FACILE FABRICATION OF A 3D-PRINTABLE (BIO)MATERIAL USE AND METHOD OF MAKING THE SAME

Abstract

A biomaterial resin is a combination of a thiourethane oligomer, at least one (meth)acrylate monomer, with a photoinitiator. The thiourethane oligomer comprises the addition product of at least one thiol monomer and at least one isocyanate monomer. The biomaterial resin can be converted into a biomaterial device that is the 3D-printed biomaterial network. This biomaterial network can be further processed thermally and/or photochemically to increase the network's crosslinking density with or without an imposed crosslinking density gradient. The biomaterial network can be used in a biomaterial device such as a tendon substitute.

Claims

1. A biomaterial resin comprising a thiourethane oligomer, at least one (meth)acrylate monomer, and at least one photoinitiator or photocatalyst, wherein the thiourethane oligomer comprises an addition product of at least one thiol monomer and at least one isocyanate monomer.

2. The biomaterial resin according to claim 1, wherein the at least one thiol monomer comprises 2,5-dimercaptomethyl-1,4-dithiane; 2,3-dimercapto-1-propanol; 2-mercapto-ethylsulfide; 2,3-(dimercaptoethylthio)-1-mercaptopropane; 1,2,3-trimercaptopropane; ethylene glycol bis(thioglycolate); ethylene glycol bis(3-mercaptopropionate); pentaerythritol tetra(3-mercaptopropionate); trimethylolpropane tris(3-mercaptopropionate); pentaerythritol tetra(2-mercaptoacetate); trimethylolpropane tris(2-mercaptoacetate); 1,6-hexanedithiol; 1,2-benzenedithiol; 1,3-benzenedithiol; isophorone diurethane thiol; or any combination thereof.

3. The biomaterial resin according to claim 1, wherein the at least one isocyanate monomer comprises isophorone diisocyanate; methylene dicyclohexyl diisocyanate; 2,4-diisocyanatotoluene; 4,4′-methylene bis-(cyclohexylisocyanate); hexamethylene diisocyanate; biuret of hexamethylene diisocyanate; hexamethylene diisocyanate isocyanurate trimer; hexamethylene diisocyanate uretdione; poly(hexamethylene diisocyanate); isophorone diisocyanate trimer; 1,3cyclohexane bis(methylisocyanate); 2,2,4,-trimethyl hexamethylene diisocyanate; or any combination thereof.

4. The biomaterial resin according to claim 1, wherein the at least one (meth)acrylate monomer comprises methyl acrylate; ethyl acrylate; methyl methacrylate; acrylic anhydride; acrylamide; methacrylamide; acrylic acid; methacrylic acid; methacrylic anhydride; ethylene glycoldi(meth)acrylate; tetraethyleneglycol-di(meth)acrylate; poly(ethylene glycol)dimethacrylate; a condensation product of bisphenol A and glycidyl methacrylate; 2,2′-bis[4-(3-methacryloxy-2-hydroxypropoxy)-phenyl]propane; hexanediol di(meth)acrylate; tripropylene glycol di(meth)acrylate; butanediol di(meth)acrylate; neopentyl glycol di(meth)acrylate; diethylene glycol di(meth)acrylate; triethylene glycol di(meth)acrylate; dipropylene glycol di(meth)acrylate; allyl(meth)acrylate trimethylolpropane triacrylate; tricyclodecane dimethanol diacrylate; or any combination thereof.

5. The biomaterial resin according to claim 1, wherein the thiourethane oligomer further comprises a catalyst.

6. The biomaterial resin according to claim 5, wherein the catalyst comprises dibutyl tin laurate; N,N,N′,N′-tetrakis(2-hydroxypropyl)ethylenediamine; 1-[N,N-bis(2-hydroxyethyl)amino]-2-propanol; 4-[N,N-bis(2-hydroxyethyl)amino]benzaldehyde; triethanol amine; tri-isopropanolamine; or any combination thereof.

7. The biomaterial resin according to claim 1, wherein the photoinitiator comprises WPBG300; benzophenone; or any combination thereof.

