Water-soluble polyurethane as support material and sacrificial material for 3D printing

Abstract

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

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 336,128, filed on April 28, 2022, and U.S. Provisional Application No. 63 / 402,700, filed on August 31, 2022, the entire contents of which are hereby incorporated by reference. Background of the Invention

[0004] Three-dimensional (3D) printing technology is used to build 3D objects from computer-aided design (CAD) models or digital 3D models and has been applied in many industries (such as architecture, aerospace, pharmaceutical and biomedical), and its application range is still expanding. Support materials are often required when printing complex geometries, overhangs and undercuts in many 3D printing technologies (such as fused deposition modeling (FDM), stereolithography (SLA), digital light processing (DLP) and material jetting). The most traditional way to achieve support is to print the same material used in the printed object, but in a lower density form so that the support can be easily removed mechanically after printing. However, this method is often time-consuming, cumbersome, and it is difficult to completely remove all support material without damaging the print, especially from small and complex features. To make it easier to remove support material, an alternative method in U.S. Patent No. 5,503,785 describes depositing a thin layer of release material between the support structure and the printed structure. The release material is usually a hydrocarbon wax or a water-soluble wax (polyethylene oxide and ethylene glycol-based polymers, polyvinyl pyrrolidone-based polymers, maleic acid-based polymers, etc.) or a conventional release material (fluorine compounds, silicone wax, etc.). Depending on the type of release material, it may leave an undesirable oily residue on the printed structure. In addition, it may also make the 3D printing process more complicated.

[0005] Solvent-soluble support materials offer a good solution to reduce or eliminate tedious work and undesirable residues, as they can be removed by solvents while maintaining the integrity of the built object. However, most require harsh conditions (such as organic solvents, acids, bases, and high temperatures) to remove, such as high-impact polystyrene (HIPS) (limonene), polylactic acid (PLA) (sodium hydroxide), VXL® (Xioneer Systems, Austria; VXL® EX detergent, alkaline), StratasysTM SR (StrataSys, Ltd, USA; alkaline solution (pH between 11-13), ≥70°C) in US Patent No. US 6,790,403, and PolyDissolveTM S (Polymaker, China; alkaline solution, above 70°C). These harsh dissolution conditions are unsafe / hazardous and limit the choice of co-printing materials (to only those that are not affected by the dissolution conditions); more importantly, they make these support materials unsuitable for biomedical applications involving cells.

[0006] In addition to being used as support materials, dissolvable 3D printed materials can also be used as sacrificial materials to create void spaces in 3D materials or constructs after their removal (US Patent No. US20180030409A1). To be useful in high-resolution applications such as tissue engineering, sacrificial materials must be soluble in non-toxic solvents (ideally water-soluble) for use in conjunction with cells and biomaterials. In addition, ideal sacrificial materials should experience minimal swelling to prevent damage to surrounding materials or structures, such as when small vascular structures are to be created next to thin basement membranes or close to other channel networks to enable short-distance diffusion.

[0007] There are very limited commercial options for water-soluble materials for 3D printing, which need to be able to dissolve under mild conditions (e.g., physiological conditions comparable to those compatible with maintaining living cells, typically temperatures of 4°C to 40°C and pH values ​​of 6.5 to 10.5). Three representative commercial options include polyvinyl alcohol (PVA), NICHIGO G-POLYMER™ (butylene glycol vinyl alcohol (BvOH), Nippon Gohsei, Japan), and AQUASYS® (Infinite Material Solutions, LLC, Wisconsin, US). Among them, AQUASYS® 120 (U.S. Patent No. 10,435,576) has been shown to dissolve the fastest in water. However, in actual use, AQUASYS® 120 may take hours, days, or even weeks to completely dissolve, depending on its size and dissolution conditions. During long-term dissolution, the material usually undergoes severe swelling before dissolution, which will lead to a loss of structural accuracy and even collapse when the surrounding building material is not strong enough to resist the swelling of the support material. Therefore, there remains a need for additional agents that can act as support or sacrificial materials. Summary of the invention

[0008] The present disclosure discloses a series of novel water-soluble polyurethanes that can dissolve rapidly in water at room temperature or 37°C at neutral pH without significant swelling. These water-soluble polyurethanes have many uses, including use as support materials in 3D printing processes and as sacrificial materials to create void spaces in 3D printed materials.

[0009] This article describes thermoplastic polyurethanes that are soluble in water at near-neutral pH at room temperature or 37°C, have melting temperatures of 50 – 240°C, and are non-cytotoxic to human renal fibroblasts. Also described are methods for synthesizing these water-soluble, non-toxic, thermoplastic polyurethane polymers, and their various uses, including use as sacrificial substrates to form internal volumes in basement membrane constructs and microfluidic devices.

[0010] Some aspects of the present disclosure relate to 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 higher molecular weight polyalkylene oxide 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; 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 50:49-20:1-30; 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 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 sequentially or simultaneously, thereby synthesizing a water-soluble, non-toxic, thermoplastic polyurethane polymer.

[0011] 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, diisocyanatocyclohexylmethane, 2,2,4-trimethylhexamethylene diisocyanate, diisocyanatomethylcyclohexane, norbornane diisocyanate, diisocyanatododecane, or a combination 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.

[0012] In some embodiments, the molecular weight of the one or more low molecular weight aliphatic diol chain extender compounds is about 60-200 g / mol. In another embodiment, the molecular weight of the one or more low molecular weight aliphatic diol chain extender compounds is about 60-150 g / mol. In other embodiments, the molecular weight of the one or more low molecular weight aliphatic diol chain extender compounds is about 80-125 g / mol.

[0013] 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-propylene glycol, 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-propylene glycol, 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. In other embodiments, the one or more low molecular weight aliphatic diol chain extender compounds include 1,4-butanediol.

[0014] In some embodiments, the one or more polyalkylene oxide compounds include polyethylene oxide, polypropylene oxide, or polybutylene oxide.

[0015] In some embodiments, the molecular weight of the one or more polyalkylene oxide compounds is 8,000-100,000 g / mol. In some other embodiments, the molecular weight of the one or more polyalkylene oxide compounds is 10,000-80,000 g / mol. In other embodiments, the molecular weight of the one or more polyalkylene oxide polymer compounds is 12,000-50,000 g / mol. In other preferred embodiments, the molecular weight of the one or more polyalkylene oxide polymer compounds is 15,000-30,000 g / mol. In particularly preferred embodiments, the molecular weight of the one or more polyalkylene oxide polymer compounds is about 20,000 g / mol.

[0016] In some particularly preferred embodiments, the one or more aliphatic diisocyanates include butene diisocyanate, pentene diisocyanate and / or hexamethylene diisocyanate, the one or more polyalkylene oxide polymer compounds include polyethylene oxide or polypropylene oxide polymers having a molecular weight of 15,000-30,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,3-propylene glycol, 1,4-butanediol, 1,5-pentanediol or 1,6-hexanediol.

[0017] In other preferred embodiments, 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.

[0018] In some embodiments, step iv) comprises 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.

[0019] 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 a combination thereof, thereby obtaining a water-soluble, non-toxic, thermoplastic polyurethane polymer.

[0020] In some embodiments, applying one or more conditions sufficient for polymerization in step v) comprises exposing the first mixture to heat >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 for polymerization in step v) comprises exposing the first mixture to heat <100°C in the presence of a catalyst, thereby synthesizing a water-soluble, thermoplastic polyurethane polymer while minimizing the formation of allophanate groups and crosslinking of the polyurethane polymer. In some embodiments, exposing the first mixture to heat <100°C comprises exposing the first mixture to a temperature of 40°C to 90°C. In some other embodiments, exposing the first mixture to heat <100°C comprises exposing the first mixture to a temperature of about 70°C.

[0021] In some embodiments, the catalyst is selected from the group consisting of: 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, ethylamine ... 2-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,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 octanoate, potassium acetate, lithium octanoate, bismuth octanoate, bismuth neodecanoate, zinc octanoate, zinc neodecanoate, zirconium octanoate, cobalt octanoate, nickel octanoate, potassium octanoate, calcium octanoate, antimony octanoate, lanthanum octanoate, zirconium acetylacetonate, titanium acetoacetate, aluminum acetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid, and diphenyl phosphate.

[0022] In some embodiments, the synthesis is carried out in a batch or continuous manner. In some embodiments, the synthesis is carried out in a reactive extruder or a continuous mixing or spinning device.

[0023] In some embodiments, step iv) comprises sequential mixing, wherein one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds are mixed to form a premix. In some embodiments, the premix comprising one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds further comprises one or more solvents to promote uniform mixing and distribution of the diisocyanate and high molecular weight polyalkylene oxide compounds throughout the premix. In other embodiments, the solvent comprises dimethyl sulfoxide (DMSO), N,N-dimethylformamide, tetrahydrofuran (THF) or N,N-dimethylacetamide.

[0024] In some embodiments, applying one or more conditions sufficient for polymerization in step v) comprises 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. In some embodiments, applying one or more conditions sufficient for polymerization in step v) comprises exposing the premixture to heat of >100°C in the absence of a catalyst, thereby synthesizing a urethane prepolymer. In some embodiments, applying one or more conditions sufficient for polymerization in step v) comprises exposing the premixture to heat of <100°C in the presence of a catalyst, thereby synthesizing a urethane prepolymer while minimizing the formation of allophanate groups and crosslinking of the polyurethane polymer. In other embodiments, exposing the first mixture to heat of <100°C comprises exposing the premixture to a temperature of 40°C to 90°C. In some embodiments, exposing the first mixture to heat of <100°C comprises exposing the premixture to a temperature of about 70°C.

[0025] In some embodiments, the catalyst is selected from the group consisting of: 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, ethylamine ... 2-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,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 octanoate, potassium acetate, lithium octanoate, bismuth octanoate, bismuth neodecanoate, zinc octanoate, zinc neodecanoate, zirconium octanoate, cobalt octanoate, nickel octanoate, potassium octanoate, calcium octanoate, antimony octanoate, lanthanum octanoate, zirconium acetylacetonate, titanium acetoacetate, aluminum acetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid, and diphenyl phosphate.

[0026] In some embodiments, sequentially 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 the 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 form urethane bonds between the prepolymer and the diol chain extender compound, thereby obtaining a water-soluble, thermoplastic polyurethane.

[0027] In some embodiments, the molar ratio of the mixture of one or more aliphatic diisocyanate compounds to the higher molecular weight polyalkylene oxide compounds to the low molecular weight diol chain extender compounds is in the range of 50:49-25:1-25. In a particularly preferred embodiment, the molar ratio of the mixture of one or more aliphatic diisocyanate compounds to the higher molecular weight polyalkylene oxide compounds to the low molecular weight diol chain extender compounds is in the range of 50:49-40:1-10.

[0028] In some further embodiments, the method further comprises the step of isolating the polymer by one or more techniques selected from the group consisting of precipitation, dialysis and freeze drying. In some embodiments, the method further comprises the step of removing excess water from one or more aliphatic diisocyanates, polyalkylene oxides, diol chain extenders, solvents or solid surfaces in contact therewith by using one or more techniques including distillation, drying and / or washing the solid surface with a silane liquid.

[0029] In some embodiments, one or more steps of providing, mixing or applying one or more conditions are performed under an inert gas. In 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 50-80°C and the second melting temperature comprises 100-130°C.

[0030] In some embodiments, the polyurethane polymer exhibits minimal swelling when exposed to water.

[0031] Some aspects of the present disclosure relate to a water-soluble, non-toxic, thermoplastic polyurethane polymer comprising a polyurethane prepared by a process comprising the steps of: i) providing one or more aliphatic diisocyanate compounds; ii) providing one or more higher molecular weight polyalkylene oxide compounds having a molecular weight of about 600-150,000 g / mol; iii) providing one or more molecular weight polyalkylene oxide compounds having a molecular weight of about 50-300 g / mol; g / mol of a low molecular weight aliphatic diol chain extender compound; iv) 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 sequentially or simultaneously in a molar ratio of 50:49-20:1-30; 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 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 sequentially or simultaneously to synthesize a water-soluble, non-toxic, thermoplastic polyurethane polymer, wherein the polyurethane has a melting temperature of 50-240°C, a soft segment content of at least 80%, is soluble in water at a pH close to neutral at room temperature or 37°C, is non-cytotoxic to human renal fibroblasts, and exhibits minimal swelling when exposed to water.

[0032] Some aspects of the present disclosure are directed to polyurethane polymer compositions comprising a water-soluble, non-toxic, thermoplastic polyurethane polymer, the polyurethane polymer being the reaction product of at least: one or more aliphatic diisocyanate compounds; one or more higher molecular weight polyalkylene oxide compounds having a molecular weight of about 600-150,000 g / mol; one or more low molecular weight aliphatic diol chain extender compounds having a molecular weight of about 50-300 g / mol; and an optional catalyst; wherein 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 are reacted in a molar ratio of 50:49-20:1-30, 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 wherein the thermoplastic polyurethane has a soft segment content of at least 80%, a melting temperature of about 50-240°C, is soluble in water having a pH close to neutral at room temperature or 37°C, and is non-cytotoxic to human renal fibroblasts.

[0033] 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, diisocyanatocyclohexylmethane, 2,2,4-trimethylhexamethylene diisocyanate, diisocyanatomethylcyclohexane, norbornane diisocyanate, diisocyanatododecane, or a combination 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 particularly preferred embodiments, the one or more aliphatic diisocyanate compounds include hexamethylene diisocyanate.

[0034] In some embodiments, one or more polyalkylene oxide compounds include polyethylene oxide, polypropylene oxide or polybutylene oxide polymers. In some embodiments, the molecular weight of one or more polyalkylene oxide compounds is 8,000-100,000 g / mol. In some embodiments, the molecular weight of one or more polyalkylene oxide compounds is 10,000-80,000 g / mol. In some embodiments, the molecular weight of one or more polyalkylene oxide compounds is 12,000-50,000 g / mol. In some embodiments, the molecular weight of one or more polyalkylene oxide compounds is 15,000-30,000 g / mol. In particularly preferred embodiments, the molecular weight of one or more polyalkylene oxide polymer compounds is about 20,000 g / mol.

[0035] In some embodiments, the molecular weight of the one or more polyalkylene oxide compounds is about 60-200 g / mol. In some embodiments, the molecular weight of the one or more low molecular weight aliphatic diol chain extender compounds is about 60-150 g / mol. In some embodiments, the molecular weight of the one or more low molecular weight aliphatic diol chain extender compounds is about 80-125 g / mol.

