Controlling the size of hydrogel objects for 3D printing using hydrophilic and hydrophobic monomers and crosslinkers

Abstract

The present disclosure provides a printable composition comprising, based on the weight of the printable composition, about 1 weight percent (wt%) to about 40 wt% of one or more hydrophilic monomers; a swelling control agent selected from a hydrophobic monomer, a short chain crosslinker, and combinations thereof; about 0.01 wt% to about 2 wt% of a photoinitiator; and 0 wt% to about 75 wt% of a vehicle comprising a protic solvent. The present disclosure further includes methods of use and manufacture of the printable composition.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 185,300, filed May 6, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Embodiments of the present disclosure relate to a printable composition comprising, based on the weight of the printable composition, about 1 weight percent (wt%) to about 40 wt% of one or more hydrophilic monomers; a swelling control agent selected from a hydrophobic monomer, a short chain crosslinker, and combinations thereof; about 0.01 wt% to about 2 wt% of a photoinitiator; and 0 wt% to about 75 wt% of a vehicle comprising a protic solvent, with the proviso that when the swelling control agent is a hydrophobic monomer, the printable composition has a weight ratio of hydrophilic monomer to hydrophobic monomer of about 20:1 to about 1:20; and when the swelling control agent is a short chain crosslinker, the printable composition comprises about 0.01 wt% to about 5 wt% of the short chain crosslinker. In some embodiments, the hydrophilic monomer is a hydroxy C 1-2 Alkyl (meth)acrylate, Poly(alkylene oxide) alkyl ether (meth)acrylate, N-hydroxy C 1-2In some embodiments, the hydrophilic monomer comprises one or more of poly(ethylene glycol) methyl ether acrylate (PEGMEA), poly(ethylene glycol) methyl ether methacrylate, poly(propylene glycol) methyl ether acrylate, poly(propylene glycol) methyl ether methacrylate, hydroxyethyl acrylate (HEA), N-hydroxyethyl acrylamide (HEAA), or mixtures thereof. In some embodiments, the one or more hydrophilic monomers are selected from the group consisting of PEGMA, HEA, and mixtures thereof. In some embodiments, the printable composition comprises from about 5% to about 35% by weight of one or more hydrophilic monomers. In some embodiments, the printable composition comprises from about 5% to about 25% by weight of one or more hydrophilic monomers. In some embodiments, the hydrophobic monomer comprises hydroxyl C 3-6 In some embodiments, the hydrophobic monomer comprises one or more of hydroxyethyl methacrylate, hydroxypropyl acrylate (HPA 3-hydroxypropyl acrylate and / or 2-hydroxypropyl acrylate), hydroxypropyl methacrylate, hydroxybutyl acrylate (HBA), hydroxybutyl methacrylate, or mixtures thereof. In some embodiments, the weight ratio of hydrophilic monomer to hydrophobic monomer is about 15:1 to about 1:15. In some embodiments, the weight ratio of hydrophilic monomer to hydrophobic monomer is about 10:1 to about 1:10. In some embodiments, the weight ratio of hydrophilic monomer to hydrophobic monomer is about 5:1 to about 1:5. In some embodiments, the weight ratio of hydrophilic monomer to hydrophobic monomer is about 1:1 to about 1:3. In some embodiments, the printable composition comprises HPA and HEA present in a weight ratio of about 3:1 to about 1:3. In some embodiments, the printable composition includes HBA and HEA present in a weight ratio of about 3:1 to about 1:3. In some embodiments, the short-chain crosslinker has a weight average molecular weight (M) of about 400 to about 20,000.w ), poly(alkylene oxide) di(meth)acrylate, diethylene glycol di(meth)acrylate, tetraethylene glycol di(meth)acrylate, N,N'-methylene bis(acylamide), (poly)lactic acid di(meth)acrylate, (poly)glycolic acid di(meth)acrylate, (poly)lactic acid coglycolide di(meth)acrylate, (poly)caprolactone di(meth)acrylate, (poly)dioxanone di(meth)acrylate, (poly)fumaric acid di(meth)acrylate, (carboxy)(methyl)cellulose di(meth)acrylate, hyaluronic acid di(meth)acrylate, heparan sulfate di(meth)acrylate, dextran di(meth)acrylate, alginic acid di(meth)acrylate, pectin di(meth)acrylate, or collagen di(meth)acrylate, or a mixture thereof. In some embodiments, the poly(alkylene oxide) di(meth)acrylate comprises poly(ethylene glycol) diacrylate. In some embodiments, the printable composition comprises about 0.5% to about 3% by weight of a short-chain crosslinker. In some embodiments, the photoinitiator comprises lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), trimethylbenzoyl-based photoinitiators, diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO nanoparticles) Irgacure class photoinitiators, ruthenium, and riboflavin, or mixtures thereof. In some embodiments, the printable composition further comprises one or more of additives comprising a polymer, a UV dye, a natural extracellular matrix, a photoinitiator, a peptide, an amino acid, a growth factor, a modified extracellular matrix, an extracellular matrix fragment, or mixtures thereof. In some embodiments, the protic solvent comprises water, polyethylene glycol, a glycol diacrylate derivative, or mixtures thereof. Summary of the Invention

