Water-soluble polyurethanes as support and sacrificial materials for 3D printing

Abstract

Described herein are water-soluble, non-toxic thermoplastic polyurethane compositions comprising the reaction product of one or more aliphatic diisocyanate compounds, one or more high molecular weight polyalkylene oxide compounds having a molecular weight of 600-150,000 g / mol, and one or more low molecular weight diol chain extender compounds having a molecular weight of 50-300 g / mol, reacted in a molar ratio of 50:49 to 20:1-30 and having a soft segment content of at least 80%, and methods of synthesis and use thereof.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 336,128, filed April 28, 2022, and U.S. Provisional Application No. 63 / 402,700, filed August 31, 2022, the contents of both of which are incorporated by reference in their entireties herein. [Background technology]

[0002] Three-dimensional (3D) printing techniques are used to build 3D objects from computer-aided design (CAD) models or digital 3D models, and are applied in numerous industries (e.g., architecture, aerospace, pharmaceuticals, and biomedicine), with their applications still expanding. Support materials are often required when printing complex shapes, overhangs, and undercuts in many 3D printing techniques, such as fused deposition modeling (FDM), stereolithography (SLA), digital light processing (DLP), and material jetting. The most conventional method for implementing supports is to print the same material used in the printed object, but in a lower density format, so that the supports can be easily removed after printing by mechanical means. However, this approach is usually time-consuming, messy, and difficult to completely remove all support material without damaging the print, especially from small and complex shapes. To make the removal of support material easier, an alternative method in U.S. Pat. No. 5,503,785 describes depositing a thin layer of release material between the support and the printed structure. The release materials are usually hydrocarbon waxes or water-soluble waxes (polyethylene oxide and glycol-based polymers, polyvinylpyrrolidone-based polymers, maleic acid-based polymers, etc.), or traditional release materials (fluorinated chemicals, silicone paraffins, etc.). Some types of release materials may leave undesirable oily residues on the printed structures. In addition, it may also make the 3D printing process more complicated.

[0003] Solvent-soluble support materials offer a good solution to reduce or remove redundant work and undesired residues, since they can be removed by solvents while preserving the integrity of the build object. However, most require harsh conditions (e.g., organic solvents, acid, alkali, and high temperature) to be removed, such as high impact polystyrene (HIPS) (limonene), polylactide (PLA) (sodium hydroxide), VXL® (Xioneer Systems, Austria; VXL® EX cleaner, alkaline), Stratasys™ SR (StrataSys, Ltd, US; alkaline solution (pH 11-13), ≥ 70°C) from US Patent No. US6,790,403, and PolyDissolve™ S (Polymaker, China; alkaline solution, > 70°C). These harsh dissolution conditions are unsafe / hazardous, limit the choice of co-printed materials (limited to those that are not affected by the dissolution conditions), and more importantly, they make those support materials unsuitable for biomedical applications involving cells.

[0004] Apart from their use as support materials, dissolvable 3D printing materials can be used as sacrificial materials to generate void spaces in the 3D material or in the construct after its removal (US Patent US20180030409A1). To be useful in high-resolution applications such as tissue engineering, sacrificial materials must be soluble (ideally water-soluble) in non-toxic solvents to allow their use in combination with cells and biomaterials. Furthermore, an ideal sacrificial material should undergo minimal swelling to prevent the destruction of surrounding materials or structures, for example when small vascular structures are created next to a thin basement membrane or near other channel networks to allow diffusion over short distances. There are very limited commercial options for water-soluble materials for use in 3D printing that can dissolve under mild conditions (e.g., temperatures typically between 4°C and 40°C, pH 6.5-10.5, corresponding to physiological conditions compatible with the maintenance of viable cells). Three representative commercial options include polyvinyl alcohol (PVA), NICHIGO G-POLYMER™ (butenediol vinyl alcohol (BvOH), Nippon Gohsei of Japan), and AQUASYS® (Infinite Material Solutions, LLC, Wisconsin, US). Among them, AQUASYS® 120 (U.S. Patent No. 10,435,576) has proven to be the fastest water-dissolving material among the other two. However, in practical use, AQUASYS® 120 may take hours, days, or even weeks to reach complete dissolution, depending on its size and dissolution conditions. During its prolonged dissolution, the material typically undergoes severe swelling before dissolution, which can cause loss of structural fidelity or even collapse if the surrounding building materials are not strong enough to resist the swelling of the support material. Thus, there remains a need for additional agents that can act as support or sacrificial materials. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 10,435,576 Summary of the Invention [Means for solving the problem]

[0006] In this disclosure, a series of novel water-soluble polyurethanes are disclosed that can be rapidly dissolved in water without appreciable swelling at room temperature or at neutral pH at 37° C. These water-soluble polyurethanes have many applications, including use as support materials in 3D printing processes and as sacrificial materials to create void spaces in 3D printing materials.

[0007] Described herein are thermoplastic polyurethanes that are soluble in water having a near neutral pH at room temperature or at 37° C., have melting temperatures between 50 and 240° C., and are non-cytotoxic to human kidney fibroblasts. Also described herein are methods for synthesizing these water-soluble, non-toxic thermoplastic polyurethane polymers, as well as various methods for their use, including as sacrificial substrates for forming interior volumes in basement membrane constructs and microfluidic devices.

[0008] Some embodiments of the present disclosure provide a method for synthesizing a water-soluble, non-toxic thermoplastic polyurethane polymer, comprising the steps of: i) providing one or more aliphatic diisocyanate compounds; ii) providing one or more high molecular weight polyalkylene oxide compounds having a molecular weight of about 600 to 150,000 g / mol; iii) providing one or more low molecular weight aliphatic diol chain extender compounds having a molecular weight of about 50 to 300 g / mol; and iv) dissolving the one or more aliphatic diisocyanate compounds, the one or more polyalkylene oxide compounds, and the one or more low molecular weight aliphatic diol chain extender compounds in a molar ratio of 50:49 to 20:1 to 30. and v) applying one or more conditions sufficient to sequentially or simultaneously polymerize the one or more aliphatic diisocyanate compounds, the one or more high molecular weight polyalkylene oxide compounds, and the one or more low molecular weight aliphatic diol chain extender compounds to synthesize a water soluble, non-toxic thermoplastic polyurethane polymer.

[0009] In some embodiments, the one or more aliphatic diisocyanate compounds are selected from the group consisting of ethylene diisocyanate, propylene diisocyanate, butylene diisocyanate, pentylene diisocyanate, hexamethylene diisocyanate, heptamethylene diisocyanate, octamethylene diisocyanate, nonamethylene diisocyanate, decamethylene diisocyanate, dicyclohexylmethane diisocyanate, bisisocyanatocyclohexylmethane, 2,2,4-trimethylhexamethylene diisocyanate, diisocyanatomethylcyclohexane, norbornane diisocyanate, diisocyanatododecane, or combinations thereof. In some embodiments, the one or more aliphatic diisocyanate compounds are selected from the group consisting of ethylene diisocyanate, propylene diisocyanate, butylene diisocyanate, pentylene diisocyanate, hexamethylene diisocyanate, heptamethylene diisocyanate, octamethylene diisocyanate, nonamethylene diisocyanate, decamethylene diisocyanate, diisocyanatododecane, or mixtures thereof. In particularly preferred embodiments, the one or more aliphatic diisocyanate compounds include hexamethylene diisocyanate.

[0010] In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 60-200 g / mol. In other embodiments, the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 60-150 g / mol. In further embodiments, the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 80-125 g / mol.

[0011] In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of ethylene glycol, diethylene glycol, triethylene glycol, 1,2-propylene glycol, 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, neopentyl glycol, dipropylene glycol, tripropylene glycol, and combinations thereof. In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, and combinations thereof. In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, and combinations thereof, hi yet other embodiments, the one or more low molecular weight aliphatic diol chain extender compounds include 1,4-butanediol.

[0012] In some embodiments, the one or more polyalkylene oxide compounds include polyethylene oxide, polypropylene oxide, or polybutylene oxide.

[0013] In some embodiments, the one or more polyalkylene oxide compounds comprise a molecular weight of 8,000 to 100,000 g / mol. In some other embodiments, the one or more polyalkylene oxide compounds comprise a molecular weight of 10,000 to 80,000 g / mol. In other embodiments, the one or more polyalkylene oxide polymer compounds comprise a molecular weight of 12,000 to 50,000 g / mol. In yet other preferred embodiments, the one or more polyalkylene oxide polymer compounds comprise a molecular weight of 15,000 to 30,000 g / mol. In particularly preferred embodiments, the one or more polyalkylene oxide polymer compounds comprise a molecular weight of about 20,000 g / mol.

[0014] In some particularly preferred embodiments, the one or more aliphatic diisocyanates include butylene diisocyanate, pentylene diisocyanate, and / or hexamethylene diisocyanate, the one or more polyalkylene oxide polymer compounds include polyethylene oxide polymers or polypropylene oxide polymers having a molecular weight of 15,000 to 30,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, or 1,6-hexanediol.

[0015] In another preferred embodiment, the one or more aliphatic diisocyanates include hexamethylene diisocyanate, the polyalkylene oxide polymer includes polyethylene oxide having a molecular weight of about 20,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,4-butanediol.

[0016] In some embodiments, step iv) includes mixing one or more aliphatic diisocyanate compounds, one or more polyalkylene oxide compounds, and one or more low molecular weight aliphatic diol chain extender compounds all simultaneously to provide a first mixture.

[0017] In some embodiments, applying one or more conditions sufficient to polymerize in step v) comprises exposing the first mixture to one or more conditions selected from the group consisting of heat, duration, catalyst, or combinations thereof, thereby obtaining a water soluble, non-toxic thermoplastic polyurethane polymer.

[0018] In some embodiments, applying one or more conditions sufficient to polymerize in step v) includes exposing the first mixture to heat above 100° C. in the absence of a catalyst, thereby synthesizing a water-soluble thermoplastic polyurethane polymer. In some embodiments, applying one or more conditions sufficient to polymerize in step v) includes exposing the first mixture to heat below 100° C. in the presence of a catalyst, thereby synthesizing a water-soluble thermoplastic polyurethane polymer while minimizing both the formation of allophanate groups and crosslinking of the polyurethane polymer. In some embodiments, exposing the first mixture to heat below 100° C. includes exposing the first mixture to a temperature between 40° C. and 90° C. In some other embodiments, exposing the first mixture to heat below 100° C. includes exposing the first mixture to a temperature of about 70° C.

[0019] In some embodiments, the catalyst is stannous octoate, dibutyltin dilaurate, dibutyltin diacetate, dioctyltin dilaurate, 1,4-diazabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2-azanorbornane, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5,7-triazabicyclo[4.4,0]dec-5-ene, bis(2-dimethylaminoethyl)ether, N-ethylmorpholine, N-methylmorpholine, N,N'-dimethylethanolamine, N,N-dimethylcyclohexylamine, trimethylamine ethylethanolamine, N,N,N',N',N"-pentamethyldiethylenetriamine, dimethylaminopropylamine. , N,N-dimethylaminoethylmorpholine, 2-methyl-2-azanorbornane, 3-hydroxy-1-azabicyclo[2.2.2]octane, tetramethylenediamine, dimethylpiperazine N-heterocyclic carbene, potassium octoate, potassium acetate, lithium octoate, bismuth octoate, bismuth neodecanoate, zinc octoate, zinc neodecanoate, zirconium octoate, cobalt octoate, nickel octoate, potassium octoate, calcium octoate, antimony octoate, lanthanum octoate, zirconium acetylacetonate, titanium acetylacetoacetate, aluminum acetylacetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid and diphenyl phosphate.

[0020] In some embodiments, the synthesis is carried out batchwise or continuously, hi some embodiments, the synthesis is carried out in a reactive extruder, or in a continuous mixing or spinning apparatus.

[0021] In some embodiments, step iv) comprises sequentially mixing, where one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds are mixed to form a pre-mixture. In some embodiments, the pre-mixture comprising one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds further comprises one or more solvents to facilitate uniform mixing and distribution of both the diisocyanate compounds and the high molecular weight polyalkylene oxide compounds throughout the pre-mixture. In further embodiments, the solvent comprises dimethylsulfoxide (DMSO), N,N-dimethylformamide, tetrahydrofuran (THF), or N,N-dimethylacetamide.

[0022] In some embodiments, applying one or more conditions sufficient to polymerize in step v) includes exposing the premix to one or more conditions selected from the group consisting of heat, duration, catalyst, or a combination thereof, thereby obtaining a urethane prepolymer. In some embodiments, applying one or more conditions sufficient to polymerize in step v) includes exposing the premix to heat above 100° C. in the absence of a catalyst, thereby synthesizing a urethane prepolymer. In further embodiments, applying one or more conditions sufficient to polymerize in step v) includes exposing the premix to heat below 100° C. in the presence of a catalyst, thereby synthesizing a urethane prepolymer while minimizing both the formation of allophanate groups and crosslinking of the polyurethane polymer. In other embodiments, exposing the first mixture to heat below 100° C. includes exposing the premix to a temperature between 40° C. and 90° C. In some embodiments, exposing the first mixture to heat below 100° C. includes exposing the premix to a temperature of about 70° C.

[0023] In some embodiments, the catalyst is stannous octoate, dibutyltin dilaurate, dibutyltin diacetate, dioctyltin dilaurate, 1,4-diazabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2-azanorbornane, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5,7-triazabicyclo[4.4,0]dec-5-ene, bis(2-dimethylaminoethyl)ether, N-ethylmorpholine, N-methylmorpholine, N,N'-dimethylethanolamine, N,N-dimethylcyclohexylamine, trimethylamine ethylethanolamine, N,N,N',N',N"-pentamethyldiethylenetriamine, dimethylaminopropylamine. , N,N-dimethylaminoethylmorpholine, 2-methyl-2-azanorbornane, 3-hydroxy-1-azabicyclo[2.2.2]octane, tetramethylenediamine, dimethylpiperazine N-heterocyclic carbene, potassium octoate, potassium acetate, lithium octoate, bismuth octoate, bismuth neodecanoate, zinc octoate, zinc neodecanoate, zirconium octoate, cobalt octoate, nickel octoate, potassium octoate, calcium octoate, antimony octoate, lanthanum octoate, zirconium acetylacetonate, titanium acetylacetoacetate, aluminum acetylacetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid and diphenyl phosphate.

[0024] In some embodiments, the sequential mixing includes providing one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds in the form of a urethane prepolymer and mixing the prepolymer with one or more low molecular weight diol chain extender compounds to obtain a second mixture. In some embodiments, the method further includes applying one or more conditions sufficient to cause the formation of carbamate bonds between the prepolymer and the diol chain extender compounds, thereby obtaining a water-soluble thermoplastic polyurethane.

[0025] In some embodiments, the mixing molar ratio range of the one or more aliphatic diisocyanate compounds to the high molecular weight polyalkylene oxide compound and the low molecular weight diol chain extender compound is 50:49 to 25:1 to 25. In a particularly preferred embodiment, the mixing molar ratio range of the one or more aliphatic diisocyanate compounds to the high molecular weight polyalkylene oxide compound and the low molecular weight diol chain extender compound is 50:49 to 40:1 to 10.

[0026] In some further embodiments, the method further comprises isolating the polymer by one or more techniques selected from the group consisting of precipitation, dialysis, and lyophilization. In some embodiments, the method further comprises removing excess water from one or more of the aliphatic diisocyanate, the polyalkylene oxide, the diol chain extender, the solvent, or from solid surfaces in contact therewith, using one or more techniques including distillation, drying, and / or washing the solid surfaces with a silane liquid.

