3D printing compositions for biomaterials

Abstract

A resin composition for 3D printing of biomaterials, comprising: (i) a compound of the general formula (-AB-): n (ii) at least one photoinitiator; and (iii) at least one light-blocking agent.

Description

[Technical Field]

[0001] The present invention relates to 3D printing compositions for biomaterials, more particularly to 3D printing compositions for biocompatible implants, methods of printing (e.g., biocompatible implants) using 3D printing compositions, biomaterials obtained thereby, uses of biomaterials, and methods of using biomaterials. [Background technology]

[0002] Over the past 50 years, biomaterials have been widely used to replace and / or restore the function of traumatic tissue or organs, or degenerated tissue or organs, and various forms of implants or other medical devices have been developed based on them. Three-dimensional (3D) printing, also known as additive manufacturing, can be used in the production of implants and other medical devices. Implants and medical devices include implantable structures such as skeletons, stents, and structural and support components. One advantage of 3D printing is the flexibility in defining parameters for creating bespoke structures that can be characterized for the end user. Another advantage is the ability to create complex structures at high resolution. This makes it possible to fabricate structures with microstructural parameters from computer-generated designs, which is particularly useful in the field of biomaterials, especially in the field of implants or other medical devices.

[0003] According to known 3D printing methods, the construction of three-dimensional structures is typically carried out layer by layer in a stepwise manner, including, for example, extrusion, direct energy deposition, powder solidification, photopolymerization, and sheet lamination. In particular, layer formation is carried out by solidification of photocurable resins under the action of visible or UV light irradiation. Alternatively, three-dimensional structures can be created continuously from liquid interfaces (see, for example, International Publication No. 2014126837 or U.S. Patent No. 7892474). All of these 3D printing methods utilize the properties of the 3D printing composition to define the microstructural parameters and, in some cases, the biochemical properties of the printed structure. Therefore, the properties of a 3D printed structure are limited not only by the capabilities of the printing method but also by the printing composition used. Compositions currently used in 3D printing of implantable structures include biodegradable polymer materials such as polylactic acid (PLA), poly-1-lysine (PLL), poly(lactic acid-co-glycolic acid) (PLGA), and poly-ε-caprolactone (PLC). While these polymers possess advantageous properties, there are still limitations to the achievable resolution of structures created by 3D printing these materials. Furthermore, many of these compositions are not photocurable and therefore can only be printed using a limited number of 3D printing techniques, and thus cannot be used with stereolithography (SLA) or digital photolithography (DLP).

[0004] High resolution is particularly desirable for biomaterials, especially implants or other medical devices, as it allows for enhanced properties such as elasticity, flexibility, or porosity, and limits their impact on cellular responses. Increasingly small structures are also possible at higher resolutions, which is a critical requirement for implantable structures. The printing resolution achieved is usually determined by the physicochemical properties of the equipment used and the resin used. An ideal biomaterial needs to be relatively inert, resistant to mechanical shock and torsion, and biodegradable. Biodegradability is particularly relevant to the repair or replacement / transplantation of damaged tissue, thereby ensuring that the presence of the structure in the body is temporary. The repair of nerve tissue is one example. If a nerve is severed or damaged, a biocompatible nerve conduit can be introduced to provide a guide for nerve regrowth (e.g., Anderson et al., 2015, Crit. Rev. Biomed. Eng., 43, 131-159). The nerve conduit may also contain nerve grafts used to replace any damaged or lost nerve tissue, and therefore the ability to accommodate and retain tissue, cells, supporting growth factors, and / or pharmaceutical compositions is highly desirable. Thus, the ability to specify and control both the microstructure and nanostructure, and in some cases the composition, of biocompatible implants such as nerve conduits is increasingly needed.

[0005] Methods for 3D printing high-resolution biocompatible implants are being investigated. International Publication No. 2016176444 describes a method for 3D printing biomedical devices using photocurable polymer-based inks containing known biodegradable polymers in the presence of UV absorbers. This publication highlights the need to rapidly fabricate microstructures such as stents with high fit. However, this method does not address the drawbacks of using these types of polymers, including the difficulty in achieving precision at the microstructure level and post-processing product defects. Yeh, et al., 2016, Biofabrication (8), 1-10 describes the production of a skeleton with increased elastic properties using acrylicated polyglycerol sebacate (Acr-PGS). This describes the synthesis and blending of two Acr-PGS macromers. Macromers with excessively high viscosity resulted in a cracked and brittle product, while those with excessively low viscosity lost structural resolution. Therefore, there remains a need for improved, commercially viable polymer-based compositions for 3D printing that can generate high-resolution structures while maintaining the mechanical tensile strength and stability required for biomaterials, particularly biocompatible and biodegradable implants. Furthermore, for applications where thin structures must be mechanically stable and high resolution must be maintained during implantation, materials that decompose through surface erosion and exhibit minimal swelling are particularly necessary and attractive. [Overview of the project]

[0006] The present invention relates to a resin composition for 3D printing for biomaterials, (i) General formula (-AB-) n A prepolymer comprising polymer units of (wherein A represents a substituted or unsubstituted ester, B represents a substituted or unsubstituted acid ester containing at least two acid ester functional groups, and n represents an integer greater than 1), (ii) at least one photoinitiator, (iii) at least one light-blocking agent and The present invention provides a composition containing [a certain substance]. The present invention also relates to a method for 3D printing biomaterials, (a) The step of 3D printing the resin composition of the present invention, (b) A step of washing the 3D printed composition with a solvent This provides a method that includes [something]. After washing, additional steps may be performed to post-cur the sample, for example, by using temperature or light.

[0007] Step (a) of the 3D printing method is: (i) A step of delivering a layer of the resin composition of the present invention based on printing parameters, (ii) Exposing a layer of the resin composition of the present invention to light to cure the resin polymer and produce a solidified resin layer, (iii) Repeat steps (i) and (ii) so that each continuous layer is stacked on top of the previous layer to obtain a 3D printed composition. It may include. The present invention also provides a biomaterial, preferably a biocompatible implant, obtained by the method of the present invention. The present invention also provides methods for repairing or supporting tissue. According to one embodiment, this relates to a method comprising applying the biomaterial of the present invention, preferably a biocompatible implant, to nerve tissue. According to another embodiment, this relates to a method comprising applying the biomaterial of the present invention, preferably a biocompatible implant, to soft tissue (including, for example, breast tissue and skin). According to yet another embodiment, this relates to a method comprising applying the biomaterial of the present invention, preferably a biocompatible implant, to bone tissue.

[0008] The present invention further provides a method for producing biomaterials obtained by the method of the present invention, preferably biocompatible implants, for various applications or functions. These may include, for example, stents, filters, valves, membranes (placeable or not), drug delivery vehicles (such as microneedles and capsules), drains, and the like. Furthermore, it may also be applicable to biocompatible resins / materials for in vitro applications, such as cell assays, lab-on-a-chip, or other organ-on-a-chip devices. [Brief explanation of the drawing]

[0009] [Figure 1] This graph shows the viscosity analysis of the resin composition for 3D printing at different temperatures according to the present invention. [Figure 2] This graph shows the viscosity analysis of 3D printing resin compositions in the presence of various solvents according to the present invention. [Figure 3] This graph shows the elastomer properties of 3D printed resin compositions containing or not containing the solvent according to the present invention. [Figure 4]It is a diagram showing the degree of shrinkage of a 3D printed resin composition with or without a solvent according to the present invention. [Figure 5] It shows a cross-sectional view of a 3D printed resin nerve conduit according to the present invention. [Figure 6] (A) It is a diagram showing a SEM image of a conduit printed with Asiga hardware in which the PGSA composition is not replenished with any solvent. (B) It is a diagram showing a CAD image transmitted to the printer for the production of the object. (1) and (2) represent measurement points. [Figure 7] (A) It is a graph showing the temperature profile of the resin during printing. (B) It is a diagram showing a SEM image of a wrap printed by 3D printing at a low temperature. [Figure 8] It is a diagram showing the geometric shape of a 3D structure with detailed features at the base and top of 1 mm, with or without the presence of BBOT. [Figure 9] A: It shows a 3D printed nerve wrap according to the present invention, B: The wrap can be easily opened with surgical forceps, C: It returns to its original shape when the forceps are removed.