[0003] Further embodiments include a method of preparing a three-dimensional article comprising printing a printable composition according to any one of the embodiments for producing a three-dimensional article. In some embodiments, the printing produces a three-dimensional article of an organ, the organ being a mammalian organ. In some embodiments, the printing comprises inkjet printing, extrusion printing, or layer-by-layer printing. In some embodiments, the three-dimensional article has a swelling percentage of less than about 300% by weight relative to the non-hydrated weight of the three-dimensional article. In some embodiments, the three-dimensional article has a swelling percentage of about 1% to less than about 300% by weight relative to the non-hydrated weight of the three-dimensional article. Further embodiments include three-dimensional articles produced according to these embodiments.

[0004] Further embodiments include a method of manufacturing a three-dimensional article, comprising: depositing a layer of a printable composition on a surface to obtain a deposited layer; irradiating the deposited layer; and repeating the depositing and irradiating steps until the deposited layer forms a three-dimensional article, wherein the printable composition comprises, based on the weight of the printable composition, about 1 weight percent (wt%) to about 40 wt% of one or more hydrophilic monomers; a swelling control agent selected from a hydrophobic monomer, a short-chain crosslinker, and combinations thereof; about 0.01 wt% to about 2 wt% of a photoinitiator; and 0 wt% to about 75 wt% of a vehicle comprising a protic solvent, with the proviso that if the swelling control agent is a hydrophobic monomer, the printable composition has a weight ratio of hydrophilic monomer to hydrophobic monomer of about 20:1 to about 1:20; and if the swelling control agent is a short-chain crosslinker, the printable composition comprises about 0.01 wt% to about 5 wt% of the short-chain crosslinker. In some embodiments, the printable composition is a printable composition according to any one of the embodiments. In some embodiments, the deposited layer is irradiated with a wavelength between 365 nm and about 405 nm. [Brief description of the drawings]

[0005] [Figure 1] FIG. 1 shows an embodiment of an HPA-PEGMEA brush copolymer. [Figure 2A]Figure 2A shows the swelling of a specific 30-45% PEGMEA hydrogel, and Figure 2B shows the swelling of a specific 25-35% PEGMEA hydrogel. [Figure 2B] Figure 2A shows the swelling of a specific 30-45% PEGMEA hydrogel, and Figure 2B shows the swelling of a specific 25-35% PEGMEA hydrogel. [Diagram 3] FIG. 3 shows swelling values ​​for certain embodiments having various weight percent ratios of hydrophobic monomer poly(ethylene glycol) methyl ether acrylate (PEGMEA) and hydrophobic monomer 2-hydroxypropyl acrylate (HPA) (1:0, 2:1, 1:1, 1:0). [Figure 4] FIG. 4 shows swelling data for additional embodiments having different HPA:PEGMEA weight percentage ratios. [Diagram 5] FIG. 5 shows a specific embodiment of 10PEGMEA where various monomers resulted in different swelling. [Figure 6] FIG. 6 shows swelling versus [HPA / HEA] content in certain embodiments. [Figure 7] FIG. 7 shows swelling versus [HBA / HEA] content in certain embodiments. [Figure 8] FIG. 8 shows certain embodiments of 25-35 PEGMEA formulations with or without N,N'-methylenebisacrylamide. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] The present disclosure includes printable compositions that include hydrophilic monomer(s), hydrophobic monomer(s), short-chain crosslinker(s), photoinitiator, solvent, and / or combinations thereof. These compositions can be hydrogels. By manipulating the content of the hydrogel, such as by varying the amount of hydrophilic and / or hydrophobic monomers, the shape of the resulting hydrogel can be controlled when exposed to an aqueous environment, including a physiological environment. The present disclosure also includes methods of preparing three-dimensional articles that include printing the printable compositions, and three-dimensional articles produced according to those methods.

