments, the extruded segments are dried for a period of time. In some embodiments, the period of time can be 1 hour or higher, 2 hours or higher, or 3 hours or higher. In some embodiments, the period of time can be 4 hours or lower, 3 hours or lower, or 2 hours or lower. Combinations of these ranges are also possible (e.g., 3 hours, or 1-4 hours).

[0151] The biologically active agent can be incorporated into the devices and / or devices described herein using any suitable method. For example, in some embodiments, a first water-soluble polymer may be mixed with water (e.g., via solution blending at a mass ratio of water-soluble polymer to water of 0.1-99.9, 1-99, 5-95, 10-90, 20-80, 30-70, 33-67, 37-63, 40-60, 42-58, 45-55, 47-53, or 50-50). In some embodiments, the biologically active agent may be suspended or solubilized in water prior to solution blending. The biologically active agent may optionally be micronized, agglomerated, and / or intact when incorporated into a solution comprising the water-soluble polymer and water. In some embodiments, the biologically active agent may be mixed with the water-soluble polymer and water before heating the solution as described herein. In some embodiments, the biologically active agent may be added as the temperature decreases during cooling after bulk incorporation of the polymer as described herein.

[0152] In some embodiments, to solubilize or suspend the active agent in water, the system may include a cosolvent, such as N,N-dimethylformamide, having a boiling point higher than the solubilization temperature of the blended mixture, a suspending agent such as an ionic or nonionic surfactant, oil, or castor oil. If the active agent is insoluble, the biologically active agent may optionally be micronized and / or nanoparticleized. The biologically active agent may optionally be mixed into the molten mixture described herein and solubilized, for example, by subjecting it to high shear.

[0153] In some embodiments, the biologically active agent may be incorporated into the body portion via sorption of the biologically active agent. In exemplary embodiments, the water-soluble polymeric material is formed to near-final dimensions via a forming process (e.g., electrospinning, electrospraying, melt spinning, wet spinning, extrusion, molding, casting, coating, and / or non-solvent entrainment). In some embodiments, the water-soluble biologically active agent may then be sprayed, absorbed, or adsorbed as a solution into and / or onto the polymer (e.g., PVA) matrix. The adsorption process may, in some cases, occur after shaping, after annealing, after crosslinking, after sterilization, or in situ prior to placing the device in a subject.

[0154] In some embodiments, the biologically active agent may be solubilized in solution at a concentration of 100 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, 15 w / w% or less, 10 w / w% or less, 5 w / w% or less, 4 w / w% or less, 3 w / w% or less, 2 w / w% or less, 1.5 w / w% or less, 1 w / w% or less, 0.5 w / w% or less, or 0.1 w / w% or less. In some embodiments, the biologically active agent may be solubilized in solution at a concentration of 0.01 w / w% or more, 0.1 w / w% or more, 0.5 w / w% or more, 1 w / w% or more, 1.5 w / w% or more, 2 w / w% or more, 3 w / w% or more, 4 w / w% or more, 5 w / w% or more, 6 w / w% or more, 7 w / w% or more, 8 w / w% or more, 9 w / w% or more, 10 w / w% or more, 15 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. Combinations of the above ranges are also possible (e.g., 0.01% to 100%). Other ranges are also possible.

[0155] In some embodiments, the biologically active agent may be present in the device (e.g., in the first configuration (e.g., moisture content less than equilibrium moisture content state such as a dehydrated state)) in an amount of 50 w / w% or less, 40 w / w% or less, 30 w / w% or less, 20 w / w% or less, 15 w / w% or less, 10 w / w% or less, 5 w / w% or less, 4 w / w% or less, 3 w / w% or less, 2 w / w% or less, 1.5 w / w% or less, 1 w / w% or less, 0.5 w / w% or less, or 0.1 w / w% or less, based on the total weight of the device (e.g., in the first configuration (e.g., moisture content less than equilibrium moisture content state such as a dehydrated state)). It may be present in the device (e.g., in the first configuration (e.g., less than equilibrium moisture content, such as a dehydrated state)) in an amount of 0.01 w / w% or more, 0.1 w / w% or more, 0.5 w / w% or more, 1 w / w% or more, 1.5 w / w% or more, 1.5 w / w% or more, 2 w / w% or more, 3 w / w% or more, 4 w / w% or more, 5 w / w% or more, 6 w / w% or more, 7 w / w% or more, 8 w / w% or more, 9 w / w% or more, 10% or more, 15% or more, 20% or more, 30% or more, or 40% or more, based on the total weight of the device (e.g., in the first configuration (e.g., less than equilibrium moisture content, such as a dehydrated state)). Combinations of the above ranges are possible (e.g., 10 w / w% or less and 0.01 w / w% or more, or 1 w / w% or more and 5 w / w% or less). Other ranges are also possible.

[0156] In some embodiments, the biologically active agent solution may be further modified to enhance solubility (e.g., by adjusting pH and / or temperature, by adding osmotic agents or cosolvents). In some embodiments, hydrolyzable bonds (esters and amides) are used to attach the active agent or active agent conjugate to the polymeric material.

[0157] In some embodiments, a biologically active agent may be encapsulated. For example, in some embodiments, a biologically active agent may be incorporated into (e.g., mixed with) a third water-soluble polymer as described above and herein.

[0158] In exemplary embodiments, the biologically active agent is added to the formulation mixture during solubilization. The biologically active agent / water-soluble polymer mixture may optionally be dehydrated and physically crosslinked, e.g., at temperatures above 120°C. Without wishing to be bound by theory, in some embodiments, after crosslinking, the material may be brittle and may be pulverized, lyophilized, and / or sieved to a powder with a maximum particle size of, e.g., 50 μm. In some embodiments, the powder is incorporated into the shape-forming process during the mixing or solubilization stage. In some embodiments, the third water-soluble polymer comprises PVA. In some embodiments, the bulk PVA used for initial encapsulation may comprise a PVA with a molecular weight higher than that of the bulk porous PVA (e.g., the first water-soluble polymer, the second water-soluble polymer). The bulk porous PVA containing the fine powder may optionally be physically crosslinked, e.g., at temperatures above 120°C. Advantageously, without wishing to be bound by theory, encapsulation and micronization of a biologically active agent may increase the release rate compared to the release rate of the biologically active agent without encapsulation or micronization.

[0159] In some embodiments, crosslinking of the third water-soluble polymer can be achieved by UV crosslinking, chemical crosslinking (e.g., glutaraldehyde, bis(hydroxyethyl) sulfone, maleic acid, etc.), and / or radiation crosslinking (e.g., gamma) prior to micronization. In some embodiments, conventional encapsulation methods can be used to micronize to less than 50 μm and / or to extend controlled release from microparticles or nanoparticles, for example, via in situ water-in-oil emulsion or water-in-oil emulsion or cavity molding.

[0160] In some embodiments, particles containing a biologically active agent can be produced in situ using a fully polymerized polymer, a prepolymer containing a crosslinker or initiator, a monomer and an initiator, or two or more monomers that self-polymerize, or a combination thereof.

[0161] As described herein, in some embodiments, a biologically active agent may be present within the plurality of pores in the body portion of the device (e.g., FIGS. 1B-1C). In some such embodiments, the biologically active agent may be released, for example, upon hydration and / or expansion / stretching of the device. Incorporation of the biologically active agent into the plurality of pores may use any suitable method. For example, in some embodiments, the biologically active agent may be mixed with a second water-soluble polymer described herein, such that the second water-soluble polymer and the biologically active agent are disposed within the plurality of pores. In some embodiments, the biologically active agent may be adsorbed / absorbed into the plurality of pores.

[0162] In some embodiments, the biologically active agent may be solubilized and injected into the body portion via channels in the device (e.g., hollow core 25 in Figures 1A-1C). Such devices are useful as delayed-release (e.g., extended-release) and / or reloadable devices.

[0163] In some embodiments, a biologically active agent with a water-soluble polymer is coextruded as a central layer between outer and inner layers comprising a non-reagent bulk polymer (e.g., PVA). In exemplary embodiments, the biologically active agent is compatible with the bulk polymer (adheres well without delamination). In some embodiments, the biologically active agent layer is spaced from the surface, allowing the bindable polymer to be adsorbed and absorbed onto those surface layers.

[0164] In another exemplary embodiment, a drug-binding complex, such as a counterion system, to which an anionic biologically active agent binds upon absorption can be added. Without wishing to be bound by theory, upon swelling with a drug-soluble solution, the biologically active agent may migrate into the matrix and bind to the central layer of the device. The exterior / interior post-cleaning may, in some cases, be more rigorously washed than would be the case without this central post-cleaning. In yet another exemplary embodiment, the biologically active agent-containing layer is on one or more surfaces or is compatible with the drug complex (e.g., allowing a conjugable polymer to be adsorbed and absorbed through the bulk).

[0165] An exemplary flow chart of a process for producing a porous solid containing bulk-incorporated polymer is shown in Figure 4A. In this process, a radiopaque (RO) agent is included in the extrusion process. The heated hydrophilic polymer solution refers to the polymer being bulk-incorporated into the pores of the extruded porous solid.

[0166] Another exemplary flow chart of a process for producing a porous solid containing bulk-incorporated polymer and biologically active agent is shown in Figure 4B. In this process, post-processing is included in the extrusion process after drying the extrudate on a steel mandrel.

[0167] Those skilled in the art, having read this disclosure, will be able to adapt its 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 can be adapted, for example, for use in a multi-zone screw extruder, where the solvent mixture is provided via a suitable injector or hopper, and the zones are controlled to provide cold extrusion. Functions such as syringe pumps can be replaced by appropriately metered and controlled liquid or solid polymer delivery systems.

[0168] Fukumori et al. (2013) in Open J. Organic Polymer Materials 3:110-116 reported a freeze-thaw process to produce a 181 MPa poly(vinyl alcohol) (PVA) material with a Young's modulus of approximately 5 MPa or greater, requiring at least three cycles for the samples tested. The process to produce these gels required multiple freeze-thaw cycles. The resulting materials were tested in a dry state, and strength measurements using EWC cannot be compared. reported that the crystalline content of the material increased with the number of freeze-thaw cycles. Fukumori et al. attributed the material's strength to the formation of large crystals with the progression of freeze-thaw cycles, which formed excellent crosslinks and increased the Tg of the material. The nature of these processes results in dry materials. Furthermore, as discussed below, the freeze-thaw process generates macropores.

[0169] In some embodiments, the processes herein do not involve a freeze-thaw process, and / or do not involve a freezing process, and / or do not involve a thawing process. Furthermore, the processes can be used to produce solid porous materials with little or no swelling, even in the absence of a covalent crosslinker, e.g., swelling of 0% to 100% w / w EWC. Those skilled in the art will readily appreciate that all ranges and values ​​between the explicitly stated boundaries are contemplated. These include 0.5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 95, and 100% w / w. % Swelling = 100 × (total weight at EWC - dry weight) / dry weight The dry weight is the weight of the material without water.

[0170] In some embodiments, the extruded sample has horizontal chain orientation and alignment along the length of the sample (extrusion direction). The orientation of the polymer chains is created by the extrusion process. Without wishing to be bound by theory, in some embodiments, this horizontal chain orientation and alignment along the length of the sample is believed to contribute to the inner and / or outer diameter increasing at a rate greater than the rate of increase in length as the sample swells.

[0171] In some embodiments, it is useful to have a combination of one or more of the following: extrusion of the hydrophilic polymer in a solvent; cold extrusion; and extrusion into a bath that rapidly removes the solvent from the extrudate. Furthermore, in some embodiments, an additional solvent removal and / or annealing process provides further utility for creating the desired porous solid.

[0172] In some embodiments, the nanoporous material requirement includes a high polymer concentration of about 10 wt. % or greater in the polymer-solvent mixture with a high level of crosslinking. Those skilled in the art will readily recognize that all ranges and values ​​between the stated boundaries are contemplated, including, for example, 10, 12, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 95, and 99 wt. % of polymer in the total weight of the polymer-solvent mixture. In some embodiments, the polymer is substantially solvated, meaning a true solution, or at least half of the polymer is dissolved and the remainder is at least suspended. In some embodiments, polymer solvation contributes to polymer chain alignment and inter-polymer crosslinking during extrusion. Without being bound by theory, it is believed that a high concentration of the starting polymer and solvent mixture can aid in this. It is also believed that, according to some embodiments, the increased likelihood of chain alignment of the material as it passes through the die promotes both intra- and inter-polymer crosslinking. When the extrudate or other formed mixture enters a desolvation environment, either gas or liquid, it is believed that, in some embodiments, the pore structure further collapses before the densely concentrated polymer is fully crosslinked, thereby improving chain proximity and promoting further crosslink density. Directly depositing the extruded or other formed material into a solvent removal environment is useful in some embodiments. In some embodiments, further solvent removal can be continued to collapse the material until a desired end point in structure and / or properties is reached. An annealing process can further contribute to strength in some embodiments.

[0173] On the other hand, freezing methods force the formation of hyperconcentrated microdomains, achieving chain proximity and improving crosslink density, while maintaining macroporosity and increasing strength through the presence of ice crystals throughout the gel structure. Desolvation forces the formation of hyperconcentrated microdomains, but does not result in the formation of macrovoids. In contrast, gels pre-established before dehydration or freezing will, by their very nature, form macropores. Furthermore, our research has shown that such nanoporous solids possess greater strength than macroporous materials.

[0174] Hydrogels can also be prepared by lowering the polymer concentration in the polymer-solvent mixture, typically to 10 wt% or less of the polymer in the polymer-solvent mixture. One of ordinary skill in the art will readily recognize that all ranges and values ​​between the stated boundaries are contemplated, and that, for example, any of 2, 5, 7, 8, 9, or 10 wt% of polymer by total weight of the polymer-solvent mixture can be used as an upper or lower limit. Additionally or alternatively, the polymer-solvent mixture is not extruded into a solvent removal environment.

[0175] Microporous materials may be made using process conditions intermediate to those of nanoporous solids and hydrogels. One embodiment is to prepare the material using conditions equivalent to those used to make nanoporous materials, but to stop solvent removal before the nanoporous solid structure is reached.

[0176] To produce high-strength materials, hydrophilic polymers can be extruded in solvents. Using solvents as the starting material for extrusion is uncommon, at least. Extrusion typically involves extruding a solid material heated to a flowable temperature and then cooling it by various methods. For example, thermoplastic extrusion of pure PVA is believed possible. However, such extrusions lack the polymer structure necessary to create a porous solid and instead exhibit properties closer to traditional thermoplastic materials. One theory of operation suggests that extrusion of pure PVA lacks the hydrogen bonding properties that occur in aqueous ionic solvents. At temperatures suitable for extruding PVA into a flowable state, the die head produces a poorly cohesive material, preventing the formation of continuous shapes. It has been difficult to extrude extruded PVA into high-aspect shapes, such as tubes, for use in extrusion. The high viscosity of PVA and other hydrophilic polymers makes them difficult to dissolve in solution. A narrow temperature working band, e.g., 85–95°C, has been observed to be particularly useful. Below about 85°C, the PVA was not truly molten and therefore not completely amorphous for extrusion. Above about 95°C, boiling and evaporation losses occurred, making the process ineffective. These temperature ranges can be offset by increasing the pressure above atmospheric, but this makes using pressurized systems and scaling up difficult. The process is preferably carried out at temperatures below the boiling points of the polymer and solvent materials.

[0177] When a polymer / solvent mixture is flowed, it has weak cohesion as it exits the die. Using a core to support the mixture in the die helps it retain its shape through the die. This contrasts with typical core extrusion, which is used as a coating process, such as coating cell phone charger wires. Because typical processes avoid the use of solvents or significant concentrations of solvents, they have relatively high cohesion as they exit the die, which helps hold the tube together, and do not rely on aggressive bonding, such as hydrogen bonding in hydrophilic polymers, to form the solid material into a coherent shape as it exits the die.