Mode for Carrying Out the Invention

[0010] Composition for 3D Printing The resin composition for 3D printing for a biomaterial according to the present invention is (i) A prepolymer containing polymer units of the general formula (-A-B-) n (wherein A represents a substituted or unsubstituted ester, B represents a substituted or unsubstituted acid ester containing at least two acid ester functional groups, and n represents an integer greater than 1), and (ii) at least one photoinitiator, and (iii) at least one light blocker and contains. The term "prepolymer" means a linear or branched polymer or monomer having the ability to further polymerize or crosslink under appropriate conditions. The prepolymers of the compositions according to the invention can be produced in several ways, including those outlined in WO 2016 / 202984. Prepolymer The prepolymers according to the invention have the general formula (-A-B-) n (where A represents a substituted or unsubstituted ester, B represents a substituted or unsubstituted acid or acid ester containing at least two acid or acid ester functional groups, and n represents an integer greater than 1) and contain polymer units of.

[0011] Component A can be derived from a polyol, such as a diol, triol, tetraol or higher, or any mixture thereof. Suitable polyols include diols such as alkanediols; triols such as glycerol, trimethylolpropane, triethanolamine; tetraols such as erythritol, pentaerythritol; and higher polyols such as sorbitol. Unsaturated diols such as tetradeca-2,12-diene-1,14-diol, or other diols including macromonomer diols such as polyethylene oxide, and N-methyldiethanolamine (MDEA) can also be used. Preferably, the polyol is a substituted or unsubstituted glycerol. Component B can be derived from a polyacid, such as a diacid or higher acid, or any mixture thereof. A wide variety of diacids or higher acids can be used. Exemplary acids include, but are not limited to, glutaric acid (5 carbons), adipic acid (6 carbons), pimelic acid (7 carbons), sebacic acid (8 carbons), and azelaic acid (9 carbons). Exemplary long-chain diacids include diacids having more than 10, more than 15, more than 20, and more than 25 carbon atoms. Non-aliphatic diacids can also be used. For example, modifications of the above diacids having one or more double bonds can be used to produce polyol-diacid copolymers. Preferably, the diacid is a substituted or unsubstituted sebacic acid.

[0012] Polyol-based polymers described in U.S. Patent Application Publication No. 2011-0008277, U.S. Patent No. 7,722,894, and U.S. Patent No. 8,143,042, whose contents are incorporated herein by reference, can also be used as prepolymers for forming elastomer polymer materials. Several substituents, such as amines, aldehydes, hydrazides, acrylates, and aromatic groups, alcohols, and carboxylic acids, can be incorporated into the carbon chain and / or on component A and / or component B. Exemplary aromatic diacids include terephthalic acid and carboxyphenoxypropane. Diacids may also contain substituents. Reactive groups, such as amines and hydroxyls, can be used to increase the number of sites available for crosslinking. Amino acids and other biomolecules can be used to modify biological properties. Aromatic groups, aliphatic groups, and halogen atoms can be used to modify interchain interactions within the polymer.

[0013] The prepolymer may further contain a polyamide or polyurethane main chain. For example, a polyamine (containing two or more amino groups) may be used to react with a polyacid together with or after a reaction with a polyol. An example poly(esteramide) is described in Cheng, et al., Adv. Mater. 2011, 23, 1195-11100, the contents of which are incorporated herein by reference. In other examples, a polyisocyanate (containing two or more isocyanate groups) may be used to react with a polyacid together with or after a reaction with a polyol. An example polyester urethane is described in U.S. Patent No. 2013231412. The mass-average molecular weight of the prepolymer, as measured by gel permeation chromatography with refractive index, may be about 1,000 daltons to about 1,000,000 daltons, preferably about 2,000 daltons to about 500,000 daltons, more preferably about 2,000 daltons to about 250,000 daltons, and most preferably about 2,000 daltons to about 100,000 daltons. The mass-average molecular weight may be less than about 100,000 daltons, less than about 75,000 daltons, less than about 50,000 daltons, less than about 40,000 daltons, less than about 30,000 daltons, or less than about 20,000 daltons. The mass-average molecular weight can be approximately 1,000 to 10,000 daltons, 2,000 to 10,000 daltons, 3,000 to 10,000 daltons, 5,000 to 10,000 daltons, or 10,000 daltons. Preferably, it is approximately 3,000 daltons.

[0014] The term "about" in this specification means within 10%, preferably within 8%, and more preferably within 5% of a given value or range. According to certain embodiments, "about X" means X. The prepolymer may have a polydispersibility of less than 20.0, more preferably less than 10.0, more preferably less than 5.0, and even more preferably less than 2.5, as measured by gel permeation chromatography with refractive index. Preferably, it is about 2.5. The prepolymer may have a melt viscosity at 80°C of 100 to 2000 cP, more preferably 200 to 1000 cP, and even more preferably 300 to 500 cP. The prepolymer may have an acid value of 1 to 200 mg KOH / g polymer, more preferably 10 to 100 mg KOH / g polymer, and even more preferably 50 to 100 mg KOH / g polymer. Preferably, it is about 80 mg KOH / g polymer. The molar ratio of polyol to polyacid in the prepolymer can be 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or 1:1. The molar ratio of polyol to polyacid can also be 2:3, 3:2, 3:4, or 4:3. The polymer may also be the result of a mixture of two or more different ratios. Preferably, it is about 1:1.

[0015] Activated prepolymer The prepolymer of the present invention is preferably activated. It can be activated by introducing functional groups that can react or be reacted to form crosslinks. The prepolymer is activated by reacting one or more functional groups on the prepolymer main chain with one or more functional groups that can react or be reacted to form crosslinks and result in a cured polymer. Suitable functional groups to be activated on the prepolymer main chain include hydroxyl groups, carboxylic acid groups, amines, and combinations thereof, preferably hydroxyl and / or carboxylic acids. Free hydroxyl or carboxylic acid groups on the prepolymer can be activated by functionalizing the hydroxyl group at a portion that can form crosslinks between polymer chains. The group to be activated may be a free hydroxyl or carboxylic acid group on portion A and / or portion B of the prepolymer.

[0016] Free hydroxyl groups or carboxylic acid groups can be functionalized with various functional groups, such as vinyl groups. Vinyl groups can be introduced by various techniques known in the art, such as vinylization or acrylication. According to the present invention, the vinyl group contains the following structure -CR1=CR2R3 (wherein R1, R2, and R3 are independently selected from the group consisting of H, alkyl such as methyl and ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, urethane, ether, and carbonyl). Preferably, the functional group is an acrylate group or contains an acrylate group. According to the present invention, the acrylate group is a portion containing a substituted or unsubstituted acryloyl group. The acrylate may contain the following group: -C(=O)-CR1=CR2R3 (wherein R1, R2, and R3 are independently selected from the group consisting of H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, urethane, ether, and carbonyl). Preferably, R1, R2, and R3 are H; or R1 is CH3 and R2 and R3 are H; or R1 and R2 are H and R3 is CH3; or R1 and R2 are H and R3 is phenyl.