[0036] 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-propylene glycol, 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-propylene glycol, 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.

[0037] In a particularly preferred embodiment, the one or more aliphatic diisocyanates include butene diisocyanate, pentene diisocyanate and / or hexamethylene diisocyanate, the one or more polyalkylene oxide polymer compounds include polyethylene oxide or polypropylene oxide polymers having a molecular weight of 15,000-30,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,3-propylene glycol, 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.

[0038] In some embodiments, the soft segment content of the polyurethane polymer is greater than 84%. In other embodiments, the soft segment content of the polyurethane polymer is greater than 90%. In other embodiments, the soft segment content of the polyurethane polymer is greater than 97%. In a preferred embodiment, the soft segment content of the polyurethane polymer is greater than 98%.

[0039] In some embodiments, the reaction is the result of simultaneously mixing all of the one or more aliphatic diisocyanate compounds, the one or more polyalkylene oxide compounds, the one or more low molecular weight aliphatic diol chain extender compounds, and optionally one or more catalysts and solvents to provide a first mixture, and then exposing the first mixture to one or more conditions selected from heat, duration, or a combination thereof, to obtain a water-soluble, non-toxic, thermoplastic polyurethane polymer.

[0040] In some embodiments, one or more aliphatic diisocyanate compounds, one or more high molecular weight polyalkylene oxide compounds, and optionally one or more catalysts and solvents are mixed to form a premix, and then exposed to one or more conditions selected from heat, duration, or a combination thereof to obtain a urethane prepolymer, which is then reacted with one or more low molecular weight diol chain extender compounds to obtain a water-soluble, non-toxic, thermoplastic polyurethane polymer.

[0041] In some embodiments, one or more low molecular weight diol chain extender compounds and optionally one or more catalysts and solvents are mixed to obtain a second mixture, followed by exposure to one or more conditions selected from heat, duration, or a combination thereof, to obtain a water-soluble, non-toxic, thermoplastic polyurethane polymer. In other embodiments, the first mixture, premix, and / or second mixture are exposed to heat above 100° C. in the absence of a catalyst. In some embodiments, the first mixture, premix, and / or second mixture are 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.

[0042] In some embodiments, the first mixture, premix, and / or second mixture is exposed to a temperature of 40° C. to 90° C. In other embodiments, the first mixture, premix, and / or second mixture is exposed to a temperature of about 70° C.

[0043] In some embodiments, the catalyst is selected from the group consisting of: 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, ethylamine ... 2-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,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 octanoate, potassium acetate, lithium octanoate, bismuth octanoate, bismuth neodecanoate, zinc octanoate, zinc neodecanoate, zirconium octanoate, cobalt octanoate, nickel octanoate, potassium octanoate, calcium octanoate, antimony octanoate, lanthanum octanoate, zirconium acetylacetonate, titanium acetoacetate, aluminum acetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid, and diphenyl phosphate.

[0044] In other embodiments, the solvent includes dimethyl sulfoxide (DMSO), N,N-dimethylformamide, N,N-dimethylacetamide or tetrahydrofuran (THF). In some embodiments, the molar ratio of one or more aliphatic diisocyanate compounds to higher molecular weight polyalkylene oxide compounds to low molecular weight diol chain extender compounds ranges from 50:49-25:1-25. In particularly preferred embodiments, the molar ratio of one or more aliphatic diisocyanate compounds to higher molecular weight polyalkylene oxide compounds to low molecular weight diol chain extender compounds ranges from 50:49-40:1-10.

[0045] 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 when dissolved in water to the dry mass of the same polyurethane before contact with water, wherein an increase in wet mass relative to dry mass of less than 2.5 times defines the polyurethane as having minimal swelling when dissolved in water.

[0046] In some embodiments, the non-toxicity of the polyurethane polymer is determined by incubating human renal fibroblasts in a cell culture medium containing 0.1 mg / mL dissolved thermoplastic polyurethane for 24 hours, wherein the thermoplastic polyurethane polymer is determined to be non-toxic if there is no decrease in cellular metabolic activity (measured by resazurin fluorescence assay) at the end of the 24 hour incubation period.

[0047] In some embodiments, the polyurethane polymer composition is readily soluble in water, as measured by a 1.75 mm diameter filament formed therefrom substantially dissolving in deionized water at room temperature, without stirring, in about 4 hours or less. 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 2 isocyanate groups per compound.

[0048] In some embodiments, said composition also comprises a water-based solvent, and its amount is about 30 % by weight to 80 % by weight of the polyurethane polymer composition weight. In some embodiments, said composition is in gel form. In some embodiments, polyurethane polymer exists with about 20 % by weight to 70 % by weight of the polyurethane polymer composition weight. In some embodiments, polyurethane polymer accounts for more than 70% of the polyurethane polymer composition and is up to and includes 100%. In a preferred embodiment, said composition is substantially composed of polyurethane polymer or is composed of polyurethane polymer.

[0049] Some aspects of the present disclosure relate to a method for manufacturing a substrate membrane construct, comprising the steps of: (a) printing a sacrificial structure comprising a water-soluble, non-toxic, thermoplastic polyurethane composition described herein onto a support structure or a thin layer comprising a functional substrate membrane material using a 3D printer thermoplastic print head, (b) applying the thin layer comprising the functional substrate membrane material to the sacrificial structure to obtain a 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 or laminating with a sacrificial material or a permanent material, and (e) dissolving the sacrificial material by exposing the sacrificial material to a water-based solvent to provide one or more internal volumes that retain the original shape and size of the printed sacrificial structure, thereby producing a substrate membrane construct, wherein the thin layer is a porous structure with a thickness of 0.25-10 μm.

[0050] In some embodiments, step (b) comprises electrospinning the fiber thin layer membrane directly onto a sacrificial structure, followed by post-production treatment to impart enhanced mechanical properties to the fiber thin layer membrane. In some embodiments, step (b) comprises applying a preformed thin layer comprising a functional base membrane to a sacrificial substrate in combination with compression and heat or solvent, thereby obtaining a sacrificial substrate wrapped with a thin layer comprising a functional base membrane.

[0051] In some embodiments, obtaining the one or more layers in step (c) comprises printing the sacrificial structure comprising a water-soluble, non-toxic, thermoplastic polyurethane composition directly on the thin layer comprising a functional substrate film material applied to the sacrificial structure in the previous step (b). In some embodiments, obtaining the one or more layers in step (c) comprises printing the sacrificial structure comprising a water-soluble, non-toxic, thermoplastic polyurethane composition on a supporting substrate or a thin layer comprising a functional substrate film (which is not the thin layer applied in the previous step (b)), and further combining the one or more additional layers obtained in step (c) with the layer obtained by initially performing steps (a) and (b) prior to embedding or lamination in step (d).

[0052] In some embodiments, prior to step (d), one or more layers of the construct obtained in step (c) and the layers obtained by initially performing steps (a) and (b) are individually or together configured into a desired three-dimensional shape.

[0053] In some embodiments, the water-soluble, non-toxic, thermoplastic polyurethane is heated to 100° C. to 250° C. during the printing process. In some embodiments, the temperature of the chamber and the bed are both maintained at 25° C. during the three-dimensional printing process.

[0054] In some embodiments, the sacrificial structure is printed in a serpentine or bifurcated pattern. In some embodiments, the products of steps (a) and (b), and optionally (c), are embedded in or layered with polydimethylsiloxane, methacrylated gelatin, bulk tissue material, or other matrix forming material.

[0055] Some aspects of the present disclosure relate to a method for making a microfluidic device, comprising the steps of: (a) printing a sacrificial structure comprising a water-soluble, non-toxic, thermoplastic polyurethane composition described herein onto a support structure or thin layer using a 3D printer thermoplastic print head; (b) embedding the product of step (a) with or without the support structure or thin layer in or laminating with a sacrificial material or a permanent material; and (c) optionally repeating steps (a) and (b) one or more times; and (d) dissolving the sacrificial material by exposing the sacrificial material to a water-based solvent to provide one or more internal volumes that substantially retain the original shape and size of the printed sacrificial structure, thereby making a microfluidic device.

[0056] 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 extended longitudinal profile, a substantially elliptical or circular cross-sectional profile, and wherein the one or more internal volumes provided comprise a channel. In some embodiments, the sacrificial structure is formed as a serpentine or bifurcated pattern with a constant or non-constant diameter. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] This patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0058] Figure 1 An exemplary water-soluble polyurethane (WPU) synthesis scheme is depicted. The feed molar ratios of polyethylene glycol (PEG), 1,6-hexamethylene diisocyanate (HDI), and 1,4-butanediol (BDO) were set at 1.5:2:0.5, 1.3:2:0.7, and 1:2:1 to produce water-soluble polyurethane polymers, named WPU1, WPU2, and WPU3, respectively.

[0059] Figure 2 Fourier transform infrared (FT-IR) spectra of WPU1, WPU2 and WPU3 are depicted.

[0060] Figure 3 Depicted by AQUASYS ®Water dissolution rates of cylinders formed from 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, cylinders made from AQUASYS ® The dry mass remaining of the cylinder of 120 was 14±6%, the wet mass remaining was 858±170%, and the swelling ratio was 758±170%, while the dry mass remaining of the cylinder of WPU3 was 28±4%, the wet mass remaining was 2010±453%, and the swelling ratio was 1910±453%.

[0061] Figure 4A-4B The dissolution characteristics of polyurethane and AQUASYS® polymer cylinders in water are depicted. Figure 4A depicts a graph of the dry mass remaining after immersion of WPU1, WPU2, WPU3, and AQUASYS® polymer cylinders in water for 24 hours. Figure 4B depicts a graph of the wet mass remaining after immersion of WPU1, WPU2, WPU3, and AQUASYS® polymer cylinders in water for 24 hours.

[0062] Figure 5 Graph depicting the swelling ratio of WPU1, WPU2, WPU3 and AQUASYS® in water over 24 hours.

[0063] Figure 6 Depicted are the cytotoxicity of WPU1, WPU2, and WPU3 on human renal fibroblasts at concentrations of 0.01 mg / mL, 0.1 mg / mL, and 1 mg / mL as measured by resazurin fluorometry.

[0064] Figures 7A-7E Depicted is a process of embedding a sacrificial substrate WPU1 in a polydimethylsiloxane material and testing the dissolution of WPU1 to provide a microfluidic device with a bifurcated channel. FIG7A depicts a sacrificial substrate WPU1 arranged on a substrate having a bifurcated pattern. FIG7B depicts a sacrificial substrate embedded in polydimethylsiloxane (PDMS). FIG7C depicts the result of punching a 3 mm hole in the PDMS material near opposite ends of the WPU1 sacrificial material. FIG7D depicts the result of sonicating the microfluidic device for 3.5 hours in water at room temperature. FIG7E depicts the WPU1 sacrificial material being sufficiently cleared so that a red dye can be perfused into the channel created by the removal of the WPU1 sacrificial material.

[0065] Figures 8A-8EDepicted is a process of embedding a sacrificial substrate AQUSYS® 120 in a polydimethylsiloxane material and testing the dissolution of AQUSYS® 120 to provide a microfluidic device with bifurcated channels. FIG8A depicts a sacrificial substrate AQUASYS® 120 disposed on a substrate having a bifurcated pattern. FIG8B depicts a sacrificial substrate embedded in PDMS. FIG8C depicts the result of punching 3 mm holes in the PDMS material near opposite ends of the pattern of the sacrificial material. FIG8D depicts the result of immersing the microfluidic device in water and sonicating for 3.5 hours at room temperature. FIG8E depicts that the red dye could not easily permeate the PDMS material because the AQUASYS® 120 sacrificial material was not adequately removed during immersion in water and sonication.

[0066] Figures 9A-9E Depicted is a process for producing a microfluidic device with a twisted eight-forked pattern channel. FIG9A depicts a mold containing a PDMS microfluidic device embedded with a twisted sacrificial substrate WPU2 printed in an eight-forked pattern. FIG9B depicts a PDMS microfluidic device removed from the mold. FIG9C depicts a microfluidic device with the sacrificial substrate removed. FIG9D-9E depict different views of a microfluidic device with dye perfused through a channel.

[0067] Figures 10A-10C Depicted are the formation of a biomicrofluidic device comprising a channel with a serpentine pattern and increasing filament spacing. FIG10A depicts a sacrificial WPU2 printed onto a support surface in a serpentine pattern with increasing filament spacing. FIG10B depicts a biomicrofluidic device formed by embedding WPU2 in methacrylated gelatin (GelMA) material. FIG10C depicts a biomicrofluidic device with red dye perfused through a channel.

[0068] Figures 11A-11D Depicted are cross-sectional images of a biomicrofluidic device fabricated using GelMA as a bulk hydrogel and using WPU2 to create channels. Figures 11A-11B depict cross-sectional images of a biomicrofluidic device with red dye perfused through the channels. Figure 11C depicts a table showing a comparison of the cross-sectional area of ​​the WPU substrate and the cross-sectional area of ​​the channels after the WPU is removed. Figure 11D depicts a magnified cross-sectional view of the biomicrofluidic device. All cross-sectional images show that all channels remain relatively circular with no channel merging.

[0069] Figures 12A-12CDepicted are the formation of a biomicrofluidic device comprising a channel with a serpentine pattern and increasing filament spacing. FIG12A depicts a sacrificial AQUASYS® 120 polymer printed onto a support surface in a serpentine pattern with increasing filament spacing. FIG12B depicts a biomicrofluidic device formed by embedding an AQUASYS® 120 polymer in a methacrylated gelatin (GelMA) material. FIG12C depicts a biomicrofluidic device attempting to perfuse a red dye through a channel.

[0070] Figures 13A-13D Depicted are cross-sectional images of a biomicrofluidic device fabricated using GelMA as a block hydrogel and using WPU2 to create channels. Figures 13A-13B depict cross-sectional images of a biomicrofluidic device with red dye perfused through the channels. Figure 13C depicts a table showing the cross-sectional area of ​​the WPU substrate compared to the cross-sectional area of ​​the channels after the removal of AQUASYS® 120. Figure 13D depicts an enlarged cross-sectional view of the biomicrofluidic device showing that some of the channels merged together due to the slow water dissolution rate and high water absorption rate of AquaSys® 120. In addition, after removal, the channels are no longer circular, but rather exhibit irregular shapes, and the channel cross-sectional area has increased by approximately 118% compared to the original print.