8. The biomaterial resin according to claim 1, further comprising a photosensitizer.

9. The biomaterial resin according to claim 8, wherein the photosensitizer comprises IPTX.

10. The biomaterial resin according to claim 1, further comprising a solvent.

11. A method of making a biomaterial resin according to claim 1, comprising: oligomerizing a mixture comprising at least one thiol monomer and at least one isocyanate monomer to form a thiourethane oligomer; and combining the thiourethane oligomer with at least one (meth)acrylate monomer and at least one photoinitiator, and optionally at least one photosensitizer to form the biomaterial resin.

12. The method according to claim 11, wherein the mixture comprises a ratio of thiol units to isocyanate units of three or more.

13. A method of forming a biomaterial network, comprising: providing a biomaterial resin according to claim 1; placing the biomaterial resin in a resin receiving or delivering stage of a 3D-printer; irradiating the biomaterial resin with UV or visible radiation to generate a polymerized portion and an unpolymerized portion; removing the unpolymerized portion from the polymerized portion to isolate the biomaterial network, and optionally heating the biomaterial network.

14. The method according to claim 13, further comprising irradiating the biomaterial resin with UV or visible light of the biomaterial network thorough a mask.

15. A biomaterial device, comprising a biomaterial network formed by the method according to claim 13, wherein the biomaterial device is for repair or replacement of tendons, ligaments, bone, or teeth.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1A shows a chart of tensile strength for PHT networks with thermal treatment for 2, 4, and 8 hours in comparison to the range displayed by a supraspinatus tendon (SST), according to embodiments.

[0011] FIG. 1B shows a chart of tensile modulus for PHT networks with thermal treatment for 2, 4, and 8 hours in comparison to the range displayed by a supraspinatus tendon (SST), according to embodiments.

[0012] FIG. 1C shows a chart of percentage of strain at failure for PHT networks with thermal treatment for 2, 4, and 8 hours, according to embodiments.

[0013] FIG. 2A shows a plot of strain vs cycling for PHT networks with thermal treatment for 2, 4, and 8 hours, according to embodiments.

[0014] FIG. 2B shows plots of dynamic, storage, and loss moduli vs cycling for PHT networks with thermal treatment 4 hours, according to an embodiment.

[0015] FIG. 2C shows a chart of cyclic creep for PHT networks with thermal treatment for 2, 4, and 8 hours, according to embodiments.

[0016] FIG. 3A shows a plot of the static creep for PHT networks with thermal treatment for 2, 4, and 8 hours relative to that of a clinically available tendon replacement (ADM), according to embodiments.

[0017] FIG. 3B shows a chart of the creep rate for PHT networks with thermal treatment for 2, 4, and 8 hours relative to that of a clinically available tendon replacement (ADM), according to embodiments.

[0018] FIG. 3C shows a chart of the maximum strain change (%) in static creep for PHT networks with thermal treatment for 2, 4, and 8 hours relative to that of a clinically available tendon replacement (ADM), according to embodiments.

[0019] FIG. 3D shows a chart of the creep recovery (%) for PHT networks with thermal treatment for 2, 4, and 8 hours relative to that of a clinically available tendon replacement (ADM), according to embodiments.

[0020] FIG. 4 shows a chart of suture retention for a 4 h-PHT network relative to that of a clinically available tendon replacement (ADM), according to an embodiment.

[0021] FIG. 5 shows picrosirius red staining and quantification of collagen expression of differentiated and control human mesenchymal stem cells cultured on the surface of the PHT networks with thermal treatment for 2, 4, and 8 hours, according to embodiments.

[0022] FIG. 6 shows immunofluorescence staining of tendon-specific markers Scleraxis (Scx), Collagen Type I (Col I), Tenascin C (Tnc) and Tenomodulin (Tnmd) on differentiated and control human mesenchymal stem cells cultured on the surface of the PHT networks with thermal treatment for 4 hours, according to an embodiment.

[0023] FIG. 7 shows the 3D-printed tunnel-shaped PHT network with an anisotropic topographical pattern inside.

