Osteoinductive materials and methods of using the same

Abstract

Osteoinductive materials and modular bioactive synthetic bone craft (MST) devices are provided. The MST devices comprise the osteoinductive materials for applications in regenerative medicine and treatment of diseases. The osteoinductive material can be characterized by a scaffold filament, a hydrogel layer cross-linked with the scaffold filament, and an osteoinductive growth factor. The hydrogel layer contains the osteoinductive growth factor, a covalent cross-linking polymer, a covalent cross-linking monomer, and a physical cross-linking polymer.

Description

[0001] OSTEOINDUCTIVE MATERIALS AND METHODS OF

[0002] USING THE SAME

[0003] FIELD OF THE INVENTION

[0004] The invention relates to osteoinductive materials and methods of preparing and using these osteoinductive materials.

[0005] BACKGROUND

[0006] Over 7 million patients in the United States suffer from orthopedic trauma each year, with more than half a million bone grafting procedures performed annually. The treatment of long bone defects and non-unions is still a major clinical and socio-economical problem. The challenge for surgeons is to avoid amputation and provide the best functional outcomes. However, no consensus guidelines are available, and the treatments of such defects differ greatly.

[0007] There is a need to treat large bone defects based on tissue engineering approaches.

[0008] SUMMARY OF THE INVENTION

[0009] The invention relates to osteoinductive materials and methods of preparing and using these osteoinductive materials. The present invention provides in one aspect an osteoinductive material. The osteoinductive material can be characterized by a scaffold filament, a hydrogel layer cross-linked with the scaffold filament, and an osteoinductive growth factor. The hydrogel layer contains the osteoinductive growth factor, a covalent cross-linking polymer, a covalent cross-linking monomer, and a physical cross-linking polymer.

[0010] The present invention provides in another aspect, an osteoinductive material prepared by a process that includes the following steps. A scaffold filament is provided, which is then treated to increase roughness and porosity. Microparticles are deposited on the treated scaffold filament, and the hydrogel layer is cross-linked with the scaffold filament. The hydrogel layer contains the osteoinductive growth factor.

[0011] The present invention provides in yet another aspect, a kit containing the following components. An osteoinductive material as described herein, an osteoconductive porous scaffold having a central channel and one or more peripheral channels, and an intermedullary nail. The intermedullary nail is shaped to be inserted into the central channel of the osteoconductive porous scaffold, and the osteoinductive material is shaped for insertion into the one or more peripheral channels of the osteoconductive porous scaffold.

[0012] The present invention provides in still another aspect, as a method of treating a bone defect, deformity or nonunion in a patient in need thereof, the method includes the steps of implanting the osteoinductive material (as taught herein) into the bone defect, deformity or nonunion. Objectives and advantages of the osteoinductive material, methods and uses are included throughout the description.

[0013] BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIGs. 1A-1C show exemplary schematics and photographs of a modular bioactive synthetic bone graft (MST) disclosed herein. Schematic of an MST device (FIG. 1A), photograph of the MST device without screws (FIG. IB), and the MST device with screws (FIG. 1C).

[0015] FIG. ID shows an exemplary schematic of coating a hydrogel onto a scaffold filament to provide the osteoinductive material disclosed herein (zoomed-in view (top panel) and zoomed-out view (bottom panel)).

[0016] FIG. IE shows photographs of the scaffold filament prior to treatment with the hydrogel (left), after treatment with the hydrogel (middle), and after freeze drying (right) to provide the osteoinductive material disclosed herein.

[0017] FIGs. 1F-1H show SEM images of the scaffold filament before (FIG. IF) and after (FIG.

[0018] 1G) hydrogel coating and (FIG. 1H) after split dose E-Beam sterilization.

[0019] FIGs. 1I-1L show mechanical strength studies of the osteoinductive material : bending and torsion mechanics (FIG. II), strength under torsional grips (FIG. 1J), compression loading (FIG. IK), and bending, torsion, and compression graphs (FIG. IL).

[0020] FIGs. 1M-1Q show characterization of the osteoinductive material: hydrogel loading efficiency of osteoinductive material with BMP-2 loadings of 0 mg, 0.5 pg, 2 pg, or 6 pg (FIG. IM), microscopy images of the osteoinductive material (FIG. IN), 3D printed PCL-TCP device and adhesion characterization (FIG. IO), BMP-2 release profile from the osteoinductive materials loaded with 0.5 pg, 2 pg or 6 pg BMP -2 over 28 days (FIG. IP), BMP-2 release profile in the fresh-made or stored osteoinductive material loaded with 2 pg BMP -2 over 28 days (FIG. IQ), and release kinetics of BMP-2 from the osteoinductive materials with one or three PCL layers for 28 days (FIG. 1R).

[0021] FIGs. 2A-2D show schematics of an MST implant with customizability that permits adjustment with different defect contours.

[0022] FIGs.3A -3B show an exemplary schematic of an in vitro release study with a rod-shaped osteoinductive material (FIG. 3A) and the in vitro release kinetics of BMP -2 encapsulated in the osteoinductive material (FIG. 3B).

[0023] FIG. 4 shows a sheep model for the use of the MST device.

[0024] FIGs. 5A-5C show images of the mandible fracture of the horse developed via large bone cyst of Example 5.

[0025] FIGs. 6A-6B show images of osteoinductive and osteoconductive materials (FIG. 6A) and assembly of the materials (FIG. 6B) for MST device of Example 5.

[0026] FIGs. 7A-7B show images of the surgical procedure (FIG. 7A) and radiographs of the bone defect before and after surgery (FIG. 7B) of the horse in Example 5.

[0027] FIGs. 8A-8B show images of CT scans of the horse pre-operation (FIG. 8A) and 18 months after the operation (FIG. 8B).

[0028] FIG. 9 shows exemplary schematics of a customizable MST device.

[0029] FIGs. 10A-10B show exemplary schematics of a flat MST device.

[0030] FIG. 11 shows exemplary schematics of a circular MST device. DETAILED DESCRIPTION

[0031] Provided herein are osteoinductive materials and modular bioactive synthetic bone graft (MST) devices comprising the osteoinductive materials for applications in regenerative medicine and treatment of diseases. The materials and devices described herein provide a number of advantages relative to current standard of care techniques and devices. The benefits include, but are not limited to: (1) promoting bone regeneration, (2) require a single procedure, (3) rely on absorbable materials (i.e., no need for a removal procedure), (4) controlled release of osteoinductive growth factors, (5) increased biocompatibility, (6) improved surgical handleability and easy fixation for irregular defections, and (7) imaging compatibility.

[0032] The MST devices of the present disclosure comprise modular building blocks (e.g., osteoinductive materials) so are customizable. For example, the shape, size, the release profile of growth factors and dosage of growth factors of the MST devices of the present disclosure may be tuned by changing the modular building blocks using methods described herein. As a result, the composition and shape of the MST devices of the present disclosure may be customized using methods described herein to treat a variety of defects with complex geometries.

[0033] In embodiments of the MST described herein, both the nail and scaffold possess a flat area. When the nail is inserted into the scaffold, the nail and scaffold interlock through the flat area to prevent and avoid rotation of the scaffold. This design helps the fit and fixation of the MST device for segmental bone defects with various irregular ending planes or surfaces to improve surgical handling properties and treatment outcome in clinics. Osteoinductive Material

[0034] Aspects of the present disclosure provide osteoinductive materials.

[0035] In embodiments, the osteoinductive material comprises:

[0036] (a) a scaffold filament;

[0037] (b) a hydrogel layer cross-linked with the scaffold filament; and

[0038] (c) an osteoinductive growth factor; wherein the hydrogel comprises the osteoinductive growth factor, a covalent cross-linking polymer, covalent cross-linking monomer, and a physical cross-linking polymer.

[0039] In embodiments, the tensile modulus of the osteoinductive material is about 100 to about 1000 Mpa, e.g., about 100 Mpa, about 150 Mpa, about 200 Mpa, about 250 Mpa, about 300 Mpa, about 400 Mpa, about 500 Mpa, about 600 Mpa, about 700 MpA, about 800 MpA, about 900 MpA, or about 10000 MpA, including all values and ranges therebetween.

[0040] In embodiments, the osteoinductive material is sterilized. In embodiments, the osteoinductive material is sterilized by an electron beam (E-beam) at splits doses (e.g., 12.5 krad, X2). In embodiments, the osteoinductive material is storage at a temperature of -20°C for about 2 hours between each of the split doses. In embodiments, following E-beam sterilization, the osteoinductive material is stored at a temperature of about 4°C.