[0071] Figures 14A-14F depict the sequential assembly of a large-scale tissue scaffold using WPU as a sacrificial material. Figure 14A depicts the 3D printing of a sacrificial WPU material into a defined channel network. Figure 14B depicts a fully printed layer containing a sacrificial WPU channel network for integration into a scaffold. Figure 14C depicts branching connection channels added to connect each layer of the scaffold. Figure 14D depicts a fully assembled scaffold skeleton with a sacrificial WPU channel network structure. Figure 14E depicts a scaffold containing a sacrificial WPU channel network skeleton structure embedded in a hydrogel block material. Figure 14F depicts a scaffold cut transversely to show the hierarchical channel network remaining inside the scaffold after removing the WPU sacrificial material.

[0072] Figures 15A-15B Depicted is the flexibility of a sacrificial WPU material used to form a network of channels within a folded pancreatic scaffold (subsequently seeded with cells). Briefly, the sacrificial WPU material was printed on a planar substrate, then folded into a U-shape and embedded in a gelatin block material. The sacrificial material was then dissolved and cells were seeded within the channels thus formed to provide a pancreatic scaffold. Fig.15A Depicted is a microscopic image showing the cell seeding channel on the first layer of the folded scaffold. Fig. 15B A complete pancreatic scaffold containing a network of folded channels is depicted.

[0073] Figures 16A-16D depict the sequential assembly of a large tissue scaffold using WPU as a sacrificial material. Figure 16A depicts a membrane with a WPU channel network pattern printed thereon, which undergoes close-range electrospinning for fiber membrane wrapping. Figure 16B depicts electrospun fibers composed of polycaprolactone (PCL) and gelatin, which are stacked on the printed WPU channel network. The collector electrode position affects the stacking position of the electrospun fibers. Figures 16C-16D Scanning electron microscopy (SEM) image depicting the cross-section of the electrospun PCL / gelatin fiber membrane wrapped on the printed WPU channel network pattern after close-range electrospinning. Figures 16C-16D The magnifications of the images in are x160 and x120 respectively.

[0074] Figures 17A-17B The morphological characteristics of the fiber membrane wrapping of the printed WPU channel pattern after heat treatment and compression are depicted. Briefly, the WPU channel pattern was 3D printed on an electrospun membrane composed of PCL and gelatin, placed between two opposing additional membrane layers, and then placed between two opposing soft silicone pads while heated to about 55°C for 18 hours. FIG. 17A depicts a 55-fold magnified SEM image of the cross-section of the 3D printed WPU channel pattern wrapped by the electrospun fiber membrane after heating and compression. FIG. 17B depicts a 180-fold magnified SEM image of the cross-section of the 3D printed WPU channel pattern wrapped by the electrospun fiber membrane after heating and compression. DETAILED DESCRIPTION

[0075] Described herein are water-soluble, nontoxic, thermoplastic polyurethanes that dissolve in water at near-neutral pH at room temperature or 37°C, have melting temperatures of 50 – 240°C, and are non-cytotoxic to human renal fibroblasts. Also described herein are methods for synthesizing these water-soluble, nontoxic, thermoplastic polyurethane polymers, and their various uses, including use as sacrificial substrates to form internal volumes in basement membrane constructs and microfluidic devices.

[0076] Some aspects of the present disclosure relate to 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 higher 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; iv) sequentially or simultaneously mixing the one or more aliphatic diisocyanate compounds, one or more polyalkylene oxide compounds, and one or more low molecular weight aliphatic diol chain extender compounds in a molar ratio of 50:49-20:1-30; 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 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 sequentially or simultaneously, thereby synthesizing a water-soluble, non-toxic, thermoplastic polyurethane polymer.

[0077] The one or more aliphatic diisocyanate compounds used to form the water-soluble, non-toxic, thermoplastic polyurethane are not limited and can be any suitable aliphatic isocyanate compound having an isocyanate functionality of 2 and capable of forming two urethane bonds when combined with a higher 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. Exemplary diisocyanates that can be used to form the water-soluble, nontoxic, 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, diisocyanatocyclohexylmethane, 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, diisocyanato dodecane 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 diisocyanate compounds include hexamethylene diisocyanate.

[0078] In certain embodiments, the one or more aliphatic diisocyanates include a mixture of at least two, at least three, at least four, or at least five or more different aliphatic diisocyanates. In another embodiment, a dibasic, tribasic, tetrabasic, or pentabasic mixture of aliphatic diisocyanates is utilized to form the water-soluble, non-toxic, thermoplastic polyurethane. In some embodiments, the mixture of aliphatic diisocyanates includes hexamethylene diisocyanate in addition to at least one other aliphatic diisocyanate.

[0079] The one or more low molecular weight aliphatic diol chain extender compounds are not particularly limited and include aliphatic compounds having at least two reactive hydroxyl groups per compound and can form two urethane bonds with one or more aliphatic diisocyanates described herein. In some embodiments, the molecular weight of the one or more low molecular weight aliphatic diol chain extender compounds is 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 molecular weight of the one or more low molecular weight aliphatic diol chain extender compounds is 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 have a molecular weight 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.

[0080] 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-propylene glycol, 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-propylene glycol, 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. In other embodiments, the one or more low molecular weight aliphatic diol chain extender compounds include 1,4-butanediol.

[0081] In certain embodiments, the one or more low molecular weight aliphatic diol chain extender compounds include 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 utilized to form a water-soluble, non-toxic, thermoplastic polyurethane. In some embodiments, the mixture of low molecular weight aliphatic diol chain extender compounds includes 1,4-butanediol in addition to at least one other low molecular weight aliphatic diol chain extender compound.

[0082] One or more higher molecular weight polyol compounds are not particularly limited, and include higher molecular weight polyol compounds containing at least two reactive hydroxyl groups, which can form two urethane bonds when reacting with one or more aliphatic diisocyanate compounds described herein. In certain embodiments, higher molecular weight polyol compounds include polyether and / or polyester compounds containing two reactive hydroxyl groups per polymer. Reactive hydroxyl groups are hydroxyl groups that react with isocyanate groups unhindered in space or other aspects. In certain embodiments, one or more higher molecular weight polyol compounds contain exactly two reactive hydroxyl groups per polymer. Typically, these reactive hydroxyl groups are located at the opposite ends of the polymer. In some preferred embodiments, higher molecular weight polyol compounds have very little branching. In other preferred embodiments, higher molecular weight polyol compounds are substantially linear. In some embodiments, higher molecular weight polyol compounds are higher molecular weight polyalkylene oxides. In some preferred embodiments, one or more polyalkylene oxide compounds include polyethylene oxide, polypropylene oxide or polybutylene oxide.

[0083] In some embodiments, the one or more higher molecular weight polyol compounds are preferably one or more polyalkylene oxide compounds having a molecular weight of 8,000-100,000 g / mol. In some other embodiments, the molecular weight of the one or more polyalkylene oxide compounds is 10,000-80,000 g / mol, 12,000-50,000 g / mol, or 15,000-30,000 g / mol. In particularly preferred embodiments, the molecular weight of the one or more polyalkylene oxide polymer compounds is about 20,000 g / mol. In some embodiments, the molecular weight of the one or more polyalkylene oxide compounds is 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, at least 7,000 g / mol, at least 7,500 g / mol, at least 8,000 g / mol, at least 8,500 g / mol, at least 9,000 g / mol, at least 9,500 g / mol, at least 10,000 g / mol, at least 10,500 g / mol, at least 11,000 g / mol, at least 11,500 g / mol, at least 12,000 g / mol g / mol, at least 12,500 g / mol, at least 13,000 g / mol, 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, at least 20,000 g / mol, at least 20,500 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 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.

[0084] In certain embodiments, the molecular weight of the one or more higher molecular weight polyalkylene oxide compounds is 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 70,000 g / mol, less than 65,000 g / mol, less than 60,000 g / mol, less than 55,000 g / mol, less than 50,000 g / mol, less than 45,000 g / mol, less than 40,000 g / mol, less than 35,000 g / mol, g / mol, less than 30,000 g / mol, less than 25,000 g / mol, less than 20,000 g / mol, less than 15,000 g / mol, less than 10,000 g / mol, less than 5,000 g / mol, or less than 2,500 g / mol. In some embodiments, the molecular weight of the one or more higher molecular weight polyalkylene oxide compounds is 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 25,000 g / mol, about 30,000 g / mol, about 40,000 g / mol, about 50,000 g / mol, about 60,000 g / mol, 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, g / mol, about 200,000 g / mol, or about 250,000 g / mol.

[0085] In certain embodiments, the one or more higher molecular weight polyalkylene oxide compounds include a mixture of at least two, at least three, or at least four or more different higher molecular weight polyalkylene oxide compounds. In another embodiment, a binary or ternary mixture of higher molecular weight polyalkylene oxide compounds is used to form a water-soluble, non-toxic, thermoplastic polyurethane. In some embodiments, the mixture of higher molecular weight polyalkylene oxide compounds, in addition to at least one other higher molecular weight polyalkylene oxide compound, also includes 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.

[0086] In some particularly preferred embodiments, the one or more aliphatic diisocyanates include butene diisocyanate, pentene diisocyanate and / or hexamethylene diisocyanate, the one or more polyalkylene oxide polymer compounds include polyethylene oxide or polypropylene oxide polymers having a molecular weight of 15,000-30,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,3-propylene glycol, 1,4-butanediol, 1,5-pentanediol and / or 1,6-hexanediol.

[0087] In other preferred embodiments, 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.

[0088] In some embodiments, step iv) comprises 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 simultaneously to provide a first mixture. The equipment used for 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 is not particularly limited, as long as it can achieve simultaneous uniform mixing of these components. In some embodiments, the apparatus used to implement the present invention includes, but is not limited to, a single-shaft, double-shaft or triple-shaft mixer, a single planetary or double planetary mixer, a high viscosity or high speed disperser, a ribbon, paddle, drum or vertical mixer, a kneading extruder, a reactive extruder or a continuous spinning device.

[0089] In some embodiments, applying one or more conditions sufficient to polymerize in step v) comprises exposing the first mixture to heat, duration, catalyst, or a combination thereof to obtain a water-soluble, non-toxic, thermoplastic polyurethane polymer.

[0090] In some embodiments, in order to promote the faster synthesis of water-soluble, non-toxic, thermoplastic polyurethane from the first mixture, a catalyst is added to the first mixture. The catalyst included in the first mixture is not limited and can include any compound that catalyzes the formation of urethane bonds from a hydroxyl-containing compound and an isocyanate-containing compound. Such catalysts can include metal carboxylates, tertiary amines, organic acids, and organic bases. Exemplary catalysts for catalyzing the formation of the polyurethane polymer from the first mixture include, but are not limited to, 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, trimethylaminoethylethanolamine, 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 octanoate, potassium acetate, lithium octanoate, bismuth octanoate, bismuth neodecanoate, zinc octanoate, zinc neodecanoate, zirconium octanoate, cobalt octanoate, nickel octanoate, potassium octanoate, calcium octanoate, antimony octanoate, lanthanum octanoate, zirconium acetylacetonate, titanium acetoacetate, aluminum acetoacetate methanesulfonic acid, trifluoromethanesulfonic acid and diphenyl phosphate.

[0091] It will be generally understood by those of ordinary skill in the art that catalysts are not generally consumed in the process of catalyzing the formation of polyurethanes. In such cases, the catalyst can be recovered, regenerated, and reused to catalyze the polymerization of other polyurethane polymers as needed. When the process involves the synthesis of polyurethane polymers in batches, in addition to the need to replace any portion of the old catalyst that is not recovered or regenerated with new catalyst, the recovered catalyst can also be added to subsequent batches. If the process is a continuous process, the catalyst can be reintroduced upstream of the point of mixing of one or more aliphatic diisocyanate compounds, one or more polyalkylene oxide compounds, and one or more low molecular weight aliphatic diol chain extender compounds, such as by adding the catalyst to a stream containing a single component. In other embodiments, the catalyst can be first introduced into a solvent and then the solvent can be added to one or all of the components when all three components are mixed simultaneously. By recovering and reusing the catalyst, a large amount of cost can be saved.

[0092] 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%, at least 98% or more of the catalyst is recovered. In some embodiments, substantially all of the catalyst is recovered. In some embodiments, some catalysts are not recovered. In further embodiments, no measures are taken to recycle the catalyst.

[0093] In some embodiments of the present invention, allow reaction to carry out predetermined period of time.This predetermined time period may be from 10 minutes to a whole week or even longer.In some embodiments, time period is to set according to the degree of the heat exposed to the first mixture and whether catalyst has been added in the first mixture.In some embodiments, make the first mixture react 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 longer.In specific embodiments, this reaction is carried out in the presence of catalyst and / or heat, and reaction is carried out to be 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.

[0094] In some embodiments, applying one or more conditions sufficient for polymerization in step v) comprises exposing the first mixture to heat >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 for polymerization in step v) comprises exposing the first mixture to heat <100°C in the presence of a catalyst, thereby synthesizing a water-soluble, thermoplastic polyurethane polymer while minimizing the formation of allophanate groups and crosslinking of the polyurethane polymer. In some embodiments, exposing the first mixture to heat <100°C comprises exposing the first mixture to a temperature of 40°C to 90°C. In some other embodiments, exposing the first mixture to heat <100°C comprises exposing the first mixture to a temperature of about 70°C.

[0095] In some embodiments, the first mixture is exposed to heat of 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 of 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 of 70°C, 37°C, or is not exposed to heat above room temperature, which for the 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 while also minimizing crosslinking of the polyurethane polymer. It should be understood that in some embodiments, when the reaction proceeds exothermically, active cooling can be used to reduce and maintain the temperature of the first mixture below a set temperature point, such as below 100°C, below 90°C, below 80°C, or below 70°C.

[0096] In some embodiments, the synthesis is carried out in a batch or continuous manner. In some embodiments, the synthesis is carried out in a reactive extruder or a continuous mixing or spinning device.

[0097] In some embodiments, step iv) comprises sequential mixing, wherein one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds are mixed to form a premix. The equipment used to mix one or more aliphatic diisocyanate compounds and one or more higher molecular weight polyalkylene oxide compounds to form a premix is ​​not particularly limited, as long as it can achieve uniform mixing of these components. In some embodiments, the apparatus used to implement the present invention can be the same as the apparatus that can be used to simultaneously mix aliphatic diisocyanate, polyalkylene oxide and chain extender compounds. These apparatuses include, but are not limited to, single-shaft, double-shaft or triple-shaft mixers, single planetary or double planetary mixers, high viscosity or high speed dispersers, ribbon, paddle, drum or vertical mixers, kneading extruders, reactive extruders or continuous spinning devices.