[0024] FIG. 8A shows mouse subcutaneous implantation of PHT network and a clinically available tendon replacement (ADM), according to embodiments.

[0025] FIG. 8B shows the hematoxylin and eosin (H&E) staining and immunohistochemistry of iNOS and CD68 on the skin sections with implanted PHT network and a clinically available tendon replacement (ADM).

[0026] FIG. 9A shows gross tissue morphology of rabbit supraspinatus tendon implanted with PHT scaffold with thermal treatment for 4 hours, with or without low dosage of growth factors (GFs-Low) collected 8 weeks after surgery, according to an embodiment.

[0027] FIG. 9B shows images of hematoxylin and eosin staining of longitudinal sections of rabbit supraspinatus tendon with PHT only (with thermal treatment for 4 hours) or PHT-GFs-Low (with thermal treatment for 4 hours), according to an embodiment, and the Histological score calculated according to defined criteria in the region of interest (ROI).

[0028] FIG. 9C shows images of picrosirius red staining of longitudinal sections of rabbit supraspinatus tendon with PHT only (with thermal treatment for 4 hours) or PHT-GFs-Low (with thermal treatment for 4 hours), according to an embodiment, and a chart of the Collagen expression in the ROI calculated as the average intensity of the red color of the fibers around the PHT scaffold.

[0029] FIG. 9D shows images of picrosirius red staining of longitudinal sections of rabbit supraspinatus tendon with PHT only (with thermal treatment for 4 hours) or PHT-GFs-Low (with thermal treatment for 4 hours), according to an embodiment, under polarized light and a chart of Collagen alignment calculated with anisotropy of the fibers around the PHT scaffold.

[0030] FIG. 10A shows representative force displacement profile of rabbit supraspinatus tendon with PHT only (with thermal treatment for 4 hours), PHT-GFs-Low (with thermal treatment for 4 hours), according to an embodiment, and contralateral control during mechanical tensile test.

[0031] FIG. 10B shows maximum force of rabbit supraspinatus tendon with PHT only (with thermal treatment for 4 hours), PHT-GFs-Low (with thermal treatment for 4 hours), according to an embodiment, and contralateral control in mechanical tensile test (load to failure).

[0032] FIG. 10C shows stiffness of rabbit supraspinatus tendon with PHT only (with thermal treatment for 4 hours), PHT-GFs-Low (with thermal treatment for 4 hours), according to an embodiment, and contralateral control in mechanical tensile test (load to failure).

[0033] FIG. 10D shows ultimate displacement of rabbit supraspinatus tendon with PHT only (with thermal treatment for 4 hours), PHT-GFs-Low (with thermal treatment for 4 hours), according to an embodiment, and contralateral control in mechanical tensile test (load to failure).

DETAILED DISCLOSURE OF THE INVENTION

[0034] In embodiments, a 3D-printable biomaterial resin for a mechanically robust tendon repair. This 3D-printed biomaterial allows point-of-care manufacturing of a biomaterial network for personalized tendon implants. The biomaterial resin has a formulation that is easily 3D-printed by a medical technician and yields a durable repair of musculoskeletal injuries, such as, but not limited to, rotator cuff tears, yet is applicable to other biomedical and non-biomedical devices. In embodiments of the invention the biomaterial resin is readily formulated with no specialized equipment or conditions. In embodiments, the biomaterial resin forms biomaterial network that exhibits mechanical properties similar to native tendons and ligaments that are highly biocompatible and can be 3D-printed to specific geometries that match specific patient anatomy. The biomaterial networks can possess stress reducing features via modulation of stiffness gradients or 3D-printed lattice structure.

[0035] The biomaterial resin has a composition that is ultimately formed from at least one multifunctional thiol monomer, at least one multifunctional isocyanate, and at least one (meth)acrylate monomer. The formulation is not typical of traditional polyurethanes where the formulation diminishes any risks of isocyanate-related toxicity to those formulating, transforming, or receiving a biomedical device from the biomaterial resin.