[0041] In embodiments, the osteoinductive material is sterilized. In embodiments, the osteoinductive material is sterilized by an electron beam (E-beam) at splits doses (e.g., 12.5 krad, X2). In embodiments, the osteoinductive material is stored at a temperature of -20°C for about 2 hours between each of the split doses. In embodiments, following E-beam sterilization, the osteoinductive material is stored at a temperature of about -80°C to about 25°C, e.g., about -80°C, about -70°C, about -60°C, about -50°C, about -40°C, about -30°C, about -20°C, -10°C, about 0°C, about 4°C, about 10°C, or about 25°C, including all values and ranges therebetween. In embodiments, the osteoinductive material is stored at a temperature of about -80°C. In embodiments, the osteoinductive material is stored at a temperature of about -20°C. In embodiments, the osteoinductive material is stored at a temperature of about 4°C. In embodiments, the osteoinductive material is stored at a temperature of about 25°C.

[0042] In embodiments, the osteoinductive material is shaped in a rod (FIG. ID).

[0043] In embodiments, the rod has a diameter of about 1 mm to about 20 mm, e.g., about 1 mm, about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 12 mm, about 14 mm, about 16 mm, about 18 mm, or about 20 mm, including all values and ranges therebetween. In embodiments, the rod has a diameter of 1 mm. In embodiments, the rod has a diameter of 3 mm. In embodiments, the rod has a diameter of 6 mm.

[0044] In embodiments, the rod has a length of about 10 mm to about 100 mm, e.g., about 10 mm, about 20 mm, about 30 mm, about 40 mm, about 50 mm, about 60 mm, about 70 mm, about 80 mm, about 90 mm, or about 100 mm, including all values and ranges therebetween. In embodiments, the rod has a length of about 10 mm to about 60 mm. In embodiments, the rod has a length of about 10 mm to about 300 mm, e.g., about 10 mm, about 20 mm, about 30 mm, about 40 mm, about 50 mm, about 60 mm, about 70 mm, about 80 mm, about 90 mm, about 100 mm, about 110 mm, about 120 mm, about 130 mm, about 140 mm, about 150 mm, about 160 mm, about 170 mm, about 180 mm, about 190 mm, about 200 mm, about 210 mm, about 220 mm, about 230 mm, about 240 mm, about 250 mm, about 260 mm, about 270 mm, about 280 mm, about 290 mm, or about 300 mm, including all values and ranges therebetween. In embodiments, the rod has a length of about 10 mm to about 60 mm. In embodiments, the rod has a length of about 10 mm to about 100 mm. In embodiments, the rod has a length of about 170 cm.

[0045] In embodiments, one or more rods are stacked together (FIG. 2B). In embodiments, two, three, four, five, or more rods are stacked together.

[0046] In embodiments, the total length of the one or more stacked rods is greater than about 10 cm, greater than about 15 cm, greater than about 20 cm, greater than about 30 cm, greater than about 40 cm, or greater than about 40 cm. In embodiments, the total length of the one or more rods stacked together is about 17 cm.

[0047] In embodiments, two rods are stacked together, wherein the first rod is 100 mm and the second rod is 70 mm. In embodiments, three rods are stacked together, wherein the first rod is 50 mm, the second rod is 50 mm, and the third rod is 70 mm. In embodiments, the sheet has a length of about 5 mm to about 50 mm, e.g., about 5 mm, about 10 mm, about 15 mm, about 20 mm, about 25 mm, about 30 mm, about 35 mm, about 40 mm, about 45 mm, or about 50 mm, including all values and ranges therebetween. In embodiments, the osteoinductive material is shaped in a sheet (FIGs. 10A-10B).

[0048] In embodiments, the sheet is circular. In embodiments, the sheet is rectangular.

[0049] In embodiments, the sheet has a width of about 5 mm to about 50 mm, e.g., about 5 mm, about 10 mm, about 15 mm, about 20 mm, about 25 mm, about 30 mm, about 35 mm, about 40 mm, about 45 mm, or about 50 mm, including all values and ranges therebetween. In embodiments, the sheet has a width of 8 mm and a length of 26 mm.

[0050] In embodiments, the sheet has a width and / or length of about 5 mm to about 200 mm, e.g., about 5 mm, about 10 mm, about 15 mm, about 20 mm, about 30 mm, about 40 mm, about 50 mm, about 60 mm, about 70 mm, about 80 mm, about 90 mm, about 100 mm, about 110 mm, about 120 mm, about 130 mm, about 140 mm, about 150 mm, about 160 mm, about 170 mm, about 180 mm, about 190 mm, or about 200 mm, including all values and ranges there between.

[0051] In embodiments, the osteoinductive material comprises a coating layer comprising resorbable polyester or resorbable polymer. In embodiments, the resorbable polyester is PCL, PLA, PLGA, and combinations thereof. In embodiment, the resorbable polymer is a polyurethane polymer.

[0052] In embodiments, the coating layer has a thickness of about 10 to about 1,000 mm, e.g., about 10 mm, about 20 mm, about 30 mm, about 40 mm, about 50 mm, about 60 mm, about 70 mm, about 80 mm, about 90 mm, about 100 mm, about 200 mm, about 300 mm, about 400 mm, about 500 mm, about 600 mm, about 700 mm, about 800 mm, about 900 mm, or about 1,000 mm, including all values and ranges therebetween.

[0053] In embodiments, the coating layer comprises one or more layers.

[0054] In embodiments, the hydrogel layer is about 100 to about 600 mm, e.g., about 100 mm, about 200 mm, about 300 mm, about 400 mm, about 500 mm, or about 600 mm, including all values and ranges therebetween.

[0055] In embodiments, the osteoinductive material releases the osteoinductive growth factor for at least 21 days, at least 28 days, at least 35 days, at least 42 days, or at least 49 days after insertion into a patient in need thereof. In embodiments, the osteoinductive material releases the osteoinductive growth factor for at least 21 days after insertion into a patient in need thereof.

[0056] In embodiments, the osteoinductive material releases about 10 pg to about 3 mg, e.g., about 10 pg, about 100 pg, about 1000 pg, 10,000 pg, about 100,000, about 1 mg, about 1.5 mg, about 2 mg, or about 3 mg, including all values and ranges therebetween, of osteoinductive growth factor per ml of osteoinductive material per day for about 21 days, about 28 days, about 35 days, about 42 days, or 49 days following insertion into a patient in need thereof.

[0057] In embodiments, the osteoinductive material releases about 10 pg to about 3 mg, e.g., about 10 pg, about 100 pg, about 1000 pg, 10,000 pg, about 100,000, about 1 mg, about 1.5 mg, about 2 mg, or about 3 mg, including all values and ranges therebetween, of osteoinductive growth factor for about 21 days, about 28 days, about 35 days, about 42 days, or 49 days following insertion into a patient in need thereof.

[0058] In embodiments, the osteoinductive material releases about 1 pg to about 40 mg, e.g., about 1 pg, 10 pg, 100 pg, about 1 ng, 10 ng, about 100 ng, 1 mg, about 10 mg, about 100 mg, about 1 mg, about 10 mg, or about 40 mg, including all values and ranges therebetween, of osteoinductive growth factor per ml of osteoinductive material per day for about 21 days, about 28 days, about 35 days, about 42 days, or 49 days following insertion into a patient in need thereof.

[0059] In embodiments, the osteoinductive material releases about 1 pg to about 100 pg, of osteoinductive growth factor per ml of osteoinductive material per day for about 21 days, about 28 days, about 35 days, about 42 days, or 49 days following insertion into a patient in need thereof.

[0060] In embodiments, the osteoinductive material releases about 1 ng to about 100 ng, of osteoinductive growth factor per ml of osteoinductive material per day for about 21 days, about 28 days, about 35 days, about 42 days, or 49 days following insertion into a patient in need thereof.

[0061] In embodiments, the osteoinductive material releases about 1 mg to about 100 mg, of osteoinductive growth factor per ml of osteoinductive material per day for about 21 days, about 28 days, about 35 days, about 42 days, or 49 days following insertion into a patient in need thereof. In embodiments, the osteoinductive material releases about 1 mg to about 40mg, of osteoinductive growth factor per ml of osteoinductive material per day for about 21 days, about 28 days, about 35 days, about 42 days, or 49 days following insertion into a patient in need thereof.

[0062] In embodiments, the osteoinductive material releases about 36 mg, of osteoinductive growth factor per ml of osteoinductive material per day for about 21 days, about 28 days, about 35 days, about 42 days, or 49 days following insertion into a patient in need thereof.

[0063] In embodiments, the osteoinductive material releases about 24 mg, of osteoinductive growth factor per ml of osteoinductive material per day for about 21 days, about 28 days, about 35 days, about 42 days, or 49 days following insertion into a patient in need thereof.