[0027] In some embodiments, one or more of the steps of providing, mixing, or applying the one or more conditions are carried out under an inert gas. In yet other embodiments, the melting temperature comprises a first melting temperature corresponding to a melting temperature of a soft segment of the thermoplastic polyurethane polymer, or a second melting temperature corresponding to a melting temperature of a hard segment of the thermoplastic polyurethane polymer. In some embodiments, the first melting temperature comprises 50-80°C, and the second melting temperature comprises 100-130°C.

[0028] In some embodiments, the polyurethane polymer exhibits minimal swelling when exposed to water.

[0029] Some embodiments of the present disclosure provide a water-soluble, non-toxic thermoplastic polyurethane composition comprising: i) providing one or more aliphatic diisocyanate compounds; ii) providing one or more high molecular weight polyalkylene oxide compounds having a molecular weight of about 600 to 150,000 g / mol; iii) providing one or more low molecular weight aliphatic diol chain extender compounds having a molecular weight of about 50 to 300 g / mol; and iv) sequentially or simultaneously mixing the one or more aliphatic diisocyanate compounds, the one or more polyalkylene oxide compounds, and the one or more low molecular weight aliphatic diol chain extender compounds in a molar ratio of 50:49 to 20:1 to 30, wherein the isocyanate groups provided by the aliphatic diisocyanate compounds and the polyalkylene oxide compounds and the diisocyanate groups are reacted with each other to form a polyurethane having a molecular weight of about 50 to 300 g / mol. and v) applying one or more conditions sufficient to sequentially or simultaneously polymerize the one or more aliphatic diisocyanate compounds, the one or more high molecular weight polyalkylene oxide compounds, and the one or more low molecular weight aliphatic diol chain extender compounds to synthesize a water soluble, non-toxic thermoplastic polyurethane polymer, the polyurethane having a melting temperature of 50-240° C., having a soft segment content of at least 80%, soluble in water having a near neutral pH at room temperature or at 37° C., is non-cytotoxic to human kidney fibroblasts, and exhibits minimal swelling when exposed to water.

[0030] Some embodiments of the present disclosure provide a polyurethane polymer composition comprising a water-soluble, non-toxic thermoplastic polyurethane polymer that is a reaction product of at least the following: one or more aliphatic diisocyanate compounds, one or more high molecular weight polyalkylene oxide compounds having a molecular weight of about 600 to 150,000 g / mol, one or more low molecular weight aliphatic diol chain extender compounds having a molecular weight of about 50 to 300 g / mol, and optionally a catalyst; and the amount of aliphatic diol chain extender compound reaches a molar ratio of 50:49 to 20:1 to 30, the ratio of isocyanate groups provided by the aliphatic diisocyanate compound to reactive hydroxyl groups provided by the combination of the polyalkylene oxide compound and the diol chain extender compound is about 1:1, the thermoplastic polyurethane has a soft segment content of at least 80%, has a melting temperature of about 50 to 240°C, is soluble in water having a nearly neutral pH at room temperature or 37°C, and is non-cytotoxic to human kidney fibroblasts.

[0031] In some embodiments, the one or more aliphatic diisocyanate compounds are selected from the group consisting of ethylene diisocyanate, propylene diisocyanate, butylene diisocyanate, pentylene diisocyanate, hexamethylene diisocyanate, heptamethylene diisocyanate, octamethylene diisocyanate, nonamethylene diisocyanate, decamethylene diisocyanate, dicyclohexylmethane diisocyanate, bisisocyanatocyclohexylmethane, 2,2,4-trimethylhexamethylene diisocyanate, diisocyanatomethylcyclohexane, norbornane diisocyanate, diisocyanatododecane, or combinations thereof. In other embodiments, the one or more aliphatic diisocyanate compounds are selected from the group consisting of ethylene diisocyanate, propylene diisocyanate, butylene diisocyanate, pentylene diisocyanate, hexamethylene diisocyanate, heptamethylene diisocyanate, octamethylene diisocyanate, nonamethylene diisocyanate, decamethylene diisocyanate, diisocyanatododecane, or mixtures thereof. In a particularly preferred embodiment, the one or more aliphatic diisocyanate compounds include hexamethylene diisocyanate.

[0032] In some embodiments, the one or more polyalkylene oxide compounds include polyethylene oxide polymers, polypropylene oxide polymers, or polybutylene oxide polymers. In some embodiments, the one or more polyalkylene oxide compounds include a molecular weight of 8,000 to 100,000 g / mol. In some embodiments, the one or more polyalkylene oxide compounds include a molecular weight of 10,000 to 80,000 g / mol. In other embodiments, the one or more polyalkylene oxide compounds include a molecular weight of 12,000 to 50,000 g / mol. In some embodiments, the one or more polyalkylene oxide compounds include a molecular weight of 15,000 to 30,000 g / mol. In a particularly preferred embodiment, the one or more polyalkylene oxide compounds include a molecular weight of about 20,000 g / mol.

[0033] In some embodiments, the one or more polyalkylene oxide compounds comprise a molecular weight of about 60-200 g / mol. In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 60-150 g / mol. In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 80-125 g / mol.

[0034] In other embodiments, the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of ethylene glycol, diethylene glycol, triethylene glycol, 1,2-propylene glycol, 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, neopentyl glycol, dipropylene glycol, tripropylene glycol, and combinations thereof. In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, and combinations thereof. In other embodiments, the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, and combinations thereof. In a preferred embodiment, the one or more low molecular weight aliphatic diol chain extender compounds include 1,4-butanediol.

[0035] In a particularly preferred embodiment, the one or more aliphatic diisocyanates include butylene diisocyanate, pentylene diisocyanate, and / or hexamethylene diisocyanate, the one or more polyalkylene oxide polymer compounds include polyethylene oxide polymers or polypropylene oxide polymers having a molecular weight of 15,000 to 30,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, or 1,6-hexanediol. In another preferred embodiment, the one or more aliphatic diisocyanates include hexamethylene diisocyanate, the polyalkylene oxide polymer includes polyethylene oxide having a molecular weight of about 20,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,4-butanediol.

[0036] In some embodiments, the polyurethane polymer has a soft segment content of greater than 84%. In other embodiments, the polyurethane polymer has a soft segment content of greater than 90%. In yet other embodiments, the polyurethane polymer has a soft segment content of greater than 97%. In one preferred embodiment, the polyurethane polymer has a soft segment content of greater than 98%.

[0037] In some embodiments, the reaction is the result of simultaneously mixing one or more aliphatic diisocyanate compounds, one or more polyalkylene oxide compounds, one or more low molecular weight aliphatic diol chain extender compounds, and optionally one or more of a catalyst, and a solvent(s) to provide a first mixture, which is then exposed to one or more conditions selected from the group consisting of heat, duration, or combinations thereof to provide a water soluble, non-toxic thermoplastic polyurethane polymer.

[0038] In some embodiments, one or more aliphatic diisocyanate compounds, one or more high molecular weight polyalkylene oxide compounds, and optionally one or more of a catalyst and solvent(s) are mixed to form a pre-mixture, which is then exposed to one or more conditions selected from the group consisting of heat, duration, or combinations thereof to obtain a urethane prepolymer prior to reaction with one or more low molecular weight diol chain extender compounds to obtain a water soluble, non-toxic thermoplastic polyurethane polymer.

[0039] In some embodiments, one or more low molecular weight diol chain extender compounds and, optionally, one or more of a catalyst and a solvent(s) are mixed to obtain a second mixture, which is then exposed to one or more conditions selected from the group consisting of heat, duration, or combinations thereof to obtain a water-soluble, non-toxic thermoplastic polyurethane polymer. In further embodiments, the first mixture, pre-mixture, and / or second mixture is exposed to heat above 100° C. in the absence of a catalyst. In some embodiments, the first mixture, pre-mixture, and / or second mixture is exposed to heat below 100° C. in the presence of a catalyst to synthesize a water-soluble, non-toxic thermoplastic polyurethane polymer or urethane prepolymer.

[0040] In some embodiments, the first mixture, pre-mixture, and / or second mixture are exposed to a temperature between 40° C. and 90° C. In other embodiments, the first mixture, pre-mixture, and / or second mixture are exposed to a temperature of about 70° C.

[0041] In some embodiments, the catalyst is stannous octoate, dibutyltin dilaurate, dibutyltin diacetate, dioctyltin dilaurate, 1,4-diazabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2-azanorbornane, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5,7-triazabicyclo[4.4,0]dec-5-ene, bis(2-dimethylaminoethyl)ether, N-ethylmorpholine, N-methylmorpholine, N,N'-dimethylethanolamine, N,N-dimethylcyclohexylamine, trimethylamine ethylethanolamine, N,N,N',N',N"-pentamethyldiethylenetriamine, dimethylaminopropylamine. , N,N-dimethylaminoethylmorpholine, 2-methyl-2-azanorbornane, 3-hydroxy-1-azabicyclo[2.2.2]octane, tetramethylenediamine, dimethylpiperazine N-heterocyclic carbene, potassium octoate, potassium acetate, lithium octoate, bismuth octoate, bismuth neodecanoate, zinc octoate, zinc neodecanoate, zirconium octoate, cobalt octoate, nickel octoate, potassium octoate, calcium octoate, antimony octoate, lanthanum octoate, zirconium acetylacetonate, titanium acetylacetoacetate, aluminum acetylacetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid and diphenyl phosphate.

[0042] In other embodiments, the solvent comprises dimethylsulfoxide (DMSO), N,N-dimethylformamide, N,N-dimethylacetamide, or tetrahydrofuran (THF). In some embodiments, the molar ratio range of the one or more aliphatic diisocyanate compounds to the high molecular weight polyalkylene oxide compound and the low molecular weight diol chain extender compound is 50:49 to 25:1 to 25. In particularly preferred embodiments, the molar ratio range of the one or more aliphatic diisocyanate compounds to the high molecular weight polyalkylene oxide compound and the low molecular weight diol chain extender compound is 50:49 to 40:1 to 10.

[0043] In some embodiments, the polyurethane polymer exhibits minimal swelling when exposed to water. In some embodiments, minimal swelling is determined by comparing the wet mass of the polyurethane during dissolution in water with the dry mass of the same polyurethane before contact with water, and a less than 2.5-fold increase in wet mass to dry mass indicates that the polyurethane has minimal swelling during dissolution in water.

[0044] In some embodiments, the non-toxicity of a polyurethane polymer is determined by incubating human kidney fibroblast cells in cell culture medium containing 0.1 mg / mL of dissolved thermoplastic polyurethane for 24 hours, and the thermoplastic polyurethane polymer is determined to be non-toxic if cellular metabolic activity, as measured by a resazurin fluorescence assay, does not decrease at the end of the 24 hour incubation period.

[0045] In some embodiments, the polyurethane polymer composition is readily soluble in water as measured by a 1.75 mm diameter filament formed from a 1.75 mm diameter filament that is substantially dissolved in deionized water in about 4 hours or less at room temperature without stirring. In some embodiments, the polyurethane polymer is linear and substantially free of crosslinking and / or branching. In other embodiments, the polyurethane polymer is substantially free of aromatic isocyanate compounds or isocyanate compounds having more than two isocyanate groups per compound.

[0046] In some embodiments, the composition further comprises an aqueous solvent in an amount of about 30 wt% to 80 wt% of the polyurethane polymer composition. In some embodiments, the composition takes the form of a gel. In some embodiments, the polyurethane polymer is present at about 20 wt% to 70 wt% of the polyurethane polymer composition. In some embodiments, the polyurethane polymer comprises more than 70% and up to 100% of the polyurethane polymer composition. In preferred embodiments, the composition consists essentially of or consists of the polyurethane polymer.

[0047] Some embodiments of the present disclosure relate to a method of making a basement membrane construct, comprising: (a) printing a sacrificial structure comprising a water-soluble, non-toxic thermoplastic polyurethane composition as described herein onto a support structure or onto a thin layer comprising a functional basement membrane material with a thermoplastic print head of a three-dimensional printer; (b) applying a thin layer comprising a functional basement membrane material to the sacrificial structure to obtain one layer of the construct; (c) optionally repeating steps (a) and (b) one or more times to obtain one or more additional layers of the construct; (d) optionally embedding or laminating the products of steps (a) and (b), and optionally (c), in or with a sacrificial or permanent material; and (e) dissolving the sacrificial material by exposing it to an aqueous solvent to provide one or more interior volumes that retain the original shape and size of the printed sacrificial structure, thereby producing a basement membrane construct, wherein the thin layer is porous and has a thickness of 0.25 to 10 μm.

[0048] In some embodiments, step (b) comprises electrospinning the fibrous lamina membrane directly onto the sacrificial structure followed by post-production processing to impart enhanced mechanical properties to the fibrous lamina membrane. In some embodiments, step (b) comprises applying a preformed lamina comprising a functional basement membrane to the sacrificial substrate using a combination of compression and either heat or solvent to obtain a sacrificial substrate covered with a lamina comprising a functional basement membrane.

[0049] In some embodiments, obtaining one or more layers in step (c) comprises printing a sacrificial structure comprising a water-soluble, non-toxic thermoplastic polyurethane composition directly onto a thin layer comprising a functional basement membrane material previously applied to the sacrificial structure in step (b). In some embodiments, obtaining one or more layers in step (c) comprises printing a sacrificial structure comprising a water-soluble, non-toxic thermoplastic polyurethane composition onto a supporting substrate or onto a thin layer comprising a functional basement membrane that is not a thin layer previously applied in step (b), and further combining the one or more additional layers obtained in step (c) with the layer obtained by first performing steps (a) and (b) prior to embedding or lamination in step (d).

[0050] In some embodiments, one or more layers of the construct obtained in step (c) and the layer obtained by initially performing steps (a) and (b) are configured, individually or together, into a desired three-dimensional shape prior to step (d).

[0051] In some embodiments, the water-soluble, non-toxic thermoplastic polyurethane is heated to between 100° C. and 250° C. during printing. In some embodiments, both the chamber and bed temperatures are held at 25° C. during the three dimensional printing process.

[0052] In some embodiments, the sacrificial structure is printed in a serpentine or branched pattern. In some embodiments, the product of steps (a) and (b), and optionally (c), is embedded in or laminated with polydimethylsiloxane, methacrylated gelatin, bulk tissue materials, or other matrix-forming materials.

[0053] Some aspects of the present disclosure relate to methods of fabricating a microfluidic device, the methods including: (a) printing a sacrificial structure comprising a water soluble, non-toxic thermoplastic polyurethane composition described herein onto a support structure or thin layer with a thermoplastic print head of a three dimensional printer; (b) embedding or laminating the product of step (a) in or with a sacrificial or permanent material, with or without a support structure or thin layer; and (c) optionally repeating steps (a) and (b) one or more times; and (d) dissolving the sacrificial material by exposing it to an aqueous solvent to provide one or more interior volumes that substantially retain the original shape and size of the printed sacrificial structure, thereby fabricating a microfluidic device.

[0054] In some embodiments, the material comprises methacrylated gelatin, polydimethylsiloxane, bulk tissue material, or other matrix-forming material. In other embodiments, the sacrificial structure comprises an expanded longitudinal profile, a substantially elliptical or circular cross-sectional profile, and the one or more internal volumes provided comprise channels. In some embodiments, the sacrificial structure is formed into a serpentine or branching pattern having a constant or non-constant diameter.

[0055] The patent or application file contains at least one color drawing. Copies of this patent or patent application publication containing color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief description of the drawings]

[0056] [Figure 1] 1 shows an exemplary synthesis scheme of water-soluble polyurethanes (WPUs). The feed molar ratios of poly(ethylene glycol) (PEG), 1,6-hexamethylene diisocyanate (HDI), and 1,4-butanediol (BDO) were set to 1.5:2:0.5, 1.3:2:0.7, and 1:2:1, which produced water-soluble polyurethane polymers named WPU1, WPU2, and WPU3, respectively.

[0057] [Diagram 2] 1 shows the Fourier transform infrared (FT-IR) spectra of WPU1, WPU2, and WPU3.