[0007] As used herein, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. For example, reference to "a cell" includes a combination of two or more cells, etc.

[0008] As used herein, "weight percent" (also referred to as "wt %") refers to the percentage of one or more components relative to the total mass of the composition. Thus, a composition having a mass of 100 grams containing 10 grams of Compound A has a weight percent of 10% relative to Compound A. As used herein, weight percent is used synonymously with mass percent.

[0009] As used herein, the terms "object" and "article" may be used interchangeably and refer to items that include the compositions of the present invention.

[0010] As used herein, the terms "comprising" or "comprise" are intended to mean that the compositions and methods include the recited elements but do not exclude others. When used to define compositions and methods, "consisting essentially of" shall mean excluding other elements that have some essential significance to the combination for the described purpose. Thus, a composition consisting essentially of the elements defined herein will not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" shall mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transitional phrases are within the scope of the present invention. When an embodiment is defined by one of these terms (e.g., "comprising"), it should be understood that the disclosure also encompasses alternative embodiments. Some of these embodiments may include "consisting essentially of" and "consisting of" for the embodiment.

[0011] As used herein, unless otherwise specified, "swelling percentage" or "percent swelling" refers to the percentage change in mass of an object before and after incubation in water. Thus, a positive percentage indicates that the object has increased in size, and a negative percentage indicates that the object has decreased in size.

[0012] As used herein, the terms "substantially" and "about" are used to describe and take into account small variations. When used with an event or circumstance, the term can mean that the event or circumstance occurs exactly or that the event or circumstance occurs approximately. When used with a numerical value, the term can mean a range of variation of ±10% or less of that numerical value, such as ±5% or less, ±4% or less, ±3% or less, ±2% or less, ±1% or less, ±0.5% or less, ±0.1% or less, or ±0.05% or less. When referring to a first numerical value being "substantially" or "approximately" the same as a second numerical value, the term can mean that the first numerical value is within a range of variation of ±10% or less of the second numerical value, such as ±5% or less, ±4% or less, ±3% or less, ±2% or less, ±1% or less, ±0.5% or less, ±0.1% or less, or ±0.05% or less.

[0013] Furthermore, amounts, ratios, and other numerical values ​​are sometimes presented in a range format in this specification. It should be understood that such range formats are used for convenience and brevity, and should be understood flexibly to include numerical values ​​explicitly specified as the limits of the range, and to include all individual numerical values ​​or subranges contained within the range, as if each numerical value and subrange were explicitly specified. For example, a ratio in the range of about 1 to about 200 should be understood to include the explicitly stated limits of about 1 and about 200, but also to include individual ratios such as about 2, about 3, and about 4, and subranges such as about 10 to about 50, about 20 to about 100, etc.

[0014] In some embodiments, the rate of change is over a period of incubation of the object or article in water, which period is selected from about 5 seconds to about 30 seconds, about 30 seconds to about 1 minute, about 1 minute to about 10 minutes, about 10 minutes to about 30 minutes, about 30 minutes to about 1 hour, about 1 hour to about 3 hours, about 3 hours to about 12 hours, about 12 hours to about 24 hours, about 24 hours to about 1 week (w), about 1 week to about 4 weeks, about 1 month to about 6 months, more than about 6 months, and any range between any two of the values.

[0015] In some embodiments, the object, article or composition achieves a steady state of mass over a period selected from about 5 seconds to about 30 seconds, about 30 seconds to about 1 minute, about 1 minute to about 10 minutes, about 10 minutes to about 30 minutes, about 30 minutes to about 1 hour, about 1 hour to about 3 hours, about 3 hours to about 12 hours, about 12 hours to about 24 hours, about 24 hours to about 1 week (w), about 1 week to about 4 weeks, about 1 month to about 6 months, greater than about 6 months, and any range between any two of these values.