[0064] In embodiments, the osteoinductive materials of the present disclosure are characterized on the basis of the weight ratio of the hydrogel layer to the scaffold filament. In embodiments, the weight ratio of the hydrogel layer to the scaffold filament is about 0.3 to about 5, e.g., about 0.3, about 0.5, about 0.7, about 1.0, about 1.3, about 1.5, about 1.7, about 2.0, about 2.3, about 2.5, about 2.7, about 3.0, about 3.3, about 3.5, about 3.7, about 4, about 4.3, about 4.5, about 4.7 or about 5, including all values and ranges therebetween.

[0065] Hydrogel

[0066] Aspects of the present disclosure provide a hydrogel that comprises one or more osteoinductive growth factors. The hydrogels of the present disclosure are coated onto porous scaffold filament to provide osteoinductive materials that are useful for osteoinductive growth factor delivery.

[0067] In embodiments, the hydrogel comprises an osteoinductive growth factor. In embodiments, the growth factor is BMP-2, PDFG, IGF-1, FGF2, VEGF, BMP-7, and combinations thereof. In embodiments, the osteoinductive growth factor comprises BMP -2. In embodiments, the osteoinductive growth factor comprises PDGF. In embodiments, the osteoinductive growth factor comprises IGF-1. In embodiments, the osteoinductive growth factor comprises FGF2. In embodiments, the osteoinductive growth factor comprises VEGF. In embodiments, the osteoinductive growth factor comprises BMP-7.

[0068] In embodiments, the hydrogel comprises an osteoinductive growth factor. In embodiments, the growth factor is BMP-2, PDFG, IGF-1, FGF2, VEGF, BMP-7, BMP-6, BMP-9, and combinations thereof. In embodiments, the osteoinductive growth factor comprises BMP -2. In embodiments, the osteoinductive growth factor comprises PDGF. In embodiments, the osteoinductive growth factor comprises IGF-1. In embodiments, the osteoinductive growth factor comprises FGF2. In embodiments, the osteoinductive growth factor comprises VEGF. In embodiments, the osteoinductive growth factor comprises BMP-7. In embodiments, the osteoinductive growth factor comprises BMP-6. In embodiments, the osteoinductive growth factor comprises BMP-9. In embodiments, the concentration of the osteoinductive growth factor in the hydrogel is about 0.1 mg / mL to about 1.5 mg / mL, e.g., about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / ml, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, or about 1.5 mg / mL, including all values and ranges therebetween. In embodiments, the concentration of the osteoinductive growth factor in the hydrogel is about 0.4 mg / mL to about 1.5 mg / mL. In embodiments, the concentration of the osteoinductive growth factor in the hydrogel is about 0.3 mg / mL to about 0.8 mg / mL. In embodiments, the concentration of the osteoinductive growth factor in the hydrogel is about 0.4 mg / mL.In embodiments, the concentration of the osteoinductive growth factor in the hydrogel is about 0.1 mg / mL to about 3 mg / mL, e.g., about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / ml, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, or about 3 mg / mL, including all values and ranges therebetween. In embodiments, the concentration of the osteoinductive growth factor in the hydrogel is about 0.4 mg / mL to about 1.5 mg / mL. In embodiments, the concentration of the osteoinductive growth factor in the hydrogel is about 0.3 mg / mL to about 0.8 mg / mL. In embodiments, the concentration of the osteoinductive growth factor in the hydrogel is about 0.4 mg / mL. In embodiments, the concentration of the osteoinductive growth factor in the hydrogel is about 1 mg / mL to about 3 mg / mL. In embodiments, the concentration of the osteoinductive growth factor in the hydrogel is about 2.5 mg / mL. In embodiments, the concentration of the osteoinductive growth factor in the hydrogel is about 2.6 mg / mL. In embodiments, the hydrogel comprises a covalent cross-linking polymer.

[0069] In embodiments, the covalent cross-linking polymer comprises gelatin methacrylate (GelMA), polyethylene glycol dimethacrylate (PEG-DMA), PEG diacrylate (PEG-DA), and combinations thereof.

[0070] In embodiments, the covalent cross-linking polymer comprises gelatin methacrylate.

[0071] In embodiments, the covalent cross-linking polymer comprises PEGDMA.

[0072] In embodiments, the covalent cross-linking polymer comprises PEG-DA.

[0073] In embodiments, the hydrogel comprises a covalent cross-linking monomer.

[0074] In embodiments, the covalent cross-linking monomer comprises crosslinkers with double bonds or other covalently reactive functional groups (e.g., NHS groups for amine reactivity or SH groups for Michael addition).

[0075] In embodiments, the covalent cross-linking monomer comprises polyethylene glycol dimethacrylate (PEGDMA), GelMA, and mixtures thereof. In embodiments, the hydrogel comprises 70% to 90%, e.g., about 70%, about 75%, about 80%, about 85%, or about 90%, by weight, including all values and ranges therebetween of the covalent cross-linking polymer. In embodiments, the covalent cross-linking polymer comprises GelMA.

[0076] In embodiments, the hydrogel comprises about 4% to about 10%, e.g., about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10%, by weight, including all values and ranges therebetween of the covalent cross-linking monomer. In embodiments, the covalent cross-linking monomer comprises PEGDMA.

[0077] In embodiments, the hydrogel comprises a physical cross-linking polymer.

[0078] In embodiments, the physical cross-linking polymer comprises polyglutamic acid, alginate, pectin, carrageenan, gellan gum, Polygalacturonic acid, anthan gum, anthum gum with locust bean gum, and mixtures thereof. In embodiments, the physical cross-linking polymer comprises alginate. In embodiments, the physical cross-linking polymer comprises polyglutamic acid.

[0079] In embodiments, the hydrogel comprises about 8% to about 15%, e.g., about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, by weight, including all values and ranges therebetween of the physical cross-linking polymer. In embodiments, the physical - linking polymer comprises alginate.

[0080] In embodiments, the hydrogel comprises an initiator. In embodiments, the initiator comprises lithium phenyl-2,4,6-trimethylbenzoylphosphinate, ammonium persulfate, and combinations thereof. In embodiments, the hydrogel comprises about 1% to about 3%, e.g., about 1%, about 1.5%, about 2%, about 2.5%, or about 3%, by weight, including all values and ranges therebetween of the initiator.

[0081] In embodiments, the hydrogel comprises an osteoinductive growth factor, covalent cross-linking polymer, covalent cross-linking monomer, and physical cross-linking polymer.

[0082] In embodiments, the hydrogel comprises an osteoinductive growth factor, covalent cross-linking polymer, covalent cross-linking monomer, physical cross-linking polymer, and an initiator.

[0083] Scaffold Filament

[0084] Aspects of the present disclosure provide a scaffold filament. The scaffold filaments of the present disclosure are treated (e.g., chemically and / or thermally) to provide porous scaffold filaments onto which a hydrogel containing an osteoinductive growth factor is coated to provide an osteoinductive material of the present disclosure.

[0085] In embodiments, the scaffold filament comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP), polylactic acid (PLA); polyglycolic acid (PGA); poly(lactic-co-glycolic acid) (PLGA); polyhydroxyalkanoates (PHAs); polybutylene succinate (PBS); polytrimethylene carbonate (PTMC), and mixtures thereof. In embodiments, the scaffold filament comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP). In embodiments, the scaffold filament comprises a ceramic. In embodiments, the ceramic comprises include calcium phosphate, tricalcium phosphate (TCP), hydroxyapatite (HA), biphasic HA / TCP, CaSO4, and mixtures thereof.

[0086] In embodiments, the scaffold filament comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP) in a weight ratio of about 4: 1.

[0087] In embodiments, the scaffold filament comprises salts deposited onto the surface of the scaffold filament. In embodiments, the salts are salts of divalent cations to include Ca2+, Mg2+, Sr2+, Zn2+, and combinations thereof. In embodiments, the salts are salts are multivalent salts to include Ti4+, Al3+, and combinations thereof.

[0088] In embodiments, the scaffold filament comprises calcium sulfate microparticles deposited onto the scaffold filament. In embodiments, the scaffold filament comprises calcium chloride microparticles deposited onto the scaffold filament.

[0089] In embodiments, the surface of the scaffold filament is modified to provide a rough microporous surface.

[0090] In embodiments, the surface of the scaffold filament is treated with a base, acid, plasma, and combinations thereof. In embodiments, the scaffold filament undergoes freeze-thaw treatments.

[0091] In embodiments, the scaffold filament is porous. In embodiments, the scaffold filament has a porosity of about 50% to about 80%, e.g., about 50%, about 60%, about 70%, or about 80%, including all values and ranges therebetween, by volume, of the total scaffold filament.