[0058] [Diagram 3] Figure 1 shows the water dissolution rates of cylinders formed with AQUASYS® 120, WPU1, WPU2, and WPU3 at 0, 1, 2, 3, 4, and 24 hours. At 24 hours, cylinders made from WPU1 and WPU2 were completely dissolved. In contrast, at 24 hours, AQUASYS® 120 cylinders had 14±6% residual dry mass, 858±170% residual wet mass, and 758±170% swelling ratio, while WPU3 cylinders had 28±4% residual dry mass, 2010±453% residual wet mass, and 1910±453% swelling ratio.

[0059] [Figure 4] Figure 1 shows the dissolution profile of polyurethane and AQUASYS® polymer cylinders in water. Figure 2 shows a plot of the residual dry mass of WPU1, WPU2, WPU3, and AQUASYS® polymer cylinders in water over 24 hours. Figure 3 shows a plot of the residual wet mass of WPU1, WPU2, WPU3, and AQUASYS® polymer cylinders in water over 24 hours.

[0060] [Diagram 5] 1 shows a plot of the swelling ratio of WPU1, WPU2, WPU3, and AQUASYS® in water over a 24 hour period.

[0061] [Figure 6] 4 shows the cytotoxicity of WPU1, WPU2, and WPU3 towards human kidney fibroblasts at concentrations of 0.01 mg / mL, 0.1 mg / mL, and 1 mg / mL as measured by resazurin fluorescence assay.

[0062] [Figure 7] The process of embedding a sacrificial substrate WPU1 in a polydimethylsiloxane material and testing the dissolution of WPU1 to provide a microfluidic device with branched channels is shown. A shows a sacrificial substrate WPU1 positioned on a substrate with a branched pattern. B shows a sacrificial substrate embedded in polydimethylsiloxane (PDMS). C shows the results of drilling 3 mm holes in the PDMS material near both ends of the WPU1 sacrificial material. D shows the results of sonicating the microfluidic device in water for 3.5 hours at room temperature. E shows that enough of the WPU1 sacrificial material has been removed so that a red dye can be perfused through the channels created by the removal of the WPU1 sacrificial material.

[0063] [Figure 8] FIG. 1 illustrates a process of embedding a sacrificial substrate AQUSYS® 120 in a polydimethylsiloxane material and testing dissolution of the AQUSYS® 120 to provide a microfluidic device with branched channels. A shows a sacrificial substrate AQUSYS® 120 placed on a substrate with a branched pattern. B shows a sacrificial substrate embedded in PDMS. C shows the result of drilling 3 mm holes in the PDMS material near both ends of the pattern of sacrificial material. D shows the result of sonicating the microfluidic device at room temperature for 3.5 hours while submerged in water. E shows that the AQUASYS® 120 sacrificial material was not sufficiently removed during the water immersion and sonication period so that the red dye could not be easily perfused through the PDMS material.

[0064] [Figure 9] Figure 1 shows the process of fabricating a microfluidic device with channels in a twisted 8-branch pattern. A shows the mold holding the PDMS microfluidic device embedded with a twisted sacrificial substrate WPU2 printed in an 8-branch pattern. B shows the PDMS microfluidic device removed from the mold. C shows the microfluidic device with the sacrificial substrate removed. D-E show different views of the microfluidic device with dye perfused through the channels.

[0065] [Figure 10] 1 shows the formation of a bio-microfluidic device containing channels with a serpentine pattern of increasing filament spacing. A shows sacrificial WPU2 printed onto a supporting surface in a serpentine pattern of increasing filament spacing. B shows a bio-microfluidic device formed by embedding WPU2 in a methacrylated gelatin (GelMA) material. C shows a bio-microfluidic device with red dye perfused through the channels.

[0066] [Figure 11] Figure 1 shows cross-sectional images of bio-microfluidic devices fabricated using GelMA as the bulk hydrogel and WPU2 to create channels. A-B show cross-sectional images of bio-microfluidic devices with red dye perfused through the channels. C shows a table showing the cross-sectional area of ​​the WPU substrate compared to the cross-sectional area of ​​the channels after removal of WPU. D shows an enlarged cross-sectional view of the bio-microfluidic device. All cross-sectional images showed that all channels maintained a relatively round shape without channel fusion.

[0067] [Figure 12] 1 shows the formation of a bio-microfluidic device containing channels with a serpentine pattern of increasing filament spacing. A shows a sacrificial AQUASYS® 120 polymer printed onto a supporting surface in a serpentine pattern of increasing filament spacing. B shows a bio-microfluidic device formed by embedding AQUASYS® 120 polymer in a methacrylated gelatin (GelMA) material. C shows a bio-microfluidic device with a red dye perfused through the channels.

[0068] [Figure 13]Figure 1 shows cross-sectional images of a bio-microfluidic device fabricated using GelMA as the bulk hydrogel and WPU2 to create channels. A-B show cross-sectional images of a bio-microfluidic device with red dye perfused through the channels. C shows a table showing the cross-sectional area of ​​the WPU substrate compared to the cross-sectional area of ​​the channels after removal of AQUASYS® 120. D shows an enlarged cross-sectional view of a bio-microfluidic device showing some of the channels fused together due to the slow water dissolution and high water absorption of AquaSys® 120. Furthermore, the channels showed irregular shapes other than round shapes after clearance, and the cross-sectional area of ​​the channels increased by about 118% compared to the original printed ones.

[0069] [Figure 14A] Figure 1 shows the sequential assembly of large-scale tissue scaffolds using WPU as a sacrificial material. Figure 2 shows the 3D printing of sacrificial WPU material into defined channel networks. [Figure 14B] Figure 1 shows sequential assembly of large-scale tissue scaffolds using WPU as a sacrificial material, showing a fully printed layer containing a sacrificial WPU channel network for integration within the scaffold. [Figure 14C] Figure 1 shows the sequential assembly of large-scale tissue scaffolds using WPU as a sacrificial material, with branched connecting channels added to connect each layer of the scaffold. [Figure 14D] 1 shows sequential assembly of large-scale tissue scaffolds using WPU as a sacrificial material. A fully assembled scaffold skeleton with a sacrificial WPU channel network structure is shown. [Figure 14E] Figure 1 shows the sequential assembly of large-scale tissue scaffolds using WPU as a sacrificial material.Scaffolds containing a sacrificial WPU channel network skeleton structure embedded in a hydrogel bulk material are shown. [Figure 14F] Figure 1 shows the sequential assembly of large-scale tissue scaffolds using WPU as a sacrificial material, with the scaffolds cut transversely to reveal the hierarchical channel network left within the interior of the scaffold after removal of the WPU sacrificial material.

[0070] [Figure 15A] Shows the flexibility of a sacrificial WPU material used to form a channel network within a folded pancreatic scaffold that is later seeded with cells. Briefly, a sacrificial WPU material is printed onto a planar substrate, which is then folded into a U-shape and embedded into a gelatin bulk material. The sacrificial material is then dissolved and cells are seeded into the channels formed to provide a pancreatic scaffold. Shows a microscopy image showing the cell-seeded channels on the first layer of the folded scaffold. [Figure 15B] We demonstrate the flexibility of a sacrificial WPU material used to form a channel network within a folded pancreatic scaffold that is later seeded with cells. Briefly, a sacrificial WPU material is printed onto a planar substrate, which is then folded into a U-shape and embedded into a gelatin bulk material. The sacrificial material is then dissolved and cells are seeded within the channels formed to provide a pancreatic scaffold. A complete pancreatic scaffold containing the folded channel network is shown.

[0071] [Figure 16A] Figure 1 shows the sequential assembly of large-scale tissue scaffolds using WPU as a sacrificial material. Figure 2 shows a membrane printed with a WPU channel network pattern with close-proximity electrospinning of fibrous membrane wrapping. [Figure 16B] Figure 1 shows the sequential assembly of large-scale tissue scaffolds using WPU as a sacrificial material. Electrospun fibers containing polycaprolactone (PCL) and gelatin are shown accumulating on a printed WPU channel network. The location of the accumulated electrospun fibers is influenced by the position of the collecting electrode. [Figure 16C] Figure 1 shows the sequential assembly of large-scale tissue scaffolds using WPU as a sacrificial material.Scanning electron microscope (SEM) image of the cross section of electrospun PCL / gelatin fibrous membrane overlaid on the printed WPU channel network pattern after proximity electrospinning.The magnification of the image in this figure is 160x. [Figure 16D]Figure 1 shows the sequential assembly of large-scale tissue scaffolds using WPU as a sacrificial material.Scanning electron microscope (SEM) image of the cross section of electrospun PCL / gelatin fibrous membrane overlaid on the printed WPU channel network pattern after proximity electrospinning.The magnification of the image in this figure is 120x.

[0072] [Figure 17] Morphological features of the heat-treated and compressed fibrous membrane wrapping of the printed WPU channel pattern. Briefly, the WPU channel pattern was 3D printed on an electrospun membrane containing PCL and gelatin, placed between two opposing additional membrane layers, and then set between two opposing soft silicone pads while being heated to about 55° C. for 18 hours. A shows a 55x SEM image of a cross-section of the 3D printed WPU channel pattern covered with electrospun fibrous membrane that was treated with heat and compression. B shows a 180x SEM image of a cross-section of the 3D printed WPU channel pattern covered with electrospun fibrous membrane that was treated with heat and compression. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0073] Described herein are water-soluble, non-toxic thermoplastic polyurethanes that are soluble in water having a near-neutral pH at room temperature or at 37° C., have melting temperatures between 50 and 240° C., and are non-cytotoxic to human kidney fibroblasts. Also described herein are methods for synthesizing these water-soluble, non-toxic thermoplastic polyurethane polymers, and methods for using the polymers, including their use as sacrificial substrates for forming interior volumes in basement membrane constructs and microfluidic devices.

[0074] Some embodiments of the present disclosure provide a method for synthesizing a water-soluble, non-toxic thermoplastic polyurethane polymer, comprising the steps of: i) providing one or more aliphatic diisocyanate compounds; ii) providing one or more high molecular weight polyol compounds having a molecular weight of about 600-150,000 g / mol; iii) providing one or more low molecular weight aliphatic diol chain extender compounds having a molecular weight of about 50-300 g / mol; and iv) mixing the one or more aliphatic diisocyanate compounds, the one or more polyalkylene oxide compounds, and the one or more low molecular weight aliphatic diol chain extender compounds in a molar ratio of 50:49 to 20:1-30. , sequentially or simultaneously mixing, wherein the ratio of isocyanate groups provided by the aliphatic diisocyanate compounds to reactive hydroxyl groups provided by the combination of the polyalkylene oxide compounds and the diol chain extender compounds is about 1:1; and v) applying one or more conditions sufficient to sequentially or simultaneously polymerize the one or more aliphatic diisocyanate compounds, the one or more high molecular weight polyalkylene oxide compounds, and the one or more low molecular weight aliphatic diol chain extender compounds to synthesize a water soluble, non-toxic thermoplastic polyurethane polymer.

[0075] The one or more aliphatic diisocyanate compounds used in forming the water soluble, non-toxic thermoplastic polyurethanes are not limited to and may be any suitable aliphatic isocyanate compounds having isocyanate functionality, which when combined with a high molecular weight polyol compound having two reactive hydroxyl groups and / or a low molecular weight aliphatic diol chain extender compound having two reactive hydroxyl groups, as described herein, can form two carbamate linkages. Exemplary diisocyanates that can be used to form the water soluble, non-toxic thermoplastic polyurethane include, but are not limited to, ethylene diisocyanate, propylene diisocyanate, butylene diisocyanate, pentylene diisocyanate, hexamethylene diisocyanate, heptamethylene diisocyanate, octamethylene diisocyanate, nonamethylene diisocyanate, decamethylene diisocyanate, dicyclohexylmethane diisocyanate, bisisocyanatocyclohexylmethane, 2,2,4-trimethylhexamethylene diisocyanate, diisocyanatomethylcyclohexane, norbornane diisocyanate, diisocyanatododecane, or combinations thereof. In some embodiments, the one or more aliphatic diisocyanate compounds are selected from the group consisting of ethylene diisocyanate, propylene diisocyanate, butylene diisocyanate, pentylene diisocyanate, hexamethylene diisocyanate, heptamethylene diisocyanate, octamethylene diisocyanate, nonamethylene diisocyanate, decamethylene diisocyanate, diisocyanatododecane, or mixtures thereof. In a particularly preferred embodiment, the one or more aliphatic diisocyanate compounds include hexamethylene diisocyanate, propylene diisocyanate, butylene diisocyanate, pentylene diisocyanate, and / or heptamethylene diisocyanate. In another particularly preferred embodiment, the one or more aliphatic diisocyanates include hexamethylene diisocyanate.

[0076] In certain embodiments, the one or more aliphatic diisocyanates comprise a mixture of at least two, at least three, at least four, or at least five or more different aliphatic diisocyanates. In other embodiments, binary, ternary, quaternary, or quinary mixtures of aliphatic diisocyanates are used to form the water-soluble, non-toxic thermoplastic polyurethane. In some embodiments, the mixture of aliphatic diisocyanates comprises hexamethylene diisocyanate in addition to at least one other aliphatic diisocyanate.

[0077] The one or more low molecular weight aliphatic diol chain extender compounds include, but are not limited to, aliphatic compounds having at least two reactive hydroxyl groups per compound and capable of forming two carbamate bonds with one or more aliphatic diisocyanates described herein. In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 60-300 g / mol, about 60-200 g / mol, about 60-150 g / mol, or about 80-125 g / mol. In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 125, 130, 140, 150, 175, 200, 250, or 300 g / mol. In further embodiments, the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of less than 300 g / mol, less than 250 g / mol, less than 225 g / mol, less than 200 g / mol, less than 180 g / mol, less than 170 g / mol, less than 160 g / mol, less than 150 g / mol, less than 140 g / mol, less than 130 g / mol, less than 125 g / mol, less than 120 g / mol, less than 110 g / mol, or less than 100 g / mol, and a molecular weight of greater than 50 g / mol, greater than 55 g / mol, greater than 60 g / mol, greater than 65 g / mol, or greater than 70 g / mol.

[0078] In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of ethylene glycol, diethylene glycol, triethylene glycol, 1,2-propylene glycol, 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, neopentyl glycol, dipropylene glycol, tripropylene glycol, and combinations thereof. In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, and combinations thereof. In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, and combinations thereof, hi yet other embodiments, the one or more low molecular weight aliphatic diol chain extender compounds include 1,4-butanediol.

[0079] In certain embodiments, the one or more low molecular weight aliphatic diol chain extender compounds comprise a mixture of at least two, at least three, at least four, or at least five or more different low molecular weight aliphatic diol chain extender compounds. In another embodiment, a binary, ternary, or quaternary mixture of low molecular weight aliphatic diol chain extender compounds is used to form a water-soluble, non-toxic thermoplastic polyurethane. In some embodiments, the mixture of low molecular weight aliphatic diol chain extender compounds comprises 1,4-butanediol in addition to at least one other low molecular weight aliphatic diol chain extender compound.

[0080] The one or more high molecular weight polyol compounds include, but are not limited to, high molecular weight polyol compounds containing at least two reactive hydroxyl groups that can form two carbamate bonds when reacted with one or more aliphatic diisocyanate compounds described herein. In certain embodiments, the high molecular weight polyol compounds include polyether and / or polyester compounds that contain two reactive hydroxyl groups per polymer. The reactive hydroxyl groups are hydroxyl groups that are not sterically or otherwise hindered from reacting with isocyanate groups. In certain embodiments, the one or more high molecular weight polyol compounds contain exactly two reactive hydroxyl groups per polymer. Generally, these reactive hydroxyl groups are found at opposite ends of the polymer. In some preferred embodiments, the high molecular weight polyol compounds have only minimal branching. In yet other preferred embodiments, the high molecular weight polyol compounds are substantially linear. In some embodiments, the high molecular weight polyol compounds are high molecular weight polyalkylene oxides. In some preferred embodiments, the one or more polyalkylene oxide compounds include polyethylene oxide, polypropylene oxide, or polybutylene oxide.