[0017] Vinyl groups can also be incorporated into the main chain of the prepolymer using free carboxyl groups on the prepolymer. For example, hydroxyethyl methacrylate can be incorporated through the COOH groups of the prepolymer using carbonyl diimidazole activation chemistry. The degree of activation may vary, and to achieve optimal best performance characteristics at room temperature or high temperatures up to 40°C, preferably 37°C, it may be 0.2 to 0.9 mol / mol polyacid or polyol, preferably 0.3 to 0.8 mol / mol polyacid or polyol, most preferably 0.4 to 0.6 mol / mol polyacid or polyol, for example, 0.5 mol / mol polyacid or polyol. It is most preferable when the degree of activation is as described above and the reactive functional group is an acrylate, i.e., the degree of acrylication is as described above.

[0018] The activated prepolymer is preferably of general formula (I): [ka] [In the formula, n and p each independently represent an integer of 1 or more, and R2 in each unit represents hydrogen or a polymer chain or -C(=O)-CR3=CR4R5 (wherein R3, R4, and R5 are independently selected from the group consisting of H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, urethane, ether, and carbonyl)] It has.

[0019] Preferably, R3, R4, and R5 are H; or R3 is CH3 and R4 and R5 are H; or R3 and R4 are H and R5 is CH3; or R3 and R4 are H and R5 is phenyl. Preferably, p is an integer between 1 and 20, more preferably between 2 and 10, and even more preferably between 4 and 10. The most preferable case is when p = 8. The preferred prepolymer has the following structure: [ka] (In the formula, n represents an integer greater than or equal to 1.) It has. In addition to acrylates or other vinyl groups, other agents can be used to activate the prepolymer. Examples of such agents include, but are not limited to, glycidyl, epichlorohydrin, triphenylphosphine, diethyl azodicarboxylate (DEAD), diazirine, divinyl adipate, and divinyl sebacate, with the use of enzymes as catalysts, phosgene-type reagents, dichlorides, bis-anhydrides, bis-halides, metal surfaces and combinations thereof. Agents may further include isocyanates, aldehydes, epoxy, vinyl ethers, thiols, DOPA residues, or N-hydroxysuccinimide functional groups.

[0020] The activated prepolymer can be further reacted with one or more additional materials to modify the crosslinking between polymer chains. For example, one or more hydrogels or other oligomers or monomers or polymer precursors (e.g., precursors that can be modified to contain acrylate groups) before or during curing / crosslinking, such as poly(ethylene glycol), dextran, chitosan, hyaluronic acid, alginates, acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, methyl acrylate, ethyl acrylate, acrylonitrile, n-butanol, methyl methacrylate, acrylic anhydride, methacrylic anhydride, and TMPTA, trimethylol trimethacrylate. Propane, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, ethylene glycol dimethacrylate, dipentaerythritol pentaacrylate, Bis-GMA (bisphenol A glycidal methacrylate), and TEGDMA (triethylene glycol dimethacrylate), sucrose acrylate, and other acrylate-based precursors; other thiol-based precursors (monomers or polymers); other epoxy-based precursors; and combinations thereof can be reacted with acrylic prepolymers (e.g., PGSA).

[0021] The activated prepolymer may be manufactured in the presence of a colorant and / or in combination with a colorant. Preferred examples of colorants are those recommended by the FDA for use in medical devices, pharmaceutical products, or cosmetics. See http: / / www.fda.gov / ForIndustry / ColorAdditives / ColorAdditiveInventories / . More preferably, the agent is FD&C1. Preferably, according to the present invention, it is desirable to control the presence of anhydrides in the composition. Preferably, according to the present invention, the molar ratio of the total content of grafted anhydrides in the composition is less than 0.05 mol / mol polyacid as measured by nuclear magnetic resonance (NMR). Preferably, there are no grafted anhydrides in the composition. More preferably, there are no grafted or ungrafted anhydrides present in the composition.

[0022] The content of grafted anhydride in the composition can be controlled during synthesis by ethanol capping or by any other nucleophilic substitution reaction. These chemical reactions are well known in the art. Suitable reagents for this reaction include alcohols, amines, or sulfhydryl compounds. The addition of ethanol is preferably carried out at a temperature in the range of 30 to 50°C, preferably 35 to 45°C, for example, 40°C. The duration of the ethanol capping step is preferably between 10 and 40 hours, more preferably between 24 hours. The volume ratio of polymer solution (about 10% w / v) to ethanol is in the range of 20:1, more preferably 10:1, and even more preferably 5:1. The method for producing the activated prepolymer of the present invention is: i) Polycondensation of a first component containing two or more functional groups of the general formula -OR (wherein R of each group is independently hydrogen or alkyl) and a second component containing two or more acid ester functional groups, ii) Activation of the prepolymer prepared by step i), iii) Control of the anhydrous content, as desired. iv) Blocking of free hydroxyl groups, and / or optionally v) Purification of the activated prepolymer prepared by step ii) and / or iii) and / or iv). Includes. The first component may be a polyol or a mixture of polyols, such as a diol, triol, tetraol, or more. Suitable polyols include diols, such as alkanediols; triols, such as glycerol, trimethylolpropane, and triethanolamine; tetraols, such as erythritol and pentaerythritol; and higher polyols, such as sorbitol. Other diols, including unsaturated diols, such as tetradeca-2,12-diene-1,14-diol, or macromonomer diols such as polyethylene oxide, and N-methyldiethanolamine (methyldiethanoamine) (MDEA) can also be used. Preferably, the polyol is substituted or unsubstituted glycerol.

[0023] The second component may be a polyacid, such as a diacid or a higher acid, or a mixture of diacids and / or polyacids. A wide variety of diacids or higher acids can be used. Exemplary acids include, but are not limited to, glutaric acid (5 carbon atoms), adipic acid (6 carbon atoms), pimelic acid (7 carbon atoms), sebacic acid (8 carbon atoms), and azelaic acid (9 carbon atoms). Exemplary long-chain diacids include diacids having more than 10, more than 15, more than 20, and more than 25 carbon atoms. Non-aliphatic diacids can also be used. For example, variations of the above diacids having one or more double bonds can be used to produce polyol-diacid copolymers. Exemplary aromatic diacids include terephthalic acid and carboxyphenoxypropane. Diacids may also contain substituents, such as amine and hydroxyl substituents. Preferably, the diacid is a substituted or unsubstituted sebacic acid.

[0024] The first and second components are added together in a molar ratio of 0.5:1 to 1.5:1, preferably 0.9:1.1, and most preferably 1:1. When the first component is glycerol and the second component is sebacic acid, and they are added in a 1:1 molar ratio, there are 2 carboxyl groups on the sebacic acid compared to 3 hydroxyl groups on the glycerol. Therefore, the extra hydroxyl groups on the glycerol are utilized during the activation step. The conditions for step i) are not particularly limited, but may include a temperature range of 100 to 140°C, preferably 120 to 130°C, an inert atmosphere preferably containing nitrogen, and under vacuum. The activator in step ii) is preferably an acrylicating agent containing an acrylate group which is a moiety containing a substituted or unsubstituted acryloyl group. The acrylate may contain the following group: -C(=O)-CR1=CR2R3 (wherein R1, R2, and R3 are independently selected from the group consisting of H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, urethane, ether, and carbonyl).