[0036] The biomaterial resin includes isocyanate monomers that contain at least two isocyanate functionalities. The isocyanate monomers can be, but is not limited to one or more of: isophorone diisocyanate; methylene dicyclohexyl diisocyanate; 2,4-diisocyanatotoluene; 4,4′-methylene-bis-(cyclohexylisocyanate); hexamethylene diisocyanate; biuret of hexamethylene diisocyanate; hexamethylene diisocyanate isocyanurate trimer; hexamethylene diisocyanate uretdione; poly(hexamethylene diisocyanate); isophorone diisocyanate trimer; 1,3-cyclohexane-bis-(methylisocyanate); and 2,2,4,-trimethylhexamethylene diisocyanate.

[0037] The biomaterial resin includes thiol monomers that contain at least two thiol functionalities. These thiol monomers can be, but are not limited to, one or more of: 2,5-dimercaptomethyl-1,4-dithiane; 2,3-dimercapto-1-propanol; 2-mercapto-ethylsulfide; 2,3-(dimercaptoethylthio)-1-mercaptopropane; 1,2,3-trimercaptopropane; ethylene glycol bis(thioglycolate); ethylene glycol bis(3-mercaptopropionate); pentaerythritol tetra(3-mercaptopropionate); trimethylolpropane tris-3-mercaptopropionate); pentaerythritol tetra(2-mercaptoacetate); trimethylolpropane tris(2-mercaptoacetate); 1,6-hexanedithiol; 1,2-benzenedithiol; 1,3-benzenedithiol; and isophorone diurethane thiol.

[0038] The biomaterial resin includes (meth)acrylate monomers including one or more of: methyl acrylate; ethyl acrylate; methyl methacrylate; acrylic anhydride; acrylamide; methacrylamide; acrylic acid; and methacrylic acid; methacrylic anhydride; ethylene glycoldi(meth)acrylate; tetraethyleneglycol-di(meth)acrylate; poly(ethylene glycol)dimethacrylates; the condensation product of bisphenol A and glycidyl methacrylate; 2,2′-bis[4-(3-methacryloxy-2-hydroxypropoxy)-phenyl]propane; hexanediol di(meth)acrylate; tripropylene glycol di(meth)acrylate; butanediol di(meth)acrylate; neopentyl glycol di(meth)acrylate; diethylene glycol di(meth)acrylate; triethylene glycol di(meth)acrylate; dipropylene glycol di(meth)acrylate; allyl(meth)acrylate trimethylolpropane triacrylate; and tricyclodecane dimethanol diacrylate.

[0039] In embodiments, the isocyanate monomers and thiol monomers are combined such that the ratio of —SH to —NCO functionality is at least three. This results in a thiourethane oligomer that is effectively free of isocyanate units and containing at least two thiol units on each homologue of the oligomer. The oligomerization can include a catalyst, such as, but not limited to, butyl tin laurate, or a tertiary amine, such as, but not limited to: N,N,N′,N′-tetrakis(2-hydroxypropyl)ethylenediamine; triethanol amine; triisopropanolamine; 1-[N,N-bis(2-hydroxyethyl)amino]-2-propanol; and 4-[N,N-bis(2-hydroxyethyl)amino]benzaldehyde. The oligomerization can be performed at ambient temperature and pressures, although heating can be performed as desired. The final thiourethane oligomer is retained at room temperature until subsequent inclusion into the biomaterial resin.

[0040] This thiourethane oligomer is combined with the (meth)acrylate monomers to form the biomaterial resin. The biomaterial resin can be combined at ambient temperature and pressure, although heating can be performed as desired. The mixture can but does not require a solvent. The mixture can include, during a single mixing or in a subsequent mixing to the oligomer-(meth)acrylate mixing, a photoinitiation component that includes a photoinitiator and, optionally, a photosensitizer, such a wide range of electromagnetic wavelengths can be used with the biomaterial resin during 3D printing and subsequent photolytic processes. The photoinitiator can be, but is not limited to, WPBG300, benzophenone, and an optional photosensitizer can be, but is not limited to IPTX. As desired or required, mixing can occur in the presence of a solvent, such as, but not limited to, acetone and/or dimethylsulfoxide (DMSO). The solvent can be included in the biomaterial resin or may be removed to yield the biomaterial resin in the form desired for subsequent processing into the biomaterial network. Additionally, if desired for a particular application, a pigment or dye can be included. As desired a filler can be combined with the biomaterial resin in a wide range of filler loadings. The filler can be, but is not necessarily, transparent to UV or visible light. The filler can be of any reasonable dimensions from nanometer to greater than micrometer dimensions. Fillers can include, but are not limited to, silica, glass, mineral, polymeric particles or fibers, graphite fibers, carbon nanotubes.