[0016] As used herein, "steady state of mass" includes the state where the mass of a composition or article remains constant even when incubated in water.

[0017] This application incorporates by reference each of the following references in their entirety: (a) U.S. Provisional Application No. 63 / 185,293, entitled "USE OF FUNCTIONALIZED AND NON-FUNCTIONALIZED ECMS, ECM FRAGMENTS, PEPTIDES AND BIOACTIVE COMPONENTS TO CREATE CELL ADHESIVE 3D PRINTED OBJECTS," filed on May 6, 2021, and U.S. nonprovisional and / or PCT applications of the same title, filed on May 6, 2022; (b) U.S. Provisional Application No. 63 / 185,302, entitled "MODIFIED 3D-PRINTED OBJECTS AND THEIR USES," filed on May 6, 2021, and U.S. nonprovisional and / or PCT applications of the same title, filed on May 6, 2022; (c) U.S. Provisional Application No. 63 / 185,302, entitled "PHOTOCURABLE 3D PRINTED OBJECTS AND THEIR USES," filed on May 6, 2021, and U.S. nonprovisional and / or PCT applications of the same title, filed on May 6, 2022; No. 63 / 185,305, entitled "REINFORCEMENT OF 3D PRINTED HYDROGEL OBJECTS," filed on May 6, 2022, and a U.S. non-provisional application and / or PCT application of the same title; (d) U.S. Provisional Application No. 63 / 185,299, entitled "ADDITIVE MANUFACTURING OF HYDROGEL TUBE FOR BIOMEDICAL APPLICATIONS," filed on May 6, 2021, and a U.S. non-provisional application and / or PCT application of the same title, filed on May 6, 2022; (e) U.S. Provisional Application No. 63 / 185,298, entitled "MICROPHYSIOLOGICAL 3-D PRINTING AND ITS APPLICATIONS," filed on May 6, 2021, and a U.S. non-provisional application and / or PCT application of the same title, filed on May 6, 2022.

[0018] composition Certain embodiments of the present disclosure relate to hydrophilic monomer(s) and / or polymers, hydrophobic monomer(s) and / or polymers, short-chain crosslinker(s), photoinitiators, solvents, and / or combinations thereof. In some embodiments, these compositions are printable, e.g., can be used in a 3D printer.

[0019] Some embodiments include a printable composition comprising about 1 weight percent (wt%) to about 40 wt% of one or more hydrophilic monomers; a swelling control agent selected from a hydrophobic monomer, a short chain crosslinker, and combinations thereof. The composition can include about 0.01 wt% to about 2 wt% of a photoinitiator and / or 0 wt% to about 75 wt% of a vehicle comprising a protic solvent, based on the weight of the printable composition.

[0020] The hydrophilic monomer of the present disclosure is not particularly limited as long as it is suitable for the intended purpose. In some embodiments, the hydrophilic monomer comprises an acrylate or methacrylate moiety and a hydrophilic side chain attached to the (meth)acrylate. In some embodiments, the hydrophilic monomer is water-soluble, e.g., the monomer or homopolymer is water-soluble. A preferred embodiment of the hydrophilic monomer is hydroxy C 1-2 Alkyl (meth)acrylate, Poly(alkylene oxide) alkyl ether (meth)acrylate, N-hydroxy C 1-2In some embodiments, the composition may comprise one or more of: alkyl(meth)acrylamides, alkyl(meth)acrylamides, and mixtures thereof. In further embodiments, the hydrophilic monomer comprises one or more of: poly(ethylene glycol) methyl ether acrylate (PEGMEA), poly(ethylene glycol) methyl ether methacrylate, poly(propylene glycol) methyl ether acrylate, poly(propylene glycol) methyl ether methacrylate, hydroxyethyl acrylate (HEA), N-hydroxyethyl acrylamide (HEAA), hydrophilic acrylate, hydrophilic vinyl, hydrophilic nonionic, hydrophilic ionic, grafted hydrophilic, hydrophobic acrylate, hydrophobic vinyl, hydrophobic nonionic, hydrophobic ionic, grafted hydrophobic, or mixtures thereof. In some embodiments, the composition may comprise a peptide, a cleavable peptide monomer, a dithiol monomer, a thiol-acrylate, a diacrylate, and a PEG-diacrylate. In certain embodiments, the one or more hydrophilic monomers are selected from the group consisting of PEGMA, HEA, and mixtures thereof. In certain embodiments, the one or more hydrophilic monomers include PEGMA and a second hydrophilic monomer. In some embodiments, the composition includes about 10, 15, 20, 25, or 30% by weight of PEGMA and optionally a second hydrophilic monomer. In some embodiments, the second hydrophilic monomer is less hydrophilic and / or has shorter side chains compared to PEGMA. In some embodiments, the PEGMA includes the following monomers: [ka] Here, a is an integer between 2 and 20 (e.g., 2, 3, 4, 8, 20, etc.). The integer a may be a mixture of single values, for example: [ka] FIG. 1 shows an embodiment of an HPA-PEGMEA brush copolymer.