[0025] Preferably, R1, R2, and R3 are H; or R1 is CH3 and R2 and R3 are H; or R1 and R2 are H and R3 is CH3; or R1 and R2 are H and R3 is phenyl. Most preferably, the acrylicating agent is acryloyl chloride. During the acrylication process, an anhydride may be formed as a result of the reaction between the acrylicated monomer and any carboxylic acid group. According to a preferred embodiment, the anhydride content is controlled in step (iii) by ethanol capping or by any other nucleophilic substitution reaction. Suitable reagents for step (iii) include alcohols, amines, or sulfhydryl compounds. The addition of ethanol is preferably carried out at a temperature in the range of 30 to 50°C, preferably 35 to 45°C, for example, 40°C. The duration of the ethanol capping step is preferably between 10 and 40 hours, more preferably between 24 hours. The volume ratio of polymer solution to ethanol is in the range of 20:1, more preferably in the range of 10:1, and even more preferably in the range of 5:1.

[0026] Hydroxyl may be blocked or protected (step iv). Techniques known in the art can be applied. Preferably, hydroxyl is blocked through an acylation reaction using a compound such as ethanol chloride. The residual level of the grafted anhydride may also preferably be at a level of less than 0.05 mol / mol of polyacid. The formation of the grafted anhydride may also be prevented by blocking any free carboxylic acid group before activation, i.e., step (iv) is performed before step (ii). Steps i) to iv) can be carried out in the presence of one or more solvents or catalysts, examples of which include dichloromethane (DCM), ethyl acetate (SiO2), dimethylaminopyridinine (DMAP), and triethylamine (TEA), or any combination thereof.

[0027] The purification step v) is carried out to ensure that any solvents and unreacted products are reliably removed from the prepolymer prepared by steps iii) and iv). This step may include a filtration and / or water washing step. When step v) includes a water washing step, conditions that allow for rapid phase separation between the organic phase and the aqueous phase should be preferred. For example, phase separation during water washing can be improved by using salts solubilized in the aqueous phase. Examples of salts include, but are not limited to, sodium chloride and sodium bicarbonate. Alternatively, salts produced during the reaction can be removed by filtration using organic solvents such as ethyl acetate, n-methyltetrahydrofuran, and tetrahydrofuran. The purification step also preferably follows one or more, more preferably all, of the following steps, which include the addition of a free radical inhibitor, such as butylated hydroxytoluene (BHT), monomethyl ether hydroquinone (MEHQ), phenylbutyl nitrone (PBN), and / or a photoinitiator, such as Irgacure 2595 or diphenyl-trimethyl-phosphine oxide (TPO), preferably solvent evaporation and / or extraction by supercritical CO2 to ensure efficient solvent and impurity removal without interfering with the activation of the prepolymer.

[0028] Preferably, the prepolymer of the composition can be photopolymerized and / or photocured by light, preferably UV light. The prepolymer becomes a crosslinked polymer material. The composition can be further cured by a Mitsunobu-type reaction, by redox pair-initiated polymerization, for example by benzoyl peroxide, N,N-dimethyl-p-toluidine, ammonium persulfate, or tetramethylenediamine (TEMED), or by a Michael-type addition reaction using a bifunctional sulfhydryl compound. The term "printing" encompasses the curing of the composition. Photoinitiator Preferably, the photoinitiator of the composition according to the present invention is diphenyl-trimethyl-phosphine oxide (TPO). Other examples of suitable photoinitiators include 2,4,6-trimethylbenzoyldiphenylphosphine oxide, 2-dimethoxy-2-phenylacetophenone, 2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure 2959), 1-hydroxycyclohexyl-1-phenyl ketone (Irgacure 184), 2-hydroxy-2-methyl-1-phenyl-1-propanone (Darocur 1173), 2-benzyl-2-(dimethylamino)(dimehylamino)-1-[4-morpholinyl)phenyl]-1-butanone (Irgacure 369), methylbenzoyl formate (Darocur MBF), and oxyphenyl-acetic acid-2-[2-oxo-2-phenylacetoxy-ethoxy]-ethyl ester (Irgacure This includes, but is not limited to, 754), 2-methyl-1-[4-(methylthio)phenyl]-2-(4-morpholinyl)-1-propanone (Irgacure 907), diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide (Darocur TPO), phosphine oxide, phenylbis(2,4,6-trimethylbenzoyl) (Irgacure 819), and combinations thereof. The photoinitiator may preferably have an absorption wavelength with a peak in the range of 365 to 420 nm.

[0029] According to another embodiment, the photoinitiator is sensitive to visible light (usually blue or green light). Examples of visible light-sensitive photoinitiators include, but are not limited to, eosin Y disodium salt, N-vinyl-2-pyrrolidone (NVP), triethanolamine, and camphorquinone. Although the photoinitiator Irgacure 2959, which causes minimal cytotoxicity (cell death) across a wide range of mammalian cell types and species, may be used, this risk can be mitigated by using non-toxic doses. Preferably, the photoinitiator content is 0.1% to 1% w / w of the prepolymer. Preferably, the concentration of the photoinitiator is in the range of 1,000 to 10,000 ppm, preferably 4,000 to 6,000 ppm, and most preferably 5,000 to 6,000 ppm. In some embodiments, the photoinitiator is TPO at a concentration of 5,048 ppm. In this embodiment, the solvent may not be present in the composition. In some embodiments, the photoinitiator is TPO at a concentration of 5,113 to 5,213 ppm, optionally 5,113 ppm, or optionally 5,213 ppm. In this embodiment, the solvent may be present in the composition, and the solvent may optionally be 12% 1-propanol.

[0030] Light-blocking agent In this specification, the term “light-blocking agent” includes any single compound or combination of compounds that absorb or reflect light rays when incorporated into the compositions of the present invention to reduce the transmission of light rays. “Light-blocking agents” are well known and commercially available. According to a particular embodiment, the “light-blocking agent” absorbs or reflects light rays selected from the group consisting of blue light rays, infrared light rays and / or ultraviolet light rays. According to a particular embodiment, the "light-blocking agent" absorbs or reflects light rays having wavelengths less than 420 nm, preferably less than 410 nm. According to a particular embodiment, the “light-blocking agent” absorbs or reflects light rays having a wavelength of 405 nanometers ± 7%. According to a particular embodiment, the "light-blocking agent" absorbs or reflects light rays having wavelengths less than 500 nm, preferably less than 480 nm. According to a particular embodiment, the "light-blocking agent" absorbs or reflects light rays having wavelengths greater than 650 nm.

[0031] According to a particular embodiment, the "light-blocking agent" absorbs or reflects all light rays. In a preferred embodiment, the “light-blocking agent” is a “UV-blocking agent.” In this specification, the term “UV-blocking agent” includes any single compound or combination of compounds that absorb or reflect UV light, when incorporated into the composition of the present invention, to reduce the transmission of UV light. A synonym for “UV-blocking agent” is “ultraviolet absorber or stabilizer.” “UV-blocking agents” are well known and commercially available. The presence of a UV blocker controls the depth of light transmission and scattering, enabling higher resolution of printed products. Preferably, the UV blocker has an absorption wavelength with a peak in the 350-500 nm range. The UV blocker may also be screened to determine the optimal concentration before performing 3D printing. A preferred UV-blocking agent according to the present invention is 2,5-bis(5-tert-butyl-benzoxazole-2-yl)thiophene (BBOT). Other examples of suitable UV-blocking agents include, but are not limited to, 2,2'-(2,5-thiophendiyl)bis(5-tert-butylbenzoxazole) (Mayzo OB+), 2-ethyl-9,10-dimethoxyanthracene, 1,4-bis(2-methylstyryl)benzene, oxybenzone, dioxybenzone, and 4-hydroxybenzophenone. Alternatively, nanoparticles or other light-blocking particles may be used instead of certain chemicals.