[0041] The biomaterial resin forms a biomaterial network when placed in a 3D printer. The biomaterial resin is then patterned by photolysis using the printer's lasers. The printed biomaterial resin can be subsequently heated as desired. The resulting poly((meth)acrylate thiourethane) forms the biomaterial network. The (meth)acrylate polymerizes with the thiourethane oligomer acting as a chain transfer reagent to connect (meth)acrylate and thiol chains within the network. This biomaterial network can be used as achieved after removal of non-polymerized resin, or the isolated biomaterial network can be additionally processed to form a biomaterial network that has a higher crosslinking density and can have a gradient of crosslinking densities to yield a biomaterial device with a gradient of mechanical properties along at least one dimension of the biomaterial device. The biomaterial device can be heated to increase the physical crosslinking density of the biomaterial. Heating can be performed in an oven or on a plate such that heat is maintained for a desired length of time to achieve desired tensile strengths and tensile moduli for a desired use of the device.

[0042] The gradient biomaterial device can be generated using a UV or visible light source in conjunction with a mask. The mask can be included in the 3D-printing process or subsequently with the biomaterial device. The mask can be used in a stationary or moving manner, such that the desired gradient can be achieved. The mask can be continuously transmissive, or maybe formed to have a desired gradient of transmissivity.

[0043] In an exemplary embodiment, a biomaterial resin was prepared from a thiourethane oligomer from pentaerythritol tetra(3-mercaptopropionate) and hexamethylene diisocyanate in a 1.5 to 1 molar ratio (3-SH/-NCO) to form approximately a pentameric thiourethane oligomer. This thiourethane oligomer can be combined with the trimethylolpropane triacrylate and catalyst to form a biomaterial network upon irradiating in a 3D-printer. The triacrylate forms a network that includes the pentameric thiourethane oligomer by chain transfer during the radical chain-growth polymerization of the acrylate units. Polymerization proceeds until the network forms with little diffusion within the network. Heating of this biomaterial network increase diffusion and the crosslinking density of the network. This network can be fabricated as a biomaterial device that displays a broad range of tensile strengths of about 3 to 28 MPa, for example, 3.06 MPa when no heating is employed to about 27.53 MPa when the equivalent biomaterial network is heated for eight hours, and a broad range of tensile modulus of about 20 to about 844 MPa, for example, 20.54 MPa for the non-heated biomaterial network and 843.7 MPa for the equivalent biomaterial network is heated for eight hours.

[0044] The biomaterial device or gradient biomaterial is useful as a tendon substitute or other biomaterials for repair or replacement of tendons, ligaments, bone, or teeth as formulated by the photolytic or combined photolytic and thermal processes.

METHODS AND MATERIALS

[0045] Pentaerythritol tetra(3-mercaptopropionate) (Sigma Aldrich), hexamethylene diisocyanate (1,6-diisocyanatohexane) (TCI (Shanghai) Development Co., Ltd), trimethylolpropane triacrylate (stabilized with MEHQ) (Sigma), N,N,N′,N′-tetrakis(2-hydroxy-propyl) ethylenediamine (quadrol or Q; Sigma Aldrich), 1,2-dicyclohexyl-4,4,5,5-tetramethylbiguanidium n-butyltriphenylborate (WPBG-300; FUJIFILM Wako Pure Chemical Co.), 2-isopropylthioxanthone (FUJIFILM Wako Pure Chemical Co.), and acetone (Honeywell International Inc) were used as received. A Kudo3D Titan 2 HR 3D printer or a 365 nm UV light source (365 nm UV LED lamp; 6000-8000 MW/cm.sup.2; ShenZhen HowSuper Technology Co. Ltd) were employed.