[0178] It is useful to pass the formed polymer-solvent mixture through a solvent-removal environment. Most extrusion processes do not use bath temperatures below room temperature. Furthermore, the use of a solvent-removal bath is atypical compared to conventional processes. Baths and other solvent-removal environments help solidify the extruded material sufficiently to maintain a stable, concentric shape on the core. Otherwise, the melt would form a teardrop, and attempts to recover it at the end of the extrusion would destroy it due to residual melt. Also, conventional water-containing baths can cause hydrophilic polymeric materials, such as PVA, to collapse due to swelling, dissolution, or both. Molding processes that involve preparing a polymer-solvent mixture, forming it in a mold, and processing it in a solvent-removal environment lack the chain alignment observed in extrusion. However, with properly controlled temperature and solvent removal, materials with high strength and controlled pore structure can be obtained.

[0179] This porous solid is highly lubricious, can be used in a hydrated state, and can be conveniently combined with other materials. In catheters, for example, extensions, luer locks, suture wings, etc., are useful. In some embodiments, extrusion of the copolymer is useful in the range of 0.1% to 10% w / w of the first polymer, or in the range of 10% w / w or less, with ranges of 5% w / w or less also being useful. Those skilled in the art will readily recognize that all ranges and values ​​between the stated boundaries are contemplated, e.g., 0.1, 0.2, 0.4, 0.5, 0.8, 1, 2, 3, 4, 5, 6, 8, 10% w / w are usable as upper or lower limits.

[0180] In some embodiments, salts are 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 functioning as low molecular weight crosslinkers between the polymer chains.

[0181] Some embodiments of the polymer blend include at least one first hydrophilic polymer and at least one second hydrophilic polymer in a solvent extruded as described herein. Examples include one or more of PVA, PAA, PEG, PVP, polyalkylene glycols, hydrophilic polymers, and combinations thereof. Concentration examples include at least one second hydrophilic polymer present at 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, and any of 1, 2, 10, 100, 1000, 1500, 2000, 2500, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or 10,000 parts can be used 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%.

[0182] Some embodiments include porous matrices conditioned with water-soluble polymers that lose no more than 20-90 w / w% of the water-soluble polymer under comparable conditions; one of ordinary skill in the art will readily understand that all ranges and values ​​between the explicitly stated boundaries are contemplated, e.g., 20, 25, 30, 33, 40, 50, 60, 70, 80, 90 w / w%, etc.

[0183] In some embodiments, the bulk embedded material may exhibit a monolayer at the surface. The term monolayer refers to a layer having a thickness of one molecule. A monolayer does not rely on the 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 corresponding to the thickness of the network formed by the crosslinked polymer. For example, while it may be possible to create a crosslinked PVA coating on a surface, such a coating relies on the interconnections between PVA molecules, which inevitably form a crosslinked network. Thus, embodiments include a water-soluble polymer present on the surface of a porous solid without being covalently bound to the surface and without the polymer being part of a network.

[0184] In some embodiments, bulk-incorporated polymers are durably incorporated. In contrast, a layer of water-soluble material simply adsorbed onto a substrate, e.g., applied by dip coating or spraying, can be essentially removed from the hydrophilic substrate in most or all circumstances, meaning that at least 90 wt% of the material can be separated from the substrate in aqueous solution, e.g., saline, at 90°C for 24 hours. Covalently bonded materials are not removed under these conditions, and while physically crosslinked networks of water-soluble polymers may not be removed, such networks may exhibit undesirable properties compared to bulk-incorporated polymers, e.g., increased thrombogenicity or reduced durability. Covalent bonding requires the use of chemically reactive sites, which can be avoided with bulk-incorporated processes.

[0185] Processing systems and parameters for making porous materials Provided herein are processes for creating biocompatible porous solids, such as microporous or nanoporous solid materials, that have low protein adsorption characteristics and can serve as the basis for non-biofouling devices. Modifications of starting polymer concentration, molecular weight, solvent removal, molding process, and curing / annealing process can be used to provide surface properties such as reduced protein adsorption. Some embodiments include extruding polymer mixtures to create various continuous shapes, which may be further cured and annealed. These processes may also be used to create tough, highly lubricious materials. Embodiments include polymer mixtures extruded into single- or multi-lumen shapes of various diameters and wall thicknesses.

[0186] One embodiment of a process for producing a nanoporous solid material involves heating a mixture containing a polymer and a solvent (the 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, cooling the mixture as it passes through the die is also useful. Without being bound by a particular theory of operation, crosslinking the polymer while passing through the die appears to initially form a porous matrix. This matrix is ​​not a true nanoporous solid material because, although there are spaces between the polymer strands, it does not have a porous structure. Removing the solvent under appropriate conditions results in the crosslinked structure becoming a nanoporous solid. Crosslinking begins when the polymer mixture is extruded through the die and the mixture is cooled. Crosslinking can continue while the solvent is being removed. The transition to form a nanoporous material occurs as the solvent is removed and is generally considered complete or essentially complete (meaning 90% or greater) at this stage. The resulting material may be further processed by annealing, with or without the presence of additional solvent or plasticizer. This process, and other extrusion or other forming processes and / or materials described herein, including bulk incorporation processes, may not include one or more of a covalent crosslinking agent, an agent that promotes covalent crosslinking, radiation to crosslink polymer chains, freezing, thawing, freeze-thaw cycles, one or more freeze-thaw cycles, ice crystal formation, a foaming agent, a surfactant, a hydrophobic polymer, a hydrophobic polymer segment, a reinforcement material, a wire, a braid, a non-porous solid, and a fiber.

[0187] The porous material may be produced by an extrusion process that includes passing the polymer mixture through a die into a cooling environment. The cooling environment may also be a solvent removal environment, such as a dehydration environment if the solvent is water. The die may have a core passing through it such that the polymer mixture forms around the core. Further solvent removal and / or annealing environments may be used.

[0188] The extrusion process of the polymer-solvent mixture may be performed as cold extrusion. Cold extrusion refers to the process of forcing a polymer-solvent mixture through a die, without the need to heat the polymer-solvent mixture above its boiling point throughout the entire process of preparing and extruding the mixture. Thus, in cold extrusion, the die head is kept below the boiling point of the polymer-solvent mixture. While many solvents can be used, water is often a useful solvent, in which case the die head is kept below 100°C, although, as mentioned above, cooler temperatures may also be useful.

[0189] The term polymer mixture refers to a polymer in solution, dissolved, or suspended in a solvent. The solvent may be, for example, water, an aqueous solution, an organic solvent, or a combination thereof. Heating the polymer mixture may involve heating the mixture to a temperature above the melting point of the polymer. Generally, upon reaching the melting point, the solution transitions from a cloudy state to a clear state. Aqueous solutions contain water, e.g., 10-100% (w / w or v / v) of the liquid. Those skilled in the art will readily understand that all ranges and values ​​between the explicitly stated boundaries, e.g., 10, 20, 30, 40, 50, 60, 70, 80, or 90%, or at least one thereof, are contemplated.

[0190] Extrusion is a useful process for forming the material. Other forming processes may also be used, such as molding, casting, or thermoforming of a polymer-solvent mixture. Typically, the polymer-solvent mixture is prepared without boiling and formed into a shape that is subjected to controlled solvent removal conditions to create a nanoporous or microporous material using the guidelines provided herein. An annealing step may also be included. Hydrogels that are not microporous or nanoporous materials can also be made.

[0191] The heated polymer mixture may be cooled while undergoing molding or shaping, or it may be immediately cooled after molding / forming. Molding is a broad term that refers to passing a material from an amorphous, molten state into a final product or an intermediate shape for further processing. Molding includes casting, layering, coating, injection molding, drawing, and extrusion. Molding can be performed using an injection molding setup, where the mold contains a material with thermally conductive properties that can be easily heated to promote flow of the injected polymer mixture and rapidly cooled in a cooling environment. In other embodiments, the molding process can be achieved by extruding the polymer mixture through a die to form a continuous material.

[0192] Cooling the polymer mixture may include cooling an extruded material, such as when passing the polymer material through a die. An example of a cooling method is a liquid bath at a temperature at least 20° C. below the boiling point of the polymer mixture, or alternatively, below the Tm of the polymer mixture, such as 20, 30, 40, 50, 60, 70, 80, 90, 100, or 110° C. below the boiling point or polymer Tm, or alternatively, a bath or other environment at a temperature of −50 to 30° C. Those skilled in the art will readily recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, and any of the following may be used as upper or lower limits: −50, −45, −25, −20, −10, −5, −4, 0, 15, 20, 25, or 30° C. Cooling may be performed in an environment that removes the solvent. Subzero temperatures may be avoided. Without being bound by any particular theory of operation, polymer chains are cooled to a temperature that promotes intermolecular hydrogen bonding and immobilizes the chains. This may be done at temperatures as high as 30 °C, or even higher if time permits. The bath may be aqueous, and may be adjusted with salts or other osmotic agents to provide an osmotic pressure that allows solvent removal for aqueous materials with relatively low osmotic pressures through osmosis and diffusion. Alternatively, the bath may contain other solvents that freeze at lower temperatures than water; temperatures below 0 °C can be used without freezing the solvent or material. When using hydrophilic copolymers in combination with PVA, for example, temperatures above 20 °C may be used, since crosslinking and chain immobilization occur at much higher temperatures.

[0193] A solvent removal environment is one in which solvent removal is significantly accelerated compared to drying under ambient conditions. Such an environment may be unheated, meaning not above ambient temperature, e.g., not above 20°C. Such an environment may be a vacuum, e.g., a vacuum chamber, a salt bath, or a bath to remove the solvent in the polymer mixture. For example, an aqueous polymer mixture may be introduced into an ethanol bath to replace the water with ethanol. The ethanol may then be removed. The salt bath may be, for example, a high salt concentration bath (1M to 6M). The treatment time in the solvent removal environment and / or the cooling step may be independently selected to be 1 to 240 hours. Those skilled in the art will readily recognize that all ranges and values ​​between the stated boundaries are contemplated, e.g., 1, 2, 5, 10, or 24 hours, or 1, 2, 5, 7, or 10 days may be used as upper or lower limits. The salt may dissociate to form singly, doubly, or triply charged ions.

[0194] The solvent removal environment may be one or more environments, or one environment may be adjusted in temperature. For example, a cooling bath may be used followed by solvent removal in an oven or vacuum oven. Washing steps may be performed before or after cooling or solvent removal, such as by immersion in a series of solvents with different concentrations, different salt solutions, different proportions of ethanol or other solvents.

[0195] 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 HO baths (fresh or replaced) for a set 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 removed from the washing step and dehydrated to remove excess water. Dehydration can be performed, for example, using temperatures ranging from 20-95°C. Dehydration is typically performed at 37°C for 24 hours or more.

[0196] In one embodiment, the polymer mixture formed, such as by extrusion, is then exposed to a high salt bath (1M to 6M) for an inversely related period of time, with the higher salt content shortening the time required for immersion, e.g., 16 to 24 hours in a 6M solution of NaCl. After immersion, the material is rinsed to remove the salt water. At this point, the material is strengthened and can be removed from the mold pieces carried over from the initial formation. Alternatively, the material can be dehydrated in a water bath after the salt bath to remove excess water. Dehydration can be performed at temperatures ranging from 20 to 95°C. Dehydration can be performed at 37°C for 4 hours or more, 24 hours or more, or for 2 to 150 hours. Those skilled in the art will readily recognize that all ranges and values ​​between the stated boundaries are contemplated, e.g., 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120, 144, or 150 hours can be used as upper or lower limits. For example, dehydration at 40°C for 6 to 24 hours has been observed to be useful.

[0197] In another embodiment, NaCl is incorporated into the starting polymer solution at a concentration ranging from 0.1 to 3M by volume of the final polymer mixture. The polymer is dissolved in a heated solution under stirring and then brought above its melting point. Dry NaCl is slowly added to this solution under stirring until completely dissolved. The slightly hazy solution is drawn into a feed for forming shapes by injection molding, casting, extrusion, drawing, or other methods. At the end of each step, a quench is performed by rapidly lowering the temperature to form a solid material. In this embodiment, no additional salt soak is required. After the material hardens, if necessary, it can be removed from the molding process, washed in water to remove salt, and dehydrated.

[0198] The term annealing, when used in the context of semicrystalline polymers or solid porous materials, refers to heat treatment at an annealing temperature comparable to the melting temperature of the polymer or polymers in the material. This temperature is typically within approximately 0-15% below the melting temperature on the absolute temperature scale. Plasticizers and other additives can usually affect the melting temperature by lowering it. For example, for pure PVA, the annealing temperature will be within approximately 10% of the PVA melting point, but if other materials are present, the annealing temperature will usually be lower. The theory of operation is that annealing is a process in which stress relief is combined with an increase in the size of the crystalline domains of the material being annealed. Unlike metals, annealing increases the strength of the annealed material. Annealing can be performed in one or more conditions, such as in air, in a gas, in the absence of oxygen, or in the absence of water, e.g., in nitrogen, vacuum nitrogen, under argon, or with the use of an oxygen scavenger. For example, experiments have been conducted on annealing dehydrated PVA nanoporous materials. Annealing is used to increase the crystallinity of the PVA network, further reduce its pore size, and reduce the adsorption properties of the final gel surface. Annealing can be performed at temperatures ranging from 100 to 200 °C, for example. In a preferred embodiment, this step is performed by submerging the dehydrated gel in a mineral oil bath. Bulk incorporation of a polymer into the porous solid can also include an annealing step, as previously described for the porous solid. Annealing may be performed after exposing the desolvated porous solid to a mixture containing the bulk-incorporated polymer. The Tg of the material may increase or decrease depending on the residual solvent content and / or the presence of a bulk-incorporated second hydrophilic polymer. As previously mentioned, the conditions of the annealing process can be adapted depending on the substrate temperature, time, ramp rate, and cooling rate.

[0199] Annealing can be performed in gas or liquid at atmospheric, elevated, or low pressure (vacuum). 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 include 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 further reduces 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 the bath medium is washed off using a series of extended immersions. The product is then dehydrated and prepared for terminal sterilization.

[0200] Various types of dies may be used, including longitudinal, angular, transverse, and spiral extrusion heads, as well as single-polymer extrusion heads used to extrude a single polymer and multi-layer extrusion heads used to simultaneously extrude multiple polymer or other layers. Continuous or cyclic operation heads may also be used. Various materials, such as reinforcing materials, fibers, wires, braids, braided wires, braided plastic fibers, etc., may be incorporated into or incorporated as layers. Similarly, such materials may be excluded. Furthermore, porous solids may have certain properties, such as Young's modulus, tensile strength, solids content, polymer composition, porous structure, or solvent content, that are known and therefore measurable excluding various other materials. Thus, embodiments include the materials disclosed herein described in terms of the material's properties, without consideration of various other incorporated materials. For example, a nanoporous solid has a known, constant Young's modulus, even when the material contains reinforcing wires that contribute additional strength.

[0201] A core may be used with an 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 used with these various types of cores. Cores made of polytetrafluoroethylene tubing (PTFE) are useful. In some embodiments, the core is a wire.

[0202] Multi-lumen tubing has multiple channels running through its profile. These extrusions can be custom engineered to fit device designs. Multi-lumen tubing has variable outer diameters (OD), numerous custom inner diameters (ID), and various wall thicknesses. This tubing comes in a variety of shapes, including round, oval, triangular, square, semicircular, and crescent. These lumens can accommodate guidewires, fluids, gases, wires, and various other needs. The number of lumens in a multi-lumen tubing is limited only by the OD. In some embodiments, the OD can be as large as 0.5 inches, the ID as small as 0.002 inches, and the web and wall thickness as thin as 0.002 inches, maintaining tight tolerances of ±0.000.5 inches. For example, any of the following outer and / or inner diameter upper and lower limits may be used: 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.

[0203] Braided tubing is available in a variety of configurations. For example, it can be braided using round or flat wire, single-ended or double-ended wire, as thin as 0.001 inches. Braided tubing can be made from a variety of materials, including stainless steel, beryllium copper, silver, and monofilament polymers. Additionally, various inch lengths of braid can be wrapped around thermoplastic materials such as nylon or polyurethane. The advantages of braided catheter shafts are their high torque and kink resistance. By varying several factors during the braiding process, the tubing's properties can be tailored to meet specific performance requirements. After braiding is complete, a second extrusion process can be performed over the braided tubing to seal the weave and achieve a smooth finish. Braided tubing can be as thin as 0.007 inches.