[0081] In some embodiments, the one or more high molecular weight polyol compounds are preferably one or more polyalkylene oxide compounds comprising a molecular weight of 8,000 to 100,000 g / mol. In some other embodiments, the one or more polyalkylene oxide compounds comprise a molecular weight of 10,000 to 80,000 g / mol, 12,000 to 50,000 g / mol, or 15,000 to 30,000 g / mol. In particularly preferred embodiments, the one or more polyalkylene oxide polymer compounds comprise a molecular weight of about 20,000 g / mol.In some embodiments, the one or more polyalkylene oxide compounds are at least 1,000 g / mol, at least 1,500 g / mol, at least 2,000 g / mol, at least 2,500 g / mol, at least 3,000 g / mol, at least 3,500 g / mol, at least 4,000 g / mol, at least 4,500 g / mol, at least 5,000 g / mol, at least 5,500 g / mol, at least 6,000 g / mol, at least 6,500 g / mol. g / mol, at least 7,000g / mol, at least 7,500g / mol, at least 8,000g / mol, at least 8,500g / mol, at least 9,000g / mol, at least 9,500g / mol, at least 10,000g / mol, at least 10,500g / mol, at least 11,000g / mol, at least 11,500g / mol, at least 12,000g / mol, at least 12,500g / mol, at least 13,000g / mol l, at least 13,500 g / mol, at least 14,000 g / mol, at least 14,500 g / mol, at least 15,000 g / mol, at least 15,500 g / mol, at least 16,000 g / mol, at least 16,500 g / mol, at least 17,000 g / mol, at least 17,500 g / mol, at least 18,000 g / mol, at least 18,500 g / mol, at least 19,000 g / mol, at least 19,500 g / mol mol, at least 20,000 g / mol, at least 20,5000 g / mol, at least 21,000 g / mol, at least 21,500 g / mol, at least 22,000 g / mol, at least 22,500 g / mol, at least 23,000 g / mol, at least 23,500 g / mol, at least 24,000 g / mol, at least 24,500 g / mol, at least 25,000 g / mol, or at least 25,500 g / mol.

[0082] In certain embodiments, the one or more high molecular weight polyalkylene oxide compounds are less than 300,000 g / mol, less than 250,000 g / mol, less than 225,000 g / mol, less than 200,000 g / mol, less than 175,000 g / mol, less than 150,000 g / mol, less than 125,000 g / mol, less than 115,000 g / mol, less than 100,000 g / mol, less than 90,000 g / mol, less than 80,000 g / mol, less than 75,000 g / mol, less than 70, In some embodiments, the molecular weight is less than 1,000 g / mol, 65,000 g / mol, 60,000 g / mol, 55,000 g / mol, 50,000 g / mol, 45,000 g / mol, 40,000 g / mol, 35,000 g / mol, 30,000 g / mol, 25,000 g / mol, 20,000 g / mol, 15,000 g / mol, 10,000 g / mol, 5,000 g / mol, or 2,500 g / mol. In some embodiments, the one or more high molecular weight polyalkylene oxide compounds are at least one of about 1,000 g / mol, about 2,000 g / mol, about 2,500 g / mol, about 5,000 g / mol, about 7,500 g / mol, about 10,000 g / mol, about 12,500 g / mol, about 15,000 g / mol, about 17,500 g / mol, about 20,000 g / mol, about 22,500 g / mol, about 23,000 g / mol, about 24,000 g / mol, about 25,000 g / mol, about 26,000 g / mol, about 27,000 g / mol, about 28,000 g / mol, about 30,000 g / mol, about 31,000 g / mol, about 32,000 g / mol, about 33,000 g / mol, about 34,000 g / mol, about 35,000 g / mol, about 36,000 g / mol, about 37,000 g / mol, about 38,000 g / mol, about 39,000 g / mol, about 40,000 g / mol, about 41,000 g / mol, about 42,000 g / mol, about 43,000 g / mol, about 44,000 g / mol, about 45,000 g / mol, about 46,000 g / mol, about 47,000 g / mol, about 48,000 g / mol, about 49,000 g / mol, about 50,000 g / mol, about 51,000 g / mol, about 52,000 g / mol, about 53,000 g / mol, about 5 mol, about 25,000 g / mol, about 30,000 g / mol, about 40,000 g / mol, about 50,000 g / mol, about 60,000, about 75,000 g / mol, about 100,000 g / mol, about 125,000 g / mol, about 150,000 g / mol, about 175,000 g / mol, about 200,000 g / mol, or about 250,000 g / mol.

[0083] In certain embodiments, the one or more high molecular weight polyalkylene oxide compounds comprise a mixture of at least two, at least three, or at least four or more different high molecular weight polyalkylene oxide compounds. In another embodiment, a binary or ternary mixture of high molecular weight polyalkylene oxide compounds is used to form a water-soluble, non-toxic thermoplastic polyurethane. In some embodiments, the mixture of high molecular weight polyalkylene oxide compounds comprises polyethylene oxide having a molecular weight of about 5,000 g / mol, about 10,000 g / mol, about 15,000 g / mol, about 20,000 g / mol, or about 25,000 g / mol in addition to at least one other high molecular weight polyalkylene oxide compound.

[0084] In some particularly preferred embodiments, the one or more aliphatic diisocyanates include butylene diisocyanate, pentylene diisocyanate, and / or hexamethylene diisocyanate, the one or more polyalkylene oxide polymer compounds include polyethylene oxide polymers or polypropylene oxide polymers having a molecular weight of 15,000 to 30,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, and / or 1,6-hexanediol.

[0085] In another preferred embodiment, the one or more aliphatic diisocyanates include hexamethylene diisocyanate, the polyalkylene oxide polymer includes polyethylene oxide having a molecular weight of about 20,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,4-butanediol.

[0086] In some embodiments, step iv) comprises mixing one or more aliphatic diisocyanate compounds, one or more polyalkylene oxide compounds, and one or more low molecular weight aliphatic diol chain extender compounds all at the same time to provide a first mixture. The equipment used to mix one or more aliphatic diisocyanate compounds, one or more polyalkylene oxide compounds, and one or more low molecular weight aliphatic diol chain extender compounds at the same time is not particularly limited as long as it achieves simultaneous homogeneous mixing of these components. In some embodiments, devices useful for carrying out the present invention include, but are not limited to, single-screw, twin-screw, or triple-screw mixers, single-screw or twin-screw planetary mixers, high viscosity or high speed dispersers, ribbon, paddle, tumble or vertical blenders, kneader extruders, reactive extruders, or continuous spinning equipment.

[0087] In some embodiments, applying one or more conditions sufficient to polymerize in step iv) includes exposing the first mixture to heat, a duration, a catalyst, or a combination thereof, thereby obtaining a water-soluble, non-toxic thermoplastic polyurethane polymer.

[0088] In some embodiments, a catalyst is added to the first mixture to promote faster synthesis of water-soluble, non-toxic thermoplastic polyurethane from the first mixture. The catalyst included in the first mixture is not limited and can include any compound that catalyzes the formation of carbamate bonds from hydroxyl-containing compounds and isocyanate-containing compounds. Such catalysts can include metal carboxylates, tertiary amines, organic acids, and organic bases. Exemplary catalysts that catalyze the formation of the polyurethane polymer from the first mixture include stannous octoate, dibutyltin dilaurate, dibutyltin diacetate, dioctyltin dilaurate, 1,4-diazabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2-azanorbornane, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5,7-triazabicyclo[4,4,0]dec-5-ene, bis(2-dimethylaminoethyl)ether, N-ethylmorpholine, N-methylmorpholine, N,N'-dimethylethanolamine, N,N-dimethylcyclohexylamine, N,N,N',N',N"-pentamethyldiethylenetriamine, ethylethanol ... These include, but are not limited to, aminopropylamine, N,N-dimethylaminoethylmorpholine, 2-methyl-2-azanorbornane, 3-hydroxy-1-azabicyclo[2.2.2]octane, tetramethylenediamine, dimethylpiperazine N-heterocyclic carbene, potassium octoate, potassium acetate, lithium octoate, bismuth octoate, bismuth neodecanoate, zinc octoate, zinc neodecanoate, zirconium octoate, cobalt octoate, nickel octoate, potassium octoate, calcium octoate, antimony octoate, lanthanum octoate, zirconium acetylacetonate, titanium acetylacetoacetate, aluminum acetylacetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid, and diphenyl phosphate.

[0089] In general, those skilled in the art will understand that catalysts are not usually consumed in the process of catalyzing the formation of polyurethane. In such circumstances, the catalyst can be recovered, regenerated as necessary, and reused to catalyze the polymerization of additional polyurethane polymers. If the process requires the synthesis of polyurethane polymers in batches, the recovered catalyst may be added to the subsequent batches in addition to any new catalyst required to replace any portion of the old catalyst that was not recovered or regenerated. If the process is a continuous process, the catalyst may be reintroduced upstream of the point where one or more aliphatic diisocyanate compounds, one or more polyalkylene oxide compounds, and one or more low molecular weight aliphatic diol chain extender compounds are mixed, such as by incorporating the catalyst into a stream containing a single component. In other embodiments, the catalyst may be introduced first into the solvent, which is then added to one or all of the components at the point where all three components are mixed simultaneously. Significant cost savings can be achieved by recovering and reusing the catalyst.

[0090] In some embodiments, 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%, or at least 98% or more of the catalyst is recovered. In some embodiments, substantially all of the catalyst is recovered. In some embodiments, no portion of the catalyst is recovered. In further embodiments, no attempt is made to recover the catalyst.

[0091] In some embodiments of the present invention, the reaction is allowed to proceed for a predetermined period of time. This predetermined period of time may range from 10 minutes to a full week or more. In some embodiments, the period of time is set based on the degree of heat to which the first mixture is exposed and whether a catalyst is added to the first mixture. In some embodiments, the first mixture is allowed to react for at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 72 hours, or at least 96 hours or more. In certain embodiments, the reaction is carried out in the presence of a catalyst and / or heat, and the reaction is allowed to proceed for less than 72 hours, less than 48 hours, less than 36 hours, less than 24 hours, less than 12 hours, less than 8 hours, less than 6 hours, less than 4 hours, or less than 2 hours.

[0092] In some embodiments, applying one or more conditions sufficient to polymerize in step v) includes exposing the first mixture to heat above 100° C. in the absence of a catalyst, thereby synthesizing a water-soluble thermoplastic polyurethane polymer. In some embodiments, applying one or more conditions sufficient to polymerize in step v) includes exposing the first mixture to heat below 100° C. in the presence of a catalyst, thereby synthesizing a water-soluble thermoplastic polyurethane polymer while minimizing both the formation of allophanate groups and crosslinking of the polyurethane polymer. In some embodiments, exposing the first mixture to heat below 100° C. includes exposing the first mixture to a temperature between 40° C. and 90° C. In some other embodiments, exposing the first mixture to heat below 100° C. includes exposing the first mixture to a temperature of about 70° C.

[0093] In some embodiments, the first mixture is exposed to heat at least 28°C, at least 30°C, at least 35°C, at least 40°C, at least 45°C, at least 50°C, at least 55°C, at least 60°C, at least 65°C, at least 70°C, at least 75°C, at least 80°C, at least 85°C, at least 90°C, or at least 95°C. In some embodiments, the first mixture is exposed to heat less than 110°C, less than 105°C, less than 100°C, less than 95°C, less than 90°C, less than 85°C, less than 80°C, or less than 75°C. In certain embodiments, the first mixture is exposed to heat at 70°C, 37°C, or not exposed to heat above room temperature, which for purposes of this application is defined as a temperature between 19°C and 23°C. In some embodiments, the temperature of the first mixture is maintained below 100°C to minimize the formation of allophanate groups and also to minimize crosslinking of the polyurethane polymer. It will be appreciated that in some embodiments, if the reaction proceeds exothermic, active cooling can be applied to reduce and maintain the temperature of the first mixture below a set temperature point, for example, below 100°C, below 90°C, below 80°C, or below 70°C.

[0094] In some embodiments, the synthesis is carried out batchwise or continuously, hi some embodiments, the synthesis is carried out in a reactive extruder, or in a continuous mixing or spinning apparatus.

[0095] In some embodiments, step iv) includes sequential mixing, where one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds are mixed to form a premixture. The device used to mix one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds to form a premixture is not particularly limited, so long as it achieves homogeneous mixing of these components. In some embodiments, the device useful for carrying out the present invention can be the same as that which can be used to simultaneously mix the aliphatic diisocyanate, polyalkylene oxide and chain extender compound. These devices include, but are not limited to, single-screw, double-screw, or triple-screw mixers, single-screw or double-screw planetary mixers, high viscosity or high speed dispersers, ribbon, paddle, tumble or vertical blenders, kneader extruders, reactive extruders, or continuous spinning equipment.

[0096] In some embodiments, the pre-mixture comprising one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds further comprises one or more solvents to facilitate uniform mixing and distribution of both the diisocyanate compounds and the high molecular weight polyalkylene oxide compounds throughout the pre-mixture. The solvent(s) used in dissolving the components of the pre-mixture are not particularly limited and include solvents that dissolve the one or more aliphatic diisocyanate compounds, the one or more high molecular weight polyalkylene oxide compounds without preventing the formation of the urethane prepolymer. In some embodiments, the solvent(s) are selected to be environmentally friendly and less toxic compared to other available solvents, and may be compatible with metal carboxylates, tertiary amines, or other catalysts. Examples of suitable solvents include, but are not limited to, dimethyl sulfoxide (DMSO), N,N-dimethylformamide, tetrahydrofuran (THF), or N,N-dimethylacetamide.

[0097] In some embodiments, applying one or more conditions sufficient to polymerize in step v) comprises exposing the pre-mixture to one or more conditions selected from the group consisting of heat, duration, catalyst, or a combination thereof, thereby obtaining a urethane prepolymer.

[0098] In some embodiments, a catalyst is added to the premix to promote faster synthesis of the premix. The catalyst included in the premix is ​​not limited and may include any compound that catalyzes the formation of carbamate bonds from hydroxyl-containing compounds and isocyanate-containing compounds. Such catalysts may include metal carboxylates, tertiary amines, organic acids, and organic bases. Exemplary catalysts that catalyze the formation of the urethane prepolymer from the premix include stannous octoate, dibutyltin dilaurate, dibutyltin diacetate, dioctyltin dilaurate, 1,4-diazabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2-azanorbornane, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, bis(2-dimethylaminoethyl)ether, N-ethylmorpholine, N-methylmorpholine, N,N'-dimethylethanolamine, N,N-dimethylcyclohexylamine, N,N,N',N',N"-pentamethyldiethylenetriamine, ethylethanol ... These include, but are not limited to, aminopropylamine, N,N-dimethylaminoethylmorpholine, 2-methyl-2-azanorbornane, 3-hydroxy-1-azabicyclo[2.2.2]octane, tetramethylenediamine, dimethylpiperazine N-heterocyclic carbene, potassium octoate, potassium acetate, lithium octoate, bismuth octoate, bismuth neodecanoate, zinc octoate, zinc neodecanoate, zirconium octoate, cobalt octoate, nickel octoate, potassium octoate, calcium octoate, antimony octoate, lanthanum octoate, zirconium acetylacetonate, titanium acetylacetoacetate, aluminum acetylacetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid, and diphenyl phosphate.