[0098] In some embodiments, the premixture comprising one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds also comprises one or more solvents to promote the uniform mixing and distribution of diisocyanate and high molecular weight polyalkylene oxide compounds in the whole premixture. The solvent for dissolving the premixture ingredients is not particularly limited, including those solvents that can dissolve one or more aliphatic diisocyanate compounds, one or more higher molecular weight polyalkylene oxide compounds and do not hinder the formation of urethane prepolymers. In some embodiments, the selected solvent is environmentally friendly and less toxic than other available solvents, and can 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.

[0099] In some embodiments, applying one or more conditions sufficient for polymerization in step v) comprises 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.

[0100] In some embodiments, in order to promote the faster synthesis of the premix, a catalyst is added to the premix. The catalyst included in the premix is ​​not limited, and may include catalysis to form any compound of a carbamate bond by a hydroxy-containing compound and an isocyanate-containing compound. Such catalysts may include metal carboxylates, tertiary amines, organic acids, and organic bases. Exemplary catalysts for catalyzing the formation of the urethane prepolymer from the premix include, but are not limited to, 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 , trimethylaminoethylethanolamine, 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 octanoate, potassium acetate, lithium octanoate, bismuth octanoate, bismuth neodecanoate, zinc octanoate, zinc neodecanoate, zirconium octanoate, cobalt octanoate, nickel octanoate, potassium octanoate, calcium octanoate, antimony octanoate, lanthanum octanoate, zirconium acetylacetonate, titanium acetoacetate, aluminum acetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid, and diphenyl phosphate.

[0101] In some embodiments, allow reaction to carry out a predetermined period of time.This predetermined time period may be from 10 minutes to a whole week or even longer.In some embodiments, the time period is to set according to the degree of the heat exposed to premixture and whether catalyst is added in the premixture.In some embodiments, make premixture react 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 longer.In some specific embodiments, this reaction is carried out in the presence of catalyst and / or heat, and reaction is carried out to be 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.

[0102] In some embodiments, applying one or more conditions sufficient to polymerize in step v) comprises exposing the premix to heat >100°C in the absence of a catalyst, thereby synthesizing a urethane prepolymer. In other embodiments, applying one or more conditions sufficient to polymerize in step v) comprises exposing the premix to heat <100°C in the presence of a catalyst, thereby synthesizing a urethane prepolymer while minimizing the formation of allophanate groups and crosslinking of the polyurethane polymer. In other embodiments, exposing the first mixture to heat <100°C comprises exposing the premix to a temperature of 40°C to 90°C. In some embodiments, exposing the first mixture to heat <100°C comprises exposing the premix to a temperature of about 70°C.

[0103] In some embodiments, the premix is ​​exposed to heat of 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 below 110°C, below 105°C, below 100°C, below 95°C, below 90°C, below 85°C, below 80°C, or below 75°C. In certain embodiments, the premix is ​​exposed to heat of 70°C, 37°C, or is not exposed to heat above room temperature, which for the purposes of this application is defined as a temperature between 19°C and 23°C. In some embodiments, the temperature of the premix is ​​maintained below 100°C to minimize the formation of allophanate groups while also minimizing crosslinking of the urethane prepolymer. It should be understood that in some embodiments, as the reaction proceeds exothermically, active cooling may be employed to reduce and maintain the temperature of the premix below a set temperature point, such as below 100°C, below 90°C, or below 80°C.

[0104] In some embodiments, sequential mixing includes providing one or more aliphatic diisocyanate compounds and one or more high molecular weight polyalkylene oxide compounds in the form of urethane prepolymers, and mixing the prepolymers with the one or more low molecular weight diol chain extender compounds to obtain a second mixture. The mixing can be carried out in the same device or apparatus in which the premix is ​​formed, or can be carried out in a separate device or apparatus. As previously described, a single-shaft, double-shaft or triple-shaft mixer, a single planetary or double planetary mixer, a high viscosity or high speed disperser, a ribbon, paddle, drum or vertical mixer, a kneading extruder, a reactive extruder or a continuous spinning device are all suitable devices for this purpose. In some embodiments, the method also includes applying one or more conditions sufficient to form urethane bonds between the prepolymer and the diol chain extender compound, thereby obtaining a water-soluble, non-toxic, thermoplastic polyurethane. These conditions may include heat, duration, and the addition of a catalyst.

[0105] In some embodiments, the molar ratio of the mixture of one or more aliphatic diisocyanate compounds to the higher molecular weight polyalkylene oxide compound to the low molecular weight diol chain extender compound is in the range of 50:49-25:1-25. In particularly preferred embodiments, the molar ratio of the mixture of one or more aliphatic diisocyanate compounds to the higher molecular weight polyalkylene oxide compound to the low molecular weight diol chain extender compound is in the range of 50:49-40:1-10. It should be understood that by increasing the ratio of the higher molecular weight polyalkylene oxide compound to the low molecular weight diol chain extender compound, the percentage of soft segments in the polyurethane polymer formed thereby can be increased. Conversely, by reducing the ratio of the higher molecular weight polyalkylene oxide compound to the low molecular weight diol chain extender compound, the percentage of hard segments in the polyurethane polymer formed thereby can be increased. Therefore, the properties of the polyurethane (e.g., water dissolution time or the rigidity of the polymer) can be adjusted by changing the ratio of the higher molecular weight polyalkylene oxide compound to the low molecular weight compound to a fixed amount of the aliphatic diisocyanate compound.

[0106] In other embodiments, the molar ratio of the mixed aliphatic diisocyanate compound(s) to the higher molecular weight polyalkylene oxide compound(s) to the low molecular weight diol chain extender compound(s) may range from 2:1:1, 2:1.7:0.3, or 2:1.5:0.5. In some embodiments, the ratio of the higher molecular weight polyalkylene oxide compound to the 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 hydroxyl groups provided by the combination of the higher 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.

[0107] In some further embodiments, the method also includes the step of separating the polymer by one or more techniques known to those skilled in the art. In some embodiments, the polymer can be separated by precipitation in a suitable liquid, which can include aqueous liquids and non-aqueous liquids in which the polyurethane has minimal solubility or is insoluble. In other embodiments, the polymer can be separated by dialysis using a dialysis membrane or dialysis tubing. The pore size selection of the dialysis membrane or dialysis tubing and the resulting molecular weight cutoff will be determined based on the target molecular weight of the desired polyurethane product. In some embodiments, the molecular weight cutoff range can be 1-100,000 kDa, 2-75,000 kDa, 5-60,000 kDa, 10-10,000 kDa, 15-5,000 kDa, 20-1,000 kDa or 25-500 kDa. In some embodiments, the molecular weight cutoff of the dialysis membrane or dialysis tubing is 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 isolate a reaction product having a molecular weight less than the target molecular weight of the desired polyurethane product. Such reaction products removed in this way can be further polymerized into larger polyurethane polymers under the action of specific conditions and reagents. In some embodiments, multiple rounds of dialysis can be performed with dialysis membranes or dialysis tubing having different molecular weight cutoffs to obtain the desired separated polyurethane product. In some embodiments, the duration of the dialysis is not particularly limited and will be selected to achieve the desired separation of the target polyurethane polymer product. In some embodiments, the length of time of the dialysis can range from a few hours or less to more than a week.

[0108] In some embodiments, the polyurethane polymer can be separated and purified by lyophilization. Lyophilization can be carried out using a well-known lyophilization program in combination with a commercially available lyophilizer to remove excess liquid from the polyurethane product by sublimation. In some embodiments, lyophilization is used in combination with one or more other separation or purification programs to provide a polyurethane polymer of desired purity. In certain embodiments, the reaction product is lyophilized and precipitated and / or dialyzed. In some embodiments, lyophilization can be carried out after precipitation and / or dialysis.

[0109] 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 acid, urea and / or carbon dioxide and the resulting foam. In some embodiments, the method further comprises the step of removing excess water from one or more reagents (including solvents) and starting materials (e.g., aliphatic diisocyanates, polyalkylene oxides, diol chain extenders) used to form the polyurethane polymer. In some embodiments, excess water can be removed by distillation and / or drying of the reagents and starting materials. In some embodiments, excess water is removed from the solid surface by drying and / or washing the solid surface in contact with any reagent or starting material with a silane liquid.

[0110] In some embodiments, one or more steps of providing, mixing or applying one or more conditions are performed under an inert gas. In other embodiments, the melting temperature includes 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 includes 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 includes 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 melt temperature comprises 100-130°C, 100-110°C, 105-115°C, 110-120°C, or 120-130°C.

[0111] In some aspects of the present invention, polyurethane polymers show minimum swelling when exposed to water. In some embodiments, there is no particular limitation on the determination of the swelling of polyurethane polymers and can include methods commonly used in the art or any method described herein. In some embodiments, minimum swelling is determined by comparing the wet mass of polyurethane when it is dissolved in water with the dry mass of the same polyurethane before contact with water, wherein the increase of wet mass relative to dry mass is less than 2.5 times, which defines that polyurethane has minimum swelling when it is dissolved in water. In some embodiments, swelling is determined by measuring the maximum volume difference of a predetermined amount of polyurethane polymer before and after being immersed in water for a period of time. In other embodiments, when the polyurethane polymer is formed into a certain shape, the difference between the cross-sectional areas of the molded polyurethane polymer before and after being immersed in water is used to determine swelling. When swelling is determined by measuring the difference in volume or cross-sectional area, minimal swelling is determined when the volume or cross-sectional area increases by less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 12.5%, less than 10%, less than 7.5%, less than 5%, less than 2.5%, less than 1%, or less than 0.5% compared to the dry volume or cross-sectional area. In certain embodiments, the polyurethane polymer has substantially no swelling in water, which is defined as an increase in volume or cross-sectional area of ​​less than 10%, less than 5%, or less than 3% at any time when immersed in water until dissolved.

[0112] Some aspects of the present disclosure relate to a water-soluble, non-toxic, thermoplastic polyurethane polymer comprising a polyurethane prepared by a process comprising the steps of: i) providing one or more aliphatic diisocyanate compounds; ii) providing one or more higher molecular weight polyalkylene oxide compounds having a molecular weight of about 600-150,000 g / mol; iii) providing one or more molecular weight polyalkylene oxide compounds having a molecular weight of about 50-300 g / mol; g / mol of a low molecular weight aliphatic diol chain extender compound; iv) 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 sequentially or simultaneously in a molar ratio of 50:49-20:1-30; 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 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 sequentially or simultaneously to synthesize a water-soluble, non-toxic, thermoplastic polyurethane polymer, wherein the polyurethane has a melting temperature of 50-240°C, a soft segment content of at least 80%, is soluble in water at a pH close to neutral at room temperature or 37°C, is non-cytotoxic to human renal fibroblasts, and exhibits minimal swelling when exposed to water.

[0113] Some aspects of the present disclosure are directed to polyurethane polymer compositions comprising a water-soluble, non-toxic, thermoplastic polyurethane polymer, the polyurethane polymer being the reaction product of at least: one or more aliphatic diisocyanate compounds; one or more higher molecular weight polyalkylene oxide compounds having a molecular weight of about 600-150,000 g / mol; one or more low molecular weight aliphatic diol chain extender compounds having a molecular weight of about 50-300 g / mol; and an optional catalyst; wherein 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 are reacted in a molar ratio of 50:49-20:1-30, 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 wherein the thermoplastic polyurethane has a soft segment content of at least 80%, a melting temperature of about 50-240°C, is soluble in water having a pH close to neutral at room temperature or 37°C, and is non-cytotoxic to human renal fibroblasts.

[0114] 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, diisocyanatocyclohexylmethane, 2,2,4-trimethylhexamethylene diisocyanate, diisocyanatomethylcyclohexane, norbornane diisocyanate, diisocyanatododecane, or a combination 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 particularly preferred embodiments, the one or more aliphatic diisocyanate compounds include hexamethylene diisocyanate.

[0115] In some embodiments, one or more polyalkylene oxide compounds include polyethylene oxide, polypropylene oxide or polybutylene oxide polymers. In some embodiments, the molecular weight of one or more polyalkylene oxide compounds is 8,000-100,000 g / mol. In some embodiments, the molecular weight of one or more polyalkylene oxide compounds is 10,000-80,000 g / mol. In some embodiments, the molecular weight of one or more polyalkylene oxide compounds is 12,000-50,000 g / mol. In some embodiments, the molecular weight of one or more polyalkylene oxide compounds is 15,000-30,000 g / mol. In particularly preferred embodiments, the molecular weight of one or more polyalkylene oxide polymer compounds is about 20,000 g / mol.

[0116] In some embodiments, the molecular weight of the one or more polyalkylene oxide compounds is about 60-200 g / mol. In some embodiments, the molecular weight of the one or more low molecular weight aliphatic diol chain extender compounds is about 60-150 g / mol. In some embodiments, the molecular weight of the one or more low molecular weight aliphatic diol chain extender compounds is about 80-125 g / mol.

[0117] 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-propylene glycol, 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-propylene glycol, 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.

[0118] In a particularly preferred embodiment, the one or more aliphatic diisocyanates include butene diisocyanate, pentene diisocyanate and / or hexamethylene diisocyanate, the one or more polyalkylene oxide polymer compounds include polyethylene oxide or polypropylene oxide polymers having a molecular weight of 15,000-30,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,3-propylene glycol, 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.

[0119] In some embodiments, the soft segment content of the polyurethane polymer is greater than 84%. In other embodiments, the soft segment content of the polyurethane polymer is greater than 90%. In other embodiments, the soft segment content of the polyurethane polymer is greater than 97%. In a preferred embodiment, the soft segment content of the polyurethane polymer is greater than 98%.

[0120] In some embodiments, the reaction is the result of simultaneously mixing all of the one or more aliphatic diisocyanate compounds, the one or more polyalkylene oxide compounds, the one or more low molecular weight aliphatic diol chain extender compounds, and optionally one or more catalysts and solvents to provide a first mixture, and then exposing the first mixture to one or more conditions selected from heat, duration, or a combination thereof, to obtain a water-soluble, non-toxic, thermoplastic polyurethane polymer.

[0121] In some embodiments, one or more aliphatic diisocyanate compounds, one or more high molecular weight polyalkylene oxide compounds, and optionally one or more catalysts and solvents are mixed to form a premix, and then exposed to one or more conditions selected from heat, duration, or a combination thereof to obtain a urethane prepolymer, which is then reacted with one or more low molecular weight diol chain extender compounds to obtain a water-soluble, non-toxic, thermoplastic polyurethane polymer.