[0021] In some embodiments, when the swelling control agent is a hydrophobic monomer, the printable composition has a weight ratio of hydrophilic monomer to hydrophobic monomer of about 100:1 to about 1:100. For example, certain embodiments include a weight ratio of hydrophilic monomer to hydrophobic monomer of about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 10:1, about 1:1, about 1:10, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, or about 1:100, or any range between any two values. For example, in some embodiments, the weight ratio of hydrophilic monomer to hydrophobic monomer is about 20:1 to about 1:20, about 15:1 to about 1:15, about 10:1 to about 1:10, about 5:1 to about 1:5, about 3:1 to about 1:3, about 1:1 to about 1:3. These weight ratios of hydrophilic monomer (or polymer) to hydrophobic monomer (or polymer) include, for example, HPA to HEA (or PEGMA) or HBA to HEA (or PEGMA). In some embodiments, hydrophobic and hydrophilic monomers can be used in place of or in addition to the monomers in the same ratios disclosed for the monomers. When a polymer is used in combination with a monomer, the disclosed ratios are the sum of the hydrophobic and hydrophilic, respectively (hydrophilic monomer + hydrophilic polymer: hydrophobic monomer + hydrophobic polymer).

[0022] The hydrophobic monomer of the present disclosure is not particularly limited, so long as it is suitable for the intended purpose. In some embodiments, the hydrophobic monomer comprises an acrylate or methacrylate moiety and a hydrophobic side chain attached to the (meth)acrylate. In some embodiments, the hydrophobic monomer is not water-soluble, e.g., the monomer or homopolymer is not water-soluble. In some embodiments, the hydrophobic monomer is relatively hydrophobic to other monomers in the composition. Non-limiting examples of hydrophobic monomers include hydroxyl C 3-10alkyl (meth)acrylates, or mixtures thereof (e.g., hydroxyethyl methacrylate, hydroxypropyl acrylate (HPA), hydroxypropyl methacrylate, hydroxybutyl acrylate (HBA), hydroxybutyl methacrylate, hydrophilic acrylate, hydrophilic vinyl, hydrophilic non-ionic, hydrophilic ionic, grafted hydrophilic, hydrophobic acrylate, hydrophobic vinyl, hydrophobic non-ionic, hydrophobic ionic, grafted hydrophobic, or mixtures thereof). In some embodiments, C 3-10 Alkyl (meth)acrylate is C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 In some embodiments, the alkyl(meth)acrylate is optionally substituted with a hydrophobic moiety, such as an aryl group or a hydrocarbon group. In some embodiments, the composition comprises a peptide monomer, a cleavable peptide monomer, a dithiol monomer, a thiol-acrylate, a diacrylate, a PEG-diacrylate, and combinations thereof.

[0023] In some embodiments, when the swelling control agent is a short chain crosslinker, the printable composition comprises from about 0.01% to about 10% by weight of the short chain crosslinker. Preferred embodiments include when the printable composition comprises from about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.5, 6., 6.5, 7., 7.5, 8, 8.5, 9, 9.5, or 10 wt.% short chain crosslinker, or any range between any two values. For example, in some embodiments, the printable composition includes from about 0.01 wt.% to about 5 wt.% short chain crosslinker.