[0204] Porous, microporous, and nanoporous materials The term "porous solid" is a broad term referring to materials with a solid phase containing open space, and it is used to refer to both truly porous materials and hydrogels with an open matrix structure. Because porous-related terms are used somewhat ambiguously in the scientific literature, it is useful to provide specific definitions herein. The term "nanoporous material" or "nanoporous solid" is used herein specifically to refer to solids made of interconnected pores with pore sizes up to about 100 nm in diameter. The term "diameter" is broad and encompasses pores of any shape, as is customary in these technical fields. The term "microporous solid" or "microporous material" is similarly used herein to specifically refer to solids made of interconnected pores with pore sizes up to about 10 μm in diameter. These nanoporous or microporous materials are characterized by an interconnected porous structure.

[0205] 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 interspersed with voids, the voids being the pores. However, the open matrix structure found in many hydrogels is not truly porous, and while it is generally convenient to refer to them as porous materials and to use analogs of pores when characterizing diffusion and other properties, such hydrogels are not nanoporous or microporous solids as those terms are used herein. The spaces between the strands of open matrix hydrogels, and the matrix strands, are not interconnected pores. Because hydrogels are crosslinked gels, insoluble in solvents, and possess great mechanical strength, they are generally conveniently referred to herein and in these technical fields as solids, but they are crosslinked gels that have solid-like properties without being truly solids. Hydrogels may have high water contents, e.g., 25% w / w or more at EWC. While practitioners in the hydrogel arts sometimes use the term porous to characterize a net molecular weight cut or to refer to the spacing between strands of an open hydrogel matrix, in this case the hydrogel does not have a true porous structure and is not a nanoporous or microporous material as these terms are used herein. Also, the definitions of nanoporous and microporous materials herein contrast with the convention that microporous materials are sometimes described as having pores less than 2 nm in diameter, macroporous materials as having pores greater than 50 nm in diameter, and mesoporous materials as being somewhere in between.

[0206] The extrusion process for producing the materials of the present invention offers several advantages. Extrusion has been shown to produce parallel polymer orientation, resulting in high tensile strength. When extruded and stretched, the polymer molecules align in the direction of the tube or fiber. Their tendency to return to a random orientation is resisted by strong intermolecular forces between the molecules. It also allows for the creation of materials and devices with higher aspect ratios than methods such as injection molding. Furthermore, extrusion allows for greater dimensional control, such as wall thickness and lumen placement. The use of high concentrations of polymer in a solvent above its melting point was useful to enable extrusion. Importantly, other attempts to create high-strength materials using similar polymers have used other techniques that are often inefficient, inefficient, and unsuitable for producing practical end-user products.

[0207] For example, polyvinyl alcohol (PVA) has been used to create nanoporous materials with superior properties, especially compared to traditionally used PVA biomaterials. Indeed, PVA is widely used in the medical device industry due to its established biocompatibility. PVA is a linear molecule with a rich history as a highly 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 for cartilage and meniscus tissue replacement. Its high biocompatibility compared to other hydrogels and its low protein adsorption, resulting in low cell adhesion, make it an attractive material for these applications.

[0208] Others have attempted to improve the properties of PVA for biomedical purposes. For example, some have experimented with freeze / thaw processes. Techniques for forming hydrogels from PVA, such as "salting-out" gelation, have been shown to produce useful polymer hydrogels of varying molecular weights and concentrations. Manipulation of Flory interactions has also been investigated in the formation of PVA gels from the combination of two solutions for use as injectable, in situ-forming gels for intervertebral disc repair (see U.S. Patent Nos. 7,845,670, 8,637,063, and 7,619,009). In general, a prior process for producing tough PVA materials was investigated in U.S. Patent No. 8,541,484. Methods without the use of radiation or chemical crosslinkers have also been previously investigated, as shown in U.S. Patent No. 6,231,605. None of this PVA-related research by others has led to the inventions described herein. Some of these other materials were useful in terms of tensile strength, but were nevertheless macroporous in nature.

[0209] In contrast, the processes herein provide high-strength materials with true porous structures and other useful properties, such as an unexpectedly favorable combination of biocompatibility and mechanical properties. Porous solid material embodiments are provided that have a combination of structural characteristics independently selected from pore size, tensile strength, Young's modulus, solids concentration, type and degree of crosslinking, internal alignment, hydrophilicity, and composition for the material, and, optionally, independently select end-user devices or intermediate materials with desired aspect ratios, lumen, multiple lumens, tubes with concentrically arranged lumens, or thickness tolerances for the molded shape; each of these is described in further detail herein.

[0210] Embodiments include nanoporous materials having pore diameters of 100 nm or less, 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., any of the following can be utilized as upper or lower limits: 1, 2, 3, 4, 5, 10, 20, 50, 60, 70, 80, 90, 100 nm.

[0211] Embodiments include nanoporous or microporous materials having a tensile strength at break, as measured by EWC, of ​​at least about 50 MPa, or from 1 to 300 MPa. One of skill in the art will readily appreciate that all ranges and values ​​between the stated boundaries are contemplated, e.g., any of 10, 20, 30, 40, 50, 60, 70, 100, 200, or 300 MPa can be utilized as an upper or lower limit.

[0212] 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 200 MPa. One of skill in the art will readily appreciate that all ranges and values ​​between the stated boundaries are contemplated, including, for example, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, and 200 MPa, which may be utilized as upper or lower limits.

[0213] Embodiments include nanoporous or microporous materials or hydrogels having an elongation at break, as measured by EWC, of ​​at least about 100% or between 50 and 1500%. One of skill in the art will readily appreciate that all ranges and values ​​between the stated boundaries are contemplated, e.g., 50, 60, 70, 80, 90, 100, 200, 300, 400, 450, or 500% (e.g., greater than or equal to 50%) can be used as upper or lower limits.

[0214] Embodiments include nanoporous or microporous materials or hydrogels having a solids content of at least 20% or 20-90% w / w, as measured by EWC. One of skill in the art will readily recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, including any of the following as upper or lower limits: 5, 10, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90% w / w solids. Percent solids are measured by comparing the total weight at EWC to the dry weight.

[0215] Tensile strength, modulus, and elongation values ​​may be used in combination within the scope of this disclosure.

[0216] Embodiments include nanoporous or microporous materials or hydrogels having physical crosslinks, covalent crosslinks, or a combination thereof. Physical crosslinks are non-covalent bonds, e.g., physical crosslinks are ionic, hydrogen, electrostatic, van der Waals, or hydrophobic packing. Materials can be free of covalent crosslinks, covalent crosslinkers, and their chemical products. Chemicals can be added during processing to create covalent crosslinks, as known in the art of polymerization. Alternatively, processes and materials can be free of such.

[0217] Embodiments include nanoporous or microporous materials or hydrogels with internal alignment of polymer structures. Alignment can be visualized using SEM images of cross sections taken along the extrusion direction, or longitudinally in the case of tubes. Alignment refers to a predominantly horizontal chain orientation along the length of the sample (extrusion direction).

[0218] Embodiments include nanoporous or microporous materials or hydrogels having hydrophilic surfaces and / or 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 90 degrees or less (the contact angle is defined as the angle through the interior of the water droplet). Embodiments include hydrophilic surfaces having contact angles between 90 degrees and 0 degrees; those skilled in the art will readily understand that all ranges and values ​​between the explicitly stated boundaries are contemplated, and that, for example, any of 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 2, or 0 degrees can be used as upper or lower limits. A material matrix is ​​hydrophilic to a solvent if the matrix is ​​hydrophilic and a droplet of the solvent on the surface is less than 90 degrees.

[0219] The materials and / or biomaterials used in the process 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, and hydroxypropyl methacrylamide. Examples include polyoxazolines, polyphosphates, polyphosphazenes, poly(vinyl acetate), polypropylene glycol, poly(N-isopropylacrylamide) (PNIPAM), polysaccharides, sulfonated hydrophilic polymers (e.g., sulfonated polyphenylene oxide, Nafion®, sulfobetaine methacrylate), and their iodine-containing counterparts (e.g., PVA-I, PVP-I) or their pendant groups, copolymers thereof, and combinations thereof. Two or more hydrophilic polymers may also be blended to form nanoporous materials. The molecular weight of the polymer influences 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 between 40 kDa and 5,000 kDa. Those skilled in the art will readily understand that all ranges and values ​​between the stated boundaries are contemplated, including, for example, any of the following molecular weights can be used as upper or lower limits: 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.

[0220] 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 the chemical moiety or MW range of the terminal groups. References to polymers described herein include all forms of polymers, including linear, branched, underbranched, 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 containing 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. A pendant group is a chemical moiety attached to a polymer, and may be the same or different from the repeating units of the polymer. Thus, the term polymer encompasses highly derivatized polymers and polymers containing 0.01 to 20 wt% or less of derivatized moieties, calculated as the combined MW of such moieties relative to the total weight of the polymer. One of ordinary skill in the art will immediately understand that all ranges and values ​​between the stated limits are contemplated, for example, any of the following can be used as upper or lower limits: 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%.

[0221] Porous solids can be formed as monolithic materials, as layers on other materials, devices, or surfaces, as multiple layers, or as one or more layers of nanoporous or nanoporous materials. Thus, for example, multiple layers may be extruded, the layers being independently selected to form one or more of nanoporous materials, microporous materials, hydrogels, single polymer materials, materials with two or more polymers, and non-nanoporous materials.

[0222] The process for making the material also affects the material's properties, such as the concentration of polymer in the polymer mixture passed through the die. Starting PVA or other hydrophilic polymer concentrations can range, for example, from 5 to 70% weight-to-volume (w / w) in water, with about 10 to 30% (w / w) generally preferred; those skilled in the art will readily understand that all ranges and values ​​between the explicitly stated boundaries are contemplated, and any of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70% can be used as upper or lower limits.

[0223] The processes described herein may be truncated before the polymers are crosslinked into true nanoporous materials or otherwise adapted to avoid nanoporous structures. Generally, such materials have low strength and toughness and low solids content. When hydrophilic polymers are used at relatively low solids contents, such materials typically become hydrogels. Thus, such materials, and even hydrogels, are contemplated herein and can produce materials with somewhat inferior properties compared to nanoporous materials, but that nevertheless outperform conventional processes and materials using the same polymers. Similarly, generally speaking, microporous solids will approach the properties of nanoporous materials and have strength superior to that of hydrogels.

[0224] Quantifying the pore size distribution of a material is common. Nanoporous, microporous, and microporous materials are disclosed herein, and control of pore size in such materials is demonstrated. Thus, embodiments include materials having a specific amount or distribution of pore sizes. These can be measured at the surface, at depth in a cross-sectional sample, or in the bulk of the material. For example, the pore size of a material at the surface, at depth, or in the bulk can be within a range of 1 nm to 20 μm, or the percentage of pore sizes above or below a certain value can be 50-100%; those skilled in the art will readily understand that all ranges and values ​​between the explicitly stated boundaries are contemplated. Examples of quantifications for depth include 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, 10,000, 15,000, or 20,000 nm. Examples of quantifications for depth include, for example, at least or in the range of 1-5,000 μm in depth, and one of skill in the art will immediately understand that all ranges and values ​​between the explicitly stated boundaries are contemplated. For example, the surface may have a certain percentage of pores with a certain diameter or less, or the depth or depth range may have a certain percentage of pores with a certain diameter or less.

[0225] Embodiments include methods for producing polymeric materials, including heating a mixture containing 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 crosslinking. 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 of ordinary skill in the art, for example, by observing the mixture as it heats and changes from a cloudy appearance to a significantly translucent appearance. Furthermore, some or all of the solvent may be removed from the mixture while it is cooling after, or as part of, a forming process using the mixture. Embodiments include removing at least 50 wt.% of the solvent in less than 60 minutes (or less than 1, 2, 5, or 10 minutes). Embodiments include removing at least 90 wt.% (or at least 70 wt., or at least 80 wt.) of the solvent in less than 60 minutes (or less than 1, 2, 5, 10, or 30 minutes).

[0226] Bulk incorporation of polymers into porous solids When the porous matrix is ​​desolvated, the porous material can be exposed to a mixture containing a solvated polymer (for bulk-incorporated polymer), drawing the polymer into the pores. The solvent of the mixture has an affinity for the matrix and is drawn into the matrix as it absorbs the solvent. The solvent of the mixture with the bulk-incorporated polymer can be chosen to have an affinity for the matrix so that it is absorbed into the desolvated matrix, but it need not be the same as the solvent of the matrix. Generally, the hydrophilic solvent in the mixture will be at least partially desolvated and absorbed into the hydrophilic porous matrix containing the hydrophilic solvent. Those skilled in the art will be able to adjust the various solvents as needed to create suitable conditions if bulk-incorporated is the intended purpose.

[0227] A hydrophilic solvent is a solvent that is freely miscible with water or that exists in a concentration in a mixture at 20°C that is freely miscible with water.

[0228] Desolvated means that the matrix is ​​solvent-free, e.g., completely dry, or below the EWC of the matrix 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. That is, the term EWC can be used in appropriate contexts for solvents other than water. For example, a hydrophilic matrix may be dissolved in an aqueous solution of alcohol and will have an EWC relative to that solvent. While embodiments include desolvated amounts 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, and 100 w / w% refer to the total weight of solvent that can be removed.

[0229] Without being bound by theory, it is believed that desolvating a porous material (or dehydrating it if the porous material's solvent is water) and then exposing it to a polymer in a solution that dissolves the porous material draws the polymer into the pores. The polymer then forms physical bonds with the matrix material that defines the pores, effectively permanently incorporating it into the bulk of the material by at least partially filling the pores and physically bonding with the matrix. Alternatively, or additionally, the polymer has a hydrodynamic radius that allows it to present a diameter that exceeds the pore opening, allowing the polymer to be permanently incorporated into the pores of the material, particularly when the material is used in aqueous or physiological solutions. Generally, if the bulk-incorporated polymer is dissolved 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. When a hydrophilic porous matrix is ​​below the EWC of the matrix, the solvent for the polymer matches the matrix material, e.g., wets the pores of the material, and thus the mixture containing the bulk-incorporated polymer is drawn in. For example, hydrophilic solvents typically wet the pores of a hydrophilic matrix.

[0230] Materials comprising porous matrices 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 be composed of physically crosslinked water-soluble polymers that define the pores. The solids concentration of these water-soluble polymers may be at least 33 wt. % of the matrix at the equilibrium water content (EWC) of the matrix, although other concentrations may also be used.

[0231] Thus, one embodiment of a process for incorporating a polymer into a porous material includes providing a material comprising a porous hydrophilic matrix in which one or more water-soluble polymers (also referred to herein as matrix polymers) are crosslinked to form a matrix. The material with the matrix is ​​exposed to a mixture comprising one or more polymers dissolved in a solvent (also referred to as bulk-incorporation polymers, where the polymers are preferably water-soluble, and the mixture is also referred to as a conditioning mixture or bulk-incorporation mixture), where the matrix is ​​at or below its EWC and is hydrophilic with respect to the solvent before exposure to the mixture. The material is desolventized before exposure to the mixture with the bulk-incorporation polymers.

[0232] In some embodiments, the bulk encapsulation process results in an outer zone of filled pores, a middle zone of mostly or predominantly filled pores, and an inner zone with little or no polymer penetration. Bulk encapsulation modifies not only surface pores but also subsurface pores, e.g., pores in the range of at least 1-5000 μm. Those skilled in the art will readily recognize that all ranges and values ​​between the stated boundaries are contemplated, e.g., 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 75, 100, 250, 500, 750, 1000, 2000, 3000, 4000, or 5000 μm. The percentage of polymer-filled pores may be assayed as previously described, and the permeability graded by percentage cutoff. For example, a first zone may have 100% pores filled, a second zone may have 50% pores filled, a third zone may have 0% pores filled, and so on.