[0122] In some embodiments, one or more low molecular weight diol chain extender compounds and optionally one or more catalysts and solvents are mixed to obtain a second mixture, followed by exposure to one or more conditions selected from heat, duration, or a combination thereof, to obtain a water-soluble, non-toxic, thermoplastic polyurethane polymer. In other embodiments, the first mixture, premix, and / or second mixture are exposed to heat above 100° C. in the absence of a catalyst. In some embodiments, the first mixture, premix, and / or second mixture are 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.

[0123] In some embodiments, the first mixture, premix, and / or second mixture is exposed to a temperature of 40° C. to 90° C. In other embodiments, the first mixture, premix, and / or second mixture is exposed to a temperature of about 70° C.

[0124] In some embodiments, the catalyst is selected from the group consisting of: 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, ethylamine ... 2-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,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 octanoate, potassium acetate, lithium octanoate, bismuth octanoate, bismuth neodecanoate, zinc octanoate, zinc neodecanoate, zirconium octanoate, cobalt octanoate, nickel octanoate, potassium octanoate, calcium octanoate, antimony octanoate, lanthanum octanoate, zirconium acetylacetonate, titanium acetoacetate, aluminum acetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid, and diphenyl phosphate.

[0125] In other embodiments, the solvent includes dimethyl sulfoxide (DMSO), N,N-dimethylformamide, N,N-dimethylacetamide or tetrahydrofuran (THF). In some embodiments, the molar ratio of one or more aliphatic diisocyanate compounds to higher molecular weight polyalkylene oxide compounds to low molecular weight diol chain extender compounds ranges from 50:49-25:1-25. In particularly preferred embodiments, the molar ratio of one or more aliphatic diisocyanate compounds to higher molecular weight polyalkylene oxide compounds to low molecular weight diol chain extender compounds ranges from 50:49-40:1-10.

[0126] 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 when dissolved in water to the dry mass of the same polyurethane before contact with water, wherein an increase in wet mass relative to dry mass of less than 2.5 times defines the polyurethane as having minimal swelling when dissolved in water.

[0127] In some embodiments, the non-toxicity of the polyurethane polymer is determined by incubating human renal fibroblasts in a cell culture medium containing 0.1 mg / mL dissolved thermoplastic polyurethane for 24 hours, wherein the thermoplastic polyurethane polymer is determined to be non-toxic if there is no decrease in cellular metabolic activity (measured by resazurin fluorescence assay) at the end of the 24 hour incubation period.

[0128] In another aspect of the present invention, the polyurethane polymer composition is soluble in water. The method for determining the dissolution rate of the polyurethane polymer composition in water is not particularly limited, and may include a dissolution test scheme known in the art or any method described herein. In some embodiments, if a predetermined amount of the polyurethane polymer composition is dissolved in water with or without stirring, if it 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 after being immersed in water, then it is determined that the polyurethane polymer composition is soluble in water. In some embodiments, the polyurethane polymer composition is soluble in water, as measured by a filament of 1.75 mm diameter formed therefrom substantially dissolved in deionized water at room temperature, without stirring, in about 4 hours or less, 3 hours or less, 2 hours or less, 1 hour or less or 15 minutes or less.

[0129] In some embodiments, polyurethane polymer is linear and substantially free of crosslinking and / or branching. In other embodiments, polyurethane polymer is substantially not formed by aromatic isocyanate compounds or isocyanate compounds having more than 2 isocyanate groups per compound. For purposes of the present invention, being substantially not formed by aromatic isocyanate compounds and isocyanate compounds having more than 2 isocyanate groups per compound is defined as utilizing an aliphatic diisocyanate source comprising less than 10 wt %, less than 5 wt %, less than 3 wt % or less than 1 wt % of aromatic isocyanate or trifunctional or higher functional isocyanate. However, in any case, if the combined content of aromatic isocyanate and trifunctional or higher functional isocyanate in a commercially available high purity aliphatic diisocyanate source is greater than 10 wt % but less than 15 wt %, it will not be considered to be excluded from the present invention.

[0130] In some embodiments, said composition also comprises a water-based solvent, and its amount is about 30 % by weight to 80 % by weight of the polyurethane polymer composition weight. In some embodiments, said composition is in gel form. In some embodiments, polyurethane polymer exists with about 20 % by weight to 70 % by weight of the polyurethane polymer composition weight. In some embodiments, polyurethane polymer accounts for more than 70% of the polyurethane polymer composition and is up to and includes 100%. In a preferred embodiment, said composition is substantially composed of polyurethane polymer or is composed of polyurethane polymer.

[0131] Some aspects of the present disclosure relate to a method for manufacturing a substrate membrane construct, comprising the following steps: (a) printing a sacrificial structure comprising a water-soluble, non-toxic, thermoplastic polyurethane composition described herein onto a support structure or a thin layer comprising a functional substrate membrane material using a 3D printer thermoplastic print head, (b) applying the thin layer comprising the functional substrate membrane material to the sacrificial structure to obtain a 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 material or a permanent material, and (e) dissolving the sacrificial material by exposing the sacrificial material to a water-based solvent to provide one or more internal volumes that retain the original shape and size of the printed sacrificial structure, thereby producing a substrate membrane construct, wherein the thin layer is a porous structure with a thickness of 0.25-10 μm.

[0132] In some embodiments, basement membrane construct can include multilayer, and each individual layer can optionally include the internal volume that is connected to form channel network.In some embodiments, the channel network direct fluid connection of the first layer and the second layer of construct or be connected by membrane interface.This film can filter the fluid that flows to the second channel network of the second layer from the first channel network of the first layer of construct by film.In some embodiments, described film is the fiber membrane that has been subjected to one or more manufacturing post-treatments selected from compression, annealing, chemical crosslinking, stretching, drawing, heat treatment and solvent welding, thus with the fiber basement membrane material that does not accept one or more manufacturing post-treatments compared, treated fiber basement membrane material has the mechanical property of enhancement and the morphological performance of change.

[0133] In some embodiments, the thin layer comprising functional basement membrane material is a fibrous membrane material. In some embodiments, the fibrous basement membrane material comprises one or more of gelatin, gelatin complex, collagen, fibrin, chitosan, nitrocellulose, polylactic acid, polycaprolactone, polyethylene glycol, polyethylene glycol diacrylate or other biopolymers, polymers or decellularized tissue or extracellular matrix that has been liquefied or homogenized.

[0134] In some embodiments, the thin layer comprising basement membrane material comprises electrostatic spinning fibers. In some embodiments, the fibrous basement membrane material comprises electrostatic spinning fibers, and the electrostatic spinning fibers comprise 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 wherein the thickness of the fibrous basement membrane is 0.5-30 μm. In some embodiments, the fibrous basement membrane material comprises a first material selected to provide a fibrous basement membrane substrate with strength, and a second material is selected to provide a substrate that can be remodeled by cells seeded thereon.

[0135] In some embodiments, the thin layer comprising a fibrous basement membrane material suppresses or prevents the subject's immune response to cells and other substances in the basement membrane construct. In some embodiments, the immune response of the subject is suppressed or prevented against cells in the luminal space of the construct, or a thin layer comprising a basement membrane material is embedded, wrapped, or surrounded or covered by the cell in the bulk material or tissue. In some embodiments, the immune response of the subject is suppressed or prevented against substances in the luminal space of the construct, or a thin layer comprising a basement membrane material is embedded, wrapped, or surrounded or covered by the substance in the bulk material or tissue. In some embodiments, when the basement membrane construct is implanted in the subject or used in vitro, the suppression or prevention of the immune response of the subject is achieved, wherein 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 in fluid communication with the construct is another luminal space in the cardiovascular system, and / or the liver, pancreas, kidney, small intestine, large intestine, brain or spine or in fluid communication with the liver, pancreas, kidney, small intestine, large intestine, brain or spine.

[0136] In some embodiments, the fiber base membrane material comprises holes of sufficient size to allow one or more bio-related molecules to diffuse. The pore size of the holes in the fiber membrane can be any suitable size and is not limited. In one embodiment, the average or median pore size diameter is about 0.05 to about 0.6 μm. In another embodiment, the average or median pore size 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 porosity (P) of the nanofiber membrane is preferably about 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. nm ) is calculated by dividing the void volume (V v ) divided by the total volume of the nanofiber membrane measured (V Tvm ) obtained (P = V v / V Tvm * 100%), can be any suitable porosity and is not limited. 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 between 20-80%, 30-70% or 40-60%.

[0137] In some embodiments, the one or more channels are capable of withstanding an internal pressure of at least 60 mmHg. In another embodiment, the one or more channels are capable of withstanding 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.

[0138] In some embodiments, the vascular channel network is capable of withstanding an internal pressure of at least 60 mmHg. In another embodiment, the vascular channel network is capable of withstanding 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.

[0139] In some embodiments, the fiber base film material has been subjected to one or more post-manufacturing treatments selected from compression, annealing, chemical crosslinking, stretching, drawing, heat treatment and solvent welding, thus compared with the fiber base film material that does not accept one or more of these post-manufacturing treatments, the treated fiber base film material is endowed with enhanced mechanical properties. In some embodiments, the enhanced mechanical properties are selected from the group consisting of enhanced tensile strength, enhanced tensile modulus, enhanced wear resistance, enhanced thermal stability, enhanced elongation at break, enhanced hardness, enhanced crystallinity and a combination thereof. In some embodiments, post-manufacturing treatment includes solvent welding. In some embodiments, solvent welding is carried out in the presence of the pressure imparted by the opposing support substrate. In some embodiments, post-manufacturing treatment includes a combination of heat treatment and the pressure imparted by the opposing support substrate.

[0140] In some embodiments, post-manufacturing treatments may be performed at temperatures between 20-22° C. or above 22° C. In some embodiments, post-manufacturing steps are performed below the glass transition temperature (Tg) of one, two, or all of the materials used to form the fiber membrane, such as at least 5° C., 10° C., 15° C., 20° C., 30° C., or more below the glass transition temperature.

[0141] In certain embodiments, the post-manufacturing step is an annealing performed at a temperature approximately equal to the glass transition temperature of the material used to form the fiber membrane. For the purposes of this application, approximately equal to the glass transition temperature (Tg) is defined as the published glass transition temperature of the material ±5°C, or ±5% of the published Tg, whichever provides a smaller temperature range. In some embodiments, the post-manufacturing step is performed at a temperature between the glass transition temperature and the melting temperature of the material used to form the fiber membrane. It should be understood by those of ordinary skill in the art that when the temperature is raised above the glass transition temperature, the appropriate post-manufacturing processing time should be carefully selected to ensure that the porosity of the membrane is not destroyed due to the large amount of melting of the fiber membrane.

[0142] In some embodiments, the fiber membrane is subjected to a post-manufacturing step at a temperature greater than 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 more. In some embodiments, the post-manufacturing step is performed for a period of 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, it is desired that post-manufacturing processing be performed for longer time periods, 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.

[0143] In some embodiments, the post-manufacturing annealing step includes applying compression to facilitate wrapping the sacrificial substrate with the fiber membrane, as described herein. In some embodiments, applying compression at elevated temperatures facilitates better or faster bonding or annealing of the fibers. In some embodiments, the post-manufacturing annealing and compression steps are performed at a temperature between 120-180°C, 40-70°C, 45-65°C, 50-60°C, or 53-57°C for 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.

[0144] The pressure amplitude used in the compression step is not particularly limited, as long as it is sufficient to promote the bonding or annealing of the fibers at their intersections while protecting the fiber membrane or substrate to which the pressure is applied from damage. In some embodiments, compression is applied by placing the fiber membrane and the substrate manufactured thereon between two opposing release substrates, the size, shape and hardness of the release substrate allowing sufficient force to be applied to induce the bonding or welding of the fibers without damaging the fiber membrane or substrate to which the force is applied. In some embodiments, the release substrate is a soft silicone pad. In certain preferred embodiments, the compression step is carried out by placing the fiber membrane and the sacrificial substrate between two silicone pads placed on a solid surface, wherein the only compression is produced by the weight of the silicone pad placed on top of it.

[0145] In some embodiments, additional compressive force can be applied by using the pressure applied by placing heavier and heavier objects on the top of the silicone pad. In some embodiments, the pressure applied to the fiber membrane and the 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 applying pressure in the presence of heat, 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 0.5-5 psi, 2-8 psi, 5-14 psi, 3-7 psi or 18-25 psi.

[0146] In some embodiments, manufacturing post-treatment includes exposing the fiber membrane to a solvent to promote partially softened or swollen fibers to be welded together at their intersections. The solvent used for solvent welding should be able to soften or swell the fibers of the fiber membrane material at least in part to promote the fibers to be welded together within a reasonable amount of time. In some embodiments, the solvent is non-toxic. In other embodiments, the solvent has a Hildebrand solubility parameter similar to the material used to form the electrospun fiber membrane. In the case where a given concentrated solvent may dissolve quickly and destroy the morphology of the fiber of the fiber membrane, the solvent can be mixed with one or more non-solvents to provide a diluted solvent formulation that can provide controlled swelling of the fiber and weld together 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-methyl pyrrolidone, propylene carbonate, lactic acid esters, ether, methylene chloride, tetrahydrofuran, ethanol and methanol. In some embodiments, the solvent is acetone in a concentrated form, such as a formulation close to 100% pure acetone (NEAT). In some embodiments, the acetone is diluted with a polar non-solvent (such as isopropanol) to provide a formulation comprising 20-80% acetone. In certain embodiments, the acetone has been diluted to a concentration of 50% or 25%.

[0147] The method of applying the solvent to the fiber membrane is not particularly limited, as long as the solvent is applied relatively uniformly to at least one side of the fiber membrane. In some embodiments, the solvent can be applied to the fiber membrane before the fiber membrane contacts the sacrificial substrate. In some embodiments, the fiber membrane is saturated with acetone. Saturating the fiber membrane with the solvent can be performed by soaking, dipping or spraying in combination with a duration that allows saturation. In some embodiments, it is not desirable to saturate the fiber membrane with the solvent. In these cases, a limited amount of solvent can be applied to the surface of the fiber membrane, such as by spraying. In some embodiments, each 100cm2 0.5-10 mL of solvent is applied to the fiber membrane. In some embodiments, every 100 cm 2 Apply 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 to the fiber membrane.