[0024] The short-chain crosslinking agent may be, for example, a polymer having a weight average molecular weight (M w ), poly(alkylene oxide) di(meth)acrylate, diethylene glycol di(meth)acrylate, tetraethylene glycol di(meth)acrylate, N,N'-methylene bis(acylamide), (poly)lactic acid di(meth)acrylate, (poly)glycolic acid di(meth)acrylate, (poly)lactic acid coglycolide di(meth)acrylate, (poly)caprolactone di(meth)acrylate, (poly)dioxanone di(meth)acrylate, (poly)fumaric acid di(meth)acrylate, (carboxy)(methyl)cellulose di(meth)acrylate, hyaluronic acid di(meth)acrylate, heparan sulfate di(meth)acrylate, dextran di(meth)acrylate, alginic acid di(meth)acrylate, pectin di(meth)acrylate, or collagen di(meth)acrylate, or a mixture thereof. In some embodiments, the poly(alkylene oxide) di(meth)acrylate comprises poly(ethylene glycol) diacrylate.

[0025] The photoinitiator is not particularly limited. In some embodiments, the photoinitiator is such that it allows for onset times of 0 to 60 seconds. In some embodiments, the photoinitiator includes lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), trimethylbenzoyl-based photoinitiators, diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO nanoparticles) Irgacure class photoinitiators, ruthenium, and riboflavin, or mixtures thereof.

[0026] The printable composition may further comprise one or more of additives including polymers, UV dyes, natural extracellular matrices, peptides, amino acids, growth factors, modified extracellular matrices, extracellular matrix fragments, or mixtures thereof. The solvent is not particularly limited as long as it is capable of 3D printing and / or polymerization. In some embodiments, the solvent is a protic solvent, such as a protic solvent including water, polyethylene glycol, glycol diacrylate derivatives, or mixtures thereof.

[0027] In some embodiments, the printable composition allows for start times of greater than 0 up to about 60 seconds (e.g., about 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 60 seconds). In some embodiments, the printable composition allows for resolutions of up to 100, 50, 25, 25, 1 micron or less in a 3D printer. In some embodiments, the printable composition results in a print composition having a green strength in the range of about 10 kPa to about 1 MPa.

[0028] method Certain embodiments of the present disclosure relate to preparing a three-dimensional article comprising printing a printable composition according to embodiments herein. In some embodiments, the printing produces a three-dimensional organ or organ component. For example, the three-dimensional object can be a mammalian organ, such as a lung, or a mammalian organ component, such as a bronchus. In some embodiments, the printing comprises inkjet printing, extrusion printing, or layer-by-layer printing. In some embodiments, the method further comprises irradiating the printing composition. In some embodiments, the composition is irradiated with a wavelength of about 365 nm to about 405 nm.

[0029] Certain embodiments of the present disclosure relate to a method of manufacturing a three-dimensional article, comprising depositing a layer of a printable composition on a surface to obtain a deposited layer; irradiating the deposited layer; and repeating the depositing and irradiating steps until the deposited layer forms a three-dimensional article, wherein the printable composition is a composition disclosed herein. In some embodiments, the deposited layer is irradiated with a wavelength of about 365 nm to about 405 nm.

[0030] In some embodiments, the printable composition comprises, based on the weight of the printable composition, from about 1 weight percent (wt%) to about 40 wt% of one or more hydrophilic monomers; a swelling control agent selected from a hydrophobic monomer, a short chain crosslinker, and combinations thereof; from about 0.01 wt% to about 2 wt% of a photoinitiator; and from 0 wt% to about 75 wt% of a vehicle comprising a protic solvent, with the proviso that when the swelling control agent is a hydrophobic monomer, the printable composition has a weight ratio of hydrophilic monomer to hydrophobic monomer of from about 20:1 to about 1:20; and when the swelling control agent is a short chain crosslinker, the printable composition comprises from about 0.01 wt% to about 5 wt% of the short chain crosslinker.

[0031] In some embodiments, the three-dimensional article has a swelling percentage of less than about 300% by weight relative to the non-hydrated weight of the three-dimensional article. In some embodiments, the swelling percentage is less than about 300%, 250%, 200%, 175%, 150% by weight relative to the non-hydrated weight of the three-dimensional article. In some embodiments, the swelling percentage is at least about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 50%, 60%, 70%, 80%, 90%, or 100% relative to the non-hydrated weight of the three-dimensional article. The three-dimensional article can also have a swelling percentage within the above values, for example, in some embodiments, the three-dimensional article has a swelling percentage of less than about 1% to about 300% by weight relative to the non-hydrated weight of the three-dimensional article.