[0233] Bulk encapsulation is preferably performed using a porous matrix containing a water-soluble polymer, although the polymer may not have hydrophobic domains, e.g., a matrix containing only PVA may be used. The polymer may be physically crosslinked to form the matrix. Thus, embodiments include materials containing no hydrophobic domains or matrices made using water-soluble polymers that do not contain hydrophobic domains. However, when using water-soluble polymers with physical crosslinks to create a hydrophilic matrix, some hydrophobic domains can be tolerated without disrupting the matrix formed thereby. Embodiments of the present invention include those in which the hydrophobic content of the polymer forming the porous matrix is ​​0, 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, or 15 wt.%.

[0234] Additionally, a porous matrix essentially containing water-soluble polymers refers to a matrix containing up to 3 wt% 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 essentially composed of physically crosslinked polymers refers to a matrix that does not contain agents that create covalent bonds between polymers or that contains such agents in small amounts so that no more than about 6% of the polymers (see Polymer Number) are crosslinked to each other with such agents, e.g., a stoichiometric ratio of Polymer Number to bifunctional crosslinker of at least 100:3. Similarly, a matrix essentially free of covalent bonds is made from crosslinked polymers in which no more than about 6% of the polymers (number) are covalently crosslinked. The number of covalent bonds in the matrix may similarly be limited to a stoichiometric ratio between 100:3 and 100:100, e.g., 100 to 3, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, or 100. For example, hydrogels made by free radical polymerization typically have 100% of the polymers bonded to each other by covalent bonds, which is a 100:100 stoichiometric ratio of polymer:covalent bonds.

[0235] As noted elsewhere, porous solids can be fabricated with a controlled pore diameter range, or can be fabricated to provide a matrix with no pores larger than a particular diameter. Diameters may be measured in a suitable context, e.g., by EWC of distilled water. Thus, embodiments include polymers encapsulated in porous matrices with no pores larger than 1-5000 μm; 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, 50, 100, 200, 250, 300, 400, 500, 750, 1000, 2000, 3000, 4000, or 5000 μm.

[0236] Porous solids, as described elsewhere herein, can have other materials present, such as radiopaque (RO) agents that are added to the matrix but are not part of it. RO agents typically contribute little to the crosslinking that provides the matrix strength. Similarly, other materials can be present within the matrix without being part of it, such as wires and reinforcing materials. A matrix made with physical crosslinks is a type of matrix that can be made from materials that define pores with diameters. This contrasts with hydrogels, which typically have polymer strands that are separated from one another and connected in a mesh network structure, such as those typically formed using free radical polymerization or by the reaction of monomers / polymers in solution. Such mesh networks generally cannot be expected to stably incorporate polymers within their pores unless they are covalently bonded using a polymer-imbibing process. Porous materials are described in detail herein, and they may be freely selected for use with bulk-incorporated polymers, guided by this disclosure. Porous materials may be selected to have bulk properties as described herein.

[0237] The bulk-incorporated polymer may be any of the polymers described elsewhere herein for 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, and hydroxypropyl methacrylamide. Examples include polyoxazolines, polyphosphates, polyphosphazenes, poly(vinyl acetate), polypropylene glycol, poly(N-isopropylacrylamide) (PNIPAM), polysaccharides, sulfonated hydrophilic polymers (e.g., sulfonated polyphenylene oxide, Nafion®, sulfobetaine methacrylate, and the like), as well as iodine-containing variations thereof (PVA-I, PVP-I, and the like) or variations with additional pendant groups, copolymers thereof, and combinations thereof. A blend may contain one or more polymers, meaning polymers of different chemical compositions, such as PVA and PEG. "Polymer" refers to one or more polymers.

[0238] The solubility of water-soluble polymers for porous matrices or 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 molecular weights between 40 kDa and 5,000 kDa; those skilled in the art will readily recognize that all ranges and values ​​between the explicitly stated boundaries are contemplated, and any of the following molecular weights may be used as upper or lower limits: 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, or 3 million. The molecular weight of the polymer can be selected taking into account the size of the pores available in the porous solid. Nanoporous or microporous materials are preferred.

[0239] The bulk incorporation polymer can be selected to be the same as the polymer forming the porous matrix, the same as at least one of the polymers comprising the matrix, or different.

[0240] The bulk-incorporation polymer concentration in the mixture, referring to the mixture at the start of the process, can be any concentration that results in the polymer going into solution, keeping in mind that unsolubilized polymer or other non-solubilized materials are not destined for the pores. In some embodiments, the concentration is 1-50 w / w%. One of ordinary skill in the art will readily recognize that all ranges and values ​​between the stated ranges are contemplated, e.g., 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 33, 35, 40, and 50 w / w%.

[0241] The solvent for the mixture is appropriately selected to provide a solvent that solvates the polymer and is absorbed by the porous solid. For hydrophilic matrices, hydrophilic solvents are generally preferred. The solvent may be water, organic, aqueous, or free of them, e.g., free of organic solvents. In some embodiments, the water concentration is 0-99, e.g., 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 95, or 99 w / w%.

[0242] The temperature of the conditioning mixture should not exceed the melting temperature of the porous solid matrix, and may range from, for example, 10 to 100°C, such as 10, 20, 30, 37, 40, 50, 60, 70, 80, or 90°C.

[0243] The exposure time is preferably the length of time required for the porous solid to reach the EWC in the mixture. In some embodiments, the length of time may be 2, 4, 6, 8, 10, 12, 16, 20, 24, and 48 hours. Agitation and temperature may be manipulated to affect the exposure time, such as to facilitate the attainment of the EWC or to control the viscosity of the mixture. The salt and / or osmolality content may be adjusted accordingly, for example, for solubility, viscosity, and / or EWC.

[0244] The examples provide guidance regarding salt concentrations in the conditioning mixture. Exemplary salt concentrations are 0.1 to 2 w / w%. Generally, it is said that singly charged cations with small atomic radii have high penetration into the depths of porous solids, while larger cations decrease penetration. Examples of salts include those with a single cation, a divalent cation, or other cations, such as sodium, potassium, lithium, copper, and quaternary ammonium (NR4 + , where R is hydrogen, alkyl, or aryl), magnesium, calcium, copper, iron, or zinc salts. Generally, a physiological pH buffered mixture is useful. The pH may be adjusted to increase or decrease permeability to the matrix, and the solvent may contain or omit buffer salts. Example pH values ​​are between 4 and 10, e.g., 4, 5, 6, 7, 8, 9, or 10.

[0245] The viscosity of a conditioning mixture containing a water-soluble polymer and a solvent is affected by pH (higher pH = higher viscosity), polymer concentration and / or molecular weight, and polymer branching, with increases in any of these generally resulting in higher viscosity. Generally, higher viscosity results in decreased permeability of the polymer into a porous solid. One embodiment is a porous material having a water-soluble polymer encapsulated within the pores of a porous matrix. The matrix may include physically crosslinked water-soluble polymers crosslinked to each other to form a matrix and define pores. The matrix may have characteristics as disclosed herein, such as polymer content, weight percent of polymer, strength, Young's modulus, degree of coverage, pore size, etc. Surface coverage of the water-soluble polymer in the porous matrix may be complete. Complete coverage under SEM conditions, where no pores are visible on the underlying surface, indicates coverage with EWC. Coverage may be less than 100%, for example, 50-100%. Those skilled in the art will readily appreciate that all ranges and values ​​between the explicitly stated boundaries are contemplated, e.g., 50, 60, 70, 80, 90, 95, 98, 99, 99.9, or 100%.

[0246] Bulk contamination can degrade the physical properties of the porous solid. Thus, embodiments include porous solids, such as those disclosed herein, that, upon conditioning with a water-soluble polymer, have a Young's modulus and / or tensile strength that is 1-20% less than the same material not conditioned with a water-soluble polymer; one of skill in the art will readily understand 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 provides a test for the exposure of materials for stable incorporation of water-soluble polymers. The test for stable incorporation of water-soluble polymers was performed by immersing a test device in a biologically representative fluid (i.e., PBS) at body temperature conditions, placing the test device directly on the head of a pump in a circulating peristaltic loop, and testing at a flow rate of 10-12 mL / sec at 150 rpm for 24 hours, with a viscosity of 0.1225 cm. 3 ·s -1 ·cm -2 The test approximated 500,000 mechanical compressions of the sample at a volumetric flow rate of 1000 psi. Testing revealed losses as high as 25%, but other test criteria may be used, such as 0-50 w / w% losses, e.g., 1, 5, 10, 15, 20, 25, 30, 40, or 50 w / w% losses. Alternatively, other tests may be proposed, such as 0-5 w / w% losses, e.g., 1, 2, 3, 4, or 5 w / w% losses, upon exposure to excess PBS for 1-52 weeks.

[0247] product Using the materials described herein, such as nanoporous materials, microporous materials, and hydrogels, it is possible to manufacture products (final products, intermediate products, materials, etc.) with a desired aspect ratio, for example, 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 stated boundaries are contemplated, and that any of the following may be used as upper or lower limits: 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 50:1, 100:1, and 1000:1. A high aspect ratio is highly advantageous for certain devices, such as many types of catheters. In principle, thin tubes can be continuously extruded without length limitations. Such devices include, for example, tubes, rods, cylinders, and cross-sections with square, polygonal, or circular profiles. One or more lumens may be provided in any of them. The device may be made of a single material, essentially a single material, or multiple materials including the various layers already described, reinforcements, fibers, wires, braids, braided wires, braided plastic fibers.

[0248] In particular, extrusion processes can have lumens arranged concentrically. Concentricity is in contrast to eccentricity, which means the lumen is off-center. In the case of multiple lumens, the lumens may be arranged symmetrically. This symmetry is in contrast to eccentric placement of lumens, which is the result of insufficient control. Embodiments include the aforementioned devices having an aspect ratio of at least 3:1 with lumens arranged non-eccentrically or with one lumen concentric with the longitudinal axis of the device.

[0249] Porous solids, such as nanoporous materials, microporous materials, and strong hydrogels, may be used to create catheters or medical textiles. These may be made with bulk incorporated polymers and may have various features similarly described. Examples of catheters include central venous, peripherally inserted central, midline, peripheral, tunneled, dialysis access, hemodialysis, vascular access ports, peritoneal dialysis, urological, neurological, peritoneal, intra-aortic balloon pumps, diagnostic, interventional, drug delivery, etc., shunts, wound drains (external, including ventricular, ventricular peritoneal, and lumboperitoneal), infusion ports, and the like. Porous solid materials may also be used to create implantable devices, including permanent or temporary, fully implantable, and percutaneously implantable. Porous solid materials may also be used to create devices that contact blood or bodily fluids, including ex vivo and / or in vivo devices and blood-contacting implants. Examples of such devices include drug delivery devices (e.g., insulin pumps), tubing, contraceptives, feminine hygiene products, endoscopes, grafts (including small diameters <6 mm), pacemakers, implantable cardioverter-defibrillators, cardiac resynchronization devices, cardiovascular device leads, and ventricular assist devices. Catheters (including cochlear implants, endotracheal tubes, tracheostomy tubes, drug delivery ports and tubing, implantable sensors (intravascular, transcutaneous, and intracranial), ventilator pumps, and ophthalmic devices, including drug delivery systems). Catheters can be constructed from tubular nanoporous materials equipped with fasteners, such as Luer fasteners or fittings, for interfacing with other devices. Radiopaque agents can be added to materials, fibers, or devices. Radiopaque agents are commonly used in the medical device industry to impart radiopacity to materials, such as barium sulfate, bismuth, or tungsten. The RO agent can be incorporated at 5-50 w / w% of the total solids weight, for example, 5, 10, 20, 30, 40, or 50%.

[0250] Medical textiles using porous solid materials have applications in sutures, threads, medical textiles, braids, meshes, knitted or woven fabrics, nonwoven fabrics, and devices. These fibers are strong and flexible. Materials can be made from these fibers to resist fatigue and abrasion.

[0251] In exemplary embodiments, the method includes administering to an external orifice of a subject a device including a body portion, the body portion comprising a polymeric material including a water-soluble polymer and a biologically active agent associated with the polymeric material. In some embodiments, the device has an aspect ratio of 3:1 or greater. In some embodiments, the biologically active agent is substantially uniformly distributed within the polymeric material. In some embodiments, the biologically active agent is non-homogeneously distributed within the polymeric material (i.e., on one or more surfaces of the polymeric material). In some embodiments, administration of a device (e.g., device 10 of FIG. 1A, device 12 of FIG. 1B, device 14 of FIG. 1C) does not include the use of a sheath introducer. The polymeric material is substantially non-thrombogenic, the polymeric material has a water content of less than 5 wt.% and greater than or equal to 0.1 wt.% in a first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state), and the polymeric material is configured to swell from the first configuration in an amount of 5 wt.% to 50 wt.% (e.g., in 60 minutes or less (e.g., 10 minutes or less, 5 minutes or less, 1 minute or less, or 10 seconds or less) from the first configuration (e.g., a water content less than an equilibrium water content state, such as a dehydrated state) to the second configuration (e.g., an equilibrium water content state).

[0252] Treatment methods In some aspects, methods of treating a subject are described. In some embodiments, the method comprises administering to a cavity of the subject a device described herein (e.g., any embodiment or combination of the devices described herein). In some embodiments, the method includes swelling the polymeric material described herein. For example, in some embodiments, the method includes swelling the device and / or polymeric material by an amount of 2 wt. % or more, 3 wt. % or more, 4 wt. % or more, 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, e.g., from a first configuration (e.g., a moisture content less than the equilibrium moisture content state, such as a dehydrated state) to a second configuration (e.g., an equilibrium moisture content state). In some embodiments, the method includes swelling the device and / or polymeric material by 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 10 w / w% or less, e.g., from a first configuration (e.g., a moisture content less than an equilibrium moisture content state, such as a dehydrated state) to a second configuration (e.g., an equilibrium moisture content state). Combinations of these ranges are also possible (e.g., 5 w / w% to 40 w / w%).

[0253] In some embodiments, the method includes swelling the polymeric material to an equilibrium moisture content state. In some embodiments, the method includes swelling the polymeric material to the equilibrium moisture content state for a duration. In some embodiments, the duration is 60 minutes or less (e.g., 10 minutes or less, 5 minutes or less, 1 minute or less, 30 seconds or less, or 10 seconds or less).

[0254] In some embodiments, the method includes swelling the polymeric material at a predetermined temperature. In some embodiments, the temperature is 4° C. or higher, 10° C. or higher, 16° C. or higher, 20° C. or higher, 25° C. or higher, or 30° C. or higher. In some embodiments, the temperature is 40° C. or lower, 30° C. or lower, 25° C. or lower, 20° C. or lower, 16° C. or lower, or 10° C. or lower. Combinations of these ranges are also possible (e.g., 20° C. to 40° C.).

[0255] In some embodiments, the method includes swelling the polymeric material such that the inner and / or outer diameter increases at a rate that is greater than the rate of increase in length (as described herein). For example, in some embodiments, the method includes swelling the polymeric material such that the inner and / or outer diameter increases by 1-20%, while the length increases by 0.1-19%.

[0256] In some embodiments, the swelling occurs after administration. In some embodiments, swelling of the polymeric material after administration into an orifice in a subject closes the opening of the orifice. For example, in some embodiments, swelling of the polymeric material increases its size to a dimension equal to or greater than the size of the orifice into which it is inserted. In some embodiments, the orifice is a wound. In some embodiments, the swelling of the polymeric material causes hemostasis. For example, in some embodiments, a subject (e.g., a human) may have a bleeding orifice (e.g., a wound) with a maximum cross-sectional diameter A, and a device described herein having a maximum outer cross-sectional diameter less than A may be administered to the orifice. In some embodiments, the maximum outer cross-sectional diameter of the device may then expand to a dimension equal to or greater than A, such that the orifice is closed. In some embodiments, this can cause hemostasis.

[0257] In some embodiments, swelling occurs prior to administration. In some embodiments, swelling comprises rehydrating the device for a duration. In some embodiments, the duration is 60 minutes or less (e.g., 10 minutes or less, 5 minutes or less, 1 minute or less, or 10 seconds or less). In some embodiments, rehydrating the device comprises use of a rehydration medium. In some embodiments, the hydration medium comprises water, lactated Ringer's solution (LRS), dextrose (D5W), phosphate buffered saline (PBS), Hanks' Balanced Salt Solution (HBSS), and / or an isotonic salt solution.