[0099] In some embodiments, the reaction is allowed to proceed for a predetermined period of time. This predetermined period of time may range from 10 minutes to a full week or more. In some embodiments, the period of time is set based on the amount of heat to which the pre-mixture is exposed and whether or not a catalyst is added to the pre-mixture. In some embodiments, the pre-mixture is allowed to react for at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 72 hours, or at least 96 hours. In some particular embodiments, the reaction is carried out in the presence of a catalyst and / or heat, and the reaction is allowed to proceed for less than 72 hours, less than 48 hours, less than 36 hours, less than 24 hours, less than 12 hours, less than 8 hours, less than 6 hours, less than 4 hours, or less than 2 hours.

[0100] In some embodiments, applying one or more conditions sufficient to polymerize in step v) includes exposing the pre-mixture to heat above 100° C. in the absence of a catalyst, thereby synthesizing a urethane prepolymer. In further embodiments, applying one or more conditions sufficient to polymerize in step v) includes exposing the pre-mixture to heat below 100° C. in the presence of a catalyst, thereby synthesizing a urethane prepolymer while minimizing both the formation of allophanate groups and crosslinking of the polyurethane polymer. In other embodiments, exposing the first mixture to heat below 100° C. includes exposing the pre-mixture to a temperature between 40° C. and 90° C. In some embodiments, exposing the first mixture to heat below 100° C. includes exposing the pre-mixture to a temperature of about 70° C.

[0101] In some embodiments, the premix is ​​exposed to heat at least 28°C, at least 30°C, at least 35°C, at least 40°C, at least 45°C, at least 50°C, at least 55°C, at least 60°C, at least 65°C, at least 70°C, at least 75°C, at least 80°C, at least 85°C, at least 90°C, or at least 95°C. In some embodiments, the first mixture is exposed to heat less than 110°C, less than 105°C, less than 100°C, less than 95°C, less than 90°C, less than 85°C, less than 80°C, or less than 75°C. In certain embodiments, the premix is ​​exposed to heat at 70°C, 37°C, or not exposed to heat above room temperature, which for purposes of this application is defined as a temperature between 19°C and 23°C. In some embodiments, the temperature of the premix is ​​kept below 100°C to minimize the formation of allophanate groups and also to minimize crosslinking of the urethane prepolymer. It will be appreciated that in some embodiments, if the reaction proceeds exothermically, active cooling can be applied to reduce and maintain the temperature of the pre-mixture below a set point, e.g., below 100°C, below 90°C, or below 80°C.

[0102] In some embodiments, the sequential mixing includes providing one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds in the form of a urethane prepolymer, and mixing the prepolymer with one or more low molecular weight diol chain extender compounds to obtain a second mixture. This mixing may be performed in the same device or apparatus that formed the premix, or in a separate device or apparatus. As previously described, single-screw, twin-screw, or triple-screw mixers, single-screw or twin-screw planetary mixers, high viscosity or high speed dispersers, ribbon, paddle, tumble or vertical blenders, kneader extruders, reactive extruders, or continuous spinning equipment are suitable devices for this purpose. In some embodiments, the method further includes applying one or more conditions sufficient to form carbamate bonds between the prepolymer and the diol chain extender compounds, thereby obtaining a water-soluble, non-toxic thermoplastic polyurethane. These conditions may include heat, duration, and inclusion of a catalyst.

[0103] In some embodiments, the molar ratio range of one or more aliphatic diisocyanate compounds to the high molecular weight polyalkylene oxide compound and the low molecular weight diol chain extender compound is 50:49 to 25:1 to 25. In a particularly preferred embodiment, the molar ratio range of one or more aliphatic diisocyanate compounds to the high molecular weight polyalkylene oxide compound and the low molecular weight diol chain extender compound is 50:49 to 40:1 to 10. It will be appreciated that by increasing the ratio of the high molecular weight polyalkylene oxide compound to the low molecular weight diol chain extender compound, the proportion of soft segments in the resulting polyurethane polymer formed thereby increases. Conversely, by decreasing the ratio of the high molecular weight polyalkylene oxide compound to the low molecular weight diol chain extender compound, the proportion of hard segments in the resulting polyurethane polymer formed thereby increases. Thus, polyurethane properties, such as water dissolution time, or polymer stiffness, can be adjusted by varying the ratio of the high molecular weight polyalkylene oxide compound to the low molecular weight compound for a fixed amount of aliphatic diisocyanate compound.

[0104] In further embodiments, the blend molar ratio range of one or more aliphatic diisocyanate compounds to high molecular weight polyalkylene oxide compounds and low molecular weight diol chain extender compounds can be 2:1:1, 2:1.7:0.3, or 2:1.5:0.5. In some embodiments, the ratio of high molecular weight polyalkylene oxide compound to low molecular weight diol chain extender compound is at least 20:30, at least 22:28, at least 25:25, at least 26:24, at least 27:23, at least 28:22, at least 29:21, at least 30:20, at least 31:19, at least 32:18, at least 33:17, at least 34:16, at least 35:15, at least 36:14, at least 37:13, at least 38:12, at least 39:11, at least 40:10, at least 41:9, at least 42:8, at least 43:7, at least 44:6, at least 45:5 or more, provided that the ratio of reactive hydroxy groups provided by the combination of the high molecular weight polyalkylene oxide compound and the low molecular weight diol chain extender compound to isocyanate groups provided by the aliphatic diisocyanate compound is about 1:1.

[0105] In some further embodiments, the method further comprises isolating the polymer by one or more techniques known to those skilled in the art. In some embodiments, the polymer may be isolated by precipitation in a suitable liquid, which may include aqueous and non-aqueous liquids in which polyurethane has minimal or no solubility. In other embodiments, the polymer may be isolated by dialysis using a dialysis membrane or tubing. The selection of the pore size of the dialysis membrane or tubing and the resulting molecular weight size cut-off will be guided by the target molecular weight of the desired polyurethane product. In some embodiments, the molecular weight cut-off may range from 1 to 100,000 kDa, 2 to 75,000 kDa, 5 to 60,000 kDa, 10 to 10,000 kDa, 15 to 5,000 kDa, 20 to 1,000 kDa, or 25 to 500 kDa. In some embodiments, the dialysis membrane or tubing has a molecular weight cutoff of less than 100,000 kDa, less than 75,000 kDa, less than 50,000 kDa, less than 30,000 kDa, less than 25,000 kDa, less than 20,000 kDa, less than 15,000 kDa, less than 10,000 kDa, less than 5,000 kDa, less than 1,000 kDa, less than 750 kDa, less than 500 kDa, less than 300 kDa, less than 200 kDa, less than 100 kDa, less than 75 kDa, less than 50 kDa, less than 40 kDa, less than 30 kDa, less than 25 kDa, less than 20 kDa, less than 15 kDa, less than 10 kDa, less than 5 kDa, or less than 3 kDa. In some embodiments, the molecular weight cutoff is selected to separate unreacted compounds from the polyurethane product. In other embodiments, the molecular weight cutoff is selected to separate reaction products having molecular weights less than the target molecular weight of the desired polyurethane product. Such reaction products thus removed may be subjected to conditions and reagents that further polymerize them into larger polyurethane polymers. In some embodiments, multiple dialysis rounds using dialysis membranes or tubing with different molecular weight cutoffs may be performed to obtain the desired isolated polyurethane product. In some embodiments, the duration of dialysis is not particularly limited and is determined to achieve the desired isolation of the target polyurethane polymer product.In some embodiments, the duration of dialysis may range from a few hours or less to more than a week.

[0106] In some embodiments, the polyurethane polymer may be isolated and purified by lyophilization. Lyophilization may be performed using well-known lyophilization procedures in combination with commercially available lyophilizing agents to remove excess liquid by sublimating it from the polyurethane product. In some embodiments, lyophilization may be utilized in combination with one or more other isolation or purification procedures to provide a polyurethane polymer of a desired purity. In certain embodiments, the reaction product is subjected to lyophilization and precipitation and / or dialysis. In some embodiments, lyophilization may be performed after precipitation and / or dialysis.

[0107] In some aspects of the invention, it is desirable to limit the amount of water present during the formation of the polyurethane polymer to prevent the formation of unstable carbamic acids, ureas and / or carbon dioxide and the resulting foaming. In some embodiments, the method further comprises removing excess water from one or more of the reagents, including the solvent, and starting materials, such as aliphatic diisocyanates, polyalkylene oxides, diol chain extenders, used to form the polyurethane polymer. In some embodiments, the removal of excess water may be accomplished through distillation and / or drying of the reagents and starting materials. In some embodiments, excess water is removed from solid surfaces in contact with either the reagents or starting materials by drying the solid surfaces and / or washing with a silane liquid.

[0108] In some embodiments, one or more of the steps of providing, mixing, or applying one or more conditions are carried out under an inert gas. In yet other embodiments, the melting temperature comprises a first melting temperature corresponding to the melting temperature of the soft segment of the thermoplastic polyurethane polymer, or a second melting temperature corresponding to the melting temperature of the hard segment of the thermoplastic polyurethane polymer. In some embodiments, the first melting temperature comprises at least 40°C, at least 45°C, at least 50°C, at least 55°C, at least 60°C, at least 65°C, at least 70°C, at least 75°C, but less than 90°C, less than 80°C, less than 75°C, or less than 70°C. In some embodiments, the second melting temperature comprises at least 100°C, at least 105°C, at least 110°C, at least 115°C, at least 120°C, at least 125°C, at least 130°C, at least 140°C, at least 150°C, at least 160°C, or at least 170°C. In some embodiments, the first melting temperature includes 50-80° C., 50-70° C., 60-70° C., 50-60° C., or 70-80° C. In some embodiments, the second melting temperature includes 100-130° C., 100-110° C., 105-115° C., 110-120° C., or 120-130° C.

[0109] In some aspects of the present invention, the polyurethane polymer exhibits minimal swelling when exposed to water. In some embodiments, the determination of the swelling of the polyurethane polymer is not particularly limited and may include any method commonly used in the art or described herein. In some embodiments, the minimal swelling is determined by comparing the wet mass of the polyurethane during dissolution in water with the dry mass of the same polyurethane before contact with water, and a less than 2.5-fold increase in wet mass to dry mass reveals that the polyurethane has minimal swelling during dissolution in water. In some embodiments, the swelling is determined by measuring the maximum volume difference of a given amount of polyurethane polymer before and after immersion in water for a period of time. In other embodiments, when the polyurethane polymer is formed into a shape, the difference in the cross-sectional area of ​​the molded polyurethane polymer before and after immersion in water is used to determine the swelling. When determining swelling by measuring the difference in volume or cross-sectional area, swelling is determined to be minimal if the volume or cross-sectional area increases by less than 50%, 40%, 30%, 25%, 20%, 15%, 12.5%, 10%, 7.5%, 5%, 2.5%, 1%, or 0.5% compared to the dry volume or cross-sectional area. In certain embodiments, the polyurethane polymer shows substantially no swelling in water and is found to show less than 10%, 5%, or 3% increase in volume or cross-sectional area at any time when immersed in water until dissolution.

[0110] Some embodiments of the present disclosure provide a water-soluble, non-toxic thermoplastic polyurethane composition comprising: i) providing one or more aliphatic diisocyanate compounds; ii) providing one or more high molecular weight polyalkylene oxide compounds having a molecular weight of about 600 to 150,000 g / mol; iii) providing one or more low molecular weight aliphatic diol chain extender compounds having a molecular weight of about 50 to 300 g / mol; and iv) sequentially or simultaneously mixing the one or more aliphatic diisocyanate compounds, the one or more polyalkylene oxide compounds, and the one or more low molecular weight aliphatic diol chain extender compounds in a molar ratio of 50:49 to 20:1 to 30, wherein the isocyanate groups provided by the aliphatic diisocyanate compounds and the polyalkylene oxide compounds and the diisocyanate groups are reacted with each other to form a polyurethane having a molecular weight of about 50 to 300 g / mol. and v) applying one or more conditions sufficient to sequentially or simultaneously polymerize the one or more aliphatic diisocyanate compounds, the one or more high molecular weight polyalkylene oxide compounds, and the one or more low molecular weight aliphatic diol chain extender compounds to synthesize a water soluble, non-toxic thermoplastic polyurethane polymer, the polyurethane having a melting temperature of 50-240° C., having a soft segment content of at least 80%, soluble in water having a near neutral pH at room temperature or at 37° C., is non-cytotoxic to human kidney fibroblasts, and exhibits minimal swelling when exposed to water.

[0111] Some embodiments of the present disclosure provide a polyurethane polymer composition comprising a water-soluble, non-toxic thermoplastic polyurethane polymer that is a reaction product of at least the following: one or more aliphatic diisocyanate compounds, one or more high molecular weight polyalkylene oxide compounds having a molecular weight of about 600 to 150,000 g / mol, one or more low molecular weight aliphatic diol chain extender compounds having a molecular weight of about 50 to 300 g / mol, and optionally a catalyst; and the amount of aliphatic diol chain extender compound reaches a molar ratio of 50:49 to 20:1 to 30, the ratio of isocyanate groups provided by the aliphatic diisocyanate compound to reactive hydroxyl groups provided by the combination of the polyalkylene oxide compound and the diol chain extender compound is about 1:1, the thermoplastic polyurethane has a soft segment content of at least 80%, has a melting temperature of about 50 to 240°C, is soluble in water having a nearly neutral pH at room temperature or 37°C, and is non-cytotoxic to human kidney fibroblasts.

[0112] In some embodiments, the one or more aliphatic diisocyanate compounds are selected from the group consisting of ethylene diisocyanate, propylene diisocyanate, butylene diisocyanate, pentylene diisocyanate, hexamethylene diisocyanate, heptamethylene diisocyanate, octamethylene diisocyanate, nonamethylene diisocyanate, decamethylene diisocyanate, dicyclohexylmethane diisocyanate, bisisocyanatocyclohexylmethane, 2,2,4-trimethylhexamethylene diisocyanate, diisocyanatomethylcyclohexane, norbornane diisocyanate, diisocyanatododecane, or combinations thereof. In other embodiments, the one or more aliphatic diisocyanate compounds are selected from the group consisting of ethylene diisocyanate, propylene diisocyanate, butylene diisocyanate, pentylene diisocyanate, hexamethylene diisocyanate, heptamethylene diisocyanate, octamethylene diisocyanate, nonamethylene diisocyanate, decamethylene diisocyanate, diisocyanatododecane, or mixtures thereof. In a particularly preferred embodiment, the one or more aliphatic diisocyanate compounds include hexamethylene diisocyanate.

[0113] In some embodiments, the one or more polyalkylene oxide compounds include polyethylene oxide polymers, polypropylene oxide polymers, or polybutylene oxide polymers. In some embodiments, the one or more polyalkylene oxide compounds include a molecular weight of 8,000 to 100,000 g / mol. In some embodiments, the one or more polyalkylene oxide compounds include a molecular weight of 10,000 to 80,000 g / mol. In other embodiments, the one or more polyalkylene oxide compounds include a molecular weight of 12,000 to 50,000 g / mol. In some embodiments, the one or more polyalkylene oxide compounds include a molecular weight of 15,000 to 30,000 g / mol. In a particularly preferred embodiment, the one or more polyalkylene oxide compounds include a molecular weight of about 20,000 g / mol.

[0114] In some embodiments, the one or more polyalkylene oxide compounds comprise a molecular weight of about 60-200 g / mol. In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 60-150 g / mol. In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 80-125 g / mol.

[0115] In other embodiments, the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of ethylene glycol, diethylene glycol, triethylene glycol, 1,2-propylene glycol, 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, neopentyl glycol, dipropylene glycol, tripropylene glycol, and combinations thereof. In some embodiments, the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, and combinations thereof. In other embodiments, the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, and combinations thereof. In a preferred embodiment, the one or more low molecular weight aliphatic diol chain extender compounds include 1,4-butanediol.