[0046] A biomaterial resin (PHT) was prepared by combining the thiol and isocyanate to produce PH oligomer solution with excess thiol, where 50.03 mmol pentaerythritol tetra(3-mercaptopropionate) (P) was mixed with 10 μL N,N,N′,N′-tetrakis(2-hydroxy-propyl) ethylenediamine (quadrol or Q) solution (33.3% v/v, in acetone) as catalyst in a 50 mL conical tube with vortexing for 30 seconds for mixing. Addition of 19.92 mmol hexamethylene diisocyanate (H) to the mixture and vortexing at 2500 rpm at RT for 20 to 30 minutes to allow complete reaction of H and generate a PH oligomer where ratio of —SH to —NCO groups was 5:1. The PH oligomer was centrifuged at 2200 g for 3 minutes to remove bubbles and 80.18 mmol trimethylolpropane triacrylate (T) was added. To the PH oligomer T mixture was added 5 mL acetone and physically mixed with a spoon until a homogeneous solution was formed (SH:NCO:Acrylate=5:1:6).

[0047] To this PHT resin was added 500 μL 1,2-dicyclohexyl-4,4,5,5-tetramethylbiguanidium n-butyltriphenylborate (WPBG-300) solution (10% w/v, in acetone) and 100 μL 2-isopropylthioxanthone (IPTX) solution (10% w/v, in acetone) as photo initiator and sensitizer. The mixture was centrifuged at 2200 g for 0.5 minutes and transferred into a modified ASTM D638-10 Type V mold. A mold was placed on the platform of a Kudo3D printer Titan 2 HR and the PHT resin was photo-crosslinked for 150 seconds.

[0048] PHT networks were removed from the mold and additionally heat cured in a vacuum oven (Shel Lab SVAC1-2 Compact Vacuum Drying Oven, Albuquerque, New Mexico) at 150° C. for 2, 4, or 8 hours. Mechanical properties of PHT networks were determined by tensile, cyclic tensile, static creep and suture retention tests.

[0049] Tensile test (load to failure) indicated that the PHT network has a tensile strength range of 3.06 MPa with no heat-curing to about 27.53 MPa with 8 hrs heat-curing (8 h-PHT) and a tensile modulus range of 20.54 MPa with no heat-curing to about 843.7 MPa for 8 h-PHT. The PHT network showed increased tensile strength and tensile moduli with increased heat-curing time and is capable to mimic physiological supraspinatus tendon-like strength and modulus, as indicated in FIGS. 1A-1C.

[0050] Cyclic tensile test were conducted on the PHT network, which exhibited: strain of 2.59±0.35% (2 hrs heat-curing; 2 h-PHT), 0.96±0.12% (4 hrs heat-curing; 4 h-PHT), and 0.64±0.10% 8 h-PHT, as shown in FIG. 2C; dynamic moduli for 2 h-PHT (705.7±2.126 MPa), 4 h-PHT (1113±9.670 MPa), and 8 h-PHT (1369±8.276 MPa); storage moduli for 2 h-PHT (672.4±2.699 MPa), 4 h-PHT (1052±9.797 MPa) and 8 h-PHT (1306±9.113 MPa); and loss moduli for 2 h-PHT (196.9±7.260 MPa), 4 h-PHT (335.8±13.09 MPa), and 8 h-PHT (363.2±22.85 MPa), as shown in FIG. 2B, during 10,000 loading cycles from 0.2 to 3 MPa tensile stress at 1 Hz. The change of strain (%) cyclic creep decreased with increased heat-curing time of the PHT networks, as shown in FIG. 2C. These results indicate that the PHT networks have robust tensile properties that withstand at least 10000 cycles of physiologic loading.