[0032] In some embodiments, the method further comprises one or more steps of surface modification, post processing to promote cell adhesion, addition of cells, mechanical stimulation: expansion, contraction, and / or perfusion.

[0033] The present disclosure also includes embodiments of three-dimensional articles produced according to the methods of the present disclosure. EXAMPLES

[0034] The following examples describe certain aspects of some embodiments of the present disclosure to illustrate and provide instruction for those of ordinary skill in the art. The examples are not to be construed as limiting the present disclosure, as they merely provide certain methodologies useful in understanding and practicing some embodiments of the present disclosure.

[0035] 30~45% PEGMEA hydrogel and 25~35% PEGMEA hydrogel A hydrogel was formed by initiating polymerization of the following composition: [Table 1]

[0036] Both compositions were weighed before and after being placed in aqueous buffer overnight. As shown in Figure 2(a), the 30–45% PEGMEA hydrogel swelled uncontrollably when placed in buffer and did not retain its shape; it showed a >300% increase in weight. As shown in Figure 2(b), reducing the PEGMEA content from 30–45% to 25–35% and introducing 1% PEGDA3.4k significantly improved sample shape retention.

[0037] Control of swelling by monomer (2-hydroxypropyl acrylate) Based on the 25–35% PEGMEA hydrogel, further hydrogels were synthesized in which a certain amount of PEGMEA was replaced with hydrophobic 2-hydroxypropyl acrylate (2-HPA). [Table 2]

[0038] As shown in FIG. 3, the swelling values ​​were as follows: 25~35PEGMEA=316.7% 2:1PEGMEA / HPA=240.1% 1:1PEGMEA / HPA=205.3% 25~35HPA=-32.4%

[0039] As shown in Figure 4, other HPA:PEGMEA ratios were investigated to modulate swelling, including 4:1, 2:1, and 3:1. [Table 3] [Table 4]

[0040] As shown in the table below, by varying the brush polymer to monomer ratio, the swelling results could be effectively controlled, and furthermore, this control was reproducible. [Table 5] [Table 6]

[0041] Control of swelling by monomers (HEA C2, HPA C3, HBA C4) Additional polymers were made using other monomers besides HPA, including HBA and HEA, demonstrating that controlled swelling can be achieved with a wide range of monomers. [Table 7]

[0042] FIG. 5 shows that 10PEGMEA containing monomers resulted in the following swelling values: 2HEA=96.21% 2HBA=79.86% 2HPA=75.89%

[0043] Polymers with increasing [HPA / HEA] and [HBA / HEA] ratios were then synthesized using the following compositions: [Table 8] [Table 9] [Table 10] [Table 11]

[0044] Figure 6 shows the swelling versus [HPA / HEA] content, and Figure 7 shows the swelling versus [HBA / HEA] content. As can be seen, control of swelling can be achieved by varying the ratio of hydrophobic to hydrophilic monomer content in the polymer.

[0045] Control of swelling by short crosslinker N,N'-methylenebisacrylamide (MBAA) Formulations of 25-35 PEGMEA without additional crosslinker and with various amounts of MBAA were synthesized. The compositions used were as follows: [Table 12] [Table 13]

[0046] The 25-35 PEGMEA formulation without any additional crosslinker swelled to 316.73%, as shown in Figure 8. The addition of 0.5% MBAA reduced the swelling by 47.6%, and the further addition of 1% MBAA reduced the swelling by 106.8%.

[0047] Although the present disclosure has been described with reference to specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents substituted without departing from the true spirit and scope of the disclosure as defined by the appended claim(s). In addition, many modifications may be made to adapt a particular situation, material, composition of matter, method, operation or operations to the objective, spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the claims appended hereto. In particular, while a particular method may be described in terms of specific operations performed in a particular order, it will be understood that those operations can be combined, divided, or reordered to form equivalent methods without departing from the teachings of the present disclosure. Thus, unless specifically indicated herein, the order and grouping of operations is not intended to limit the disclosure.