[0258] kit In some aspects, kits are described. The kits may include any suitable items described herein. In some embodiments, the kits include a device (e.g., any embodiment or combination of devices described herein).

[0259] In some embodiments, the kit further comprises a humidity control sponge. The humidity control sponge may be composed of a woven, nonwoven, porous, and / or solid material containing water and / or a hydration medium. In some embodiments, the humidity control sponge is a water-swollen porous cellulose nonwoven. In some embodiments, the humidity control sponge further comprises an antiseptic or anti-infective agent (e.g., bleach, sodium hypochlorite, peroxide, and / or peracetic acid).

[0260] In some embodiments, the kit further comprises a hydration medium. Non-limiting examples of suitable hydration media include water, lactated Ringer's solution (LRS), dextrose (D5W), phosphate-buffered saline (PBS), Hanks' Balanced Salt Solution (HBSS), and / or isotonic salt solutions. In some embodiments, the kit includes a sufficient amount of hydration medium necessary to fully hydrate the device to EWC. In some embodiments, the hydration medium is stored in a container, fluid reservoir, tubing, syringe, bag, fluid pump, and / or packet. In some embodiments, the hydration medium is sterilized. In some embodiments, the hydration medium is buffered at or near physiological pH (e.g., 6.8-7.8).

[0261] In some embodiments, the kit is sterile (or aseptic). In some embodiments, the kit is sealed.

[0262] In some embodiments, the kit comprises instructions for use. In some embodiments, the instructions describe the methods of treatment described herein.

[0263] In some embodiments, the kit includes packaging. In some embodiments, the packaging comprises a flexible container. In some embodiments, the flexible container comprises flash-spun high-density polyethylene fibers. In some embodiments, the packaging comprises a tray into which the device can be placed for shipping.

[0264] Further definitions "Medically acceptable" means a non-toxic material that is highly purified to be free of contaminants. "Consists essentially of" is used in the context of biomaterials or medical devices to refer to a material or device that contains 3% (w / w) or less of other materials or components, provided that the 3% does not render the device unsuitable for its intended medical use. Equilibrium moisture content (EWC) is the moisture content at which a material reaches a constant wet weight before degradation occurs. Materials with high solids content are generally found to reach equilibrium moisture content within 24 to 48 hours. Distilled water is used to measure EWC unless otherwise specified.

[0265] 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 biologically acceptable materials intended for use in biomedical applications, such as implants, catheters, blood-contacting materials, tissue-contacting materials, diagnostic assays, medical kits, tissue sample processing, or other medical purposes. Furthermore, materials suitable for biomedical applications, but not limited thereto, can also be formulated as general-purpose materials. Physiological saline refers to a phosphate buffer solution with a pH of 7-7.4 at 37°C and an osmolality comparable to human physiological values.

[0266] 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 cross-linked. When the distance between cross-links is specified, it is the weight-average MW between the cross-links unless otherwise specified. k is an abbreviation for thousand, M is for ten thousand, and G is for billion, so 50kMW means 50,000 MW. The Dalton is also a unit of MW, and similarly refers to the weight-average when used for polymers.

[0267] All publications, journals, patents, and patent applications referred to herein are incorporated herein for all purposes, with the present specification taking precedence in the event of a conflict. Features of the embodiments described herein can be mixed and matched as guided by the need to produce an operable process or product.

[0268] As used herein, the term "therapeutic agent," also referred to as "drug," refers to an agent that is administered to a subject to treat or prevent a disease, disorder, or other clinically recognized condition, and that has a clinically significant effect on the subject's body to treat and / or prevent the disease, disorder, or condition.

[0269] As used herein, when an element is said to be "adjacent" to another element, it may be directly adjacent to (e.g., in contact with) that element, or there may be one or more intervening elements present. An element that is "directly adjacent" to another element means that there are no intervening elements present.

[0270] "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, and guinea pigs. Generally, the present invention is directed to use in humans. In some embodiments, a subject can exhibit health benefits, for example, upon administration of a self-standing device.

[0271] As used herein, "fluid" has its usual meaning, i.e., a liquid or a gas. A fluid cannot maintain a defined shape and flows over an observable time frame, filling the container in which it is placed. Thus, a fluid can have any suitable viscosity that allows it to flow. When two or more fluids are present, each fluid can be independently selected by one skilled in the art from essentially any fluid (liquid, gas, etc.). [Example]

[0272] 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.

[0273] Example 1: Evaluation of thrombogenicity of PVA gel PVA extrudate samples were prepared by placing 200 g of distilled water in a jacketed reactor at 95°C and increasing the temperature. 40 g of PVA (Sigma, 146k-186k) was added over a 5-minute period while stirring at 200 RPM. The polymer was mixed at 300 RPM for 1.5 hours. The polymer was degassed at 90°C for 2 hours. The polymer was then extruded into ethanol at -23°C and then stored in a freezer at -25°C for 24 hours. The sample was allowed to dry for 6 hours. After drying, the samples were immersed in glycerol at 120°C for 17 hours. After annealing, the samples were removed, cooled, and rinsed with ethanol. After rinsing, the cores were removed. The samples were dried at 50°C for 12 hours.

[0274] A barium sulfate-containing PVA sample was prepared by heating 50g of water to 90°C in a jacketed reactor. 4g of barium sulfate and 50g of water were homogenized in a side vessel at 11k RPM for 15 minutes and then added to the jacketed vessel. This mixture was mixed and heated for 10 minutes. After heating, 16g of PVA (Sigma, 146k-186k) was added and mixed at 360 RPM for approximately 2 hours. The PVA-RO polymer mixture was heated to 90°C and extruded into ethanol at -16°C. The extrudate was dehydrated at -25°C for 24 hours. The core was removed, and the sample was dried in an incubator at 50°C for approximately 6 hours. After drying, the sample was immersed in glycerol (Sigma) at 120°C for 17 hours. After annealing, the sample was removed, cooled, and washed with distilled water. The sample was dried at 50°C for 12 hours and packaged for testing.

[0275] The specimens were evaluated for non-thrombogenic durability at Thrombodyne (Salt Lake City, Utah). Each specimen was cut to a length of 15 cm, with N = 5 per specimen group. Prior to testing, the specimens were sterilized with ethylene oxide for 12 hours. Additionally, a hydrostatic test was performed in distilled water for approximately 48 hours, simulating clinical use.

[0276] 111 Fresh heparinized bovine blood containing In-labeled platelets was divided into test and control samples. The 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 throughout the study. Samples were first checked for the presence of thrombi after 45 minutes in the blood flow loop and then removed after 120 minutes. At the end of the experiment, the devices were removed from the tubing, washed with saline, and placed in a gamma counter for thrombus quantification. Experimental parameters are listed in Table 1. Each experiment consisted of separate flow systems for test sample and / or control circulating blood from the same animal to allow for simultaneous comparisons without crossover effects.

[0277] Samples were assayed for radioactivity and qualitatively evaluated for specific types of thrombus accumulation (i.e., adhesion or fibrin accumulation). The results are shown in Table 1. Thrombosis rates were calculated per animal in which blood was circulated, relative to the average total thrombus rate observed across all test and control groups. The results for thrombus accumulation are provided in Tables 2-3 and depicted in Figure 5A. Visual assessment of thrombus formation is shown in Figure 5B using the commercial control catheter, the 17% PVA extrudate, and the 17% PVA-barium sulfate extrudate.

[0278] TIFF2026027371000002.tif41141

[0279] TIFF2026027371000003.tif62157

[0280] TIFF2026027371000004.tif78148

[0281] Results: Compared with commercially available PICCs, PVA formulations reduced thrombus formation. PVA-RO (barium as RO agent) formulations were not superior to the control. Possible reasons for this include the lack of barium atomization and the presence of large barium particles on the surface of the extrudate.

[0282] Example 2: 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.

[0283] 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 replacement components were heated in a sealed polypropylene bottle and mixed in a Flaktech Speedmixer.

[0284] 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.

[0285] The cubed polymer was extruded using a Brabender 3 / 4" single-screw ATR. The heated polymer was placed in an ethanol bath at approximately 10°C and extruded into a 0.039" acetal core filament. The extruded PVA tubing (extrudate) was cut into 24" to 30" 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.

[0286] 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.

[0287] All samples were immersed in Carbopol 907 solution in a stainless steel circulating bath at 37°C for 16 hours.

[0288] After the indicated time, the samples were removed from immersion and mounted on a stainless steel mandrel. The dried samples were annealed 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.

[0289] The dried samples were cut into approximately 20 mm long sections. 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). All air was expelled from the lumen using a syringe.

[0290] At various time intervals, the samples were removed from the PBS, gently tapped with a lint-free lab wipe to remove excess PBS from the lumen and surface, and their length and mass were recorded before quickly placing them back into the PBS. The samples were allowed to hydrate for a total of 22 hours. The inner and outer diameters were measured again after 1 and 22 hours.

[0291] The rate of change of length, mass, and inner diameter (ID) / outer diameter (OD) is calculated using the following formula: Calculations were performed using TIFF2026027371000005.tif1682. The rate of change for each variable was calculated as the average value at each time point (see Table 4).

[0292] TIFF2026027371000006.tif93148

[0293] The rate of mass gain during rehydration varied slightly between 22.9% and 33.3% over the 22-h rehydration period, but no significant differences in mass gain were observed at any time point.

[0294] The rate of increase in length of the sample had a smaller standard deviation than the rate of increase in mass, making it a representative indicator of the level of hydration of the sample. The length increased by 2.9% after 2.5 minutes of hydration and 4.5% after 5 minutes. However, the increase in length leveled off after about 10 minutes of hydration, and no significant increase in length was observed thereafter (see Table 4).

[0295] The inner and outer diameters increased by 4.9% and 18.8% at 60 and 1320 minutes, respectively. Without wishing to be bound by theory, the large difference between the ID and OD is likely due to the fact that the ID is restricted in shrinkage by the core diameter during ethanol dehydration, drying, and annealing, resulting in greater retention of its initial sizing, whereas the OD is not restricted by post-extrusion processing and is therefore able to swell more upon hydration. The OD did not change significantly between 1 and 22 hours after hydration.

[0296] A 4F catheter extruded with a 0.039 inch core filament showed no further increase in length after hydration in 1×PBS at 21° C. for 10 minutes.

[0297] Example 3: Formation of macropores containing biologically active agents The following example illustrates the formation of a device containing a plurality of pores containing a biologically active agent. 1. A polyvinyl alcohol slurry is prepared by adding water and a porogen. The porogen may or may not be miscible with water. In some cases, the porogen may be a supersaturated salt solution (e.g., containing alkalis, alkaline earth materials, and halides, partially neutralized inorganic acids, and neutralized organic acids). For example, the porogen may be comprised of an oil (e.g., having a boiling point above 140°C). In some cases, the porogen may be dissolved in an alcohol. 2. The slurry is extruded into a continuous shape and cut to size. 3. Co-extrude the slurry onto the base substrate. 4. The base material is air, metal mesh, metal tube, thermoplastic polyurethane, thermoplastic elastomer, silicone, polyvinyl alcohol (88% or more hydrolyzed), poly(ethylene vinyl acetate), polyvinyl chloride, PETE, PETG, nylon, or PEEK. 5. Remove the porogen with water, alcohol, and / or surfactant. 6. Fill the macropores with a therapeutic solution containing a biologically active agent. 7. Dry and sterilize the device. 8. In use, the device is wetted with pressurized fluid, inserted, and expanded to release the biologically active agent.

[0298] Example 4: Solids content The following examples demonstrate the release of biologically active agents from one or more devices as described herein.

[0299] Chlorhexidine-loaded PVA materials were made using 2.5 w / w% or 6.0 w / w% chlorhexidine (CHX) free base (EMD Chemicals), 26 w / w%, 30 w / w%, and 33 w / w% poly(vinyl alcohol) of approximately 145 kg / mol molecular weight (28 cPs per 4 w / w%, 99+% hydrolyzed; EMD Chemicals), and a ratio of bismuth subcarbonate (Shepard) to PVA ranging from 1 to 2.85. The composites were then heated to 95°C in a ¾-inch Brabender extruder equipped with a 1:1 compression screw and extruded onto acetal (Dunn Industries) cores into 4 Fr tubing with an internal diameter of 0.90 mm. They were then dried and physically crosslinked. Table 5 provides the independent variables for Figures 6 and 7. There is a decrease in release rate with increasing PVA and bismuth subcarbonate. This release rate was generally independent of CHX loading. Figure 11 shows the release of CHX from exemplary devices (D-017-092-B3 and D-017-092-A3) compared to a commercially available product (Comparative Control 6) and an extruded hydrophilic polyurethane treated with the CHA soaking and annealing method (RSM-029-002) (Comparative Control 5).

[0300] TIFF2026027371000007.tif36140

[0301] Example 5: Drug-eluting patch A solution of 600 ppm chlorhexidine free base (CHX) in methanol was prepared. The CHX / methanol solution appeared to saturate near 1000 ppm. This solution was serially diluted, and concentrations above 200 ppm resulted in UV-Vis overload. To avoid UV-Vis overload, absorbance values ​​were collected at concentrations below 100 ppm. Figure 8 and Table 6 show the absorbance data collected from the chlorhexidine free base standard.

[0302] TIFF2026027371000008.tif25124

[0303] To convert the free radical version of chlorhexidine to the digluconate version, Table 7 and Equation 1 were used. Upon introduction of the salt, the biguanide group of chlorhexidine is protonated.

[0304] TIFF2026027371000009.tif41149

[0305] To convert the mass balance between different salts of chlorhexidine, use Equation 1: TIFF2026027371000010.tif20159 was used. "A" is the conversion coefficient.

[0306] Analysis of Comparative Control 3, Comparative Control 4, and the exemplary sample (Sample E30) revealed that the exemplary sample released 93% of the theoretical dose (2.28% dry) in 0.9% saline, while Comparative Controls 3 and 4 released less than 10% of the total chlorhexidine amount, as shown in Figure 9 (total chlorhexidine released in 2.21 mL of 0.9% saline per squeeze).

[0307] TIFF2026027371000011.tif57140

[0308] To determine whether common bacteria were fully covered, the MBC and MIC were compared with the squeeze-test release rates of Control 3, Control 4, and Sample E30. Comparing the maximum MBC (P. aeruginosa, 128 μg / mL) with the daily squeeze-test release rates, Control 3 was ineffective, Control 4 was effective for 2–3 days, and Sample E30 was effective for 4–5 days. When preparing an incision site, physicians typically use PVP-I or ChloraPrep®. Both are effective in reducing bacterial and yeast growth by at least 3 logs. If the incision site is properly cleansed, inhibiting bacterial and yeast growth is generally not necessary. Comparing the maximum MIC (A. baumannii, 64 μg / mL) with the daily squeeze-test release rates, Control 3 was effective for 1–2 days, Control 4 for 6–7 days, and Sample E30 for 5–6 days (Figure 10). Figure 10 shows a comparison of saturated release rates of foams containing chlorhexidine (normalized to the free base salt form). The highest known minimum bactericidal concentration (MBC) of chlorhexidine is for P. aeruginosa, and the widely known minimum inhibitory concentration (MIC) of chlorhexidine is for A. baumannii.

[0309] Example 6: Incorporation of Bupivacaine The following examples demonstrate the release of biologically active agents from one or more devices as described herein.

[0310] Bupivacaine-loaded PVA materials were made using 1.1 w / w% bupivacaine (Cayman Chemical), 26 w / w% poly(vinyl alcohol) with a molecular weight of approximately 145 kg / mol (28 cPs per 4 w / w%, 99+% hydrolyzed; EMD Chemicals), and bismuth subcarbonate (Shepard) to PVA ratios of 1 to 2.85 in 6.3 g / L aqueous monosodium phosphate (Sigma-Aldrich). The blend was then heated to 95°C in a ¾-inch Brabender extruder equipped with a 1:1 compression screw and extruded onto an acetal (Dunn Industries) core into 4 Fr tubing with a 0.90 mm inner diameter. The material was then dried and physically crosslinked using a forced-air convection oven. A plot of the % release profile of bupivacaine from the test device (DD010-176) is shown in Figure 12.