[0116] In a particularly preferred embodiment, the one or more aliphatic diisocyanates include butylene diisocyanate, pentylene diisocyanate, and / or hexamethylene diisocyanate, the one or more polyalkylene oxide polymer compounds include polyethylene oxide polymers or polypropylene oxide polymers having a molecular weight of 15,000 to 30,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, or 1,6-hexanediol. In another preferred embodiment, the one or more aliphatic diisocyanates include hexamethylene diisocyanate, the polyalkylene oxide polymer includes polyethylene oxide having a molecular weight of about 20,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,4-butanediol.

[0117] In some embodiments, the polyurethane polymer has a soft segment content of greater than 84%. In other embodiments, the polyurethane polymer has a soft segment content of greater than 90%. In yet other embodiments, the polyurethane polymer has a soft segment content of greater than 97%. In one preferred embodiment, the polyurethane polymer has a soft segment content of greater than 98%.

[0118] In some embodiments, the reaction is the result of simultaneously mixing one or more aliphatic diisocyanate compounds, one or more polyalkylene oxide compounds, one or more low molecular weight aliphatic diol chain extender compounds, and optionally one or more of a catalyst, and a solvent(s) to provide a first mixture, which is then exposed to one or more conditions selected from the group consisting of heat, duration, or combinations thereof to provide a water soluble, non-toxic thermoplastic polyurethane polymer.

[0119] In some embodiments, one or more aliphatic diisocyanate compounds, one or more high molecular weight polyalkylene oxide compounds, and optionally one or more of a catalyst and solvent(s) are mixed to form a pre-mixture, which is then exposed to one or more conditions selected from the group consisting of heat, duration, or combinations thereof to obtain a urethane prepolymer prior to reaction with one or more low molecular weight diol chain extender compounds to obtain a water soluble, non-toxic thermoplastic polyurethane polymer.

[0120] In some embodiments, one or more low molecular weight diol chain extender compounds and, optionally, one or more of a catalyst and a solvent(s) are mixed to obtain a second mixture, which is then exposed to one or more conditions selected from the group consisting of heat, duration, or combinations thereof to obtain a water-soluble, non-toxic thermoplastic polyurethane polymer. In further embodiments, the first mixture, pre-mixture, and / or second mixture is exposed to heat above 100° C. in the absence of a catalyst. In some embodiments, the first mixture, pre-mixture, and / or second mixture is exposed to heat below 100° C. in the presence of a catalyst to synthesize a water-soluble, non-toxic thermoplastic polyurethane polymer or urethane prepolymer.

[0121] In some embodiments, the first mixture, pre-mixture, and / or second mixture are exposed to a temperature between 40° C. and 90° C. In other embodiments, the first mixture, pre-mixture, and / or second mixture are exposed to a temperature of about 70° C.

[0122] In some embodiments, the catalyst is stannous octoate, dibutyltin dilaurate, dibutyltin diacetate, dioctyltin dilaurate, 1,4-diazabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2-azanorbornane, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5,7-triazabicyclo[4.4,0]dec-5-ene, bis(2-dimethylaminoethyl)ether, N-ethylmorpholine, N-methylmorpholine, N,N'-dimethylethanolamine, N,N-dimethylcyclohexylamine, trimethylamine ethylethanolamine, N,N,N',N',N"-pentamethyldiethylenetriamine, dimethylaminopropylamine. , N,N-dimethylaminoethylmorpholine, 2-methyl-2-azanorbornane, 3-hydroxy-1-azabicyclo[2.2.2]octane, tetramethylenediamine, dimethylpiperazine N-heterocyclic carbene, potassium octoate, potassium acetate, lithium octoate, bismuth octoate, bismuth neodecanoate, zinc octoate, zinc neodecanoate, zirconium octoate, cobalt octoate, nickel octoate, potassium octoate, calcium octoate, antimony octoate, lanthanum octoate, zirconium acetylacetonate, titanium acetylacetoacetate, aluminum acetylacetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid and diphenyl phosphate.

[0123] In other embodiments, the solvent comprises dimethylsulfoxide (DMSO), N,N-dimethylformamide, N,N-dimethylacetamide, or tetrahydrofuran (THF). In some embodiments, the molar ratio range of the one or more aliphatic diisocyanate compounds to the high molecular weight polyalkylene oxide compound and the low molecular weight diol chain extender compound is 50:49 to 25:1 to 25. In particularly preferred embodiments, the molar ratio range of the one or more aliphatic diisocyanate compounds to the high molecular weight polyalkylene oxide compound and the low molecular weight diol chain extender compound is 50:49 to 40:1 to 10.

[0124] In some embodiments, the polyurethane polymer exhibits minimal swelling when exposed to water. In some embodiments, minimal swelling is determined by comparing the wet mass of the polyurethane during dissolution in water with the dry mass of the same polyurethane before contact with water, and a less than 2.5-fold increase in wet mass to dry mass indicates that the polyurethane has minimal swelling during dissolution in water.

[0125] In some embodiments, the non-toxicity of a polyurethane polymer is determined by incubating human kidney fibroblast cells in cell culture medium containing 0.1 mg / mL of dissolved thermoplastic polyurethane for 24 hours, and the thermoplastic polyurethane polymer is determined to be non-toxic if cellular metabolic activity, as measured by a resazurin fluorescence assay, does not decrease at the end of the 24 hour incubation period.

[0126] In another aspect of the present invention, the polyurethane polymer composition is easily soluble in water.The method for determining the dissolution rate of the polyurethane polymer composition in water is not particularly limited and can include dissolution test protocols known in the art or any method described herein.In some embodiments, the polyurethane polymer composition is determined to be easily soluble in water if a predetermined amount of the polyurethane polymer composition dissolves in water with or without stirring and is substantially dissolved within 48 hours, 36 hours, 30 hours, 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 60 minutes, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes of immersion in water. In some embodiments, the polyurethane polymer composition is readily soluble in water, without stirring, at room temperature in about 4 hours or less, 3 hours or less, 2 hours or less, 1 hour or less, 30 minutes or less, or 15 minutes or less, as measured by a 1.75 mm diameter filament formed from a 1.75 mm diameter filament that is substantially dissolved in deionized water.

[0127] In some embodiments, the polyurethane polymer is linear and substantially free of crosslinking and / or branching. In other embodiments, the polyurethane polymer is substantially free of aromatic isocyanate compounds or isocyanate compounds having more than two isocyanate groups per compound. For purposes of the present invention, substantially free of aromatic isocyanate compounds and isocyanate compounds having more than two isocyanate groups per compound is defined as utilizing an aliphatic diisocyanate source that contains less than 10%, less than 5%, less than 3%, or less than 1% aromatic isocyanate or trifunctional or higher isocyanate by weight. However, in any case, commercially available high purity aliphatic diisocyanate sources are not considered to be excluded from the present invention if they contain more than 10% and less than 15% by weight of a combination of aromatic isocyanate and trifunctional or higher isocyanate.

[0128] In some embodiments, the composition further comprises an aqueous solvent in an amount of about 30 wt% to 80 wt% of the polyurethane polymer composition. In some embodiments, the composition takes the form of a gel. In some embodiments, the polyurethane polymer is present at about 20 wt% to 70 wt% of the polyurethane polymer composition. In some embodiments, the polyurethane polymer comprises more than 70% and up to 100% of the polyurethane polymer composition. In preferred embodiments, the composition consists essentially of or consists of the polyurethane polymer.

[0129] Some embodiments of the present disclosure relate to a method of making a basement membrane construct, comprising: (a) printing a sacrificial structure comprising a water-soluble, non-toxic thermoplastic polyurethane composition as described herein onto a support structure or onto a thin layer comprising a functional basement membrane material with a thermoplastic print head of a three-dimensional printer; (b) applying a thin layer comprising a functional basement membrane material onto the sacrificial structure to obtain one layer of the construct; (c) optionally repeating steps (a) and (b) one or more times to obtain one or more additional layers of the construct; (d) optionally embedding the product of steps (a) and (b), and optionally (c), in a sacrificial or permanent material; and (e) dissolving the sacrificial material by exposing it to an aqueous solvent to provide one or more interior volumes that retain the original shape and size of the printed sacrificial structure, thereby producing a basement membrane construct, wherein the thin layer is porous and has a thickness of 0.25 to 10 μm.

[0130] In some embodiments, the basement membrane construct may include multiple layers, and each individual layer may optionally include an internal volume that connects to form a channel network. In some embodiments, the channel networks of the first and second layers of the construct are directly fluidly connected or are interfacially connected through a membrane. The membrane can filter fluid passing through the membrane from the first channel network of the first layer to the second channel network of the second layer of the construct. In some embodiments, the membrane is a fibrous membrane that has been subjected to one or more post-manufacturing treatments selected from compression, annealing, chemical cross-linking, stretching, drawing, heat treatment, and solvent bonding, thereby imparting enhanced mechanical properties and altered morphological properties to the treated fibrous basement membrane material compared to a fibrous basement membrane material that has not been subjected to one or more of the post-manufacturing treatments.

[0131] In some embodiments, the lamina comprising a functional basement membrane material is a fibrous membrane material, hi some embodiments, the fibrous membrane comprises one or more of gelatin, gelatin composite, collagen, fibrin, chitosan, nitrocellulose, polylactic acid, polycaprolactone, polyethylene glycol, polyethylene glycol diacrylate, or other biopolymers, polymers, or liquefied or homogenized decellularized tissue or extracellular matrix.

[0132] In some embodiments, the thin layer comprising a basement membrane material comprises electrospun fibers. In some embodiments, the fibrous basement membrane material comprises electrospun fibers comprising a first component selected from the group consisting of polycaprolactone, polyethylene glycol, and polyethylene glycol diacrylate, and a second component selected from the group consisting of gelatin, collagen, and fibrin, and the fibrous basement membrane has a thickness of 0.5 to 30 μm. In some embodiments, the fibrous basement membrane material comprises a first material selected to provide strength to the fibrous basement membrane substrate, and a second material selected to provide a substrate that can be remodeled by cells seeded thereon.

[0133] In some embodiments, the thin layer comprising fibrous basement membrane material inhibits or prevents an immunological response by a subject against cells and other substances within the basement membrane construct. In some embodiments, the inhibition or prevention of an immunological response by a subject is against cells within the luminal space of the construct or against bulk materials or tissues in which the thin layer comprising basement membrane material is embedded, enveloped, or surrounded or covered. In some embodiments, the inhibition or prevention of an immunological response by a subject is against substances within the luminal space of the construct or against bulk materials or tissues in which the thin layer comprising basement membrane material is embedded, enveloped, or surrounded or covered. In some embodiments, the inhibition or prevention of an immunological response by a subject is achieved when the basement membrane construct is implanted in a subject or used outside the body, and the luminal space of the construct is in fluid communication with the luminal space of the subject. In some embodiments, the luminal space of the subject with which the construct is in fluid communication and / or another luminal space within or in fluid communication with the liver, pancreas, kidney, small intestine, large intestine, brain, or spine is the cardiovascular system.

[0134] In some embodiments, the fibrous basement membrane material comprises pores of a size sufficient to allow the diffusion of one or more biologically relevant molecules. The pores of the fibrous membrane may have any suitable size, without limitation. In one embodiment, the average or median pore diameter is about 0.05 to about 0.6 μm. In another embodiment, the average or median pore diameter is about 0.05 μm, 0.1 μm, 0.15 μm, 0.2 μm, 0.25 μm, 0.3 μm, 0.35 μm, 0.4 μm, 0.45 μm, 0.5 μm, 0.55 μm, or about 0.6 μm. The volume of the voids (V v ) is the total volume of the measured nanofiber membrane (V Tvm ) is obtained by dividing by (P=V v / V Tvm × 100%), porosity of the nanofiber membrane (P nm) can be any suitable porosity, without limitation. In some embodiments, the porosity is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more. In other embodiments, the porosity is 20-80%, 30-70%, or 40-60%.

[0135] In some embodiments, one or more of the channels can withstand an internal pressure of at least 60 mmHg, hi other embodiments, one or more of the channels can withstand an internal pressure of at least 80 mmHg, 100 mmHg, 150 mmHg, 200 mmHg, 250 mmHg, 300 mmHg, 350 mmHg, 400 mmHg, 450 mmHg, 500 mmHg, 550 mmHg, or at least 600 mmHg.

[0136] In some embodiments, the vascular channel network can withstand an internal pressure of at least 60 mmHg. In other embodiments, the vascular channel network can withstand an internal pressure of at least 80 mmHg, 100 mmHg, 150 mmHg, 200 mmHg, 250 mmHg, 300 mmHg, 350 mmHg, 400 mmHg, 450 mmHg, 500 mmHg, 550 mmHg, or at least 600 mmHg.

[0137] In some embodiments, the fibrous basement membrane material has been subjected to one or more post-manufacturing treatments selected from compression, annealing, chemical crosslinking, stretching, drawing, heat treatment, and solvent bonding, which imparts enhanced mechanical properties to the treated fibrous basement membrane material compared to a fibrous basement membrane material that has not been subjected to one or more of the post-manufacturing treatments. In some embodiments, the enhanced mechanical properties are selected from the group consisting of enhanced tensile strength, enhanced tensile modulus, enhanced abrasion resistance, enhanced thermal stability, enhanced elongation at break, enhanced hardness, enhanced crystallinity, and combinations thereof. In some embodiments, the post-manufacturing treatment comprises solvent bonding. In some embodiments, the solvent bonding is performed in the presence of pressure applied by an opposing support substrate. In some embodiments, the post-manufacturing treatment comprises a combination of heat treatment and pressure applied by an opposing support substrate.

[0138] In some embodiments, post-manufacturing processing can be performed at temperatures between 20-22° C. or above 22° C. In some embodiments, the post-manufacturing process is performed at a temperature below the glass transition temperature (Tg) of one, two, or all of the materials used to form the fibrous membrane, e.g., at least 5° C., 10° C., 15° C., 20° C., 30° C., or more below the glass transition temperature.

[0139] In certain embodiments, the post-fabrication step is annealing, which is performed at a temperature approximately equal to the glass transition temperature of the material used to form the fibrous membrane. For purposes of this application, approximately equal to the glass transition temperature (Tg) is defined as ±5°C of the published glass transition temperature of the material, or ±5% of the published Tg, whichever provides the smaller temperature range. In some embodiments, the post-fabrication step is performed at a temperature between the glass transition temperature and the melting temperature of the material used to form the fibrous membrane. Those skilled in the art will recognize that care must be taken to select an appropriate post-fabrication treatment time so that the porosity of the membrane is not destroyed by significant melting of the fibrous membrane as the temperature is increased above the glass transition temperature.

[0140] In some embodiments, the fibrous membrane is subjected to a post-fabrication process at a temperature of 25° C., 30° C., 35° C., 40° C., 45° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., 80° C., 85° C., 90° C., 100° C., 125° C., 150° C., 160° C., 170° C., 180° C. or higher. In some embodiments, the post-fabrication process is carried out for 1 second, 5 seconds, 10 seconds, 15 seconds, 30 seconds, 45 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, or 1 hour. In certain embodiments, post-production processing may occur for longer periods of time, including 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 25 hours, 1 day, 2 days, 3 days or more.

[0141] In some embodiments, the post-fabrication annealing step includes applying compression to facilitate the envelopment of the sacrificial substrate by the fibrous membrane, as described herein. In some embodiments, applying compression at elevated temperatures promotes better or more rapid bonding or annealing of the fibers. In some embodiments, the post-fabrication annealing and compression steps are performed at temperatures of 120-180° C., 40-70° C., 45-65° C., 50-60° C., or 53-57° C. for a time period of 11-25 hours, 13-22 hours, 15-20 hours, or 17-19 hours. In certain preferred embodiments, the compression and annealing steps are performed at about 55° C. for about 18 hours.