[0092] In embodiments, the scaffold filament has pores ranging in size of 100 nm to 30 mm, e.g., about 100 nm, about 500 nm, about 1000 nm, 10 mm, 15 mm, 20 mm, 30 mm, or 40 mm, including all values and ranges therebetween.

[0093] In embodiments, the scaffold filament has pores with diameters ranging in size from about 2 mm to about 5 mm, e.g., about 2 mm, about 3 mm, about 4 mm, or about 5 mm, including all values and rangers therebetween.

[0094] In embodiments, the scaffold filament has pores ranging in size of 10 nm to 50 mm, e.g., about 10 nm, about 20 nm, about 30 nm, about 40 nm, about 50 nm, about 60 nm, about 70 nm, about 90 nm, about 100 nm, about 500 nm, about 1000 nm, about 10 mm, about 15 mm, about 20 mm, about 30 mm, about 40 mm, or about 50 mm, including all values and ranges therebetween.

[0095] In embodiments, the hydrogel is chemically crosslinked to the scaffold filament. In embodiments, the hydrogel crosslinked to the scaffold filament has a thickness of about 10 mm to 1 mm, e.g., about 10 mm, about 100 mm, about 200 mm, about 300 mm, about 400 mm, about 500 mm, about 600 mm, about 700 mm, about 800 mm, about 900 mm, or about 1 mm, including all values and ranges therebetween.

[0096] Intermedullary Attachment

[0097] Aspects of the present disclosure provide an intermedullary attachment that attaches the osteoinductive material to bone.

[0098] In embodiments, the intermedullary attachment is a nail. In embodiments, the intermedullary nail is inserted to lie within a central cavity of a bone defect.

[0099] In embodiments, the intermedullary attachment is a plate. In embodiments, the intermedullary plate is fixed to the side of a bone defect.

[0100] In embodiments, the intermedullary attachment comprises titanium, titanium alloy, cobaltchromium alloys, magnesium alloys, zinc alloys, and mixtures thereof.

[0101] In embodiments, the intermedullary attachment comprises titanium alloy.

[0102] Osteoconductive Porous Scaffold

[0103] Aspects of the present disclosure provide an osteoconductive porous scaffold. In embodiments, the osteoconductive porous scaffold comprises a central channel. In embodiments, the central channel is for insertion of an intermedullary nail. In embodiments, the central channel comprises a flat area to accommodate an intermedullary nail that is rod-shaped with a flat area on the length of the rod.

[0104] In embodiments, the osteoconductive porous scaffold comprises one or more peripheral channels. In embodiments, the one or more peripheral channels are for insertion of the scaffold filament.

[0105] In embodiments, the osteoconductive porous scaffold comprises one, two, three, four, five, six, or more peripheral channels. In embodiments, the osteoinductive porous scaffold comprises six peripheral channels.

[0106] In embodiments, the osteoconductive porous scaffold comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP).

[0107] In embodiments, the osteoconductive porous scaffold is prepared by 3-D printing.

[0108] FIG. 9 shows exemplary schematics of a customizable MST device 100. As shown, the device includes a scaffold 110 configured to receive a plurality of osteoinductive inserts (i.e., “inserts”) 120. The scaffold 110 may include or be formed from an osteoconductive material. In some embodiments, the scaffold 110 may form a shape corresponding to a bone fracture type or bone structure. The shape of the scaffold 110 may be customizable based on the bone fracture and / or may correspond to the shape of the bone. In some embodiments, the scaffold 110 may define a substantially flat surface having a predetermined radius of curvature. In some embodiments, the radius of curvature may correspond to the bone structure. As shown in FIG. 9, the scaffold 110 forms an irregular shape in which a portion of the scaffold 110 structure curves.

[0109] The scaffold 110 may form a grid or lattice structure. For example, the scaffold 110 can define a plurality of openings (e.g., apertures, cells, etc.) 112 configured to receive at least a portion of an insert. In some embodiments, the scaffold 110 may include a plurality of rods 116 (e.g., extensions, bars, struts, etc.) that intersect to form the lattice structure or lattice-like structure (i.e., to define the plurality of openings). In some embodiments, the shape of each of the openings 112 defined in the scaffold 110 may be customizable depending on the bone fracture. In some embodiments, the rods 116 can be substantially parallel to one another to form a plurality of square or rectangular openings 112. In some embodiments, the openings 112 can have any suitable shape such as, for example, a square, a rectangle, a triangle, diamond, parallelogram, a circle, an oval, or an irregular shape. In some embodiments, the scaffold 110 can define the openings 112 along a first axis (“x”) and second axis (“y”), and can define a plurality of slots 114a, 114b along the second axis and a third axis (“z”). For example, the rods 116 defining each opening 112 may also define slots 114a, 114b such that the inserts 120 can be disposed therethrough to align with the opening 112. In some embodiments, the scaffold 110 may include a pair of rods including a space therebetween to form a slot 114b. The plurality of slots 114a, 114b may be configured to receive the inserts 120 therethrough such that a portion of the insert 120 (i.e., at least a portion of the large face of the insert 120) is exposed through the plurality of openings 112. In some embodiments, the plurality of slots 114a, 114b may have a shape corresponding to a cross-sectional shape of the insert 120 (i.e., of a cross-section taken along a plane perpendicular to the largest faces of the insert 120). For example, the slots 114a may include a circular shape to receive a cylindrical insert (i.e., Spec 5 or Spec 6). In some embodiments, the slots 114b may include a rectangular shape to receive square or rectangular inserts (i.e., Spec 1-4). In some embodiments, the inserts 120 can be moved through the slots 114a, 114b (i.e., along the x axis or y axis) until the large faces of the inserts align with a respective opening 112, as shown in FIG. 9 on the right.

[0110] In some embodiments, the inserts 120 can have any suitable shape such as, for example, a square, rectangular, cylindrical, circular, oval, triangular, or irregular shape. In some embodiments, the shape of the insert 120 may correspond to a shape of the corresponding openings 112 of the scaffold 110. In some embodiments, the insert 120 may be configured to span across a plurality of openings 112 of the scaffold 110. As shown, the inserts 120 (e.g., Spec 3 and Spec 4) are configured to span across three openings 112 defined in the scaffold 110. In some embodiments, a number of inserts 120 and the arrangement of the inserts 120 in the scaffold 110 can be adjusted based on the fracture to treat. In some embodiments, each of the inserts 120 may have different predetermined specifications. For example, the inserts 120 may have different dosages, release rates, shapes, sizes, or more.

[0111] FIGs. 10A-10B show exemplary embodiments of a flat MST device 200. As shown, the MST device 200 includes a scaffold 210 defining a plurality of openings 212 and a plurality of slots 213 configured to receive a plurality of inserts such that the inserts align with the plurality of openings 212. In some embodiments, the scaffold 210 may be substantially flat. The scaffold 210 may form a grid defining M rows and N columns of openings 212. In some embodiments, the scaffold may include between 1 row and between 50 rows, inclusive of all ranges and subranges therebetween. In some embodiments, the scaffold may include between 1 column and between 50 columns, inclusive of all ranges and subranges therebetween. For example, as shown in FIG. 10A (top), the scaffold includes 4 rows and 3 columns, and defines rectangular openings. In some embodiments, the scaffold may include 3 rows and 4 columns and may define square openings. The MST device 200 may be structurally and / or functionally similar to the MST device 100 described in FIG.9, and therefore certain details are not described herein again with respect to FIG. 10 A.

[0112] FIG. 10B shows the scaffold 210 receiving different inserts. The scaffold may be configured to receive any combination of inserts. For example, the scaffold may receive inserts configured to cover a single opening.

[0113] FIG. 11 shows exemplary schematics of a MST device 300 having a round cross-sectional shape. In some embodiments, the scaffold 310 may be 3-dimensional and have a cross-sectional shape corresponding to the bone structure. As shown, the scaffold 310 includes a substantially tear drop cross-section. However, the scaffold 310 may have a cross-section that includes, for example, a circle, an oval, a football shape, a pear shape, or the like. The scaffold 310 may define a plurality of rings 315 connected by rods or bars 316 to define one or more a cylindrical structures (i.e., frames, cavities, etc.) having longitudinal axes that are parallel to one another. For example, the scaffold 310 may include two cylindrical frames. In some embodiments, the scaffold 310 may include additional rods or bars 318 to provide additional structural support. In some embodiments, the cylindrical frames may share rods and / or one or more portions of the cylindrical frames may be monolithically formed. In some embodiments, the cylindrical frames may each be configured to receive a cylindrical insert 320 therethrough. In some embodiments, a subset of the cylindrical frames may be configured to receive cylindrical inserts 320 therethrough. The MST device 300 may be structurally and / or functionally similar to the MST device 100 described in FIGs. 9-10B, and therefore certain details are not described herein again with respect to FIG. 11.