[0311] Example 7: Zone of Inhibition The following examples demonstrate the presence of a Zone of Inhibition (ZOI) for various organisms in response to the exemplary devices described herein.

[0312] This study evaluated the antimicrobial activity of two test and two control devices against three microorganisms: Staphylococcus Auereus (S. Auereus, MRSA), Escherichia coli (E. coli), and Candida albicans (C. albicans). The microorganisms were streaked onto Trypticase Soy Agar (TSA) plates and incubated at 37°C for approximately 24 hours. After incubation, the cultures were individually harvested in sterile PBS using a sterile inoculating loop. The concentration of each suspension was approximately 1 × 10 8The inoculum concentration was adjusted to CFU / mL. Serial dilutions of each suspension were prepared to confirm the inoculum concentration. A series of 1:10 dilutions were prepared on Mueller Hinton (MH) agar using the spread plating method to confirm the inoculum concentration used for the bacterial lawns. From the prepared suspensions, two (20) MH agar plates were inoculated with each challenge organism to create confluent microbial lawns. In each case, a sterile cotton swab was dipped into the prepared microbial suspension, excess liquid was squeezed out from the tip, and the swab was used to streak the surface of a 150 mm MH plate. Each test and control device was applied directly to the surface of three MH agar plates, each inoculated with a different microorganism. MH control plates, each inoculated with three different microorganisms, were treated with tetracycline discs and sterile blank discs (negative control discs). To ensure sterility, 0.1 mL of PBS was plated onto the MH agar using the spread plating method. All plates were incubated at 37°C for 24 hours. The zone of inhibition (ZOI), defined as the area of ​​growth inhibition on the plate, was observed under each test device and control and its perimeter was measured in millimeters. The zone for each control was measured through the diameter of the disk. The zone for each test device was measured across the diameter of the cylinder.

[0313] The inoculum test concentration was 1.8×10 8 CFU / mL, E. coli was 4.1 × 10 9 CFU / mL, C. albicans 3 × 10 6 The ZOI was calculated as CFU / mL. Each inoculum produced a heavy microbial lawn on the plate. Table 9 shows the ZOI measurements for the control and test devices, respectively. The control device, a PVA / PAA PICC device (containing poloxamer), did not exhibit a ZOI for any of the challenge organisms tested, but growth was observed under the test device. The positive control device (Comparative Control 7) and two compositions of PVA / PAA tubing containing chlorhexidine exhibited a ZOI of at least 5 mm for all organisms tested.

[0314] TIFF2026027371000012.tif57144

[0315] Example 8: Multilayer extrusion The following examples illustrate exemplary processes for forming the multilayer devices described herein.

[0316] Multilayer extruded tubing can be made using established multilayer thermoplastic extrusion techniques in combination with the forming techniques described herein. Two or more single-screw extruders can also be connected with a multilayer extrusion die head. Figure 13A shows an example of a two-layer system. In this example, to design a tubing with a drug-eluting lumen and a therapeutic-agent-free lumen surface, extruder A processes a batched aqueous suspension containing PVA, bismuth subcarbonate, sodium phosphate, and chlorhexidine, while extruder B processes a batched aqueous suspension containing PVA, bismuth subcarbonate, and sodium phosphate. The two extruders meet at a multilayer crosshead, with polymer B forming the outer layer and polymer A forming the inner layer. A solid, liquid, or gas core can be passed through the center of polymer A to form the lumen as described herein. To create a tubing with a drug-eluting abluminal surface and a therapeutic-agent-free lumen, a reverse process can be designed in which chlorhexidine is added to the suspension in extruder B but not to the suspension in extruder A.

[0317] Figure 13B shows an example of a three-layer system. Building on the previous example, three separate extruder systems are connected to a single multi-layer crosshead. Each layer can have a different therapeutic agent choice (Drug 1, Drug 2, Drug 3, No Drug). In one example, a first therapeutic agent (e.g., chlorhexidine) is added to the center layer, and a second therapeutic agent (e.g., bupivacaine) is added to the abluminal layer, with no therapeutic agent present on the abluminal side. In this example, the core (innermost layer) is fed to the crosshead, while extruder A delivers a polymer suspension containing bupivacaine (surrounding the innermost layer), extruder B delivers a polymer suspension containing chlorhexidine (peach), and extruder C delivers a polymer suspension without a therapeutic agent (outer layer). Removal of the core filament results in a three-layer tube containing different layers of homogeneously dispersed therapeutic agents.

[0318] Example 9: Increasing the inner and outer diameters The following examples show the increase in inner and outer diameter. A PVA-bismuth subcarbonate polymer solution (e.g., a first water-soluble polymer) was prepared using 42.0 g of bismuth subcarbonate, 179.25 g of 6.2 w / w% monobasic sodium phosphate solution, and poly(vinyl alcohol) 28-99. The mixture was heated in a sealed polypropylene bottle and mixed in a Flaktech Speedmixer.

[0319] 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.

[0320] The cube-shaped polymer was extruded using a Brabender 3 / 4" single-screw ATR. The heated polymer was placed in an ethanol bath at approximately 10°C and extruded into a 0.039" acetal core filament. The extruded PVA (extrudate) was cut into 24" to 30" segments. After dehydration in ethanol for approximately 16 hours, the core filament was removed, a PTFE-covered stainless steel mandrel was inserted into the lumen, and the sample was dried in a forced air convection oven at 95°C for 3 hours.

[0321] A hydrophilic solution was prepared using Carbopol 907, USP water, and PBS. The solution was heated and mixed until the solids were completely dissolved. All samples were immersed in the Carbopol 907 solution at 37°C for 17 hours and placed in a stainless steel circulating bath.

[0322] After the indicated time, the samples were removed from immersion and mounted on a stainless steel mandrel. The dried samples were annealed on the mandrel in a forced air oven at 150°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 55°C for 3 hours.

[0323] The dimensional changes of 24 prepared samples were measured using an optical microscope before and after swelling in 1x PBS at 37°C for 2 hours. The water content of the samples was approximately 4-6 w / w% in the "dehydrated" state and 30-35 w / w% in the EWC state.

[0324] Figure 14 shows the distribution of inner diameters (in millimeters) of the samples in the dry state, with an average inner diameter of 0.95 mm. Figure 15 shows the inner diameters of the samples in the swollen state, in millimeters, with an average inner diameter of 1.00 mm. It can be seen that the average inner diameter increased from 0.95 mm to 1.00 mm, a 5.3% increase.

[0325] Figure 16 shows the distribution of outer diameters in millimeters for the same sample in the dry state, with an average outer diameter of 1.30 mm. Figure 17 shows the distribution of outer diameters in millimeters for the same sample in the swollen state, with an average outer diameter of 1.38 mm. This shows an increase in the average outer diameter from 1.3 mm to 1.38 mm, a 6.2% increase.

[0326] Example 10: Mechanical Properties The following examples demonstrate the mechanical properties of PVA / PAA hydrogels. Uniaxial constant strain rate tensile tests were employed to observe the effect of varying the heat treatment temperature on the mechanical response of the composite PVA / PAA hydrogels. Uniaxial tensile tests of dry and fully hydrated hydrogel tubes were performed using an Instron 3343 tensile tester equipped with a 500 N load cell. Tubular specimens (N = 5 for each specimen set) were cut to a length of approximately 50 mm and stretched at a constant crosshead speed of 406.4 mm / min with a gauge length of 20.3 mm (constant strain rate of 0.33 s). -1 (corresponding to ). Load-displacement data were converted to engineering stress versus engineering strain using the specimen's initial cross-sectional area and gauge length, respectively. Specimens defined as "dry" were dehydrated in a forced-air convection oven at 55°C for 3 hours, and specimens defined as "hydrated" were conditioned in 1x PBS at 37°C for at least 2 hours before testing. Tests were conducted at ambient conditions using 25mm wide, rubber-coated, 1kN pneumatic grips.

[0327] Representative stress-strain curves of the heat-treated PVA / PAA composite hydrogels are shown in Figure 18. As shown in Figure 18, an increase in Young's modulus and yield stress was observed with increasing heat treatment temperature.

[0328] Example 11: Swelling properties The following example demonstrates the swelling properties of PVA / PAA hydrogels. The swelling of composite PVA / PAA hydrogels at various heat-treatment temperatures was evaluated at 10, 30, 60, 120, 240, and 480 min of hydration. Swelling from the dry state was performed under biological conditions (in an isotonic saline solution at 37 °C) to assess the time it takes implanted PVA / PAA hydrogels to reach their EWC. Most PVA-based hydrogels require several hours to reach their EWC and often exhibit mass swelling of more than 100% from the dry state. The heat-treated composite PVA / PAA hydrogels obtained in this study showed rapid initial swelling and a plateau where they reached their EWC in approximately 30–60 min.

[0329] According to the theory of rubber elasticity, the crosslink density of a polymer network structure and Young's modulus have the following relationship: TIFF2026027371000013.tif16157 where E is Young's modulus, ρ is density, R is the ideal gas constant, T is temperature, and Mc is the molecular weight between crosslinks. The average molecular weight between crosslinks of a hydrogel can also be calculated from equilibrium swelling theory. Assuming a Gaussian distribution of crosslinked polymer chains, the Flory and Rehner equation can be used to estimate the average molecular weight between crosslinks of non-ionic hydrogels. TIFF2026027371000014.tif21165 where v is the specific volume of the polymer (0.769 cm for 99% hydrolyzed PVA). 3 / g), V1 is the molar volume of water (18.1 cm 3 / mol), Mn is the number average molecular weight of the uncrosslinked polymer (~145,000 g / mol for 28-99 PVA), x is the polymer-solvent interaction parameter (x = 0.50 at 37 °C for water-PVA), V 2,S is the polymer volume fraction, which is determined as follows: TIFF2026027371000015.tif17158 where M S / M0 is the mass swelling ratio of the hydrogel at EWC, ρ p is the polymer density (1.30 g / cm for 99% hydrolyzed PVA) 3 ), ρ W is the solvent density (1.00 g / cm for water)3 ) Crosslink density, ρ c is M C It can be calculated from TIFF2026027371000016.tif15155

[0330] Figure 19 shows a plot of the measured average Young's modulus for each heat treatment group versus the crosslink density calculated based on Equation 5. As shown in Figure 19, there is a strong correlation between the two values ​​(R = 0.9687), indicating that the increase in Young's modulus of the PVA / PAA composite hydrogels was mainly due to an increase in physical crosslink density with the heat treatment temperature.

[0331] Figure 20 shows representative stress-strain curves for the untreated PVA / PAA composite hydrogel, the PVA / PAA composite hydrogel heat-treated at 150°C, and two conventional TPUs. As shown in Figure 20, the curve for the unhydrated PVA / PAA hydrogel exhibited significantly lower Young's modulus, break stress, and tensile energy to break (toughness) than the control TPU sample. Heat-treating the PVA / PAA composite at 150°C for 90 minutes transformed it from a ductile elastomer in the dry state to a brittle fracture behavior, whereas in the hydrated state, the heat-treated hydrogel exhibited mechanical properties comparable to those of polyurethanes currently used in vascular catheters. The mechanical properties achieved by heat-treating the PVA / PAA hydrogel at 150°C in this example were more than an order of magnitude better than those of a comparable high-strength PVA hydrogel material fabricated by the freeze-thaw method. The composite hydrogel of this example exhibited a Young's modulus of 24.21±3.98 MPa, whereas the control PVA hydrogel had a Young's modulus of less than 1 MPa when fully hydrated.

[0332] Table 10 summarizes the mechanical and swelling properties of the PVA / PAA hydrogels investigated in Examples 10 and 11 as a function of the temperature of heat treatment.

[0333] TIFF2026027371000017.tif57150

[0334] Example 12: Resistance of composite hydrogels to thrombotic occlusion The following example demonstrates the resistance of composite hydrogels to thrombotic occlusion. In this example, an established two-phase in vitro blood flow loop model was used to evaluate the resistance of samples to thrombotic occlusion. N=6 4F PVA / PAA hydrogel devices, along with a TPU sample comprising a control device, were hydrated in sterile saline for approximately 24 hours before testing. Fresh bovine blood was collected by cardiac puncture and heparinized to a concentration of 0.75 U / mL. Catheter samples were inserted into a 1 / 4-inch (6.4 mm) inner diameter polyvinyl chloride tubing blood flow loop for approximately 120 minutes (Phase 1: Flow). Blood was maintained at 37°C and continuously metered through the loop at 200 mL / min using a peristaltic pump throughout the test period to simulate physiological blood flow through the device. CaCl2 and minimal heparin were also spiked into fresh citrated bovine blood and dispensed into separate vials. After the flow phase, the device was removed from the heparinized blood circuit, and the distal tip of the catheter sample was inserted into a recalcified blood vial and incubated at 37°C until a clot formed (second phase: resting). After the clot formation phase, the device was removed from the vial and gently rinsed with saline to remove loose blood, taking care not to dislodge any attached clot. To assess luminal patency, a four-way stopcock was attached to the Luer hub of each catheter. A pressure gauge was attached to one port, and a syringe containing saline was attached to the other port. Pressure was applied to the syringe to flush saline into the lumen, and the maximum injection pressure was recorded. This two-phase in vitro blood loop model is useful for evaluating device resistance to thrombotic occlusion. While a qualitatively large amount of clot was observed at the tip of the conventional TPU catheter device (Comparative Example 1), only minimal clot accumulation was observed at the tip of the Comparative Example 2 catheter and the PVA / PAA composite hydrogel sample. One of the PVA / PAA hydrogel samples leaked at the junction of the overmolded suture wings during patency check and was therefore excluded from further analysis.

[0335] Figure 21 is a box plot of the mean ± standard deviation of the maximum injection pressure of the TPU control samples compared to the composite hydrogel devices. As shown in Figure 21, the composite PVA / PAA hydrogel devices exhibited an average of 67% lower maximum injection pressure compared to conventional TPU. Furthermore, typical pressures for adult intravenous infusion devices are less than 150 mmHg; therefore, maximum pressures greater than 150 mmHg are considered occluded. While seven of the 12 comparative control catheters exhibited characteristics of occlusion, none of the composite PVA / PAA hydrogel devices (N=0) exhibited maximum injection pressures greater than 150 mmHg, and therefore, all were considered patent.

[0336] Example 13: Contact angle measurements of dry and hydrated PVA-based hydrogels The following example demonstrates contact angle measurements of dried and hydrated PVA-based hydrogels. Contact angle measurements were performed on PVA tubing, PVA / PAA composite hydrogels, and two control catheter bodies. Measurements were performed after 1 hour of exposure to 1x PBS at 37°C, both in the as-packaged and dehydrated state. Contact angle measurements were performed using a custom-built contact angle goniometer with an Excelis Accu-scope digital camera attached to a Unitron Z850 optical stereo microscope (20x magnification). Contact angles were determined by fitting at least three drop profiles using ImageJ software and averaging the left and right contact angles, for a total of six angle measurements per sample group. Initial contact angles were recorded within 10 seconds of placing a standard 2 μL drop on the hydrogel or polymer surface using a pipette.

[0337] Figure 22 shows representative optical images of 2 μL water droplets on a dehydrated PVA / PAA composite hydrogel tube (Figure 22A), a hydrated PVA / PAA composite hydrogel tube (Figure 22B), a hydrated TPU tube of Comparative Control 1 (Figure 22C), and a hydrated TPU tube of Comparative Control 2 (Figure 22D). The scale bar for each image is 1 mm. Table 2 shows the mean ± standard deviation results for each group. As shown in Table 2, the contact angles of the commercially available TPUs were slightly hydrophobic in the packaged state (93 ± 7° for Comparative Example 1 and 99 ± 7° for Comparative Example 2) compared to the hydrophilic surface of the dehydrated PVA / PAA hydrogel material (17 ± 6°). After rehydration, the contact angles of the commercially available TPU catheters slightly decreased, but the PVA / PAA hydrogel materials were found to be completely wetted.

[0338] TIFF2026027371000018.tif41126

[0339] Example 14: Use of glycerol as a moisturizing agent The following example demonstrates the use of glycerol as a humidifying agent. In contrast to poloxamer, the use of glycerol accelerated the initial hydration of the catheter, eliminating curling and pigtailing during the first 5 minutes of hydration. The catheters using glycerol continued to grow after 1 hour. After 60 minutes, the hydration profile of the catheters using glycerol matched that of 10% poloxamer 407.