[0032] Preferably, the UV-blocking agent content is 0.02% to 0.3% w / w of the prepolymer. Preferably, the concentration of the UV-blocking agent is in the range of 50 to 2500 ppm, more preferably 500 to 2500 ppm, preferably 1500 to 1800 ppm, and most preferably 1600 to 1700 ppm. In some embodiments, the UV-blocking agent is BBOT at a concentration of 1679 ppm. In this embodiment, the solvent may not be present in the composition. In some embodiments, the UV-blocking agent is at a concentration of 1800 to 1823 ppm, optionally 1800 ppm, optionally 1823 ppm, and optionally 1809 ppm. In this embodiment, the solvent may be present in the composition and may optionally be 12% 1-propanol.

[0033] solvent The inventors have further understood that biocompatible polymers such as PGSA may exhibit increased viscosity at room temperature. Room temperature is generally the operating temperature for many 3D printing platforms. Therefore, according to one particular embodiment, the composition further comprises at least one solvent. More specifically, this solvent is added to the composition when the printing step is carried out at room temperature (e.g., below 30°C, e.g., 25°C). According to a preferred embodiment, the solvent has a boiling point of at least 90°C, more preferably at least 100°C, and even more preferably at least 160°C. One preferred solvent is 1-propanol, which, for a particularly preferred PGSA, demonstrates good solubility of the prepolymer and no swelling while maintaining optimal viscosity at room temperature. Other preferred solvents are ethylene glycol, propylene glycol, and N-methyl-2-pyrrolidone, which have higher boiling points (197.3°C, 188°C, and 202°C, respectively). These prevent evaporation at room temperature and maintain optimal viscosity. 3D products obtained using a solvent in the composition have good structural properties such as high stability and resolution. Other suitable solvents include, but are not limited to, glycerol, methanol, dimethyl sulfoxide, ethanol, nitromethane, dimethylformamide, dimethyl fumarate, isopropanol, acetonitrile, dioxane, pyridine, xylene, and combinations thereof.

[0034] The solvent content may be 50% w / w or less of the prepolymer, preferably 5% to 20% w / w, and particularly 12%. In a preferred embodiment, at a printing temperature of 25°C, the composition contains 25% ethanol w / w of the prepolymer and has a viscosity of 220 cP or less. In another preferred embodiment, at a print temperature of 25°C, the composition contains 15% 1-propanol w / w of the prepolymer and has a viscosity of 1300 cP or less. In a preferred embodiment, at a print temperature of 25°C, the composition contains 25% DMSO w / w of the prepolymer or polymer and has a viscosity of 1850 cP or less. According to another embodiment, the composition of the present invention does not contain any solvent. The inventors have further shown that the viscosity of the composition of the present invention can be reduced by increasing the temperature during the printing step (e.g., to a temperature of about 30°C to about 40°C, more specifically to about 35°C) as needed (e.g., to improve printability), particularly when no solvent is present in the composition. Different combinations of solvent and printing temperature can also be considered within the scope of the present invention.

[0035] According to one embodiment, the viscosity of the composition is in the range of 10 to 30,000 cP, preferably in the range of 100 to 25,000 cP, and more preferably in the range of 7,000 to 14,000 cP. Preferably, the viscosity of the composition is in the range of 100 to 6000 cP. According to a preferred embodiment, the viscosity of the composition is measured at 25°C. Preferably, for compositions with a viscosity of 11,000 cP or less, a print temperature of 30°C is desirable; for viscosity of 4,300 cP or less, 40°C is desirable; for viscosity of 2,200 cP or less, 50°C is desirable; for viscosity of 900 cP or less, 65°C is desirable; and for viscosity of 200 cP or less, 100°C is desirable. Viscosity analysis can be performed using a Brookfield DV-II+Pro viscometer equipped with a 2.2 mL chamber and an SC4-14 spindle. The analysis speed varies from 5 to 80 rpm. The composition may also contain radiopaque agents or contrast agents, such as iodioxinal, ioxagreate, iohyexyl, iopromide, or combinations thereof. This allows the implant to be visualized in its location using known imaging techniques.

[0036] others The composition may further contain one or more pharmaceuticals, therapeutic agents, prophylactic agents, and / or diagnostic agents. The agents may be small molecule agents, for example, with molecular weights less than 2000, 1500, 1000, 750, or 500 Da, and may be biomolecules, such as peptides, proteins, enzymes, nucleic acids, polysaccharides, growth factors, cell adhesion sequences, such as RGD sequences or integrins, extracellular matrix components, or combinations thereof. These may be agents that support cytological growth and survival. Exemplary classes of small molecule agents include, but are not limited to, anti-inflammatory agents, immunosuppressants, neuroprotective agents, antithrombotic agents, agents that support cytological growth and survival, analgesics, antimicrobial agents, and combinations thereof. Exemplary growth factors include, but are not limited to, neurotrophic factors, TGF-β, acid fibroblast growth factor, basic fibroblast growth factor, epidermal growth factor, IGF-I and II, vascular endothelial growth factor, bone morphogenetic protein, platelet-derived growth factor, heparin-binding growth factor, hematopoietic growth factor, peptide growth factors, or nucleic acids and combinations thereof. The compositions may further contain natural polymers and biopolymers comprising extracellular matrix components. Exemplary extracellular matrix components include, but are not limited to, collagen, fibronectin, laminin, elastin and combinations thereof. Proteoglycans and glycosaminoglycans can also be associated with the compositions of the present invention by covalent or non-covalent bonds.

[0037] Functional groups on the prepolymer can be used to covalently bond with one or more drugs, such as small molecule drugs and / or biomolecules. Alternatively, one or more drugs can be physically encapsulated within the 3D printed composition by mixing them with the composition of the present invention before 3D printing and curing the composition in the presence of the drugs. The composition may further contain salts, proteins, or glycans. These can be used, for example, as pore-forming agents to give the structure porosity during implantation. Examples include glycans such as trehalose, glucose, hyaluronic acid, and cyclodextrin. 3D printing methods The method for 3D printing biomaterials according to the present invention is: (a) The step of 3D printing a resin composition according to the present invention, (b) A step of washing the 3D printed composition with a solvent Includes.

[0038] Step (a) of the 3D printing method is: (i) A step of delivering a layer of the resin composition of the present invention based on desired printing parameters, (ii) Exposing a layer of the resin composition of the present invention to light to cure the resin polymer and produce a solidified resin layer, (iii) Repeat steps (i) and (ii) so that each continuous layer is stacked on top of the previous layer to obtain a 3D printed composition. It may include. Alternatively, the resin compositions of the present invention can be further used in a continuous manufacturing process for generating 3D objects (see, for example, the methods disclosed in International Publication No. 2014126837 or U.S. Patent No. 7892474). Preferably, the 3D printing method is digital photopolymerization (DLP). DLP typically requires a vat of photoreactive material selectively exposed to light to create solid layers that are stacked together to form a 3D structure. Other examples of 3D printing methods include, but are not limited to, laser-based stereolithography (SLA), continuous liquid interface fabrication (CLIP), inkjet printing, projection stereolithography, and combinations thereof.

[0039] The 3D printing system is preferably Asiga, 3D Systems, or Envisiontech. Other examples of platforms include, but are not limited to, the Autodesk Ember platform. Preferably, vats containing PDMS, Teflon, or fluoropolymer films are used. In 3D printing methods for resins, it is necessary to define printing parameters that take into account the chemical composition of the resin before generating the final structure. Digital representations of biomaterials can be created using computer-aided design (CAD) modeling. These printing parameters can be customized to suit individual bespoke structures, polymer formulations, and / or the mechanical properties of the object, or a library of printing parameters can be created to meet the requirements of, for example, implants for specific medical applications. This promotes a high degree of fit between printed structures. Therefore, other aspects of this method, such as washing, depressurization, or heating, can be adapted to specific implants for specific medical applications.