[0051] Static creep testing of PHT networks exhibited 4.323±0.2993% (2 h-PHT), 2.918±0.1167% (4 h-PHT) and 0.8478±0.0263% (8 h-PHT) strain following a 30 min hold at 3 MPa tensile stress and recovered for 80.89±2.300%, 83.01±1.450% and 92.71±4.039% following a 10 min recovery period for 2 h-, 4 h- and 8 h-PHT, respectively, as indicated in FIG. 3A, which was superior to that displayed by a clinically available ADM. The creep rate is shown in FIG. 3B relative to ADM for 2 h-, 4 h-, and 8 h-PHT were 0.1441±0.0099%, 0.09726±0.0038%, and 0.02823±0.00087% per min, respectively. Furthermore, the 4 h-PHT and 8 h-PHT showed less strain (%) change for the static creep during the 30 min hold at 3 MPa, as shown in FIG. 3C, and greater percentage of creep recovery after 10 min, as shown in FIG. 3D compared to the clinically available ADM demonstrating its robust fatigue and recovery properties that can be achieved with PHT networks.

[0052] A suture retention test was performed on a PHT network after 4 h heat-curing, exhibiting an 8.56-fold smaller suture migration during a pull-to-failure (at 15 N) relative to the clinically available ADM, as shown in FIG. 4. The suture migration for the 4 h-PHT, being less than 0.5 mm is excellent relative to state-of-the-art tendon substitutes.

[0053] It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. In addition, any elements or limitations of any invention or embodiment thereof disclosed herein can be combined with any and/or all other elements or limitations (individually or in any combination) or any other invention or embodiment thereof disclosed herein, and all such combinations are contemplated with the scope of the invention without limitation thereto.

EMBODIMENTS

[0054] Embodiment 1. A biomaterial resin comprising a thiourethane oligomer, at least one (meth)acrylate monomer, and at least one photoinitiator, wherein the thiourethane oligomer comprises an addition product of at least one thiol monomer and at least one isocyanate monomer.

[0055] Embodiment 2. The biomaterial resin according to embodiment 1, wherein the at least one thiol monomer comprises 2,5-dimercaptomethyl-1,4-dithiane; 2,3-dimercapto-1-propanol; 2-mercapto-ethylsulfide; 2,3-(dimercaptoethylthio)-1-mercaptopropane; 1,2,3-trimercaptopropane; ethylene glycol bis(thioglycolate); ethylene glycol bis(3-mercaptopropionate); pentaerythritol tetra(3-mercaptopropionate); trimethylolpropane tris(3-mercaptopropionate); pentaerythritol tetra(2-mercaptoacetate); trimethylolpropane tris(2-mercaptoacetate); 1,6-hexanedithiol; 1,2-benzenedithiol; 1,3-benzenedithiol; isophorone diurethane thiol; or any combination thereof.

[0056] Embodiment 3. The biomaterial resin according to embodiment 1, wherein the at least one isocyanate monomer comprises isophorone diisocyanate; methylene dicyclohexyl diisocyanate; 2,4-diisocyanatotoluene; 4,4′-methylene bis-(cyclohexylisocyanate); hexamethylene diisocyanate; biuret of hexamethylene diisocyanate; hexamethylene diisocyanate isocyanurate trimer; hexamethylene diisocyanate uretdione; poly(hexamethylene diisocyanate); isophorone diisocyanate trimer; 1,3cyclohexane bis(methylisocyanate); 2,2,4,-trimethyl hexamethylene diisocyanate; or any combination thereof.

[0057] Embodiment 4. The biomaterial resin according to embodiment 1, wherein the at least one (meth)acrylate monomer comprises methyl acrylate; ethyl acrylate; methyl methacrylate; acrylic anhydride; acrylamide; methacrylamide; acrylic acid; methacrylic acid; methacrylic anhydride; ethylene glycoldi(meth)acrylate; tetraethyleneglycol-di(meth)acrylate; poly(ethylene glycol)dimethacrylate; a condensation product of bisphenol A and glycidyl methacrylate; 2,2′-bis[4-(3-methacryloxy-2-hydroxypropoxy)-phenyl]propane; hexanediol di(meth)acrylate; tripropylene glycol di(meth)acrylate; butanediol di(meth)acrylate; neopentyl glycol di(meth)acrylate; diethylene glycol di(meth)acrylate; triethylene glycol di(meth)acrylate; dipropylene glycol di(meth)acrylate; allyl(meth)acrylate; trimethylolpropane triacrylate; tricyclodecane dimethanol diacrylate; or any combination thereof.