[0340] The results of this example showed that using a higher concentration of glycerol increased the hydration rate during the first 5 minutes of hydration, but did not significantly improve or decrease the rate at which the catheter grew from 5 minutes to 24 hours. The glycerol / poloxamer mixture showed a decreased change in length from 1 hour to 24 hours compared to the pure glycerol group.

[0341] We also found that prolonged exposure to heat following accelerated aging protocols and ISTA 2A conditioning of glycerol-infused catheters altered their hydration profile. After 5 minutes, pigtailing occurred, resulting in failure to meet the 5-minute hydration criteria. To address this issue, a humidity control sponge (Humidichip®, Andersen Products) was placed inside the catheter overpouch and sealed in a Tyvek pouch. After 5 minutes, this group passed both visual and quantitative criteria.

[0342] Figure 23 is a bar graph showing the percent length change over time for the 30% glycerol group compared to the 10% Poloxamer 407 group. As shown in Figure 23, significant lengthening continues even after 1 hour.

[0343] Figure 24 is a bar graph showing that adding a humidity control sponge inside the packaging improved thermal stability by eliminating curling and pigtailing after 5 minutes of hydration after exposure to extreme changes in temperature.

[0344] Example 15: Glycerol Removal During Hydration The following example demonstrates how much glycerol mass was removed from a catheter body during 5 minutes of hydration. Glycerol is a powerful humectant, drawing moisture from the surrounding environment and creating its own solution. This property made it an ideal material for maintaining moisture in the catheter body during storage and hydration of PVA / PAA PICC devices (containing glycerol). While intravenous administration of glycerol is well tolerated and understood, it was important to evaluate the amount of glycerol to which patients were exposed. In this example, six PVA / PAA PICC devices (containing glycerol) were used. They were sterilized in Tyvek pouches and packaged in a secondary foil pouch with a moisture-regulating sponge. This method only removes glycerol by exposure to normal saline and then oven-drying to remove residual moisture. Due to the high boiling point and vapor pressure of glycerol, it was expected that only a small amount would evaporate when exposed to a drying temperature of 55°C, while a significant amount of water would evaporate. The catheter body was cut at the suture wings to a length of 55 cm when hydrated.

[0345] TIFF2026027371000019.tif57129

[0346] The catheter body, removed from the foil pouch and sterile barrier, contained 11.0% ± 0.3% mobile mass by weight. Mobile mass was defined as liquid-removable material. 4.5% ± 0.3% was determined to be water and 5.6% ± 0.3% was determined to be glycerol. The catheter was understood to retain water through hydrogen bonding. This bound water was believed to be permanently bound to the catheter as it was shipped, hydrated, and in use during normal use. This bound water began to be removed from the catheter body material at temperatures above 90°C.

[0347] After 5 minutes of hydration with saline, the catheter body was found to contain 0.6% ± 0.3% by weight of glycerol and an additional 25% ± 2% by weight of saline. Of the total glycerol, 90% ± 6% by weight of the tart catheter body was removed within the first 5 minutes.

[0348] TIFF2026027371000020.tif36149

[0349] The total glycerol content per 55 cm segment was 0.030 g ± 0.002 g. After 5 minutes of hydration, the glycerol content decreased to 0.003 g ± 0.002 g (3 mg ± 2 mg). 3 mg ± 2 mg is considered a safe level for venous exposure.

[0350] TIFF2026027371000021.tif47136

[0351] In this example, the catheter was dried and then hydrated, which increased the amount of water required to hydrate the catheter compared to when the physician hydrated it from the pouch or kit. This additional drying step increased the drying time compared to a catheter hydrated directly from the pouch. For these reasons, the additional drying step (D1) was considered the worst-case scenario.

[0352] According to the IFU, the majority of the glycerol was removed from the catheters within 5 minutes of hydration. Gravimetric measurements showed further glycerol removal between 5 minutes and 48 hours after hydration of the catheter body (n = 6, paired t-test, p = 0.007, CI 95%). Additionally, the mass of glycerol dissolved after 5 minutes of hydration was measured. When immersed in saline from the as-packaged state for 5 minutes (per IFU), the catheters gained 31 ± 2 wt% saline and lost 5.6 ± 0.7 wt% glycerol. The net mass gain after 5 minutes of hydration was 25 ± 2 wt% after removal from the pouch.

[0353] Illustrative Embodiments 1. A process for producing a hydrophilic porous solid, comprising heating a mixture comprising at least one water-soluble polymer, a solvent, and at least one therapeutic agent to a temperature above the melting point of the polymer-solvent mixture, and passing the mixture through a solvent removal environment. 2. The process of claim 1, wherein forming the mixture comprises extruding, molding, casting, or thermoforming the mixture through a die. 3. The process of claim 1, wherein forming the mixture includes extruding the mixture through a die, the mixture is not heated above the boiling point of the mixture, and the mixture is formed from a temperature below the melting point of the polymer-solvent mixture. 4. The process of paragraph 1, wherein forming the mixture comprises extruding the mixture through a die, and further comprises passing a core through the die, wherein a porous solid is formed around the core. 5. The process according to paragraph 1, wherein the porous solid is a hydrophilic nanoporous solid, and the size of the pores in the solid is 100 nm or less.

[0354] 6. The process of paragraph 5, wherein the porous solid has a Young's modulus of at least 5 MPa at the EWC of the porous solid. 7. The process of paragraph 1, wherein the porous solid is a hydrophilic microporous solid containing pores with a diameter of 100 nm or more, and the pores of the solid have a size of 1 μm or less. 8. The process of paragraph 1, wherein the at least one polymer comprises poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, or poly(vinylpyrrolidone), polyalkyleneimine, polyacrylamide, hydroxypropylmethacrylamide, polyoxazoline, polyphosphate, polyphosphazene, hyaluronic acid, chitosan, or a polysaccharide. 9. The process of paragraph 1, 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 polymers and solvent in the mixture. 10. The process of paragraph 1, further comprising a radiopaque agent in the polymer mixture.

[0355] 11. The process of paragraph 1, carried out without covalently crosslinking at least one water-soluble polymer. 12. The process of paragraph 1, wherein the porous solid has an aspect ratio of at least 10:1. 13. A medical device (or catheter) for vascular access, comprising a porous, dehydrated, physically crosslinked, synthetic hydrophilic polymer hydrogel having a Young's modulus of at least 5 MPa, further comprising a therapeutic agent dispersed throughout the hydrogel for sustained release of an effective amount through the lumen or luminal surface into the bloodstream (or target site) for at least about one day at the equilibrium water content (EWC) of the solid, wherein the hydrogel has a water content of at least about 10% by weight or volume when fully hydrated. 14. The catheter according to item 13, characterized in that the solid is a hydrophilic nanoporous solid, the pores of which are 100 nm or less in size. 15. The catheter according to item 13, wherein the porous solid comprises at least one polymer, and 50 w / w% or more of the at least one polymer is poly(vinyl alcohol) (PVA).

[0356] 16. The catheter according to item 13, which is made of a porous solid having a lumen and is a central venous catheter, a peripherally inserted central catheter (PICC), a tunneled catheter, a dialysis catheter, a central venous catheter, a peripheral central catheter, a midline catheter, a peripheral catheter, or a tunneled catheter. The catheter is a peripheral catheter, a tunneled catheter, a dialysis access catheter, a urinary system catheter, a neurological system catheter, a peritoneal catheter, an intra-aortic balloon pump catheter, a diagnostic catheter, an interventional catheter, a vascular access port, or a drug delivery catheter. 17. A device comprising a body portion, the body portion being formed from a polymeric material comprising a first water-soluble polymer and a biologically active agent associated with the polymeric material, the biologically active agent being substantially homogeneously distributed within the polymeric material, the device having an elongation at break of 50% or greater, and / or the device having an increase in overall length in the equilibrium hydration state of 1% or greater compared to its overall length in the dehydrated state. 18. A device comprising a body portion, the body portion formed from a polymeric material comprising a first water-soluble polymer, the body portion comprising a plurality of pores, a second water-soluble polymer disposed within at least a portion of the plurality of pores of the body portion, and a biologically active agent associated with the first water-soluble polymer and / or the second water-soluble polymer, wherein the biologically active agent is substantially uniformly distributed within the first water-soluble polymer. 19. The device according to paragraph 17 or 18, wherein the device is substantially non-thrombogenic.

[0357] 20. A device comprising a body portion, the body portion being formed from a polymeric material comprising a first water-soluble polymer and a biologically active agent associated with the polymeric material, the biologically active agent being substantially homogeneously distributed within the polymeric material, the polymeric material having a Young's modulus of elasticity of 500 MPa or greater in a dehydrated state and a Young's modulus of elasticity of 300 MPa or less and 5 MPa or greater in an equilibrium water content state. 21. A device including a body portion, the body portion being formed from a polymeric material including a first water-soluble polymer and including a biologically active agent associated with the polymeric material, the biologically active agent being substantially homogeneously distributed within the polymeric material, the polymeric material having a water content of less than 5 wt.% and greater than or equal to 0.5 wt.% in a dehydrated state, the device being configured to swell from the dehydrated state to an equilibrium moisture content state by an amount of greater than or equal to 50 wt.% in 60 minutes or less (e.g., 10 minutes or less, 20 minutes or less) at 25°C (e.g., 10 minutes or less, 5 minutes or less, 1 minute or less, or 10 seconds or less). 22. A device comprising a body portion, the body portion being formed from a polymeric material comprising a water-soluble polymer and a biologically active agent associated with the polymeric material, the biologically active agent being present in the device in an amount of 0.01 w / w% or greater, based on the total weight of the device in a dehydrated state, and the polymeric material having a Young's modulus of 500 MPa or greater in a dehydrated state and a Young's modulus of 300 MPa or less and 5 MPa or greater in a state of equilibrium moisture content. 23. A device comprising a body portion, the body portion being formed from a polymeric material comprising a first water-soluble polymer and a biologically active agent associated with the polymeric material, the biologically active agent being substantially homogeneously distributed within the polymeric material, and the device being configured so that the biologically active agent is released from the polymeric material at a first average rate determined 24 hours after release and at a second average rate after 30 days that is at least about 1% of the first average rate. 24. A catheter configured for administration to a subject, the catheter comprising a body portion formed from a polymeric material comprising a first water-soluble polymer and a biologically active agent substantially homogeneously dispersed within the polymeric material. 25. A catheter configured for administration to a subject, comprising: a body portion formed from a polymeric material comprising a first water-soluble polymer and a biologically active agent dispersed within the bulk of the polymeric material, wherein the biologically active agent is present in the catheter in an amount of 0.01% by weight based on the total weight of the catheter in a dehydrated state.

[0358] 26. A method of forming a device, the method comprising: extruding a mixture comprising a first water-soluble polymer and a salt, wherein the first water-soluble polymer is present in the mixture in an amount of 13 wt% or more based on the total weight of the mixture, onto a core at a temperature of 65°C or more to form a polymeric material disposed on the core; and exposing the polymeric material to a non-solvent for the polymeric material at a temperature of 28°C or less for 15 minutes or more; introducing a solution comprising a biologically active agent into the polymeric material; heating the polymeric material and the solution to a temperature of 30°C or more; flowing the solution adjacent to the polymeric material; and drying the polymeric material, wherein the biologically active agent is substantially uniformly distributed within the polymeric material and is within 50% or less of the average loading of the biologically active agent within the polymeric material. 27. The method of claim 26, wherein the solution comprises a second water-soluble polymer, which is the same as or different from the first water-soluble polymer. 28. The method of any preceding claim, wherein a second solution comprising a second water-soluble polymer, the second water-soluble polymer being the same as or different from the first water-soluble polymer, is allowed to flow adjacent to the polymeric material for one hour or more. 29. The method of any preceding claim, comprising annealing the polymeric material at a temperature of 100°C or greater at atmospheric pressure for 30 minutes or more. 30. The method according to the preceding paragraph, characterized in that the core material is a gas.

[0359] 31. A method comprising administering to an external orifice of a subject a device comprising a body portion, wherein the body portion comprises a polymeric material comprising a water-soluble polymer and a biologically active agent associated with the polymeric material, the device having an aspect ratio of 3:1 or greater, and the biologically active agent being substantially homogeneously distributed within the polymeric material. 32. The method of claim 31, wherein the polymeric material is substantially non-thrombogenic. 33. The method of any preceding claim, wherein the biologically active agent is present in the device in an amount of 0.01 w / w% or greater, based on the total weight of the device. 34. The method of any preceding paragraph, wherein the polymeric material has a water content of less than 5 wt / w% and greater than or equal to 0.1 wt / w% in a dehydrated state, and the polymeric material is allowed to return from the dehydrated state to an equilibrium moisture content state in an amount greater than or equal to 5 wt / w% and less than 50 wt / w% in 60 minutes or less (e.g., 10 minutes or less, 5 minutes or less, 1 minute or less, or 10 seconds or less). 35. The device of any preceding paragraph, further comprising 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.

[0360] 36. A device according to any one of items 1 to 3 above, characterized in that the polymer 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 in an equilibrium moisture content state. 37. The device of any preceding paragraph, 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.%; and wherein the polymeric material can be hydrated from the dehydrated state to an equilibrium moisture content state in an amount greater than or equal to 50 wt.% and less than or equal to 50 wt.% in 60 minutes or less (e.g., 10 minutes or less, 5 minutes or less, 1 minute or less, or 10 seconds or less) at 25°C. 38. The device described in any one of items 1 to 3 above, wherein the plurality of pores have an average pore size of 500 nm or less and 10 nm or more. 39. The device of the preceding paragraph, wherein at least 50% of the plurality of pores have a diameter of 1 μm or less. 40. The device of any preceding paragraph, configured to swell from a dehydrated state to an equilibrium moisture content state by an amount of at least 5 w / w% and not more than 50 w / w%.

[0361] 41. A device according to any preceding paragraph, wherein the device has a coefficient of friction of 0.10 or less at equilibrium moisture content. 42. A device according to any preceding paragraph, wherein the device comprises an osmotic agent present in the polymeric material in an amount of not less than 0.0.5 w / w% and not more than 2 w / w% based on the total weight of the device. 43. The device of any of the preceding paragraphs, wherein the osmotic agent is selected from the group including phosphates, borates, sodium chloride, citrates, ethylenediaminetetraacetates, sulfites, hyposulfites, metal oxides, selenium dioxide, selenium trioxide, selenic acid, selenic acid, nitrates, silicates, and peony acid. 44. A device according to any preceding claim, wherein the polymeric material has a water contact angle of 45 degrees or less at equilibrium water content. 45. The device of any preceding paragraph, wherein the first water-soluble polymer does not comprise a covalent crosslinker.

[0362] 46. ​​The device of any preceding paragraph, wherein the first water-soluble polymer is selected from the group including poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylic acid sulfobetaine), poly(acrylic sulfobetaine), poly(methacrylic acid carboxybetaine), poly(acrylic carboxybetaine), povidone, polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof. 47. The device of any preceding paragraph, wherein the second water-soluble polymer is selected from the group including poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, or poly(vinylpyrrolidone), poly(methacrylic acid sulfobetaine), poly(acrylic sulfobetaine), poly(methacrylic acid carboxybetaine), poly(acrylic carboxybetaine), povidone polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof. 48. The device of any preceding paragraph, wherein the device is configured for use with a medical device such as a catheter, balloon, shunt, wound drain, injection port, drug delivery device, tubing, contraceptive device, feminine hygiene product, endoscope, graft, pacemaker, implantable cardioverter defibrillator, cardiac resynchronization device, lead for cardiovascular device, ventricular assist device, endotracheal tube, tracheostomy tube, implantable sensor, ventilator pump, ophthalmic device. 49. The device of paragraph 48, wherein the catheter is selected from the group comprising a central venous catheter, a peripheral central catheter, a midline catheter, a peripheral catheter, a tunneled catheter, a dialysis access catheter, a urinary system catheter, a neurological system catheter, a percutaneous transluminal angioplasty catheter, and a peritoneal catheter. 50. The device of any preceding paragraph, wherein the second water-soluble polymer is disposed within the bulk of the first water-soluble polymer. 51. The device of any preceding paragraph, 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 flushing the device with 5 volumes of water or normal saline.