[0040] Preferably, step (a) is carried out at a temperature ranging from room temperature to 110°C, most preferably 25°C to 95°C, more preferably 35°C to 95°C, and even more preferably 30°C to 60°C. Preferably, the pressure is atmospheric pressure. Step (a) can be carried out at room temperature in the presence of at least one solvent. Examples of suitable solvents include, but are not limited to, glycerol, ethylene glycol, 1-propanol, propylene glycol, methanol, dimethyl sulfoxide, ethanol, nitromethane, dimethylformamide, dimethyl fumarate, isopropanol, acetonitrile, dioxane, N-methyl-2-pyrrolidone (NMP), preferably 5-20% NMP, pyridine, xylene, and combinations thereof. According to a preferred embodiment, the solvent is selected from 1-propanol, ethylene glycol, propylene glycol, and N-methyl-2-pyrrolidone. Step (a) can be carried out in the absence of any solvent. Preferably, step (a) is carried out at an optical wavelength of 365 to 415 nm, most preferably 405 nm. Preferably, the power supply is 20 to 100 mW / cm². 2 Most preferably 100 mW / cm² 2 It is within the range. Preferably, the solvent in step (b) is mixed with the 3D printed composition in a preferred mass ratio at a temperature of 4°C to 40°C. Alternatively, the solvent in step (b) is mixed with the 3D printed composition in a preferred mass ratio at room temperature to 40°C. The solvent can be mixed in a sealed vial by stirring and / or sonication. Alternatively, the solvent is mixed with the composition before 3D printing.

[0041] Preferably, the solvent in step (b) is selected from a class of oxygenated organic solvents, such as alcohols, glycol ethers, methyl acetate, ethyl acetate, ketones, esters, and glycol ether / esters. Suitable solvents include, but are not limited to, isopropyl alcohol, acetone, ethyl acetate, diethyl ether, tetrahydrofuran, dichloromethane, N-methyl-2-pyrrolidone, and dimethyl sulfoxide. According to a preferred embodiment, the solvent in step (b) is ethanol, which is less toxic and easily removed. Step (b) may be performed to remove any uncured resin from the 3D printed composition, to remove excess UV blocker, and / or excess photoinitiator. The printed biomaterial is immersed in a solvent, preferably at a rate of 1 ml of solvent per 10 mg of printed biomaterial. Preferably, the solvent is vortexed, sonicated, and / or dynamically stirred for a period of 18 to 24 hours. Preferably, the solvent is changed 3 to 6 times during step (b).

[0042] Step (b) may remove up to 96% of the UV-blocking agent. Step (b) may remove up to 45% of the photoinitiator. This results in 3D-printed biomaterials (e.g., biocompatible implants) characterized by low toxicity (including cytotoxicity). The method may further include the step of (c) reducing the pressure of the cleaned 3D printed composition. Preferably, the reduction is carried out at less than 50 mbar for at least 1 hour. The inventors have found that if this step is not performed, cracks in the sample may be observed with surprising frequency. This step therefore greatly improves the integrity and resolution of the structure. The method may further include the step of (d) post-curing the 3D printed composition by exposure to light, preferably UV or blue light. The method may further include the step of (e) heating the cleaned 3D printed composition. This step may result in the removal of excess solvent. Step (e) also results in the thermal curing of the printed composition, which allows for enhanced mechanical properties and sample shrinkage, especially if the composition was printed in the presence of a solvent.

[0043] Preferably, the heating in step (e) is carried out in a ramp-like manner to prevent thermal shock and potential cracking. Preferably, step (e) is carried out at a temperature in the range of 120°C to 150°C for 1 to 5 days, most preferably at 120°C to 140°C for 1 to 4 days. Preferably, the 3D printed composition includes printed layers with a planar resolution of 25 μm to 50 μm and an axial resolution of 1 μm to 100 μm, preferably 10 μm to 100 μm, most preferably 50 μm, and even more preferably 10 μm. Preferably, the final printed composition contains less than 150 ppm of solvent, preferably less than 134 ppm (limit of quantification). This results in a printed composition with low toxicity. Preferably, the final printed composition exhibits less than 30% volume shrinkage, more preferably less than 20%, and even more preferably less than 10% volume shrinkage during the 3D printing process and possibly during post-processing. The shrinkage of the printed composition can be used to reduce the overall size of the printed structure while maintaining the same relative dimensions.

[0044] Biomaterials Also provided herein are biomaterials, such as biocompatible implants or other medical devices, that have non-implantable functions and are obtained by methods according to the present invention. The biomaterial of the present invention is preferably sufficiently elastic to withstand the movement of underlying tissues, such as the contraction of the heart and blood vessels. The biomaterial, such as a biocompatible implant, is preferably biodegradable and biocompatible and causes minimal in vivo inflammatory response. The biomaterial is preferably an elastomer. Biodegradability can be evaluated in vitro, for example, in phosphate-buffered saline (PBS) or under acidic or alkaline conditions. Biodegradability can also be evaluated in vivo, for example, in animals such as mice, rats, dogs, pigs, or humans. The rate of degradation can be evaluated in vitro or in vivo by measuring the decrease in mass and / or thickness of the biocompatible implant over time.

[0045] The biomaterial may contain and / or be coated with one or more pharmaceuticals, therapeutic agents, prophylactic agents, and / or diagnostic agents. The agents may be small molecule agents, for example, with molecular weights less than 2000, 1500, 1000, 750, or 500 Da, and may be biomolecules, such as peptides, proteins, enzymes, nucleic acids, polysaccharides, growth factors, cell adhesion sequences, such as RGD sequences or integrins, extracellular matrix components, or combinations thereof. Exemplary classes of small molecule agents include, but are not limited to, anti-inflammatory agents, antithrombotic agents, agents that support cytological growth and survival, analgesics, antimicrobial agents, and combinations thereof. Exemplary growth factors include, but are not limited to, neurotrophic factors, TGF-β, acid fibroblast growth factor, basic fibroblast growth factor, epidermal growth factor, IGF-I and II, vascular endothelial growth factor, bone morphogenetic proteins, platelet-derived growth factor, heparin-binding growth factor, hematopoietic growth factor, peptide growth factors, or nucleic acids and combinations thereof. Exemplary extracellular matrix components include, but are not limited to, collagen, fibronectin, laminin, elastin and combinations thereof. The use of biodegradable materials can lead to the leaching of medication from the implant over time.