[0142] The amount of pressure used in the compression step is not particularly limited, as long as it is sufficient to promote fiber-to-fiber bonding or annealing at the fiber crossing locations, while protecting the fibrous membrane or substrate on which the pressure is applied from damage.In some embodiments, compression is applied by placing the fibrous membrane and the substrate on which the fibrous membrane is manufactured between two opposing release substrates of a size, shape, and hardness that allows the application of sufficient force to induce fiber-to-fiber bonding or adhesion without damaging the fibrous membrane or substrate on which compression is applied.In some embodiments, the release substrate is a soft silicone pad.In a particular preferred embodiment, the compression step is performed by placing the fibrous membrane and the sacrificial substrate between two silicone pads placed on a solid surface, and the only compression is caused by the weight of the silicone pads placed on top.

[0143] In some embodiments, additional compressive force may be applied using pressure applied by placing objects of increasing weight on the upper silicone pad. In some embodiments, the pressure applied to the fibrous membrane and sacrificial substrate in the compression process is less than 25 psi, less than 20 psi, less than 18 psi, less than 15 psi, less than 12 psi, less than 10 psi, less than 8 psi, less than 7 psi, less than 6 psi, less than 5 psi, less than 4 psi, less than 3 psi, less than 2 psi, less than 1 psi, less than 0.5 psi, less than 0.4 psi, less than 3 psi, less than 2 psi, or less than 0.1 psi. In some preferred embodiments, when pressure is applied under heating, the pressure is 0.05 psi to 2 psi, 0.05 psi to 1 psi, or 0.1 to 0.8 psi. In some further embodiments, the pressure applied during the compression process is 0.5 to 5 psi, 2 to 8 psi, 5 to 14 psi, 3 to 7 psi, or 18 to 25 psi.

[0144] In some embodiments, post-fabrication treatment includes exposing the fibrous membrane to a solvent to promote adhesion at the intersections of the partially softened or swollen fibers. The solvent used for solvent bonding should be capable of at least partially softening or swelling the fibers of the fibrous membrane material in a reasonable time to promote adhesion between the fibers. In some embodiments, the solvent is non-toxic. In other embodiments, the solvent has a Hildebrand solubility parameter similar to that of the material used to form the electrospun fibrous membrane. In situations where a particular concentrated solvent may rapidly dissolve and destroy the morphology of the fibers of the fibrous membrane, the solvent may be mixed with one or more non-solvents to provide a dilute solvent formulation that can provide controlled swelling of the fibers and adhesion between the fibers without destroying the morphology of these fibers. In some embodiments, the solvent is selected from one or more of acetone, methyl ethyl ketone, dimethylacetamide, ethyl acetate, methyl acetate, N-methylpyrrolidone, propylene carbonate, lactate, diethyl ether, dichloromethane, tetrahydrofuran, ethanol, and methanol. In some embodiments, the solvent is acetone in concentrated form, e.g., a formulation close to 100% pure (undiluted). In some embodiments, the acetone is diluted with a polar non-solvent, such as isopropanol, to obtain a formulation containing 20-80% acetone. In certain embodiments, the acetone is diluted to a concentration of 50% or 25%.

[0145] The method of applying the solvent to the fibrous membrane is not particularly limited, so long as the solvent is applied relatively uniformly to at least one surface of the fibrous membrane. In some embodiments, the solvent can be applied to the fibrous membrane before the membrane is contacted with the sacrificial substrate. In some embodiments, the fibrous membrane is saturated with acetone. Saturation of the fibrous membrane with the solvent can be performed by permeation, immersion, or spraying, in combination with a length of time to allow for saturation. In some embodiments, it is not desirable to saturate the fibrous membrane with the solvent. In these circumstances, the solvent can be applied to the surface of the fibrous membrane in a limited amount, such as by spraying. In some embodiments, the solvent can be applied to a 100 cm 2 surface of the fibrous membrane. 2In some embodiments, 0.5 to 10 mL of solvent is applied per 100 cm of fibrous membrane. 2 Per injection, 0.5-1.5 mL, 1.0-2.5 mL, 2.0-4.0 mL, 3.0-4.5 mL, 4.0-5.5 mL, 5.0-6.5 mL, 6.0-7.5 mL, 7.0-8.5, or 8.0-9.5 mL of solvent is applied.

[0146] In some embodiments, the solvent bonding is accompanied by the application of compression to further induce morphological changes in the fibrous membrane when applied to a sacrificial substrate and / or to strengthen the adhesion between the fibers of the fibrous membrane. The particular pressure used in the compression step to induce morphological changes in the membrane and adhesion between the fibers can be any pressure disclosed herein and is not particularly limited, so long as the pressure does not cause the substrate to which the fibrous membrane is applied to collapse. In some embodiments, the compression is used in combination with the solvent bonding and includes a compressive force of at least 0.1 to 25 Newtons, which is generated by compressing opposing release substrates that sandwich the fibrous membrane and the sacrificial substrate to which the fibrous membrane is applied.

[0147] In some embodiments, the application of compression during the post-production solvent bonding process reduces the time required to achieve strong bonds between the fibers. The specific time required to provide high strength bonds under compression is not particularly limited and includes those times disclosed herein. In some embodiments, the fibrous membrane is exposed to pressure and / or solvent for at least 30 seconds, 45 seconds, 60 seconds, 75 seconds, 90 seconds, 105 seconds, 120 seconds, 2.5 minutes, 3 minutes, 3.5 minutes, 4 minutes, 4.5 minutes, 5 minutes, 5.5 minutes, 6 minutes, 6.5 minutes, 7 minutes, 7.5 minutes, 8 minutes, 8.5 minutes, 9 minutes, 9.5 minutes, 10 minutes or more.

[0148] In some embodiments, post-manufacturing treatments include physical or chemical cross-linking of the fibers. In some embodiments, cross-linking is achieved by exposure to ultraviolet light, gamma radiation, or plasma, or by adding one or more cross-linking agents, or a combination thereof. Cross-linking agents that can be used to promote cross-linking of fibers include, but are not limited to, those that induce the formation of covalent bonds between compounds found in adjacent fibers. In some cases, cross-linking agents include glyoxal, isocyanates, glutaraldehyde, formaldehyde, carbodiimides, epoxides, citric acid, tannin, ferulic acid, glyceraldehyde, genepin, or transglutaminase.

[0149] In some embodiments, post-manufacturing treatments change the morphology of the fibrous membrane and / or improve the mechanical properties of the fibrous membrane. Improved mechanical properties may include, but are not limited to, one or more of: improved tensile strength, improved tensile modulus, improved abrasion resistance, improved thermal stability, improved elongation at break, improved hardness, and improved crystallinity. Changes in morphology include, but are not limited to, one or more of: increased fiber diameter, decreased fiber diameter, increased porosity, decreased porosity, increased pore tortuosity, and decreased pore tortuosity.

[0150] In some embodiments, step (b) comprises electrospinning the fibrous lamina membrane directly onto the sacrificial structure followed by post-production processing to impart enhanced mechanical properties to the fibrous lamina membrane. In some embodiments, step (b) comprises applying a preformed lamina comprising a functional basement membrane to the sacrificial substrate using a combination of compression and either heat or solvent to obtain a sacrificial substrate covered with a lamina comprising a functional basement membrane.

[0151] In some embodiments, obtaining one or more layers in step (c) comprises printing a sacrificial structure comprising a water-soluble, non-toxic thermoplastic polyurethane composition directly onto a thin layer comprising a functional basement membrane material previously applied to the sacrificial structure in step (b). In some embodiments, obtaining one or more layers in step (c) comprises printing a sacrificial structure comprising a water-soluble, non-toxic thermoplastic polyurethane composition onto a supporting substrate or onto a thin layer comprising a functional basement membrane that is not a thin layer previously applied in step (b), and further combining the one or more additional layers obtained in step (c) with the layer obtained by first performing steps (a) and (b) prior to the embedding in step (d).

[0152] In some embodiments, one or more layers of the construct obtained in step (c) and the layer obtained by initially performing steps (a) and (b) are configured, individually or together, into a desired three-dimensional shape prior to step (d).

[0153] In some embodiments, the water-soluble, non-toxic thermoplastic polyurethane is heated to between 100° C. and 250° C. during printing. In some embodiments, both the chamber and bed temperatures are held at 25° C. during the three dimensional printing process.

[0154] In some embodiments, the sacrificial structure is printed in a serpentine or branched pattern. In some embodiments, the product of steps (a) and (b), and optionally (c), is embedded in or laminated with polydimethylsiloxane, methacrylated gelatin, bulk tissue material, or other matrix-forming material. Bulk tissue material, or other matrix-forming material, is a non-toxic material recognized in the art for use in tissue constructs or bioscaffolds that provide structure and promote the growth and integration of cells and tissues therein. Specific examples include, but are not limited to, type I collagen, fibrin, fibronectin, entactin, elastin, elastin-like polypeptides, gelatin, laminins such as laminin 511, homogenized or liquefied extracellular matrix or decellularized tissue, and combinations thereof. In some embodiments, the product of steps (a) and (b), and optionally (c), is embedded in a material when the material is in a liquid state. In some embodiments, the embedding process utilizes a mold having a shape and size selected to facilitate injection into a desired location within a patient or to allow for a desired function of the finished product. In yet other embodiments, the products of steps (a) and (b), and optionally (c), are overlaid with a material that exists in a gelled or solid state.

[0155] In some embodiments, the products of steps (a) and (b), and optionally (c), are embedded in or layered with cell-seeded or cell-containing materials. The types of cells and bulk tissues seeded and disposed on or within the products of steps (a), (b), and / or optionally (c) are not particularly limited and include any of the cell or bulk tissue types described herein. In preferred embodiments, the cells include stem cells, endothelial cells, cardiomyocytes, parietal epithelial cells, hepatocytes, bile duct epithelial cells, stellate cells, adipocytes, osteoblasts, osteoclasts, enterocytes, goblet cells, enteroendocrine cells, Paneth cells, microfold cells, cup cells, brush cells, or other cells present in the kidney, pancreas, lung, cardiac muscle, liver, spleen, small intestine, large intestine, nervous tissue, skeletal muscle, composite tissue, adipose tissue, bone tissue, or skin.

[0156] Some aspects of the present disclosure relate to methods of fabricating a microfluidic device, the methods including: (a) printing a sacrificial structure comprising a water soluble, non-toxic thermoplastic polyurethane composition as described herein onto a support structure or into a thin film layer with a thermoplastic print head of a three dimensional printer; (b) embedding the product of step (a) into a sacrificial or permanent material, with or without a support structure or thin film layer; and (c) optionally repeating steps (a) and (b) one or more times; and (d) dissolving the sacrificial material by exposing it to an aqueous solvent to provide one or more interior volumes that substantially retain the original shape and size of the printed sacrificial structure, thereby fabricating a microfluidic device.

[0157] In some embodiments, the material comprises methacrylated gelatin, polydimethylsiloxane, or other matrix-forming material. In other embodiments, the sacrificial structure comprises an expanded longitudinal profile, a substantially elliptical or circular cross-sectional profile, and the one or more internal volumes provided comprise channels. In some embodiments, the sacrificial structure is formed into a serpentine or branching pattern having a constant or non-constant diameter. EXAMPLES

[0158] Working Example

[0159] method

[0160] Synthesis of water-soluble polyurethane (WPU)

[0161] In one embodiment, WPU polymer was synthesized via a two-step process using poly(ethylene glycol) (PEG; Mw=20,000, Sigma), 1,6-hexamethylene diisocyanate (HDI, Sigma), and 1,4-butanediol (BDO, Sigma) (Figure 1). PEG was first dissolved in dimethylsulfoxide (DMSO, Sigma) at 70°C in a three-neck flask under N2 protection. HDI was then added to the flask, followed by stannous octoate (Sn(Oct)2, Sigma) catalyst. Then, after 3 hours, BDO / DMSO solution was added dropwise to the prepolymer solution in the flask. The final polymer concentration was 4% (w / v). The reaction was carried out at 70°C for 4 days. The polymer was purified via dialysis and lyophilization. The feed molar ratios of PEG, HDI, and BDO were varied to provide tunable dissolution capabilities, as summarized in Table 1. [Table 1]

[0162] Characterization of WPUs

[0163] The chemical structure of the polymer was verified using a Fourier transform infrared spectrometer (FTIR, Agilent 680). The melting temperatures (Tm) were measured from −40 to 200 °C using a differential scanning calorimeter (DSC, Perkin-Elmer Pyris 1) at a heating rate of 10 °C / min with nitrogen flow.

[0164] 3D printing of WPU

[0165] The polyurethane was printed on BIO X™ (Cellink, Sweden) using a BIO X™ thermoplastic printhead. The polyurethane was heated to different temperatures between 150° C. and 200° C. Both the chamber and bed temperatures were kept at 25° C. Different patterns were printed with nozzle travel speeds of 1-5 mm / s and a nozzle inner diameter of 400 μm.

[0166] Dissolution in water

[0167] The polyurethane was molded into cylindrical specimens with a diameter of 1.75 mm and a length of 4.5 mm and immersed in deionized water (DI water) at room temperature. The dissolution of the specimens was monitored as a function of time. At each given time point, the remaining material (n=3) was removed and weighed (W1), then dried and weighed (W2). The residual wet mass and residual dry mass were calculated as follows:

[0168] Residual wet mass (%)=W1 / W0×100%

[0169] Residual dry mass (%)=W2 / W0×100%

[0170] AquaSys® 120 spools were cut into test specimens with the same dimensions as the control.

[0171] Swelling behavior

[0172] A weighed WPU cylinder (W0) was immersed in 100 mL of deionized water at 25° C. At each given time point, polyurethane samples (n=3) were taken out to remove residual water on the surface and weighed (W2). The swelling ratio was calculated as (W2-W0) / W0×100%. AquaSys® 120 printing cylinder of the same dimensions as the control group (FIG. 5).

[0173] Cytotoxicity of WPU

[0174] Polyurethanes were dissolved in cell culture medium at 0.01 mg / mL, 0.1 mg / mL, and 1 mg / mL, respectively, and then sterilized by 0.22 μm membrane filters before cell culture studies. Human kidney fibroblasts (HKFs) were seeded into 12-well cell culture plates at 8 × 10 cells per well. 4 Cells were seeded in medium at a density of 0.01, 0.1, and 1 mg / mL. After 1 day of incubation, polyurethane / water solutions were added to each well at final concentrations of 0.01, 0.1, and 1 mg / mL. After 24 hours of culture, cell metabolic activity (n=4) was measured using a resazurin fluorescence assay.

[0175] Example 1 - WPU embedded in PDMS

[0176] WPU1 was printed into a branched pattern (0.4 mm wide, 0.8 mm high, 0.8 mm branch spacing) and then embedded in polydimethylsiloxane (PDMS; Sylgard® 184, Dow Corning). WPU-embedded PDMS devices were formed by drilling two holes on the two distal ends of the print with a 3 mm biopsy punch for Luer connections after 5 h curing under 55 °C. The WPU / PDMS device was then immersed in a water bath under sonication for 3.5 h, followed by red dye perfusion, to examine its clearance. An AquaSys® 120 pattern with the same dimensions embedded in PDMS was used as a control.

[0177] Example 2 - Twisting of WPU

[0178] An 8-branch pattern (0.4 mm wide, 0.4 mm high, 1 mm branch spacing) was printed from WPU2, twisted, and then embedded in PDMS. After curing at 55 °C for 5 h, the twisted WPU / PDMS construct was immersed in a water bath under sonication for 3.5 h to remove the WPU, followed by heating in an oven for 1 h to remove trapped water vapor. A red dye solution was perfused through the twisted channels to check their clearance.