[0363] While several embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily recognize and appreciate that a variety of other means and / or structures for performing the functions and / or obtaining the results and / or advantages described herein are readily apparent, 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 recognize 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 particular application for which the teachings of the present invention are used. Many equivalents to the several embodiments of the present invention described herein will be recognized by those skilled in the art, or will be ascertainable using no more than routine experimentation. It is to be understood that the foregoing embodiments are presented hereby by way of example only, that within the scope of the appended claims and their equivalents, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, and / or method described herein. Also, any combination of two or more such features, systems, articles, materials, and / or methods, if such combinations are not mutually inconsistent, is within the scope of the present invention.

[0364] As used in the specification and claims, the indefinite articles "a" and "an" should be understood to mean "at least one," unless expressly indicated otherwise.

[0365] As used in the specification and claims, the phrase "and / or" should be understood to mean "either or both" of conjugated elements, i.e., elements that are present conjunctively in some cases and present separately in others. Unless expressly indicated, other elements may optionally be present other than the elements specifically identified by the "and / or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "A and / or B," when used in conjunction with open-ended language such as "comprising," means, in one embodiment, A without B (optionally including elements other than B); in another embodiment, B without A (optionally including elements other than A); in yet another embodiment, both A and B (optionally including other elements); and so forth.

[0366] As used in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" is inclusive, i.e., It should be construed to include at least one, including more than one, of a number or list of elements, and optionally, additional unlisted items. Only an explicitly stated item, e.g., "only one of" or "exactly one of," or, when used in the claims, "consisting of," means including exactly one of a number or list of elements. Generally, the term "or" as used herein will only be construed as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." When used in the claims, "consisting essentially of" has its ordinary meaning as used in the field of patent law.

[0367] As used in the specification and claims, the phrase "at least one" in reference to a list of one or more elements should be understood to mean at least one element selected from one or more elements in the list of elements, but not necessarily including at least one of each element specifically listed in the list of elements, and not necessarily excluding combinations of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements, meaning related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can mean, in one embodiment, at least one, including optionally more than one, A (optionally including elements other than B) without B; in another embodiment, at least one, including optionally more than one, B (optionally including elements other than A) without A; in yet another embodiment, at least one, including optionally more than one, A and at least one, including optionally more than one, B (optionally including other elements); etc.

[0368] Throughout the claims, as well as throughout the specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," and the like, are intended to be open-ended, i.e., to mean including, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" are closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0369] The terms used herein relate, for example, to the shape, orientation, alignment, and / or geometric relationships of one or more devices, structures, forces, fields, flows, directions / trajectories, and / or subcomponents thereof, and / or combinations thereof, and / or other tangible or intangible elements not listed above that are characterized by such terms. Unless otherwise defined or indicated, it is understood that absolute conformance to the mathematical definition of such terms is not required, but rather indicates conformance to the mathematical definition of such terms to the extent possible given the requirements characterized, as understood by one of ordinary skill in the art closest to such requirements. Examples of terms related to shape, direction, and / or geometric relationships include, but are not limited to, terms describing: shape - e.g., circle, square, rubber block, circle / circle, rectangle / rectangle, triangle / triangle, cylinder / cylinder, ellipse / ellipse, (n)polygon / (n)polygonal body, etc.; angular direction - e.g., perpendicular, orthogonal, parallel, perpendicular, horizontal, collinear, etc.; contour and / or trajectory - e.g., perpendicular, orthogonal, parallel, perpendicular, horizontal, collinear, etc.; contour and / or trajectory (plane, coplanar, hemisphere, hemihemispheric, line, straight, hyperbola, parabola, plane, curve, straight, arc, sinusoidal, tangent / tangent, etc.); orientation (north, south, east, west, etc.). Surface and / or bulk material properties and / or spatial / temporal resolution and / or distribution (smooth, reflective, transparent, clear, opaque, rigid, impermeable, uniform, inert, non-wettable, insoluble, stable, immutable, constant, homogeneous, etc.), as well as many others that will be apparent to one of ordinary skill in the relevant art. As one example, a fabricated device described herein as "square" does not require that such device be perfectly planar or straight, having faces or sides that intersect at exactly 90-degree angles (indeed, such a device may exist only as a mathematical abstraction); rather, the shape of such a device should be understood to approximate a "square" as mathematically defined, to the extent that is typically achievable and achievable for the fabrication techniques described, as one of ordinary skill in the art would understand, or as specifically described.As another example, two or more fabricated devices described herein as "aligned" need not have perfectly aligned faces or sides (indeed, such devices exist only as a mathematical abstraction); rather, the arrangement of such devices should be understood to approximate "aligned" as mathematically defined to the extent that it is typically achievable for the described fabrication technology, as understood by one of ordinary skill in the art or as specifically described. [Explanation of symbols]

[0370] 10, 12, 14, 100, 320, 340 … devices 20 … Main body part 25... Core 30 … Hole 40...Water-soluble polymer 50...Biologically active agents 102 ... Syringe pump 104... Syringe 106 ... Die head 108 ... Heating element 109 ... Power cable 110 ... Distribution spool 112... Core 114 ... spool 116 ... Bath 117 ... Extrusion materials 118 … Heat exchanger 120...Heat exchange pipe 122 ... supply line 212 ... Porous solid matrix 214 ... Bulk-Incorporated Polymers 216...Outermost Zone 218... Intermediate Zone 220... Inner Zone 300 … overall length 301...inner diameter 302 … outer diameter 304...inner diameter 305...Outer diameter

Claims

1. A main body portion formed from a polymer material containing a first water-soluble polymer, and Biological activators related to the polymer material Includes, The biological activator is substantially uniformly distributed within the polymer material. A device having an elongation at break of 50% or more, and / or whose total length at equilibrium moisture content is 1% or more greater than its total length in the dehydrated state.

2. A main body portion formed from a polymer material containing a first water-soluble polymer, and Biological activators related to the polymer material Includes, The biological activator is substantially uniformly distributed within the polymer material. A device in which the polymer material has a Young's modulus of 500 MPa or more in a dehydrated state and a Young's modulus of 5 MPa or more and 300 MPa or less in an equilibrium moisture content state.

3. A main body portion formed from a polymer material containing a first water-soluble polymer, and Biological activators related to the polymer material Includes, The biological activator is substantially uniformly distributed within the polymer material. The polymer material has a water content of less than 5 w / w% and 0.1 w / w% or more in a dehydrated state. A device in which the polymer material is configured to swell from a dehydrated state to an equilibrium moisture content state by an amount of 5 w / w% to 50 w / w% within 60 minutes at 25°C.

4. A main body portion formed from a polymer material containing a water-soluble polymer, and Biological activators related to the polymer material Includes, The biological activator is present in the device in an amount of 0.01 w / w% or more relative to the total weight of the dehydrated device. A device in which the polymer material has a Young's modulus of 500 MPa or more in a dehydrated state and a Young's modulus of 5 MPa or more and 300 MPa or less in an equilibrium moisture content state.

5. A main body portion formed from a polymer material containing a first water-soluble polymer, and Biological activators related to the polymer material Includes, The biological activator is substantially uniformly distributed within the polymer material. A device configured such that the biological activator is released from the polymer material at a first average rate determined 24 hours after release, and at a second average rate of at least about 1% of the first average rate after 30 days.

6. A main body portion formed from a polymer material containing a first water-soluble polymer, and A biologically active agent substantially uniformly distributed within the polymer material. A catheter configured to administer to a target, including the following:

7. A main body portion formed from a polymer material containing a first water-soluble polymer, and A biologically active agent substantially uniformly distributed within the polymer material. Includes, A catheter configured for administration to a subject, wherein the biological activator is present in the catheter at an amount of 0.01 w / w% relative to the total weight of the dehydrated catheter.

8. The device according to any one of claims 1 to 5, wherein the polymer material is configured to swell by an amount of 5 w / w% or more relative to the equilibrium water content state.

9. The device according to any one of claims 1 to 5 and 8, wherein the polymer material is configured to swell to an equilibrium water content state within a period of 60 minutes or less at 25°C.

10. The device according to any one of claims 1 to 5 and 8 to 9, wherein the device comprises a humectant.

11. The main body portion has an inner diameter, an outer diameter, and a length. The device according to any one of claims 1 to 5 and 8 to 10, wherein the polymer material is configured to swell such that the inner diameter and / or outer diameter increases at a rate greater than the rate of increase of the length.

12. The device according to any one of claims 1 to 5 and 8 to 11, wherein the main body portion has a plurality of holes.

13. The device according to any one of claims 1 to 5 and 8 to 12, further comprising a biological activator.

14. The device according to any one of claims 1 to 5 and 8 to 13, wherein the biological activator is present in the device in an amount of 0.01 w / w% or more relative to the total weight of the device.

15. The polymer material has a water content of less than 5 w / w% and 0.1 w / w% or more in a dehydrated state. The device according to any one of claims 1 to 5 and 8 to 14, wherein the polymer material is configured to swell from a dehydrated state to an equilibrium moisture content state in an amount of 5 w / w% to 50 w / w% within 60 minutes.

16. The device according to any one of claims 1 to 5 and 8 to 15, wherein the device is a catheter.

17. The device according to any one of claims 1 to 5 and 8 to 16, wherein the aforementioned period is 10 minutes or less.

18. The device according to any one of claims 1 to 5 and 8 to 17, wherein the aforementioned period is 5 minutes or less.

19. The device according to any one of claims 1 to 5 and 8 to 18, wherein the aforementioned period is 1 minute or less.

20. The device according to any one of claims 1 to 5 and 8 to 19, wherein the period is 30 seconds or less.

21. The device according to any one of claims 1 to 5 and 8 to 20, wherein the aforementioned period is 10 seconds or less.

22. The device according to any one of claims 1 to 5 and 8 to 21, wherein the humectant comprises a sugar alcohol and / or poloxamer.

23. The device according to any one of claims 1 to 5 and 8 to 22, wherein the humectant comprises poloxamer, polyethylene glycol, glycerol, propylene glycol, ethylene glycol, butylene glycol, erythritol, slaytol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fukitol, iditol, inositol, boremitol, maritol, lactitol, maltotriitol, maltotetraitol, and / or polyglycitol.

24. The device according to any one of claims 1 to 5 and 8 to 23, wherein the humectant comprises poloxamer, sorbitol, mannitol, glycerol, ethylene glycol, and / or xylitol.

25. The device according to any one of claims 1 to 5 and 8 to 24, wherein the humectant comprises glycerol.

26. A device according to any one of claims 1 to 5 and 8 to 25, comprising 0.1 to 30 w / w% of a humectant.

27. A device according to any one of claims 1 to 5 and 8 to 26, comprising 1 to 10 w / w% of a humectant.

28. The device according to any one of claims 1 to 5 and 8 to 27, wherein at least a portion of the humectant is disposed on the surface of the main body portion.

29. The device according to any one of claims 1 to 5 and 8 to 28, wherein at least a portion of the humectant is located inside the bulk of the main body.

30. The device according to any one of claims 1 to 5 and 8 to 29, wherein the inner diameter and / or outer diameter increases by 1 to 20%, while the length increases by 0.1 to 19%.

31. The device according to any one of claims 1 to 5 and 8 to 30, wherein the equilibrium water content state is 20 w / w% or more and 80 w / w% or less.

32. The device according to any one of claims 1 to 5 and 8 to 31, wherein the water content is 6 w / w% or more and 40 w / w% or less.

33. The device according to any one of claims 1 to 5 and 8 to 32, wherein the water content is 2 w / w% or more and 10 w / w% or less.

34. The device according to any one of claims 1 to 5 and 8 to 33, wherein the main body portion further comprises a second water-soluble polymer which is the same as or different from the first water-soluble polymer and is disposed within at least a portion of the plurality of pores.

35. The device according to any one of claims 1 to 5 and 8 to 34, wherein the polymer material has a Young's modulus of 500 MPa or more in a dehydrated state and a Young's modulus of 5 MPa or more and 300 MPa or less in an equilibrium moisture content state.

36. The polymer material has a water content of less than 5 w / w% and 0.1 w / w% or more in a dehydrated state. The device according to any one of claims 1 to 5 and 8 to 35, wherein the polymer material is configured to swell from a dehydrated state to an equilibrium moisture content state by an amount of 5 w / w% to 50 w / w% within 60 minutes at 25°C.

37. The device according to any one of claims 1 to 5 and 8 to 36, wherein the plurality of holes have an average pore size of 10 nm to 500 nm.

38. The device according to any one of claims 1 to 5 and 8 to 37, wherein at least 50% of the plurality of holes have a diameter of 1 μm or less.

39. The device is configured to swell from a dehydrated state to an equilibrium moisture content state in an amount of 5 w / w% to 50 w / w% or less, according to any one of claims 1 to 5 and 8 to 38.

40. The device according to any one of claims 1 to 5 and 8 to 39, wherein the device has a coefficient of friction of 0.10 or less in an equilibrium moisture content state.

41. The device according to any one of claims 1 to 5 and 8 to 40, wherein the device contains an osmotic agent present in the polymer material in an amount of 0.05 w / w% to 2 w / w% with respect to the total weight of the device.

42. The device according to any one of claims 1 to 5 and 8 to 41, wherein the osmotic agent is selected from the group comprising phosphates, borates, sodium chloride, citrates, ethylenediaminetetraacetates, sulfites, sulfates, hyposulfites, metal oxides, selenium dioxide, selenium trioxide, selenite, selenic acid, nitrates, silicates, and plant acids.

43. The device is according to any one of claims 1 to 5 and 8 to 42, wherein the polymer material has a water contact angle of 45 degrees or less in an equilibrium water content state.

44. The device according to any one of claims 1 to 5 and 8 to 43, wherein the first water-soluble polymer does not contain a covalent crosslinking agent.

45. The device according to any one of claims 1 to 5 and 8 to 44, wherein the first water-soluble polymer is selected from the group consisting of poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, poly(vinylpyrrolidone), poly(methacrylate sulfobetaine), poly(acrylate sulfobetaine), poly(methacrylate carboxybetaine), poly(acrylate carboxybetaine), povidone, polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof.

46. The device according to any one of claims 1 to 5 and 8 to 45, wherein the second water-soluble polymer is selected from the group consisting of poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol, or poly(vinylpyrrolidone), poly(methacrylate sulfobetaine), poly(acrylate sulfobetaine), poly(methacrylate carboxybetaine), poly(acrylate carboxybetaine), povidone polyacrylamide, poly(N-(2-hydroxypropyl)methacrylamide), polyoxazoline, polyphosphate, polyphosphazene, polyvinyl acetate, polypropylene glycol, poly(N-isopropylacrylamide), poly(2-hydroxymethyl methacrylate), and combinations thereof.

47. The device according to any one of claims 1 to 5 and 8 to 46, wherein the device is configured to be used in conjunction with medical devices such as catheters, balloons, shunts, wound drains, infusion ports, drug delivery devices, tubes, contraceptives, female hygiene devices, endoscopes, grafts, pacemakers, implantable cardiac defibrillators, cardiac resynchronization devices, cardiovascular device leads, ventricular assist devices, endotracheal tubes, tracheostomy tubes, implantable sensors, ventilator pumps, and ophthalmic devices.

48. The device according to claim 47, 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 tunnel catheter, a dialysis access catheter, a urethral catheter, a neurological catheter, a percutaneous transluminal angioplasty catheter, and a peritoneal catheter.

49. The device according to any one of claims 1 to 5 and 8 to 48, wherein the second water-soluble polymer is disposed within a bulk of the first water-soluble polymer.

50. The device according to any one of claims 1 to 5 and 8 to 49, wherein less than 0.5 w / w% of the therapeutic agent is sorbed onto the bulk of the first water-soluble polymer at an equilibrium water content after flushing the device with five times its volume of water or saline solution.

51. The device according to any one of claims 1 to 5 and 8 to 50, wherein the device and / or polymer material is substantially non-thrombotic.

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