[0046] Biomaterials, such as biocompatible implants, can be custom printed according to the target organism receiving the implant. Biomaterials can be custom printed according to the intended application, such as improving the length or flexibility of nerve conduits. Biomaterials can also be custom printed according to the duration for which they are intended to remain in place and / or perform a specific function. The implant may include complex microstructures, such as projected microchannels, ridges, positive and / or negative grooves and / or projections. Preferably, the biomaterial obtained by the method, such as a biocompatible implant, has one or more of the following characteristics: complete recovery after 60% compression (rebound test), complete recovery after 90% bending (three-point bending test), and / or fracture at 20-50% elongation. Preferably, the biomaterial obtained by the method is a biocompatible implant. Preferably, the biocompatible implant obtained by the method is a nerve conduit. Preferably, the implant has a wall thickness of 50 to 500 μm. Biomaterials can be used both internally and externally within the body, and therefore can be used for human or veterinary purposes. Implants may also be used for research or educational purposes. Also provided herein are methods for repairing nerve tissue, which include applying a biomaterial, preferably a biocompatible implant, obtained by a method according to the present invention, to the nerve tissue. The biomaterial may also contain one or more types of cells, such as connective tissue cells, organocytes, muscle cells, nerve cells, and combinations thereof. The material may be seeded with one or more types of tendon cells, fibroblasts, ligament cells, endothelial cells, lung cells, epithelial cells, smooth muscle cells, cardiomyocytes, skeletal muscle cells, pancreatic islet cells, nerve cells, hepatocytes, kidney cells, bladder cells, urothelial cells, chondrocytes, and osteogenic cells. Combinations of cells and material can be used to support tissue repair and regeneration. Biomaterials can perform support functions by being used as tissue supports or skeletons. Such implants may perform functions such as holding or cross-linking two tissues together, or positioning tissues in specific locations inside or outside the body.

[0047] The implant can be covered with cells and / or tissue, such as a nerve graft, and implanted adjacent to or in contact with the damaged nerve. The cells and / or tissue can be cultured on or within the lumen of the implant prior to in vivo conditions, based on commonly known cell culture methods. Implants can also be custom-printed based on desired porosity, elasticity, or shape for optimal cell culture and support. Porosity can be mesoscale (less than 1 μm). The present invention further relates to the use of the composition according to the present invention as a bio-ink. In this case, a colorant may further be included. Next, the present invention will be described with reference to the following embodiments, but the present invention is not limited thereto. [Examples]

[0048] The following describes the production of PGSA based on International Publication No. 2016 / 202984. (Example 1) Solvent-free and solvent-free printing To enable PGSA resin printing, two PGSA resin compositions were prepared. The first was used for printing at high temperatures (e.g., 100-110°C) in the absence of a solvent. The viscosity at different temperatures is shown in Figure 1. A second composition was prepared for printing at room temperature in the presence of a solvent. The viscosity of the PGSA resin compositions in the presence of various solvents is shown in Figure 2. All compositions were included (TPO 5000 ppm and BBOT 1600 ppm range - see below). 405 nm LED, power supply 90 mW / cm 2 The composition was 3D printed at atmospheric pressure using a commercially available Autodesk Ember 3D printer equipped with [specific equipment / features] and employing the digital photopolymerization (DLP) method. The printed parts were then removed from the printer and washed in ethanol to remove uncured resin, BBOT, and TPO. The 3D structures were immersed in an extraction solvent (1 mL / 10 mg structure) and diffusion was promoted by vortexing or dynamic stirring for 18–24 hours. The solvent was changed 3–6 times. The table below shows the results of solvent extraction using different solvents. [Table 1]

[0049] Next, the ethanol was removed using a stepwise method. The first step was solvent evaporation under reduced pressure (less than 50 mbar) for at least one hour. Failure to perform this step resulted in observed cracking of the sample. The second step involved heating at 140°C for four days to remove any remaining solvent. The initial heat lamp prevented thermal shock and potential cracking, and allowed for enhanced mechanical properties. The mechanical properties (elasticity, modulus of elasticity) of the final conduit could be improved by adjusting the post-processing conditions. Some shrinkage may occur when printing in the presence of the tested solvent, 1-propanol. The results are shown in Figures 3 and 4. Figure 5 shows 3D printed products using PGSA alone (containing 5048 ppm TPO and 1679 ppm BBOT) and PGSA with 1-propanol (containing 5113 ppm TPO and 1809 ppm BBOT), which are suitable as implantable nerve conduits. The conduits were washed with ethanol before scanning electron microscopy (SEM) imaging.

[0050] (Example 2) Printing in the absence of solvent A PGSA composition containing 5200 ppm TPO and 1800 ppm BBOT, free of any solvent, is used at atmospheric pressure with a 405 nm LED and a power supply of 70 mW / cm². 2 The print was created using an ASIGA PICO2 HD DLP printer equipped with [specific features / equipment], and employing the digital light processing (DLP) method. The printer chamber temperature was set to 50°C during printing. The 3D printed part (Figure 6) was then removed from the printer and cleaned with ethanol to remove uncured resin, BBOT, and TPO. Scanning electron microscope images of the obtained printed parts were taken. The wall thickness of the object sent to the print was 100 μm, and the wall thickness of the printed part was 131.88 ± 10.71 μm (see "1" in Figure 6). The support of the object sent to the print was 100 μm, and the support of the printed part was 124.67 ± 14.62 μm (see "2" in Figure 6).

[0051] (Example 3) Printing in the absence of solvent A PGSA composition containing 5213 ppm TPO and 1823 ppm BBOT, free of any solvent, was printed using a 3D Systems DLP printer. The initial temperature of the composition in the vat was measured to be 29°C (see section 7A(a) in Figure 7). The viscosity value of this composition at this temperature was 13250 cP. During the 3D printing process, the temperature of the composition initially rose to 35°C due to the long exposure time set for printing the base layer (Figure 7A section (b)). At this temperature, the viscosity of the composition was estimated to be 7859 cP. In section 7A(c) of Figure 7, the temperature profile during printing is reported, and the temperature decreases because the exposure time is shorter than the time set for the base layer. Figure 7B shows the nerve wrap generated under the above conditions. More specifically, this demonstrates that the printing result was successful despite the high viscosity of the PGSA composition at low temperatures.

[0052] (Example 4) Effect of UV blocking agents on the printability of resins To confirm the potential of PGSA as a resin for 3D printing, two PGSA resin compositions were tested. The first formulation was a PGSA composition in the absence of BBOT, while the second formulation was supplemented with 1800 ppm BBOT. Both compositions contained 5000 ppm TPO. 405nm LED, power 70mW / cm 2 The mixture was 3D printed at atmospheric pressure using a commercially available ASIGA PICO2 HD printer equipped with [specific technology / features] and employing the DLP (Digital Light Processing) method. The printed parts were then removed from the printer, washed in ethanol to remove uncured resin, and dried under reduced pressure. The 3D structure, as shown in Figure 8 (drawing), consists of an 8mm x 8mm base with a thickness of 1mm and a series of small detail features with a height of 100μm. The printed 3D structure was placed inside a scanning electron microscope (SEM) to observe the presence of detail features on the base, as shown in Figure 8 (SEM image). Figure 8 shows that detailed features are present on the 3D structure printed with the first formulation, and that detailed features are not present on the 3D structure printed with the second formulation. The base was successfully printed with both formulations.

[0053] (Example 5) Elasticity of 3D-printed biomaterials A PGSA resin composition containing 5213 ppm TPO and 1823 ppm BBOT was printed on a 3D Systems DLP printer without the use of additional solvents. The post-treatment consists of continuous ethanol washing, drying under reduced pressure for 30 minutes, and then heat curing at 140°C for 4 days. As can be seen in Figure 9B, the wrap can be easily opened with surgical forceps, and it returns to its original shape when the forceps are removed (Figure 9C).

[0054] (Example 6) Biocompatibility of 3D-printed biomaterials A PGSA resin composition containing 5113 ppm TPO, 1809 ppm BBOT, and 12% 1-propanol to reduce resin viscosity was printed using an Ember DLP printer. The resulting parts were post-processed according to the protocol described above. Briefly, after printing, the samples were washed in a continuous ethanol bath (3) with stirring for 18 hours. The samples were then dried under reduced pressure for 1 hour and then heat-cured at 140°C for 4 days. The printed part (catheter) was then implanted at the level of the sciatic nerve of a rat model for 4 months. Tissue samples were fixed with 10% formalin, embedded in paraffin, and sectioned. Hematoxylin and eosin staining was performed to evaluate the tissue response to the material. A minimal to mild inflammatory reaction was observed at the level of the nerve tissue in response to the 3D printed material, exemplifying the biocompatibility of the 3D printed biomaterial.