[0148] In some embodiments, solvent welding is accompanied by applying compression to further promote the induction of the morphological change of the fiber membrane when it is applied to the sacrificial substrate and / or enhance the welding between the fibers of the fiber membrane. The specific pressure used in the compression step to promote the morphological change of the membrane and the welding of the fibers together can be any pressure disclosed herein and is not particularly limited, as long as the pressure does not cause the substrate to which the fiber membrane is applied to collapse. In some embodiments, compression is used in combination with solvent welding and comprises a compressive force of at least 0.1-25 Newtons, which is generated by compressing the relative release substrate that clamps the fiber membrane and the sacrificial substrate to which the fiber membrane is applied.

[0149] In some embodiments, applying compression during the manufacturing rear solvent welding step can reduce the time required for the firm welding between the fibers. The specific time required for giving firm welding under compression is not particularly limited and includes the duration as disclosed herein. In some embodiments, the fiber 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 longer.

[0150] In some embodiments, post-manufacturing treatment comprises physical or chemical crosslinking of the fibers. In some embodiments, the crosslinking is achieved by exposure to ultraviolet light, gamma radiation or plasma, by incorporating one or more crosslinking agents, or a combination thereof. The crosslinking agents that can be used to promote crosslinking of the fibers are not particularly limited, but include crosslinking agents that induce the formation of covalent bonds between compounds present in adjacent fibers. In some cases, the crosslinking agent includes glyoxal, isocyanate, glutaraldehyde, formaldehyde, carbodiimide, epoxide, citric acid, tannin, ferulic acid, glyceraldehyde, genepin, or transglutaminase.

[0151] In some embodiments, manufacturing post-processing changes the morphology and / or enhances the mechanical properties of the fiber membrane. The enhanced mechanical properties may include, but are not limited to, one or more of enhanced tensile strength, enhanced tensile modulus, enhanced wear resistance, enhanced thermal stability, enhanced elongation at break, enhanced hardness, and enhanced crystallinity. The change in morphology includes, but is not limited to, one or more of increased fiber diameter, reduced fiber diameter, increased porosity, reduced porosity, increased pore tortuosity, and reduced pore tortuosity.

[0152] In some embodiments, step (b) comprises electrospinning the fiber thin layer membrane directly onto a sacrificial structure, followed by post-production treatment to impart enhanced mechanical properties to the fiber thin layer membrane. In some embodiments, step (b) comprises applying a preformed thin layer comprising a functional base membrane to a sacrificial substrate in combination with compression and heat or solvent, thereby obtaining a sacrificial substrate wrapped with a thin layer comprising a functional base membrane.

[0153] In some embodiments, obtaining the one or more layers in step (c) comprises printing the sacrificial structure comprising the water-soluble, non-toxic, thermoplastic polyurethane composition directly on the thin layer comprising the functional substrate film material applied to the sacrificial structure in the previous step (b). In some embodiments, obtaining the one or more layers in step (c) comprises printing the sacrificial structure comprising the water-soluble, non-toxic, thermoplastic polyurethane composition on a supporting substrate or a thin layer comprising a functional substrate film (which is not the thin layer applied in the previous step (b)), and further combining the one or more additional layers obtained in step (c) with the layer obtained by initially performing steps (a) and (b) prior to embedding in step (d).

[0154] In some embodiments, prior to step (d), one or more layers of the construct obtained in step (c) and the layers obtained by initially performing steps (a) and (b) are individually or together configured into a desired three-dimensional shape.

[0155] In some embodiments, the water-soluble, non-toxic, thermoplastic polyurethane is heated to 100° C. to 250° C. during the printing process. In some embodiments, the temperature of the chamber and the bed are both maintained at 25° C. during the three-dimensional printing process.

[0156] In some embodiments, wherein the sacrificial structure is printed with a serpentine or bifurcated pattern. In some embodiments, the product of steps (a) and (b) and optional (c) is embedded in polydimethylsiloxane, methacrylated gelatin, block tissue material or other matrix forming material or stacked together with it. Block tissue material or other matrix forming material is a non-toxic material recognized in the art for tissue constructs or bioscaffolds to 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, nestin, elastin, elastin-like polypeptides, gelatin, laminin (such as laminin 511), homogenization or liquefaction of extracellular matrix or decellularized tissue and combination thereof. In some embodiments, when the material is in liquid state, the product of steps (a) and (b) and optional (c) is embedded in the material. In some embodiments, the embedding process utilizes a mold with a selected shape and size, so as to be implanted in the desired position in the patient's body or allow the finished product to realize the desired function. In other embodiments, the products of steps (a) and (b), and optionally (c), are layered with a material that is in a gel or solid state.

[0157] In some embodiments, the product of step (a) and (b) and optional (c) is embedded in or stacked with the material of seeded cells or cells. The type of cells and bulk tissues inoculated and placed on or in the product of step (a), (b) and / or optional (c) is not particularly limited, and comprises any cell or bulk tissue type listed herein. In a preferred embodiment, the cell comprises stem cell, endothelial cell, cardiomyocyte, parietal epithelial cell, hepatocyte, bile duct cell, stellate cell, adipocyte, osteoblast, osteocyte, osteoclast, enterocyte, goblet cell, enteroendocrine cell, Paneth cell, microfold cell, goblet cell, plexus cell, or is present in kidney, pancreas, lung, myocardium, liver, spleen, small intestine, large intestine, nervous tissue, skeletal muscle, composite tissue, adipose tissue, bone tissue or other cells in skin.

[0158] Some aspects of the present disclosure relate to a method for making a microfluidic device, comprising the steps of: a) printing a sacrificial structure comprising a water-soluble, non-toxic, thermoplastic polyurethane composition described herein onto a support structure or a film layer using a 3D printer thermoplastic print head; b) embedding the product of step (a) with or without the support structure or film layer in a sacrificial material or a permanent material; and c) optionally repeating steps (a) and (b) one or more times; and d) dissolving the sacrificial material by exposing the sacrificial material to a water-based solvent to provide one or more internal volumes that substantially retain the original shape and size of the printed sacrificial structure, thereby making a microfluidic device.

[0159] In some embodiments, the material comprises methacrylated gelatin, polydimethylsiloxane or other matrix forming materials. In other embodiments, the sacrificial structure comprises an extended longitudinal profile, a substantially elliptical or circular cross-sectional profile, and wherein the one or more internal volumes provided comprise a channel. In some embodiments, the sacrificial structure is formed as a serpentine or bifurcated pattern with a constant or non-constant diameter.

[0160] Example

[0161] method

[0162] Synthesis of Water-Soluble Polyurethane (WPU)

[0163] In one embodiment, WPU polymer ( Figure 1 ). Under N2 protection, PEG was initially dissolved in dimethyl sulfoxide (DMSO; Sigma) at 70°C in a three-necked flask. HDI was then added to the flask, followed by the addition of stannous octoate (Sn(Oct)2; Sigma) catalyst. After 3 h, the 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 by dialysis and lyophilization. The feed molar ratios of PEG, HDI, and BDO were varied to obtain adjustable solubility, as shown in Table 1.

[0164] Table 1. Water-soluble polyurethane formulations

[0165]

[0166] WPU Characterization

[0167] The chemical structure of the polymers was verified by Fourier transform infrared spectroscopy (FTIR, Agilent 680). The melting temperatures (Tm) were determined in the range of −40 to 200 °C at a heating rate of 10 °C / min under nitrogen flow using a differential scanning calorimeter (DSC, Perkin-Elmer Pyris 1).

[0168] 3D printing at WPU

[0169] Using BIO X TM Thermoplastic Printheads in BIO X TMPolyurethane was printed on a 3D printer (Cellink, Sweden). The polyurethane was heated to different temperatures, from 150°C to 200°C. The temperature of both the chamber and the bed was kept at 25°C. Different patterns were printed with a nozzle moving speed of 1-5 mm / s and a nozzle inner diameter of 400 µm.

[0170] Dissolution in water

[0171] The polyurethane was molded into cylindrical samples 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 sample was monitored over time. At each predetermined time point, the remaining material (n=3) was removed and weighed (W1), then dried and weighed (W2). The remaining wet mass and the remaining dry mass were calculated as follows:

[0172] Remaining wet mass (%) = W1 / W0×100%

[0173] Remaining dry mass (%) = W2 / W0×100%

[0174] AquaSys ® The 120 wire spools were cut into samples of the same size as the control.

[0175] Swelling behavior

[0176] The weighed WPU cylinder (W0) was immersed in 100 mL of deionized water at 25°C. At each predetermined time point, the polyurethane sample (n=3) was removed, the residual water on the surface was removed, and it was weighed (W2). The swelling ratio was calculated as (W2- W0) / W0 ×100%. AquaSys ® 120 The size of the printed cylinder is the same as that of the control group ( Figure 5 ).

[0177] Cytotoxicity of WPU

[0178] Polyurethane was dissolved in cell culture medium at concentrations of 0.01 mg / mL, 0.1 mg / mL, and 1 mg / mL, and then sterilized by passing through a 0.22 μm membrane filter before cell culture studies. Human kidney fibroblasts (HKF) were seeded in 12-well cell culture plates at a cell density of 8 × 10 4 cells / well. After 1 day of incubation, polyurethane / water solution with final concentrations of 0.01, 0.1, and 1 mg / mL was added to each well. After 24 hours of incubation, cell metabolic activity was measured using resazurin fluorescence assay (n = 4).

[0179] Example 1 - WPU embedded in PDMS

[0180] WPU1 was printed into a bifurcated pattern (width 0.4 mm, height 0.8 mm, bifurcation spacing 0.8 mm) and then embedded in polydimethylsiloxane (PDMS; Sylgard®184, Dow Corning). After curing at 55°C for 5 h, the WPU-embedded PDMS device was formed, and two holes were punched above the two distal ends of the print using a 3 mm biopsy punch for Luer connection. The WPU / PDMS device was then immersed in a water bath and treated under ultrasound for 3.5 h, followed by red dye perfusion to check its clearance. AquaSys® of the same size embedded in PDMS was used. ® The 120 pattern was used as a control.

[0181] Example 2 - WPU twisting

[0182] An eight-branch pattern (0.4 mm in width, 0.4 mm in height, and 1 mm in branch spacing) was printed with WPU2, twisted, and then embedded in PDMS. After curing at 55°C for 5 hours, the twisted WPU / PDMS construct was immersed in a water bath, treated under ultrasound for 3.5 hours to remove the WPU, and then heated in an oven for 1 hour to remove entrapped water vapor. A red dye solution was perfused through the twisted channel to verify its removal rate.

[0183] Example 3 - Spacing

[0184] WPU2 was printed into a serpentine pattern with increasing spacing of 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) and then photocrosslinked under near-visible light (wavelength of 395 nm) for 5 min. The WPU / GelMA device was then soaked in PBS and placed at 37°C for 30 min to achieve complete WPU removal. Red dye perfusion was performed to check the channel gap. The WPU / GelMA device was cut into cross-sections, and the channel size and spacing were measured under a microscope. AquaSys® 120 pattern of the same size embedded in 12% GelMA was used as a control.

[0185] Results and Discussion

[0186] WPU Characterization

[0187] In FTIR spectroscopy ( Figure 2 ), 1101 cm −1 The peak at 1728 cm is mainly attributed to the ether group in the PEG soft segment, which also corresponds to the C−O−C stretching vibration absorption of the urethane group. Due to the high content of PEG segment, the characteristic peak intensity of the urethane group, such as 1728 cm-1 The C=O stretching vibration peak at 3300-3500cm -1 The NH stretching vibration peak at becomes weaker.

[0188] As shown in Table 2, all water-soluble polyurethanes have two melting temperatures (Tm). The low Tm originates from the semi-crystalline PEG soft segment and ranges from 62°C to 65°C. The high Tm originates from the hard segment in the polyurethane backbone and ranges from 105°C to 111°C.

[0189] Table 2. Melting temperature of water-soluble polyurethane

[0190]

[0191] Water soluble

[0192] Figure 3 The water dissolution behavior of water-soluble polyurethanes was recorded over time. Figure 3 As shown, WPU1 and WPU2 were significantly reduced in size. The WPU1 sample completely disappeared after 2 hours of dissolution, and the WPU2 sample was essentially invisible in the water after 4 hours of dissolution. In contrast, the AquaSys® 120 sample swelled significantly, retaining 14±6% of its initial dry weight after 24 hours of dissolution. The WPU3 sample was also in a swollen state, retaining 28±4% of its initial dry weight after 24 hours of dissolution. It is believed that both WPU1 and WPU2 have a faster water dissolution rate than AquaSys® 120, while WPU3 has the lowest water dissolution rate among the four groups.

[0193] To further quantify the remaining samples, dry and wet weight measurements were performed and plotted in Figures 4A-B. In terms of remaining dry mass (Figure 4A, left), WPU1 completely dissolved after immersion in deionized water for 120 min. WPU2 retained only 6 ± 3% of its dry mass at 240 min. WPU3 and AquaSys® 120 retained 60 ± 6% and 53 ± 3% of their dry mass at 240 min, respectively. The remaining wet mass (Figure 4B, right) is a joint result of polymer dissolution and swelling. Both WPU1 and WPU2 first showed an increase in wet weight followed by a significant weight loss. Specifically, WPU1 had a remaining wet mass of 0 at 120 min, indicating that it had the fastest water dissolution rate among the 3 WPU groups. The initial increase in weight was due to partial polymer dissolution, which allowed the polymer network to have a greater water absorption capacity. The subsequent weight loss was due to the high degree of polymer solubility in water, which destroyed the polymer network and caused the polyurethane to disappear. In contrast, the remaining wet weights of WPU3 and AquaSys® 120 only showed an increasing trend within 240 min, but no decreasing trend, which means that their water solubility is relatively low compared with WPU1 and WPU2 (both retained more than 50% of their dry weight after 240 min of dissolution in water).

[0194] Swelling behavior

[0195] Figure 5 The swelling rate of water-soluble polyurethanes changes with time. WPU1 and WPU2 both show an upward trend in the initial stage, and the swelling rate reaches a peak of 188±15% and 1067±69% after 50 and 120 minutes of dissolution in water, respectively. The swelling rate of the latter two groups drops sharply to -36±43% and 293±92% at 120 and 240 minutes, respectively. As mentioned above, the upward trend of the swelling rate is due to the dissolution of part of the polymer, while the downward trend of the swelling rate indicates that a large amount of polyurethane has been dissolved and can no longer hold water. After immersion in water for 240 minutes, the swelling rate of WPU3 and AquaSys®120 increases to 1675±218% and 560±40%, respectively. The lack of a decrease in swelling rate within 240 minutes indicates that WPU3 and AquaSys®120 dissolve slowly in water.