[0114] Kits (modular bioactive synthetic bone craft (MST)

[0115] Aspects of the present disclosure provide a kit comprising:

[0116] (a) the osteoinductive material described herein;

[0117] (b) an osteoconductive porous scaffold comprising a central channel and one or more peripheral channels; and

[0118] (c) an intermedullary nail, wherein the intermedullary nail is shaped to be inserted into the central channel of the osteoconductive porous scaffold, and the osteoconductive material is shaped for insertion into the one or more peripheral channels of the osteoconductive porous scaffold.

[0119] In embodiments, the present disclosure provides a kit comprising:

[0120] (a) the osteoinductive material described herein; and

[0121] (b) an osteoconductive porous scaffold comprising a central channel and one or more peripheral channels; wherein the osteoconductive material is shaped for insertion into the one or more peripheral channels of the osteoconductive porous scaffold. In embodiments, the osteoconductive porous scaffold comprises six peripheral channels.

[0122] In embodiments, the intermedullary nail is rod-shaped with a flat area on the length of the rod.

[0123] In embodiments, the intermedullary nail comprises a titanium alloy.

[0124] In embodiments, the intermedullary nail comprises a means for affixing the intermedullary nail to bone.

[0125] In embodiments, the affixing means comprises one or more bone screws.

[0126] In embodiments, the osteoconductive porous scaffold comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP).

[0127] In embodiments, the osteoconductive porous scaffold is prepared by 3-D printing.

[0128] Methods of Manufacturing

[0129] Aspects of the present disclosure provide methods of preparing the osteoinductive materials described herein. In embodiments, an osteoinductive material described herein is prepared by a process comprising:

[0130] (a) providing a scaffold filament;

[0131] (b) treating the scaffold filament to increase roughness and porosity;

[0132] (c) depositing microparticles on the treated scaffold filament; and

[0133] (d) cross-linking a hydrogel layer with the scaffold filament of step c), wherein the hydrogel layer comprises the osteoinductive growth factor.

[0134] In embodiments, an osteoinductive material described herein is prepared by a process comprising:

[0135] (a) providing a scaffold filament;

[0136] (b) treating the scaffold filament to increase hydrophilicity, roughness and porosity;

[0137] (c) cross-linking a hydrogel with the scaffold filament of step b) to form a first hydrogel layer;

[0138] (c) depositing microparticles on the treated scaffold filament; and

[0139] (d) cross-linking a hydrogel layer with the scaffold filament of step c) to form a second hydrogel layer, wherein the first and second hydrogel layers comprise an osteoinductive growth factor. In embodiments, the scaffold filament comprises polycaprolactone-beta-tricalcium phosphate (PCL- TCP).

[0140] In embodiments, the scaffold filament is treated in step (b) with a base to increase roughness and porosity. In embodiments, the base is NaOH. In embodiments, the scaffold filament is treated with NaOH for about 6 to about 12 hours or / and about 12 hours to about 24 hours at room temperature. In embodiments, the scaffold filament is treated with about 5 N to about 10 N, e.g., about 5 N, about 6 N, about 7 N, about 8 N, about 9 N, or about 10 N, including all values and ranges therebetween, of an NaOH solution.

[0141] In embodiments, the scaffold filament is treated with an aqueous NaOH solution. In embodiments, the concentration of the aqueous NaOH solution is about ION. In embodiments, the concentration of the aqueous NaOH solution is about 5 N.

[0142] In embodiments, calcium microparticles are microdeposited on the treated scaffold filament of step (b). In embodiments, calcium microparticles are microdeposited on the treated scaffold filament of step (b) after treatment with NaOH. In embodiments, the calcium microparticles comprise CaSO4. In embodiments, the treated scaffold filament of step (b) is soaked in a suspension comprising CaSO4 to provide the microdeposited calcium microparticles.

[0143] In embodiments, cross-linking the scaffold filament of with a hydrogel layer (i.e., step (d)) comprises treating the scaffold filament of step (c) with a hydrogel precursor solution.

[0144] In embodiments, the hydrogel precursor solution comprises covalent cross-linking polymer, covalent crosslinking monomer, and a physical cross-linking polymer. In embodiments, the hydrogel precursor solution comprises an initiator. In embodiments, the hydrogel precursor solution comprises 10% to 20%, e.g., about 10%, about 12%, about 14%, about 16%, about 18%, or about 20%, including all values and ranges therebetween, of the covalent-crosslinking polymer. In embodiments, the hydrogel precursor solution comprises about 13% to about 15% of GelMA.

[0145] In embodiments, the hydrogel precursor solution comprises 1% to about 3%, e.g., about 1%, about 1.5%, about 2%, about 2.5%, or about 3%, including all values and ranges therebetween, of the covalent-crosslinking polymer. In embodiments, the hydrogel precursor solution comprises 2% of PEGDMA.

[0146] In embodiments, the hydrogel precursor solution comprises about 1% to about 3%, e.g., about 1%, about 1.5%, about 2%, about 2.5%, or about 3%, including all values and ranges therebetween, of the physical-crosslinking polymer. In embodiments, the hydrogel precursor solution comprises 1.25% alginate.

[0147] In embodiments, the hydrogel precursor solution comprises about 0.1% to about 1% e.g., about 0.1%, about 0.5%, or about 1%, including all values and ranges therebetween, of the initiator. In embodiments, the hydrogel precursor solution comprises 0.3% of initiator.

[0148] In embodiments, the osteoinductive material is freeze-dried.

[0149] In embodiments, the osteoinductive material is sterilized. In embodiments, the osteoinductive material is sterilized with an electron beam.

[0150] In embodiments, the hydrogel layer comprises a covalent cross-linking polymer, covalent crosslinking monomer, and a physical cross-linking polymer.

[0151] In embodiments, the covalent cross-linking polymer comprises gelatin methacrylate, gelatin, collagen, collagen methacrylate, and combinations thereof.

[0152] In embodiments, the covalent cross-linking monomer comprises polyethylene glycol dimethacrylate.

[0153] In embodiments, the physical cross-linking polymer comprises alginate.

[0154] In embodiments, the hydrogel layer is crosslinked to the scaffold filament through cross-linking of the physical-crosslinking polymer to the covalent cross-linking polymer and covalent crosslinking monomer.

[0155] Methods of Use

[0156] Aspects of the present disclosure provide methods for promoting bone regeneration with the osteoinductive materials described herein. In embodiments, the methods include treating bone defects, correcting bone deformities, or healing a bone nonunion. In embodiments, prior to implantation, the osteoinductive material is inserted into one or more peripheral channels in an osteoconductive porous scaffold, wherein the osteoconductive porous scaffold comprises a central channel and one or more peripheral channels.

[0157] In embodiments, prior to implantation, an intermedullary nail is inserted into the central channel of the osteoconductive porous scaffold.

[0158] In embodiments, after implantation, the osteoinductive material is inserted into one or more peripheral channels in an osteoconductive porous scaffold, wherein the osteoconductive porous scaffold comprises a central channel and one or more peripheral channels.

[0159] In embodiments, after implantation, an intermedullary nail is inserted into the central channel of the osteoconductive porous scaffold.

[0160] In embodiments, the intermedullary nail is fixed to bone by one or more bone screws.

[0161] In embodiments, the osteoconductive porous scaffold is fixed to bone by a metallic plate.

[0162] In embodiments, the osteoinductive material and osteoconductive porous scaffold are modified to the contours of the bone defect, deformity, or non-union. In embodiments, the modification takes place in the operating room. In embodiments, the osteoinductive materials described herein are implanted between two bone segments, a bone tunnel, or fractured bone.

[0163] In embodiments, the present disclosure provides methods of treating bone defects with the osteoinductive materials described herein. In embodiments, the methods comprise inserting the osteoinductive materials into the distal and proximal bone segments through a defect gap, wherein the osteoinductive materials is secured using screws that connect the intermedullary attachment to the distal and proximal bone.

[0164] In embodiments, the present disclosure provides methods of bone lengthening and bone transport. In embodiments, the methods comprise inserting the osteoinductive materials anterogradely or retrogradely into the bone, wherein the osteoinductive materials are secured using screws that connect the intermedullary attachment, external frames, or fixator (see, e.g., International Patent Publication Nos. WO 2023 / 114103 and WO 2023 / 114104, which are hereby incorporated by reference in their entireties for all purposes) to the bone.