[0179] Example 3 - Spacing

[0180] WPU2 was printed in a serpentine pattern with increasing spacing at 1 mm, 1.2 mm, 1.4 mm, 1.6 mm, and 1.8 mm. The WPU2 prints were then embedded in 12% methacrylated gelatin (GelMA) followed by photocrosslinking under near-visible light (wavelength 395 nm) for 5 min. The WPU / GelMA devices were then immersed in PBS and left at 37°C for 30 min to reach full clearance of WPU. Red dye perfusion was performed to check channel clearance. The WPU / GelMA devices were cross-sectioned and the channel dimensions and spacing were measured under a microscope. An AquaSys® 120 pattern with the same dimensions embedded in 12% GelMA was used as a control.

[0181] Results and Discussion

[0182] Characterization of WPUs

[0183] In the FTIR spectrum (Figure 2), -1 The peaks were mainly assigned to the ether groups of the PEG soft segments, and also corresponded to the COC stretching absorption from the urethane groups. As the content of PEG segments increased, the intensity of the characteristic peaks from the urethane groups, e.g., 1728 cm -1 C=O stretching at 3300-3500cm -1 The NH stretching at is weakened.

[0184] All water-soluble polyurethanes had two melting temperatures (Tms), as summarized in Table 2. The lower Tms arose from the semi-crystalline PEG soft segments, ranging from 62°C to 65°C. The higher Tms were due to the hard segments of the polyurethane backbone, ranging from 105°C to 111°C. [Table 2]

[0185] water soluble

[0186] The water dissolution behavior of the water-soluble polyurethanes as a function of time was recorded in FIG. 3. As shown in FIG. 3, the dimensions of WPU1 and WPU2 were visibly and significantly reduced. The WPU1 specimen completely disappeared after 2 hours of dissolution, and the WPU2 specimen was essentially invisible in water after 4 hours of dissolution. In contrast, the AquaSys® 120 specimen was obviously swollen and remained at 14±6% of its initial dry weight after 24 hours of dissolution. The WPU3 specimen was also in a swollen state and remained at 28±4% of its initial dry weight after 24 hours of dissolution. Although both WPU1 and WPU2 show faster water dissolution than AquaSys® 120, WPU3 is considered to have the lowest water dissolution of the four groups.

[0187] To further quantify the remaining samples, both dry and wet weight measurements were performed and plotted in Figures 4A-B. For the residual dry mass (Figure 4A, left), WPU1 was immersed in DI water for 120 min and completely dissolved. WPU2 retained only 6±3% of the dry mass at 240 min. Both WPU3 and AquaSys® 120 retained 60±6% and 53±3% of the dry mass, respectively, at 240 min. The residual wet mass (Figure 4B, right) was the result of bonding from polymer dissolution and swelling. Both WPU1 and WPU2 showed an increase in wet weight at the beginning, followed by a noticeable weight loss. Notably, WPU1 had 0 residual wet mass at 120 min, indicating the fastest water dissolution of the three WPU groups. The initial weight increase was the result of partial polymer dissolution, which allowed the polymer network to absorb a larger amount of water. The weight loss below is caused by the high water solubility of the polymer, which breaks the polymer network and causes the polyurethane to disappear. In contrast, both WPU3 and AquaSys® 120 showed only an increasing trend of residual wet mass within 240 minutes compared to WPU1 and WPU2, but no decreasing trend, implying a relatively low degree of water dissolution (both retained more than 50% of the dry weight after 240 minutes of water dissolution).

[0188] Swelling behavior

[0189] The swelling ratio of water-soluble polyurethanes as a function of time is plotted in FIG. 5. Both WPU1 and WPU2 showed an increasing trend at the beginning, with maximum swelling ratios of 188±15% and 1067±69% after 50 and 120 minutes of water dissolution, respectively. The swelling ratios of these two groups then dramatically decreased to -36±43% and 293±92% at 120 and 240 minutes, respectively. As mentioned above, the increasing trend in swelling ratio is due to partial dissolution of the polymer, while the decreasing trend suggests that a large amount of polyurethane has dissolved and therefore can no longer hold water. The swelling ratios of WPU3 and AquaSys® 120 increased to 1675±218% and 560±40%, respectively, after 240 minutes of water immersion. The lack of a decrease in swelling ratio within 240 minutes indicates that WPU3 and AquaSys® 120 have a slow water dissolution.

[0190] The swelling performance of water-soluble polyurethanes is crucial for the use of polyurethanes as sacrificial materials, especially when they are embedded in soft materials to create hollow structures. If the soft material does not have enough strength to resist the swelling of the sacrificial material, the resolution or even shape integrity of the hollow structure will be compromised. Both WPU1 and WPU2 exhibit fast water dissolution (completely dissolved within 2 and 4 hours in DI water at room temperature) and limited swelling, making them outstanding candidates as water-soluble sacrificial polymers for creating precise overhang or undercut structures.

[0191] Cytotoxicity of WPU

[0192] The cytotoxicity of WPU was evaluated using human kidney fibroblasts. As shown in Figure 6, the cell viability in cell culture medium containing 0.01, 0.1, and 1 mg / mL WPU did not show significant difference from that of the medium control (p>0.05). Significant difference only existed between 0.1 mg / mL and 1 mg / mL in the WPU1 group (p<0.05), which may be due to the high amount of PEG segments. This result confirms that water-soluble polyurethane has no obvious cytotoxicity and suggests that it has a high potential to be used in biomedical applications.

[0193] Example 1 - WPU embedded in PDMS

[0194] PDMS is a commonly used material to fabricate microfluidic devices with channels for fluid or air / gas perfusion. One of its defining features includes its high waterproofness. The common practice for fabricating channels inside PDMS is to fabricate the channels on the surface of a PDMS block and then bond this to another PDMS block, which has the risk of leaks occurring at the bonding site. By creating channels inside a monolithic PDMS block, the potential risk of leaks is effectively prevented and the shortening of redundant fabrication processes is also achieved.

[0195] In Example 1 (Figure 7A-E), WPU1 branched print was embedded in PDMS and reached full clearance for about 3.5 hours under water sonication. In contrast, AquaSys® 120 (Figure 8A-E) with the same dimensions was barely dissolved under the same clearance conditions as WPU1, which was further confirmed by red dye perfusion. This example shows the application scenario of WPU1 creating channels inside one PDMS as a microfluidic device.

[0196] Example 2 - Twisting of WPU

[0197] Example 2 is to demonstrate the good flexibility of WPU2, as well as its good water solubility, by embedding and dissolving an 8-branched WPU2 pattern in PDMS (Figure 9A-E). Complete clearance of the WPU2 print was achieved by sonication in a water bath for 3.5 h, and then confirmed by red dye perfusion.

[0198] Example 3 - Spacing

[0199] In Example 3, bio-microfluidic devices were fabricated by using GelMA as the bulk hydrogel and WPU2 to create channels (FIGS. 10A-C). WPU2 was printed in a serpentine pattern with an increased filament spacing from 1 mm to 1.8 mm. WPU2 was completely removed by leaving the device in PBS at 37° C. for 30 min. Cross-sectional images showed that all channels maintained a relatively round shape without channel fusion (FIGS. 11A-D). The channels showed a slight increase in cross-sectional area (approximately 1.3%, from 0.235 to 0.238 mm) compared to the original WPU2 print. 2 ) and essentially maintains its shape fidelity.

[0200] The same pattern of AquaSys® 120 was used as a control (FIGS. 12A-C). It required a significantly longer time (about 18 h) to be removed under the same conditions as WPU2. Both dye perfusion and cross-sectional images showed some of the channels fused together due to the slow water dissolution and high water absorption of AquaSys® 120 (FIGS. 13A-D). Furthermore, the channels showed irregular shapes other than round shapes after clearance, and the cross-sectional area of ​​the channels increased by about 118% compared to the original printed ones.

[0201] Example 3 provides another application scenario of WPU creating channels in soft hydrogels with good shape retention as bio-microfluidic devices.

Claims

1. A method for synthesizing a water-soluble, non-toxic thermoplastic polyurethane polymer, i) A step of providing one or more aliphatic diisocyanate compounds, ii) A step of providing one or more high molecular weight polyalkylene oxide compounds having a molecular weight of approximately 600 to 150,000 g / mol, iii) A step of providing one or more low molecular weight aliphatic diol chain extender compounds having a molecular weight of approximately 50 to 300 g / mol, iv) The one or more aliphatic diisocyanate compounds, the one or more polyalkyl A step of sequentially or simultaneously mixing a ylene oxide compound and one or more low molecular weight aliphatic diol chain extender compounds in a molar ratio of 50:49 to 20:1 to 30, wherein the ratio of isocyanate groups provided by the aliphatic diisocyanate compound to reactive hydroxyl groups provided by the combination of the polyalkylene oxide compound and the diol chain extender compound is approximately 1:1, and v) The method comprising the step of synthesizing a water-soluble, non-toxic thermoplastic polyurethane polymer having a melting temperature of 50 to 240°C, a nearly neutral pH, and having a soft segment content of at least 80%, and being non-cytotoxic to human kidney fibroblasts, by applying one or more conditions sufficient to sequentially or simultaneously polymerize one or more aliphatic diisocyanate compounds, one or more high molecular weight polyalkylene oxide compounds, and one or more low molecular weight aliphatic diol chain extender compounds.

2. A method for synthesizing a water-soluble thermoplastic polyurethane polymer according to claim 1, wherein the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 60 to 200 g / mol.

3. A method for synthesizing a water-soluble thermoplastic polyurethane polymer according to claim 1, wherein one or more polyalkylene oxide polymer compounds have a molecular weight of 12,000 to 50,000 g / mol.

4. A method for synthesizing a water-soluble thermoplastic polyurethane polymer according to claim 1, comprising step iv) simultaneously mixing all of the one or more aliphatic diisocyanate compounds, the one or more polyalkylene oxide compounds, and the one or more low molecular weight aliphatic diol chain extender compounds to provide a first mixture, and step v) exposing the first mixture to one or more conditions selected from the group consisting of heat, duration, catalyst, or a combination thereof, thereby obtaining the water-soluble, non-toxic thermoplastic polyurethane polymer.

5. A method for synthesizing a water-soluble thermoplastic polyurethane polymer according to claim 1, wherein applying one or more conditions sufficient for polymerization in step v) includes exposing the first mixture to a heat above 100°C in the absence of a catalyst to synthesize the water-soluble thermoplastic polyurethane polymer, or exposing the first mixture to a heat below 100°C in the presence of a catalyst to synthesize the water-soluble thermoplastic polyurethane polymer while minimizing both the formation of allophanate groups and the crosslinking of the polyurethane polymer.

6. A method for synthesizing a water-soluble thermoplastic polyurethane polymer according to claim 1, comprising step iv) sequentially mixing one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds to form a premixture, and step v) applying one or more conditions sufficient for polymerization, which involves exposing the premixture to one or more conditions selected from the group consisting of heat, duration, catalyst, or a combination thereof, thereby obtaining a urethane prepolymer.

7. A method for synthesizing a water-soluble thermoplastic polyurethane polymer according to claim 6, comprising applying one or more conditions sufficient for polymerization in step v) by exposing the pre-mixture to heat above 100°C in the absence of a catalyst, or by exposing the pre-mixture to heat below 100°C in the presence of a catalyst, thereby synthesizing the urethane prepolymer.

8. A method for synthesizing a water-soluble thermoplastic polyurethane polymer according to claim 6, comprising: sequential mixing providing one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds in the form of the urethane prepolymer; mixing the urethane prepolymer with one or more low molecular weight diol chain extender compounds to obtain a second mixture; and further applying one or more conditions sufficient to form a carbamate bond between the prepolymer and the diol chain extender compounds, thereby obtaining the water-soluble thermoplastic polyurethane.

9. A water-soluble, non-toxic thermoplastic polyurethane composition comprising polyurethane produced by the process described in claim 1, wherein the polyurethane composition has a melting temperature of 50 to 240°C, contains at least 80% soft segments, dissolves in water having a nearly neutral pH at room temperature or 37°C, is non-cytotoxic to human renal fibroblasts, and exhibits minimal swelling upon exposure to water.

10. At least the following: One or more aliphatic diisocyanate compounds, One or more high molecular weight polyalkylene oxide compounds having a molecular weight of approximately 600 to 150,000 g / mol, One or more low molecular weight aliphatic diol chain extender compounds having a molecular weight of approximately 50 to 300 g / mol, and Optional catalyst, A polyurethane polymer composition comprising a water-soluble, non-toxic thermoplastic polyurethane polymer, which is a reaction product of the following, wherein the molar ratio of the one or more aliphatic diisocyanate compounds, the one or more polyalkylene oxide compounds, and the one or more low molecular weight aliphatic diol chain extender compounds reaches 50:49 to 20:1 to 30, and the ratio of isocyanate groups provided by the aliphatic diisocyanate compounds to reactive hydroxyl groups provided by the combination of the polyalkylene oxide compounds and the diol chain extender compounds is approximately 1:

1. The polyurethane polymer composition wherein the thermoplastic polyurethane has a soft segment content of at least 80%, a melting temperature of about 50 to 240°C, dissolves in water with a nearly neutral pH at room temperature or 37°C, and is non-cytotoxic to human renal fibroblasts.

11. The polyurethane polymer composition according to claim 10, wherein one or more polyalkylene oxide compounds have a molecular weight of 12,000 to 50,000 g / mol.

12. The polyurethane polymer composition according to claim 10, wherein the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 60 to 150 g / mol.

13. The polyurethane polymer composition according to claim 10, wherein the polyurethane polymer has a soft segment content of more than 90%.

14. The polyurethane polymer composition according to claim 10, wherein the polyurethane polymer composition is formed from a 1.75 mm diameter filament that is substantially dissolved in deionized water at room temperature in about 4 hours or less without stirring, and is easily dissolved in water as measured by a 1.75 mm diameter filament.

15. The polyurethane polymer composition according to claim 10, wherein the polyurethane polymer is linear and substantially free of crosslinking and / or branching.

16. The polyurethane polymer composition according to claim 10, wherein the polyurethane polymer is not formed from substantially aromatic isocyanate compounds or isocyanate compounds having more than two isocyanate groups per compound.

17. The polyurethane polymer composition according to claim 10, wherein the composition further comprises an aqueous solvent in an amount of about 30 wt% to 80 wt% of the polyurethane polymer composition.

18. The polyurethane polymer composition according to claim 17, wherein the composition takes the form of a gel.

19. A method for fabricating a basement membrane structure, a. Printing a sacrificial structure containing the water-soluble, non-toxic thermoplastic polyurethane composition described in claim 10 onto a support structure or onto a thin layer containing a functional basement membrane material using a thermoplastic print head of a three-dimensional printer. b. Obtaining one layer of the structure by applying a thin layer containing a functional basement membrane material to the sacrificial structure. c. Optionally, repeat steps (a) and (b) one or more times to obtain one or more additional layers of the structure. d. Optionally, embed or laminate the products of steps (a) and (b), and optionally (c), in or together with the sacrificial material or permanent material, and e. The process includes dissolving the sacrificial material by exposing it to an aqueous solvent to produce a base membrane structure by providing one or more internal volumes that retain the original shape and size of the printed sacrificial structure, The method wherein the thin layer is porous and has a thickness of 0.25 to 10 μm.

20. A method for fabricating microfluidic devices, a. A step of printing a sacrificial structure containing the water-soluble, non-toxic thermoplastic polyurethane composition described in claim 10 onto a support structure or as a thin layer using a thermoplastic print head of a three-dimensional printer. b. A step of embedding or laminating the product of step (a) in or together with the sacrificial material or permanent material, with or without the presence of the support structure or the thin layer, and c. Optionally, a process in which steps (a) and (b) are repeated one or more times, and d. The method comprising the step of fabricating a microfluidic device by dissolving the sacrificial material by exposing it to an aqueous solvent to provide one or more internal volumes that substantially retain the original shape and size of the printed sacrificial structure.

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