[0055] (Example 7) Biodegradability of 3D Printed Biomaterials A PGSA resin composition containing 5113 ppm TPO, 1809 ppm BBOT, and 12% 1-propanol to reduce resin viscosity was printed with an Ember DLP printer. The produced parts were post-treated based on the above protocol. Briefly, the samples were washed in a continuous ethanol bath (3) with stirring for 18 h after printing. The samples were then dried under reduced pressure for 1 h and thermally cured at 140 °C for 4 days. The biodegradability of the samples was evaluated in vitro by exposing them to a 0.05 M aqueous NaOH solution. The shape of the parts was monitored for 7 days. This experiment showed that biodegradability was observed over time. Another aspect of the present invention may be as follows: [1] A resin composition for 3D printing for biomaterials, (i) General formula (-AB-) n A prepolymer comprising polymer units of (wherein A represents a substituted or unsubstituted ester, B represents a substituted or unsubstituted acid ester containing at least two acid ester functional groups, and n represents an integer greater than 1), (ii) at least one photoinitiator, (iii) at least one light-blocking agent and A composition containing the following: [2] The prepolymer is of the following formula (I) [C1] TIFF0007836642000004.tif45100 The formula has such that n and p each independently represent an integer of 1 or more, and R in each unit 2 However, hydrogen or polymer chain or -C(=O)-CR 3 =CR 4 R 5 (In the formula, R 3 、R 4 、R 5 (These are independently selected from the group consisting of H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, urethane, ether, and carbonyl.) The composition described in [1] above. [3] The prepolymer is the following formula [Case 2] TIFF0007836642000005.tif3769 The expression has a function where n represents an integer of 1 or greater, The composition described in [1] above. [4] The composition according to [1] or [3], wherein the photoinitiator is 2,4,6-trimethylbenzoyldiphenylphosphine oxide (TPO). [5] The composition according to any one of the above items [1] to [4], wherein the concentration of the photoinitiator is in the range of 1,000 to 10,000 ppm. [6] The composition according to any one of the above [1] to [5], wherein the light-blocking agent is a UV-blocking agent, preferably 2,5-bis(5-tert-butyl-benzoxazole-2-yl)thiophene (BBOT). [7] The composition according to any one of the above items [1] to [6], wherein the concentration of the light-blocking agent is in the range of 1200 to 2000 ppm. [8] The composition according to any one of [1] to [7], further comprising a solvent. [9] The composition according to [8], wherein the solvent is one of 1-propanol, ethylene glycol, propylene glycol, or N-methyl-2-pyrrolidone.

[10] The composition according to any one of the above items [1] to [9], wherein the viscosity is in the range of 10 to 30,000 cP at 25°C.

[11] A method for 3D printing biomaterials, (a) The step of 3D printing the resin composition described in any one of the above items [1] to

[10] , (b) A step of washing the 3D printed composition with a solvent Methods that include...

[12] The method according to

[11] , wherein the solvent is ethanol.

[13] The method according to

[11] or

[12] , wherein step (a) is carried out at a temperature in the range of 35°C to 95°C.

[14] The method according to

[11] or

[12] , wherein step (a) is carried out at room temperature in the presence of a solvent, the solvent may optionally be 1-propanol, ethylene glycol, propylene glycol, or N-methyl-2-pyrrolidone.

[15] (c) The method according to any one of the above

[11] to

[14] , further comprising the step of reducing the pressure of the cleaned 3D printed composition.

[16] (d) A step of post-curing the component using light, and / or (e) step of heating the cleaned 3D printed composition The method described in any one of the above

[11] to

[15] , further including the following: The method according to

[16] , wherein

[17] (e) is carried out for 3 to 5 days at a temperature in the range of 130 to 150°C.

[18] A biomaterial obtained by the method described in any one of the above items

[11] to

[17] .

[19] The following characteristics; Complete recovery after 60% compression (rebound test) and / or complete recovery after 90% bending (three-point bending test) The biomaterial according to

[18] , having one or more of the above.

[20] Use of the biomaterial described in

[18] or

[19] above as a nerve conduit.

[21] A method for repairing nerve tissue, comprising applying the biomaterial described in

[18] or

[19] above to the nerve tissue.

[22] A biocompatible implant, the biomaterial described in any one of items [1] to

[21] above.

[23] Use of any one of the biomaterials described in items [1] to

[22] above as a bioink.

Claims

1. A method for 3D printing biomaterials using digital photoprocessing (DLP) technology, (a) A step of 3D printing a resin composition by digital photoprinting (DLP) at a temperature in the range of 25°C to 95°C and in the absence of a solvent, (b) A step of washing the 3D printed composition with a solvent, (c) The step of reducing the pressure of the cleaned 3D printed composition, (e) A step of heating the cleaned 3D printed composition, wherein step (e) is carried out at a temperature in the range of 130 to 150°C for 3 to 5 days. The resin composition includes, (i) The following equation (I) The formula has such that n represents an integer of 1 or more, p represents an integer from 1 to 20, and R in each unit 2 However, hydrogen or polymer chain or -C(=O)-CR 3 =CR 4 R 5 (In the formula, R 3 , R 4 and R 5 teeth, Are R3, R4 and R5 H? Is R3 CH3 and R4 and R5 H? R3 and R4 are H and R5 is CH3, or Is R3 and R4 H and R5 phenyl? a prepolymer selected from any of (), and here R is for at least one individual unit of the prepolymer 2 is -C(=O)-CR 3 =CR 4 R 5 wherein (ii) at least one photoinitiator, (iii) at least one type of light-blocking agent and Methods that include...

2. The prepolymer is given by the following formula The formula has a function where n represents an integer of 1 or greater, The method according to claim 1.

3. The method according to claim 1 or 2, wherein the photoinitiator is 2,4,6-trimethylbenzoyldiphenylphosphine oxide (TPO).

4. The method according to any one of claims 1 to 3, wherein the concentration of the photoinitiator is in the range of 1,000 to 10,000 ppm.

5. The method according to any one of claims 1 to 4, wherein the light-blocking agent is a UV-blocking agent.

6. The method according to claim 5, wherein the UV blocking agent is 2,5-bis(5-tert-butyl-benzoxazole-2-yl)thiophene (BBOT).

7. The method according to any one of claims 1 to 6, wherein the concentration of the light-blocking agent is in the range of 1200 to 2000 ppm.

8. The method according to any one of claims 1 to 7, wherein the resin composition has a viscosity in the range of 10 to 30,000 cP at 25°C.

9. The method according to any one of claims 1 to 8, wherein the solvent in step (b) is ethanol.

10. The method according to any one of claims 1 to 9, wherein the solvent of step (b) is mixed with the composition 3D printed at a temperature of 4°C to 40°C.

11. The method according to any one of claims 1 to 10, wherein step (a) is carried out at a temperature in the range of 30°C to 60°C.

12. The method according to any one of claims 1 to 11, wherein in step (c), decompression is carried out at less than 50 mbar for at least 1 hour.

13. (d) A step of post-curing the parts using light. The method according to any one of claims 1 to 12, further comprising:

14. The method according to any one of claims 1 to 13, wherein step (e) is performed in a ramp-like manner.

15. A biomaterial obtained by the method described in any one of claims 1 to 14.

16. The biomaterial according to claim 15, used in a method for repairing nerve tissue.

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