Claims

1. 1. A printable composition comprising: Based on the weight of the printable composition, 1 weight percent (wt %) to 40 wt % of one or more hydrophilic monomers; a swelling control agent selected from a hydrophobic monomer or a combination of a hydrophobic monomer and a short chain crosslinker; A photoinitiator; and a vehicle comprising 0% to 75% by weight of a protic solvent; Including, however, when the swelling control agent is a hydrophobic monomer, the printable composition has a weight ratio of the hydrophilic monomer to the hydrophobic monomer of from 20:1 to 1:20; and When the swelling control agent is a short-chain crosslinker, the printable composition comprises 0.01% to 5% by weight of the short-chain crosslinker. Provided that, the hydrophilic monomer comprises one or more of a hydroxy C 1-2 alkyl (meth)acrylate, a poly(alkylene oxide) alkyl ether (meth)acrylate, an N-hydroxy C 1-2 alkyl (meth)acrylamide, or a mixture thereof; the hydrophobic monomer comprises one or more of hydroxypropyl acrylate (HPA), hydroxypropyl methacrylate, hydroxybutyl methacrylate, or a mixture thereof; and The short-chain crosslinking agent has a weight average molecular weight (Mw) of 400 to 20,000. ), diethylene glycol di(meth)acrylate, tetraethylene glycol di(meth)acrylate, N,N'-methylene bis(acylamide), (poly)lactic acid di(meth)acrylate, (poly)glycolic acid di(meth)acrylate, (poly)lactic acid coglycolide di(meth)acrylate, (poly)caprolactone di(meth)acrylate, (poly)dioxanone di(meth)acrylate, (poly)fumaric acid di(meth)acrylate, (carboxy)(methyl)cellulose di(meth)acrylate, hyaluronic acid di(meth)acrylate, heparan sulfate di(meth)acrylate, dextran di(meth)acrylate, alginic acid di(meth)acrylate, pectin di(meth)acrylate, or collagen di(meth)acrylate, or mixtures thereof.

2. 2. The printable composition of claim 1, wherein the hydrophilic monomer comprises one or more of poly(ethylene glycol) methyl ether acrylate (PEGMEA), poly(ethylene glycol) methyl ether methacrylate, poly(propylene glycol) methyl ether acrylate, poly(propylene glycol) methyl ether methacrylate, hydroxyethyl acrylate (HEA), N-hydroxyethylacrylamide (HEAA), or mixtures thereof.

3. The printable composition of claim 1 , wherein the one or more hydrophilic monomers are selected from the group consisting of PEGMA, HEA, and mixtures thereof.

4. 2. The printable composition of claim 1, wherein the printable composition comprises from 5% to 35% by weight of the one or more hydrophilic monomers, preferably from 5% to 25% by weight of the one or more hydrophilic monomers.

5. 2. The printable composition of claim 1, wherein the weight ratio of hydrophilic to hydrophobic monomers is from 15:1 to 1:15, preferably from 10:1 to 1:10, more preferably from 5:1 to 1:5, even more preferably from 1:1 to 1:

3.

6. The printable composition of claim 1 , wherein the printable composition comprises HPA and HEA present in a weight ratio of 3:1 to 1:

3.

7. The printable composition of claim 1 , wherein the printable composition comprises HBA and HEA present in a weight ratio of 3:1 to 1:

3.

8. The printable composition of claim 1 , wherein the poly(alkylene oxide) di(meth)acrylate comprises poly(ethylene glycol) diacrylate.

9. The printable composition of claim 1 , wherein the printable composition comprises from 0.5% to 3% by weight of the short chain crosslinker.

10. 2. The printable composition of claim 1, wherein the photoinitiator comprises lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), a trimethylbenzoyl-based photoinitiator, diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO nanoparticles), ruthenium, riboflavin, or a mixture thereof.

11. 10. The printable composition of claim 1, wherein the printable composition further comprises one or more of additives including polymers, UV dyes, natural extracellular matrices, photoinitiators, peptides, amino acids, growth factors, modified extracellular matrices, extracellular matrix fragments, or mixtures thereof.

12. The printable composition of claim 11 , wherein the protic solvent comprises water, polyethylene glycol, or a mixture thereof.

13. 13. A method of preparing a three-dimensional article, comprising printing the printable composition of claim 1 to produce said three-dimensional article.

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