[0196] The swelling properties of water-soluble polyurethanes are critical for their applications as sacrificial materials, especially when they are embedded in soft materials to form hollow structures. If the soft material is not strong enough to resist the swelling of the sacrificial material, the resolution and even the shape integrity of the hollow structure will be compromised. Both WPU1 and WPU2 exhibit fast water dissolution rates (complete dissolution in 2 and 4 hours in deionized water at room temperature) and limited swelling, making them outstanding candidates as water-soluble sacrificial polymers to create complex overhanging or undercut structures.

[0197] WPU cytotoxicity

[0198] Human renal fibroblasts were used to evaluate WPU cytotoxicity. Figure 6 As shown, there was no significant difference in cell viability in cell culture media containing 0.01, 0.1, and 1 mg / mL WPU compared to the culture medium control (p > 0.05). Only within the WPU1 group was there a significant difference between 0.1 mg / mL and 1 mg / mL (p < 0.05), which may be attributed to the larger number of PEG segments. The results showed that water-soluble polyurethane had no obvious cytotoxicity, indicating that it has great potential in biomedical applications.

[0199] Example 1 - WPU embedded in PDMS

[0200] PDMS is a commonly used material for making microfluidic devices with fluid or air / gas perfusion channels. One of its notable features is that it is highly waterproof. The common practice of creating channels inside PDMS is to create the channels on the surface of a PDMS block and then bond it to another PDMS block, which may cause leakage at the bonding site. By creating channels within a single PDMS block, the risk of potential leakage can be effectively prevented, while also enabling a simpler manufacturing process.

[0201] In Example 1 (Figure 7A-E), a WPU1 bifurcated print was embedded in PDMS and completely cleared after about 3.5 hours of water sonication. In contrast, AquaSys® 120 (Figure 8A-E) of the same size showed little dissolution under the same clearing conditions as WPU1, which was further confirmed by red dye perfusion. This example demonstrates the application scenario of WPU1, that is, creating channels inside a piece of PDMS as a microfluidic device.

[0202] Example 2 - WPU twisting

[0203] Example 2 demonstrates the good flexibility and water solubility of WPU2 by embedding an eight-branched WPU2 pattern into PDMS and removing it (Figure 9A-E). The WPU2 printing traces were completely removed by ultrasonic treatment in a water bath for 3.5 hours, and then confirmed by red dye perfusion.

[0204] Example 3 - Spacing

[0205] In Example 3, a biomicrofluidic device was fabricated using GelMA as a block hydrogel and WPU2 to create channels (Figures 10A-C). WPU2 was printed into a serpentine pattern with filament spacing increasing from 1 mm to 1.8 mm. The device was placed in PBS at 37°C for 30 minutes, and WPU2 was completely removed. All cross-sectional images showed that all channels remained relatively circular with no channel merging (Figures 11A-D). Compared to the original WPU2 print, the channels basically maintained their shape fidelity with a slight increase in cross-sectional area (approximately 1.3%, from 0.235 to 0.238 mm 2 ).

[0206] AquaSys® 120 with the same pattern was used as a control (Figure 12A-C), which took significantly longer (about 18 hours) to clear under the same conditions as WPU2. Both dye perfusion and cross-sectional images showed that some channels merged together due to the slow water dissolution rate and high water absorption rate of AquaSys® 120 (Figure 13A-D). In addition, after clearing, the channels were no longer circular, but showed irregular shapes, and the cross-sectional area of ​​the channels increased by about 118% compared with the original print.

[0207] Example 3 provides another application scenario of WPU, namely, creating channels in soft hydrogels and maintaining good shapes as biological microfluidic devices.

Claims

1. A method for synthesizing a water-soluble, non-toxic, thermoplastic polyurethane polymer, comprising the following steps: i) providing one or more aliphatic diisocyanate compounds; ii) providing one or more higher molecular weight polyalkylene oxide 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; 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 sequentially or simultaneously in a molar ratio of 50:49-20:1-30; 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 about 1:1; and v) sequentially or simultaneously applying one or more conditions sufficient to 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 having a melting temperature of 50-240°C, being soluble in water having a near neutral pH at room temperature or 37°C, having a soft segment content of at least 80%, and being non-cytotoxic to human renal fibroblasts.

2. The method for synthesizing a water-soluble, thermoplastic polyurethane polymer as claimed in claim 1, wherein 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, diisocyanatocyclohexylmethane, 2,2,4-trimethylhexamethylene diisocyanate, diisocyanatomethylcyclohexane, norbornane diisocyanate, diisocyanatododecane or a combination thereof.

3. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as claimed in any one of claims 1 to 2, wherein 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.

4. The method for synthesizing a water-soluble, thermoplastic polyurethane polymer according to any one of claims 1 to 3, wherein the one or more aliphatic diisocyanate compounds comprise hexamethylene diisocyanate.

5. The method for synthesizing a water-soluble, thermoplastic polyurethane polymer according to any one of claims 1 to 4, wherein the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 60 to 200 g / mol.

6. The method for synthesizing a water-soluble, thermoplastic polyurethane polymer according to any one of claims 1 to 5, wherein the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 60 to 150 g / mol.

7. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as claimed in any one of claims 1 to 6, wherein the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 80 to 125 g / mol.

8. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as claimed in any one of claims 1 to 7, wherein 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-propylene glycol, 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.

9. The method of synthesizing a water-soluble, thermoplastic polyurethane polymer according to any one of claims 1 to 8, wherein the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of ethylene glycol, 1,3-propylene glycol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, and combinations thereof.

10. The method of synthesizing a water-soluble, thermoplastic polyurethane polymer according to any one of claims 1 to 9, wherein 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.

11. The method of synthesizing a water-soluble, thermoplastic polyurethane polymer of any one of claims 1-10, wherein the one or more low molecular weight aliphatic diol chain extender compounds comprises 1,4-butanediol.

12. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as claimed in any one of claims 1 to 11, wherein the one or more polyalkylene oxide compounds comprise polyethylene oxide, polypropylene oxide or polybutylene oxide.

13. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as claimed in any one of claims 1 to 12, wherein the molecular weight of the one or more polyalkylene oxide compounds is 8,000 to 100,000 g / mol.

14. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as claimed in any one of claims 1 to 13, wherein the molecular weight of the one or more polyalkylene oxide compounds is from 10,000 to 80,000 g / mol.

15. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as claimed in any one of claims 1 to 14, wherein the molecular weight of the one or more polyalkylene oxide polymer compounds is from 12,000 to 50,000 g / mol.

16. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as claimed in any one of claims 1 to 15, wherein the molecular weight of the one or more polyalkylene oxide polymer compounds is from 15,000 to 30,000 g / mol.

17. The method for synthesizing a water-soluble, thermoplastic polyurethane polymer as claimed in any one of claims 1 to 16, wherein the one or more polyalkylene oxide polymer compounds have a molecular weight of about 20,000 g / mol.

18. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in any of claims 1 to 17, wherein the one or more aliphatic diisocyanates include butene diisocyanate, pentene diisocyanate and / or hexamethylene diisocyanate, the one or more polyalkylene oxide polymer compounds include polyethylene oxide or polypropylene oxide polymers having a molecular weight of 15,000-30,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds include 1,3-propylene glycol, 1,4-butanediol, 1,5-pentanediol or 1,6-hexanediol.

19. The method of synthesizing a water-soluble, thermoplastic polyurethane polymer of claim 18, wherein the one or more aliphatic diisocyanates comprise hexamethylene diisocyanate, the polyalkylene oxide polymer comprises 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 comprise 1,4-butanediol.

20. The method for synthesizing a water-soluble, thermoplastic polyurethane polymer according to any one of claims 1 to 19, wherein step iv) comprises 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.

21. The method for synthesizing a water-soluble, thermoplastic polyurethane polymer according to any one of claims 1 to 20, wherein applying one or more conditions sufficient for polymerization in step v) comprises 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.

22. The method for synthesizing a water-soluble, thermoplastic polyurethane polymer according to any one of claims 1 to 21, wherein applying one or more conditions sufficient for polymerization in step v) comprises exposing the first mixture to heat >100°C in the absence of a catalyst, thereby synthesizing the water-soluble, thermoplastic polyurethane polymer.

23. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in any one of claims 1-21, wherein applying one or more conditions sufficient for polymerization in step v) comprises exposing the first mixture to heat <100°C in the presence of a catalyst, thereby synthesizing the water-soluble, thermoplastic polyurethane polymer while minimizing the formation of allophanate groups and crosslinking of the polyurethane polymer.

24. The method of synthesizing a water-soluble, thermoplastic polyurethane polymer of claim 23, wherein exposing the first mixture to heat <100°C comprises exposing the first mixture to a temperature of 40°C to 90°C.

25. The method of synthesizing a water-soluble, thermoplastic polyurethane polymer of claim 23, wherein exposing the first mixture to heat <100°C comprises exposing the first mixture to a temperature of about 70°C.

26. The method of synthesizing a water-soluble, thermoplastic polyurethane polymer of claim 21, wherein the catalyst is selected from the group consisting of: 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, trimethylaminoethylethanolamine, 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 octanoate, potassium acetate, lithium octanoate, bismuth octanoate, bismuth neodecanoate, zinc octanoate, zinc neodecanoate, zirconium octanoate, cobalt octanoate, nickel octanoate, potassium octanoate, calcium octanoate, antimony octanoate, lanthanum octanoate, zirconium acetylacetonate, titanium acetoacetate, aluminum acetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid, and diphenyl phosphate.

27. A process for synthesizing a water-soluble, thermoplastic polyurethane polymer as claimed in any one of claims 1 to 26, wherein the synthesis is carried out in a batch or continuous manner.

28. A process for the synthesis of a water-soluble, thermoplastic polyurethane polymer as claimed in any one of claims 1 to 27, wherein the synthesis is carried out in a reactive extruder or a continuous mixing or spinning device.

29. The method for synthesizing a water-soluble, thermoplastic polyurethane polymer according to any one of claims 1 to 19, wherein step iv) comprises sequential mixing, and wherein the one or more aliphatic diisocyanate compounds and the one or more high molecular weight polyalkylene oxide compounds are mixed to form a premix.

30. The method for synthesizing a water-soluble, thermoplastic polyurethane polymer of claim 29, wherein the premix comprising the one or more aliphatic diisocyanate compounds and the one or more high molecular weight polyalkylene oxide compounds further comprises one or more solvents to promote uniform mixing and distribution of the diisocyanate and high molecular weight polyalkylene oxide compounds throughout the premix.

31. The method for synthesizing a water-soluble, thermoplastic polyurethane polymer of claim 30, wherein the solvent comprises dimethyl sulfoxide (DMSO), N,N-dimethylformamide, tetrahydrofuran (THF), or N,N-dimethylacetamide.

32. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in claim 30 or 31, wherein applying one or more conditions sufficient for polymerization in step v) comprises 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.

33. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in claim 32, wherein applying one or more conditions sufficient for polymerization in step v) comprises exposing the premix to heat >100°C in the absence of a catalyst, thereby synthesizing the urethane prepolymer.

34. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in claim 32, wherein applying one or more conditions sufficient for polymerization in step v) comprises exposing the premix to heat <100°C in the presence of a catalyst to synthesize the urethane prepolymer while minimizing the formation of allophanate groups and crosslinking of the polyurethane polymer.

35. The method of synthesizing a water-soluble, thermoplastic polyurethane polymer of claim 34, wherein exposing the first mixture to heat <100°C comprises exposing the premix to a temperature of 40°C to 90°C.

36. The method of synthesizing a water-soluble, thermoplastic polyurethane polymer of claim 34, wherein exposing the first mixture to heat <100°C comprises exposing the premix to a temperature of about 70°C.

37. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in claim 32, wherein the catalyst is selected from the group consisting of: 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, trimethylaminoethylethanolamine, 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 octanoate, potassium acetate, lithium octanoate, bismuth octanoate, bismuth neodecanoate, zinc octanoate, zinc neodecanoate, zirconium octanoate, cobalt octanoate, nickel octanoate, potassium octanoate, calcium octanoate, antimony octanoate, lanthanum octanoate, zirconium acetylacetonate, titanium acetoacetate, aluminum acetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid, and diphenyl phosphate.

38. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in claim 32, wherein the sequential mixing comprises providing the one or more aliphatic diisocyanate compounds and the one or more high molecular weight polyalkylene oxide compounds in the form of the urethane prepolymer, and mixing the prepolymer with the one or more low molecular weight diol chain extender compounds to obtain a second mixture.

39. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as claimed in claim 38, wherein said method further comprises applying one or more conditions sufficient to form urethane bonds between said prepolymer and a diol chain extender compound, thereby obtaining said water-soluble, thermoplastic polyurethane.

40. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in any one of claims 1 to 39, wherein the mixing molar ratio of one or more aliphatic diisocyanate compounds to higher molecular weight polyalkylene oxide compounds to low molecular weight diol chain extender compounds ranges from 50:49-25:1-25.

41. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in any one of claims 1 to 39, wherein the mixing molar ratio of one or more aliphatic diisocyanate compounds to higher molecular weight polyalkylene oxide compounds to low molecular weight diol chain extender compounds ranges from 50:49-40:1-10.

42. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in any one of claims 1-41, wherein the method further comprises the step of isolating the polymer by one or more techniques selected from the group consisting of precipitation, dialysis and lyophilization.

43. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in any of claims 1-42, wherein the method further comprises the step of removing excess water from the one or more aliphatic diisocyanates, polyalkylene oxides, diol chain extenders, solvents, or solid surfaces in contact therewith by using one or more techniques including distillation, drying, and / or washing the solid surface with a silane liquid.

44. The method for synthesizing a water-soluble, thermoplastic polyurethane polymer of any one of claims 1-43, wherein one or more of the steps of providing, mixing, or applying one or more conditions are performed under an inert gas.

45. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in any of claims 1-44, wherein the melting temperature comprises a first melting temperature corresponding to the melting temperature of a soft segment of the thermoplastic polyurethane polymer or a second melting temperature corresponding to the melting temperature of a hard segment of the thermoplastic polyurethane polymer.

46. ​​The method of synthesizing a water-soluble, thermoplastic polyurethane polymer of claim 45, wherein the first melt temperature comprises 50-80°C and the second melt temperature comprises 100-130°C.

47. A method for synthesizing a water-soluble, thermoplastic polyurethane polymer as described in any of claims 1-46, wherein the polyurethane polymer exhibits minimal swelling when exposed to water.