[0165] In embodiments, the present disclosure provides methods of treating a non-union (e.g., fracture). In embodiments, the methods comprise inserting the osteoinductive materials into the anterogradely or retrogradely into the bone segments through a defect gap, wherein osteoinductive materials are secured using screws that connect the intermedullary attachment to the distal and proximal bone. In embodiments, the methods of treating bone defects, correcting bone deformities, or healing a bone nonunion, the hydrogel covers the length of the defect.

[0166] NUMBERED EMBODIMENTS #1

[0167] 1. An osteoinductive material, comprising: a) a scaffold filament; b) a hydrogel layer cross-linked with the scaffold filament, and c) an osteoinductive growth factor; wherein the hydrogel layer comprises the osteoinductive growth factor, a covalent crosslinking polymer, a covalent cross-linking monomer, and a physical cross-linking polymer.

[0168] 2. The osteoinductive material of embodiment 1, wherein the scaffold filament comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP).

[0169] 3. The osteoinductive material of embodiment 1 or 2, wherein the scaffold filament comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP) in a weight ratio of about 4:1.

[0170] 4. The osteoinductive material of any one of embodiments 1-3, wherein the scaffold filament comprises calcium sulfate microparticles deposited onto the scaffold filament. 5. The osteoinductive material of any one of embodiments 1-4, wherein the surface of the scaffold filament is modified to provide a rough and microporous surface.

[0171] 6. The osteoinductive material of any one of embodiments 1-4, wherein the scaffold filament has pores ranging from 100 nm to 30 mm.

[0172] 7. The osteoinductive material of any one of embodiments 1-6, wherein the osteoinductive growth factor comprises BMP-2.

[0173] 8. The osteoinductive material of any one of embodiments 1-7, wherein the concentration of the osteoinductive growth factor in the hydrogel layer is about 0.1 mg / ml to 1.5 mg / ml.

[0174] 9. The osteoinductive material of any one of embodiments 1-8, wherein the osteoinductive material releases the osteoinductive growth factor for at least 21 days after insertion into a patient in need thereof.

[0175] 10. The osteoinductive material of any one of embodiments 1-9, wherein the osteoinductive material releases 10 pg / mL to 3 mg / mL per day of the osteoinductive growth factor for about 21 days following insertion into a patient in need thereof. 11. The osteoinductive material of any one of embodiments 1-10, wherein the covalent crosslinking polymer comprises gelatin methacrylate, gelatin, collagen, collagen methacrylate, and combinations thereof.

[0176] 12. The osteoinductive material of any one of embodiments 1-11, wherein the covalent crosslinking monomer comprises polyethylene glycol dimethacrylate, polyethylene glycol diacrylate (PEG-DA), and combinations thereof.

[0177] 13. The osteoinductive material of any one of embodiments 1-12, wherein the physical crosslinking polymer comprises alginate.

[0178] 14. The osteoinductive material of any one of embodiments 1-13, wherein the tensile modulus of the osteoinductive material is about 100 MPa to aboutl,000MPa

[0179] 15. The osteoinductive material of any one of embodiments 1-14, wherein the material is sterilized.

[0180] 16. The osteoinductive material of any one of embodiments 1-15, wherein the material is shaped in a rod.

[0181] 17. The osteoinductive material of embodiment 16, wherein the diameter of the rod is 1 mm to 20 mm. 18. The osteoinductive material of embodiment 16 or 17, wherein the length of the rod is 10 mm to 100 mm.

[0182] 19. An osteoinductive material prepared by a process comprising: a) providing a scaffold filament; b) treating the scaffold filament to increase roughness and porosity; c) depositing microparticles on the treated scaffold filament; and d) cross-linking a hydrogel layer with the scaffold filament of step c), wherein the hydrogel layer comprises the osteoinductive growth factor.

[0183] 20. The osteoinductive material of embodiment 19, wherein the material is freeze-dried.

[0184] 21. The osteoinductive material of embodiment 19 or 20, wherein the material is sterilized.

[0185] 22. The osteoinductive material of embodiment 21, wherein the material is sterilized with an electron beam.

[0186] 23. The osteoinductive material of any one of embodiments 19-22, wherein the material is microdeposited with calcium microparticles. 24. The osteoinductive material of embodiment 23, wherein the calcium microparticles comprise CaSO4.

[0187] 25. The osteoinductive material of any one of embodiments 19-24, wherein the material is treated with a base to increase roughness and porosity.

[0188] 26. The osteoinductive material of embodiment 24, wherein the base is NaOH.

[0189] 27. The osteoinductive material of any one of embodiments 19-26, wherein the scaffold filament comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP).

[0190] 28. The osteoinductive material of any one of embodiments 19-27, wherein the hydrogel comprises a covalent cross-linking polymer, covalent crosslinking monomer, and a physical crosslinking polymer.

[0191] 29. The osteoinductive material of embodiment 28, wherein the covalent cross-linking polymer comprises gelatin methacrylate, gelatin, collagen, collagen methacrylate, and combinations thereof.

[0192] 30. The osteoinductive material of embodiment 28, wherein the covalent cross-linking monomer comprises polyethylene glycol dimethacrylate. 31. The osteoinductive material of embodiment 28, wherein the physical cross-linking polymer comprises alginate.

[0193] 32. The osteoinductive material of any one of embodiments 28-31, wherein the hydrogel is crosslinked to the scaffold through cross-linking of the physical-crosslinking polymer to the covalent cross-linking polymer and covalent cross-linking monomer.

[0194] 33. A kit comprising: a) the osteoinductive material of any one of the preceding claims; b) an osteoconductive porous scaffold comprising a central channel and one or more peripheral channels; and c) an intermedullary nail, wherein the intermedullary nail is shaped to be inserted into the central channel of the osteoconductive porous scaffold and the osteoinductive material is shaped for insertion into the one or more peripheral channels of the osteoconductive porous scaffold.

[0195] 34. The kit of embodiment 33, wherein the osteoconductive porous scaffold comprises six peripheral channels.

[0196] 35. The kit of embodiment 33 or 34, wherein the intermedullary nail is rod-shaped with a flat area on the length of the rod. 36. The kit of claim of any one of embodiments 33-35, wherein the osteoconductive porous scaffold and intermedullary nail interlock through a flat area to avoid rotation.

[0197] 37. The kit of any one of embodiments 33-36, wherein the intermedullary nail comprises a titanium alloy.

[0198] 38. The kit of any one of embodiments 33-37, wherein the intermedullary nail comprises a means for affixing the intermedullary nail to bone.

[0199] 39. The kit of any one of embodiments 33-38, the affixing means comprises one or more bone screws.

[0200] 40. The kit of any one of embodiments 33-39, wherein the osteoconductive porous scaffold comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP).

[0201] 41. The kit of any one of embodiments 33-40, wherein the osteoconductive porous scaffold is prepared by 3-D printing.

[0202] 42. A method of treating a bone defect, deformity or nonunion in a patient in need thereof, the method comprising implanting the osteoinductive material of any one of claims 1 to 18 into the bone defect, deformity or nonunion. 43. The method of embodiment 42, wherein prior to implantation, the osteoinductive material is inserted into one or more peripheral channels in an osteoconductive porous scaffold, wherein the osteoconductive porous scaffold comprises a central channel and one or more peripheral channels.

[0203] 44. The method of embodiment 43, wherein prior to implantation, an intermedullary nail is inserted into the central channel of the osteoconductive porous scaffold.

[0204] 45. The method of embodiment 42 or 43, wherein the intermedullary nail is fixed to bone by one or more bone screws.

[0205] 46. The method of any one of embodiments 42-44, wherein the osteoconductive porous scaffold is fixed to bone by a metallic plate.

[0206] 47. The method of any one of embodiments 42-46, wherein the osteoinductive material and osteoinductive porous scaffold are modified to the contours of the bone defect, deformity, or nonunion.

[0207] 48. The method of embodiment 47, wherein the modification takes place in the operating room. NUMBERED EMBODIMENTS #2

[0208] 1. An osteoinductive material, comprising: a) a scaffold filament; b) a hydrogel layer cross-linked with the scaffold filament, and c) an osteoinductive growth factor; wherein the hydrogel layer comprises the osteoinductive growth factor, a covalent crosslinking polymer, a covalent cross-linking monomer, and a physical cross-linking polymer.

[0209] 2. The osteoinductive material of embodiment 1, wherein the scaffold filament comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP).

[0210] 3. The osteoinductive material of embodiment 1 or 2, wherein the scaffold filament comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP) in a weight ratio of about 4:1.

[0211] 4. The osteoinductive material of any one of embodiments 1-3, wherein the scaffold filament comprises calcium sulfate microparticles deposited onto the scaffold filament.

[0212] 5. The osteoinductive material of any one of embodiments 1-4, wherein the surface of the scaffold filament is modified to provide a hydrophilic, rough and microporous surface.