[0058] Embodiment 5. The biomaterial resin according to embodiment 1, wherein the thiol monomer is pentaerythritol tetra(3-mercaptopropionate), the isocyanate monomer is hexamethylene diisocyanate, and the (meth)acrylate monomer is trimethylolpropane triacrylate.

[0059] Embodiment 6. The biomaterial resin according to embodiment 1, wherein the thiol monomer and isocyanate monomer are combined in ratio of thiol to isocyanate equal to or greater than three.

[0060] Embodiment 7. The biomaterial resin according to embodiment 1, wherein the thiourethane oligomer further comprises a catalyst.

[0061] Embodiment 8. The biomaterial resin according to embodiment 7, wherein the catalyst comprises dibutyl tin laurate; N,N,N′,N′-tetrakis(2-hydroxypropyl)ethylenediamine; 1-[N,N-bis(2-hydroxyethyl)amino]-2-propanol; 4-[N,N-bis(2-hydroxyethyl)amino]benzaldehyde; triethanol amine; or tri-isopropanolamine.

[0062] Embodiment 9. The biomaterial resin according to embodiment 1, wherein the photoinitiator comprises WPBG300 or benzophenone.

[0063] Embodiment 10. The biomaterial resin according to embodiment 1, further comprising a photosensitizer.

[0064] Embodiment 11. The biomaterial resin according to embodiment 10, wherein the photosensitizer comprises IPTX.

[0065] Embodiment 12. The biomaterial resin according to embodiment 1, further comprising a solvent.

[0066] Embodiment 13. The biomaterial resin according to embodiment 12, wherein the solvent is acetone or dimethylsulfoxide.

[0067] Embodiment 14. A method of making a biomaterial resin according to embodiment 1, comprising: [0068] oligomerizing a mixture comprising at least one thiol monomer and at least one isocyanate monomer to form a thiourethane oligomer; and [0069] combining the thiourethane oligomer with at least one (meth)acrylate monomer and at least one photoinitiator, and optionally at least one photosensitizer to form the biomaterial resin.

[0070] Embodiment 15. The method according to embodiment 14, wherein the mixture comprises a ratio of thiol units to isocyanate units of three or more.

[0071] Embodiment 16. The method according to embodiment 14, wherein the oligomerizing is in the presence of a catalyst.

[0072] Embodiment 17. A method of forming a biomaterial network, comprising: [0073] providing a biomaterial resin according to embodiment 1; [0074] placing the biomaterial resin in a resin receiving or delivering stage of a 3D-printer; [0075] irradiating the biomaterial resin with UV or visible radiation to generate a polymerized portion and an unpolymerized portion; [0076] removing the unpolymerized portion from the polymerized portion to isolate the biomaterial network, and [0077] optionally heating the biomaterial network.

[0078] Embodiment 18. The method according to embodiment 17, further comprising irradiating the biomaterial resin or the biomaterial network thorough a mask.

[0079] Embodiment 19. The method according to embodiment 18, further comprising changing the relative position of the mask relative to the biomaterial resin and/or the biomaterial network, whereby the biomaterial network has a gradient of crosslink density.

[0080] Embodiment 20. A biomaterial device, comprising a biomaterial network formed by the method according to embodiment 17, wherein the biomaterial device is for repair or replacement of tendons, ligaments, bone, or teeth.

[0081] Embodiment 21. The biomaterial device according to embodiment 20, wherein the biomaterial device is a tendon substitute.

[0082] Embodiment 22. The biomaterial device according to embodiment 20, wherein the biomaterial network has a tensile strength of about 3 MPa to about 28 Mpa and a tensile modulus of about 21 Mpa to about 844 Mpa.