48. A water-soluble, non-toxic, thermoplastic polyurethane composition comprising a polyurethane prepared by the method of claim 1, wherein the polyurethane composition has a melting temperature of 50-240°C, a soft segment content of at least 80%, is soluble in water with a pH value close to neutral at room temperature or 37°C, is non-cytotoxic to human renal fibroblasts, and exhibits minimal swelling when exposed to water.

49. A polyurethane polymer composition comprising a water-soluble, non-toxic, thermoplastic polyurethane polymer, said polyurethane polymer being the reaction product of at least: one or more aliphatic diisocyanate compounds; one or more higher molecular weight polyalkylene oxide compounds having a molecular weight of about 600-150,000 g / mol; one or more low molecular weight aliphatic diol chain extender compounds having a molecular weight of about 50-300 g / mol; and optional catalyst; wherein 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 are reacted in a molar ratio of 50:49-20:1-30, 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 The thermoplastic polyurethane has a soft segment content of at least 80%, a melting temperature of about 50-240° C., is soluble in water with a pH value close to neutral at room temperature or 37° C., and has no cytotoxicity to human renal fibroblasts.

50. The polyurethane polymer composition of claim 49, wherein 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, diisocyanatocyclohexylmethane, 2,2,4-trimethylhexamethylene diisocyanate, diisocyanatomethylcyclohexane, norbornane diisocyanate, diisocyanatododecane, or combinations thereof.

51. The polyurethane polymer composition of any one of claims 49-50, wherein 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.

52. The polyurethane polymer composition of any one of claims 49-51, wherein the one or more aliphatic diisocyanate compounds comprises hexamethylene diisocyanate.

53. The polyurethane polymer composition of any one of claims 49-52, wherein the one or more polyalkylene oxide compounds comprise polyethylene oxide, polypropylene oxide, or polybutylene oxide polymers.

54. The polyurethane polymer composition of any of claims 49-53, wherein the one or more polyalkylene oxide compounds have a molecular weight of 8,000-100,000 g / mol.

55. The polyurethane polymer composition of any of claims 49-54, wherein the one or more polyalkylene oxide compounds have a molecular weight of 10,000 to 80,000 g / mol.

56. The polyurethane polymer composition of any of claims 49-55, wherein the one or more polyalkylene oxide compounds have a molecular weight of 12,000 to 50,000 g / mol.

57. The polyurethane polymer composition of any of claims 49-56, wherein the one or more polyalkylene oxide compounds have a molecular weight of 15,000-30,000 g / mol.

58. The polyurethane polymer composition of any of claims 49-57, wherein the one or more polyalkylene oxide compounds have a molecular weight of about 20,000 g / mol.

59. The polyurethane polymer composition of any of claims 49-58, wherein the one or more polyalkylene oxide compounds have a molecular weight of about 60-200 g / mol.

60. The polyurethane polymer composition of any of claims 49-59, wherein the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 60-150 g / mol.

61. The polyurethane polymer composition of any of claims 49-60, wherein the one or more low molecular weight aliphatic diol chain extender compounds have a molecular weight of about 80-125 g / mol.

62. The polyurethane polymer composition of any of claims 49-61, wherein 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-propylene glycol, 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.

63. The polyurethane polymer composition of any of claims 49-62, wherein the one or more low molecular weight aliphatic diol chain extender compounds are selected from the group consisting of ethylene glycol, 1,3-propylene glycol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, and combinations thereof.

64. The polyurethane polymer composition of any of claims 49-63, wherein 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.

65. The polyurethane polymer composition of any of claims 49-64, wherein the one or more low molecular weight aliphatic diol chain extender compounds comprises 1,4-butanediol.

66. The polyurethane polymer composition of any one of claims 49-65, wherein the one or more aliphatic diisocyanates comprise butene diisocyanate, pentene diisocyanate and / or hexamethylene diisocyanate, the one or more polyalkylene oxide polymer compounds comprise polyethylene oxide or polypropylene oxide polymers having a molecular weight of 15,000-30,000 g / mol, and the one or more low molecular weight aliphatic diol chain extender compounds comprise 1,3-propylene glycol, 1,4-butanediol, 1,5-pentanediol or 1,6-hexanediol.

67. The polyurethane polymer composition of any of claims 49-66, wherein the one or more aliphatic diisocyanates comprise hexamethylene diisocyanate, the polyalkylene oxide polymer comprises 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 comprise 1,4-butanediol.

68. The polyurethane polymer composition of any one of claims 49-67, wherein the polyurethane polymer has a soft segment content greater than 84%.

69. The polyurethane polymer composition of any one of claims 49-68, wherein the polyurethane polymer has a soft segment content greater than 90%.

70. The polyurethane polymer composition of any one of claims 49-69, wherein the polyurethane polymer has a soft segment content greater than 97%.

71. The polyurethane polymer composition of any one of claims 49-70, wherein the soft segment content of the polyurethane polymer is greater than 98%.

72. The polyurethane polymer composition of any one of claims 49-71, wherein the reaction is the result of simultaneously mixing all of the one or more aliphatic diisocyanate compounds, the one or more polyalkylene oxide compounds, the one or more low molecular weight aliphatic diol chain extender compounds, and optionally one or more catalysts and solvents to provide a first mixture, and then exposing the first mixture to one or more conditions selected from heat, duration, or a combination thereof, to obtain the water-soluble, non-toxic, thermoplastic polyurethane polymer.

73. The polyurethane polymer composition of any one of claims 49-71, wherein the one or more aliphatic diisocyanate compounds, the one or more high molecular weight polyalkylene oxide compounds, and optionally one or more catalysts and solvents are mixed to form a premix, and then exposed to one or more conditions selected from heat, duration, or a combination thereof to obtain a urethane prepolymer, and then reacted with the one or more low molecular weight diol chain extender compounds to obtain the water-soluble, non-toxic, thermoplastic polyurethane polymer.

74. The polyurethane polymer composition of claim 73, wherein the urethane prepolymer, the one or more low molecular weight diol chain extender compounds, and optionally one or more catalysts and solvents are mixed to obtain a second mixture and subsequently exposed to one or more conditions selected from heat, duration, or a combination thereof to obtain the water soluble, non-toxic, thermoplastic polyurethane polymer.

75. The polyurethane polymer composition of any of claims 72-74, wherein the first mixture, premix, and / or second mixture is exposed to heat greater than 100°C in the absence of a catalyst.

76. A polyurethane polymer composition as described in any of claims 72-74, wherein the first mixture, premixture and / or second mixture is exposed to heat below 100°C in the presence of a catalyst to synthesize the water-soluble, non-toxic, thermoplastic polyurethane polymer or urethane prepolymer.

77. The polyurethane polymer composition of any of claims 72-74, wherein the first mixture, premix, and / or second mixture is exposed to a temperature of 40°C to 90°C.

78. The polyurethane polymer composition of any one of claims 72-74, wherein the first mixture, premix, and / or second mixture is exposed to a temperature of about 70°C.

79. The polyurethane polymer composition of any one of claims 72-78, wherein the catalyst is selected from the group consisting of 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, trimethylaminoethylethanolamine, 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 octanoate, potassium acetate, lithium octanoate, bismuth octanoate, bismuth neodecanoate, zinc octanoate, zinc neodecanoate, zirconium octanoate, cobalt octanoate, nickel octanoate, potassium octanoate, calcium octanoate, antimony octanoate, lanthanum octanoate, zirconium acetylacetonate, titanium acetoacetate, aluminum acetoacetate, methanesulfonic acid, trifluoromethanesulfonic acid, and diphenyl phosphate.

80. The polyurethane polymer composition of any one of claims 72-79, wherein the solvent comprises dimethyl sulfoxide (DMSO), N,N-dimethylformamide, N,N-dimethylacetamide, or tetrahydrofuran (THF).

81. The polyurethane polymer composition of any one of claims 49-80, wherein the molar ratio of the one or more aliphatic diisocyanate compounds to the higher molecular weight polyalkylene oxide compound to the low molecular weight diol chain extender compound ranges from 50:49-25:1-25.

82. The polyurethane polymer composition of any one of claims 49-81, wherein the molar ratio of the one or more aliphatic diisocyanate compounds to the higher molecular weight polyalkylene oxide compound to the low molecular weight diol chain extender compound ranges from 50:49-40:1-10.

83. The polyurethane polymer composition of claim 45, wherein the polyurethane polymer exhibits minimal swelling when exposed to water.

84. A polyurethane polymer composition as described in claim 83, wherein the minimum swelling is determined by comparing the wet mass of the polyurethane when dissolved in water with the dry mass of the same polyurethane before contact with water, wherein an increase in wet mass relative to dry mass of less than 2.5 times defines that the polyurethane has minimum swelling when dissolved in water.

85. The water-soluble, nontoxic, thermoplastic polyurethane polymer of any one of claims 49-84, wherein the non-toxicity of the polyurethane polymer is determined by incubating human kidney fibroblasts in a cell culture medium containing 0.1 mg / mL dissolved thermoplastic polyurethane for 24 hours, wherein the thermoplastic polyurethane polymer is determined to be non-toxic if there is no decrease in cellular metabolic activity (as measured by resazurin fluorescence assay) at the end of the 24 hour incubation period.

86. The polyurethane polymer composition of any one of claims 49-85, wherein the polyurethane polymer composition is readily soluble in water as measured by 1.75 mm diameter filaments formed therefrom substantially dissolving in deionized water at room temperature without stirring in about 4 hours or less.

87. The polyurethane polymer composition of any one of claims 49-86, wherein the polyurethane polymer is linear and substantially free of crosslinking and / or branching.

88. The polyurethane polymer composition of any one of claims 49-87, wherein the polyurethane polymer is substantially not formed from aromatic isocyanate compounds or isocyanate compounds having more than 2 isocyanate groups per compound.

89. The polyurethane polymer composition of any one of claims 49-88, wherein the composition further comprises about 30% to 80% by weight of a water-based solvent, based on the weight of the polyurethane polymer composition.

90. The polyurethane polymer composition of claim 89, wherein the composition is in the form of a gel.

91. The polyurethane polymer composition of claim 89 or 90, wherein the polyurethane polymer is present in an amount of about 20% to 70% by weight, based on the weight of the polyurethane polymer composition.

92. The polyurethane polymer composition of any one of claims 49-88, wherein the polyurethane polymer comprises greater than 70% and up to and including 100% of the polyurethane polymer composition.

93. The polyurethane polymer composition of claim 92, wherein the composition consists essentially of or consists of the polyurethane polymer.

94. A method for making a basement membrane construct, comprising: a. Printing a sacrificial structure comprising the water-soluble, non-toxic, thermoplastic polyurethane composition of claim 49 onto a support structure or a thin layer of a functional substrate film material using a 3D printer thermoplastic print head; b. applying a thin layer comprising a functional base membrane material to the sacrificial structure, thereby obtaining a 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 or laminating with a sacrificial material or a permanent material; and e. dissolving the sacrificial material by exposing the sacrificial material to a water-based solvent to provide one or more internal volumes retaining the original shape and size of the printed sacrificial structure, thereby producing the basement membrane construct, The thin layer is a porous structure with a thickness of 0.25-10 μm.

95. The method of claim 94, wherein step (b) comprises electrospinning a fibrous sheet membrane directly onto the sacrificial structure followed by post-production processing to impart enhanced mechanical properties to the fibrous sheet membrane.

96. A method as claimed in claim 94, wherein step (b) comprises applying a preformed thin layer comprising a functional base film to the sacrificial substrate in combination with compression and heat or solvent, thereby obtaining a sacrificial substrate wrapped with a thin layer comprising a functional base film.

97. A method as claimed in claim 94, wherein obtaining the one or more layers in step (c) comprises printing a sacrificial structure comprising a water-soluble, non-toxic, thermoplastic polyurethane composition directly onto the thin layer comprising a functional base film material applied to the sacrificial structure in the previous step (b).

98. A method as claimed in claim 94, wherein obtaining the one or more layers in step (c) includes printing a sacrificial structure comprising a water-soluble, non-toxic, thermoplastic polyurethane composition on a supporting substrate or a thin layer comprising a functional substrate film (which is not the thin layer applied in the previous step (b)), and before embedding in step (d), further combining the one or more additional layers obtained in step (c) with the layer obtained by initially performing steps (a) and (b).

99. A method as claimed in claim 94, wherein prior to step (d), one or more layers of the construct obtained in step (c) and the layers obtained by initially performing steps (a) and (b) are individually or together configured into a desired three-dimensional shape.

100. The method of manufacturing a substrate membrane construct of claim 94, wherein the water-soluble, non-toxic, thermoplastic polyurethane is heated to 100°C to 250°C during printing.

101. The method for manufacturing a basement membrane construct as described in any one of claims 94-99, wherein the temperature of the chamber and the bed are both maintained at 25°C during the three-dimensional printing process.

102. A method for manufacturing a basement membrane construct as described in any one of claims 94-101, wherein the sacrificial structure is printed in a serpentine or bifurcated pattern.

103. A method for making a basement membrane construct as described in any one of claims 94-102, wherein the products of steps (a) and (b) and optionally (c) are embedded in or layered with polydimethylsiloxane, methacrylated gelatin, bulk tissue material or other matrix-forming material.

104. A method of manufacturing a microfluidic device, comprising the steps of: a. Printing a sacrificial structure comprising the water-soluble, non-toxic, thermoplastic polyurethane composition of claim 49 onto a support structure or a thin layer using a 3D printer thermoplastic print head; b. embedding the product of step (a) with or without the support structure or thin layer in a sacrificial material or a permanent material or laminating it together; and c. optionally repeating steps (a) and (b) one or more times; and d. Dissolving the sacrificial material by exposing the sacrificial material to a water-based solvent to provide one or more interior volumes that substantially retain the original shape and size of the printed sacrificial structure, thereby producing a microfluidic device.

105. A method of making the microfluidic device of claim 104, wherein the material comprises methacrylated gelatin, polydimethylsiloxane, bulk tissue material, or a matrix-forming material.

106. A method of manufacturing the microfluidic device of claim 104 or 105, wherein the sacrificial structure comprises an extended longitudinal profile, a substantially elliptical or circular cross-sectional profile, and wherein the one or more internal volumes provided comprise a channel.

107. A method of making the microfluidic device of any one of claims 104-106, wherein the sacrificial structure is formed into a serpentine or bifurcated pattern having a constant or non-constant diameter.

Images