[0213] 6. The osteoinductive material of any one of embodiments 1-4, wherein the scaffold filament has pores ranging from 10 nm to 50 mm. 7. The osteoinductive material of any one of embodiments 1-6, wherein the osteoinductive growth factor comprises BMP-2.

[0214] 8. The osteoinductive material of any one of embodiments 1-7, wherein the concentration of the osteoinductive growth factor in the hydrogel layer is about 0.1 mg / ml to 3 mg / ml.

[0215] 9. The osteoinductive material of any one of embodiments 1-8, wherein the osteoinductive material releases the osteoinductive growth factor for at least 21 days after insertion into a patient in need thereof.

[0216] 10. The osteoinductive material of any one of embodiments 1-9, wherein the osteoinductive material releases 10 pg / mL to 3 mg / mL per day of the osteoinductive growth factor for about 21 days following insertion into a patient in need thereof.

[0217] 11. The osteoinductive material of any one of embodiments 1-10, wherein the covalent crosslinking polymer comprises gelatin methacrylate, gelatin, collagen, collagen methacrylate, and combinations thereof.

[0218] 12. The osteoinductive material of any one of embodiments 1-11, wherein the covalent crosslinking monomer comprises polyethylene glycol dimethacrylate, polyethylene glycol diacrylate (PEG-DA), and combinations thereof. 13. The osteoinductive material of any one of embodiments 1-12, wherein the physical crosslinking polymer comprises alginate.

[0219] 14. The osteoinductive material of any one of embodiments 1-13, wherein the tensile modulus of the osteoinductive material is about 100 MPa to about l,000MPa.

[0220] 15. The osteoinductive material of any one of embodiments 1-14, wherein the material is sterilized.

[0221] 16. The osteoinductive material of any one of embodiments 1-15, wherein the material is shaped in a rod.

[0222] 17. The osteoinductive material of embodiment 16, wherein the diameter of the rod is 1 mm to 20 mm.

[0223] 18. The osteoinductive material of embodiment 16 or 17, wherein the length of the rod is 10 mm to 200 mm.

[0224] 19. The osteoinductive material of any one of embodiments 1-15, wherein the material is shaped in a sheet. 20. The osteoinductive material of embodiment 19, wherein the sheet has a width of 5 mm to about 50 mm and a length of about 5 mm to about 50 mm.

[0225] 21. An osteoinductive material prepared by a process comprising: a) providing a scaffold filament; b) treating the scaffold filament to increase hydrophilicity, roughness and porosity; c) depositing microparticles on the treated scaffold filament; and d) cross-linking a hydrogel layer with the scaffold filament of step c), wherein the hydrogel layer comprises the osteoinductive growth factor.

[0226] 22. The osteoinductive material of embodiment 21, comprising crosslinking a hydrogel layer with the scaffold filament after step b).

[0227] 23. The osteoinductive material of embodiment 21 or 22, wherein the material is freeze-dried.

[0228] 24. The osteoinductive material of any one of embodiments 21-23, wherein the material is sterilized.

[0229] 25. The osteoinductive material of embodiment 24, wherein the material is sterilized with an electron beam. 26. The osteoinductive material of any one of embodiments 21-25, wherein the material is microdeposited with calcium microparticles.

[0230] 27. The osteoinductive material of embodiment 26, wherein the calcium microparticles comprise CaSO4.

[0231] 28. The osteoinductive material of any one of embodiments 21-27, wherein the material is treated with a base to increase hydrophilicity, roughness and porosity.

[0232] 29. The osteoinductive material of embodiment 28, wherein the base is NaOH.

[0233] 30. The osteoinductive material of any one of embodiments 21-29, wherein the scaffold filament comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP).

[0234] 31. The osteoinductive material of any one of embodiments 21-30, wherein the hydrogel comprises a covalent cross-linking polymer, covalent crosslinking monomer, and a physical crosslinking polymer.

[0235] 32. The osteoinductive material of embodiment 31, wherein the covalent cross-linking polymer comprises gelatin methacrylate, gelatin, collagen, collagen methacrylate, and combinations thereof. 33. The osteoinductive material of embodiment 31, wherein the covalent cross-linking monomer comprises polyethylene glycol dimethacrylate.

[0236] 34. The osteoinductive material of embodiment 31, wherein the physical cross-linking polymer comprises alginate.

[0237] 35. The osteoinductive material of any one of embodiments 31-34, wherein the hydrogel is crosslinked to the scaffold through cross-linking of the physical-crosslinking polymer to the covalent cross-linking polymer and covalent cross-linking monomer.

[0238] 36. A kit comprising: a) the osteoinductive material of any one of the preceding claims; b) an osteoconductive porous scaffold comprising a central channel and one or more peripheral channels; and wherein the osteoinductive material is shaped for insertion into the one or more peripheral channels of the osteoconductive porous scaffold.

[0239] 37. The kit of embodiment 36, further comprising an intermedullary nail, wherein the intermedullary nail is shaped to be inserted into the central channel of the osteoconductive porous scaffold. 38. The kit of embodiment 36 or 37, wherein the osteoconductive porous scaffold comprises six peripheral channels.

[0240] 39. The kit of embodiment 37 or 38, wherein the intermedullary nail is rod-shaped with a flat area on the length of the rod.

[0241] 40. The kit of any one of embodiments 37-39, wherein the osteoconductive porous scaffold and intermedullary nail interlock through a flat area to avoid rotation.

[0242] 41. The kit of any one of embodiments 37-39, wherein the intermedullary nail comprises a titanium alloy.

[0243] 42. The kit of any one of embodiments 37-39, wherein the intermedullary nail comprises a means for affixing the intermedullary nail to bone.

[0244] 43. The kit of claim 42, wherein the affixing means comprises one or more bone screws.

[0245] 44. The kit of any one of embodiments 36-43, wherein the osteoconductive porous scaffold comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP).

[0246] 45. The kit of any one of embodiments 36-44, wherein the osteoconductive porous scaffold is prepared by 3-D printing. 46. A method of treating a bone defect, deformity or nonunion in a patient in need thereof, the method comprising implanting the osteoinductive material of any one of claims 1 to 20 into the bone defect, deformity or nonunion.

[0247] 47. The method of embodiment 46, wherein prior to implantation, the osteoinductive material is inserted into one or more peripheral channels in an osteoconductive porous scaffold, wherein the osteoconductive porous scaffold comprises a central channel and one or more peripheral channels.

[0248] 48. The method of embodiment 47, wherein prior to implantation, an intermedullary nail is inserted into the central channel of the osteoconductive porous scaffold.

[0249] 49. The method of embodiment 47, wherein after implantation, an intermedullary nail is inserted into the central channel of the osteoconductive porous scaffold.

[0250] 50. The method of embodiment 46 or 49, wherein the intermedullary nail is fixed to bone by one or more bone screws.

[0251] 51. The method of any one of embodiments 46-47, wherein the osteoconductive porous scaffold is fixed to bone by a metallic plate. 52. The method of any one of embodiments 46-51, wherein the osteoinductive material and osteoinductive porous scaffold are modified to the contours of the bone defect, deformity, or nonunion.

[0252] 53. The method of embodiment 52, wherein the modification takes place in the operating room.

[0253] EXAMPLES

[0254] Example 1: Manufacturing Process

[0255] Exemplary Device Description:

[0256] An exemplary Modular Bioactive Synthetic Bone Graft (MST) device is shown in FIGs. 1A-1C. The device is comprised of three parts: osteoinductive hydrogel filament, osteoconductive porous scaffold, and metallic intramedullary nail for fixation and mechanical support. Both the nail and scaffold possess a flat area. When the nail is inserted into the scaffold, the nail and scaffold interlock through the flat area to prevent and avoid rotation of the scaffold. This design helps the fit and fixation of the MST device for segmental bone defects with various irregular ending planes or surfaces to improve surgical handling properties and treatment outcome in clinics.

[0257] Osteoinductive Material:

[0258] FIG. ID shows a schematic for the coating of the filaments with the hydrogel. BMP -2-laden hydrogen was loaded onto the surface of filaments (FIG. ID). Before the hydrogel loading, the filaments were treated with NaOH to introduce hydrophilic functional groups to increase the roughness and microporosity, followed by covalent crosslinking a GelMA hydrogel coating, and then deposited with CaSCU microparticles as crosslinkers. A porous BMP-2-laden hydrogel layer was formed on the surface of the filaments by the surface-initiated physical crosslinking of alginate followed by covalent crosslinking of GelMA and PEGDMA, and the construct was then freeze-dried. This process is similarly depicted in FIG. IE showing the scaffold (left), followed by infiltration of the BMP -2 hydrogel (middle), and freeze drying and electron beam sterilization (right) to provide the resulting hydrogel scaffold filament.

[0259] The hydrogel coating process involves surface initiated crosslinking via ion diffusion of a prepolymer solution into the scaffold filament. First, the alginate is ionically crosslinked, forming a thick soft viscous gel-like structure that functions as a glue holding the aqueous GelMa and PEGDMA within the scaffold filament. The scaffold filament is then exposed to visible light to photocrosslink the GelMA and GEDMA by forming a covalent bond network. Both the ion diffusion distance and the initial ionic crosslinking dictate the thickness of the alginate viscous gel and the loading of the growth factor within the scaffold filament. On the other hand, the photocrosslinking of the GeLMA and PEGDMA dictates the controlled and sustained release of the growth factor due to the tight hydrogel mesh network formed from the covalent bonds. The release kinetics of the growth factor are tunable by varying the calcium ion concentration during the alginate crosslinking step as well as by adjusting the light exposure time and photoinitiator concentration during the GelMA-PEGDMA photocrosslinking step. Moreover, the e-beam sterilization can create a dense outermost surface of the hydrogel coating, resulting in a more prolonged release of the growth factor.

[0260] FIGs. 1F-1H are SEM images of 3D structures of the porous graft (i.e., osteioinductive material) after surface treatments showing homogeneous distribution of calcium particles on the surface (FIG. IF). After coating with the hydrogel, the surface of the construct becomes highly porous, as shown in FIG. IG. The density of the micro-pores after electron beam (E-Beara) sterilization decreases significantly (FIG. 1H), indicating that the E-Beam irradiation has partially melted the surface, blocking the smaller pores and creating an effectively denser and less microporous surface.

[0261] Mechanical Testing of the Osteoconductive Materials:

[0262] FIGs. 1I-1K are photos depicting the mechanical testing of the osteoconductive material. The mechanical testing shows that there are no significant differences in mechanical properties of samples before and after E beam sterilization (FIG. II). Torsional testing and compression testing is shown in FIGs. 1 J-1K.

[0263] Hydrogel coating increased the wet weight (FIG. IM). The hydrogel layer was attached firmly to the filament after freeze-drying, showing a smooth transition from the hydrophobic filament to the hydrophilic hydrogel at the interface (FIG. IN) and robust adhesion strength (FIG. IO), with an average interfacial stiffness equaling of (0.609 ± 0.194) MPa. BMP -2 was released from the freeze-dried hydrogel -loaded implant in a sustained and dose-dependent manner over 21 days (FIG. IP). BMP-2 released from the stored implants stored for 2 months at 4 °C showed similar release kinetics to the freshly prepared implants (FIG. IQ), indicating a minimum extended shelflife of at least 2 months. A prolonged release of BMP-2 could be achieved by coating the IM implant with additional layers of PCL. The amount of BMP-2 released within 28 days reduced from 84% in the original IM implant to 62% or 24% when coated with one or three layers of PCL, respectively (FIG. 1R). This modified HyTEC (mHyTEC) technique using a multilayer coating approach could be used for a prolonged release in future studies involving large animal models and humans. These studies indicate that with the HyTEC technique, a unique surface coating technique can incorporate a broad range of BMP -2 dosages on the surface of the scaffolds and can allow for tunable sustained release kinetics.

[0264] Osteoconductive Cage Fabrication:

[0265] A 3D design of the graft cage was developed to meet the following criteria: graft size, porosity, mechanical strength, surgical implantation, and capability of fabrication via 3D printing technology. The geometry of the scaffold consists of interconnected 3D printable struts which form a tubular outer structure and a central channel for fixation on an intramedullary (IM) nail (FIG. 1A). Also, six side channels are designed around the central channel for holding the osteoinductive materials (FIG. 1A).

[0266] To fabricate the porous bone graft cage from a biocompatible and biodegradable material, a composite of polycaprolactone (PCL) and P-tricalcium phosphate (P-TCP) was developed which is compatible with 3D printing technology. The solid CAD model of the scaffold is postprocessed in a 3D printing software for 3D slicing and generation of a layer-by-layer printable digital 3D model. The 3D printing parameters such as speed and temperature are iteratively tuned. Due to complex geometry and large pore sizes of the graft cage, a water-soluble support structure is implemented in 3D printing process to support overhangs while printing. Polyvinyl alcohol (PVA) is used as the water-soluble material for support structure. A dual nozzle 3D printer (Ultimaker S3) is used for fabrication of the bone graft cage. After finishing the print, the PVA support is dissolved in DI water and the remained 3D printed part is the bone graft cage. MST Device:

[0267] FIGs. 2A-2D show the flexibility and easy surgical handling of the MST device for placing and repairing bone defects with different lengths, and contours. FIG.2A is a schematic showing repairing of a bone defect. In the left panel, the multiple MST can be stacked to repair a larger bone defect. In the middle and right panels, the MST can be trimmed to match any defects of different contours to easy fixation and surgical operations. FIGs. 2B-2D are the schematics and photos of the MST trimming and placement of the defects of different contours in a surgical setting.

[0268] Example 2: In Vitro Release of Bone Morphogenetic Protein-2 (BMP-2)

[0269] An in vitro study of the hydrogel scaffold filaments was performed to study the release kinetics of BMP -2 encapsulated in the hydrogel scaffold filaments.

[0270] Sterilized hydrogel scaffold filaments were placed into new 1.5 mL Eppendorf tubes for constructs smaller than 1 cm in length or conical tubes for larger constructs. Phosphate buffer solution (PBS) was added to fully immerse the constructs, with 1.2 mL added to the 1 mm x 18 mm rod-shaped implants and 1 mL added to the 1cm porous grafts. The tubes were then placed into a 37°C incubator to start the release study. At designated time points determined by the length of the study (Day 1, 3, 7, and so on), the PBS media were removed and frozen at -80°C. The samples were then replaced with fresh PBS and placed into a new container. The rod-shaped 1 mm x 18 mm implant in vitro study were carried out for 28 days, and the 3 mm x 1 cm porous graft were sustained for 13 weeks to emulate the in vivo defect model timelines (FIG. 3A). Frozen samples (-80°C) from the release kinetics studies were thawed at 37°C for 1 hour. A sandwich enzyme-linked immunosorbent assay (ELISA) was used to assess the BMP -2 concentration present at each time point, following the manufacturer’s protocol. Briefly, a serial dilution of lyophilized recombinant BMP -2 will be made using a 3 ng / mL stock solution to create a BMP-2 standard curve. Release samples were diluted to stay within the linear range based on the theoretical loading. 100 pL of all samples and standards were added to the coated 96-well ELISA plate, incubated for 2.5 hours on a shaking platform, and then removed. Each well was washed four times using lx wash buffer and a multichannel pipette, taking care to completely aspirate and dry each well. The biotinylated detection antibody was added next, incubated for 1 hour on the shaker, and followed by the same washing procedure. The detection streptavidin peroxidase solution was then added and incubated for 45 minutes before removing and washing. Finally, the colorimetric substrate was added, protected from light using aluminum foil, and incubated for 30 minutes with gentle shaking. The reaction was stopped using the provided stop solution, and the absorbance values at 450 nm will be read immediately using a microplate reader. The BMP-2 release profile is shown in FIG. 3B.

[0271] Example 3: Animal Study

[0272] This was a study to compare the osteoinductive material to an autograft in a sheep 5 cm metatarsal segmental bone defect model (n=l for the osteoinductive material, and n=2 for autograft) (Tables 1-2, FIG. 4). The osteoinductive material contained 2 mg of BMP2 based on 0.4mg / ml of BMP2 for 5 cm bone defect. Autograft of 5 to 6 cc was harvested from ilium and transplanted for repairing the defect. This study was terminated 6 months after implantation. Micro-CT quantification analysis of the regenerating bone volume in the defects showed 5126 mm3for the osteoinductive biomaterial sheep, and 2578 mm3and 2466 mm3for the two autograft sheep, respectively. The regenerating bone volume in the defects repaired by the osteoinductive material was twice as large as that repaired by autografts. Study demonstrated that the osteoinductive material significantly accelerates bone union, increases bone volume, and enhances bone healing compared to autograft methods.

[0273] Table 1. Proposed Animal Study Design for MST

[0274] Table 2. Study Design

[0275] Example 4: Patient Study

[0276] The following example describes treatment of a racing horse with a mandibular cyst and defect using an MST device described herein.

[0277] The horse initially suffered a mandibular bone fracture, which led to the development of a bone cyst in her mandible (FIG. 5A). After the first surgical treatment, the bone cyst recurred within a few months (FIGs. 5B-5C). In order to treat the mandibular defect following surgical removal of the cyst, a customized MST device designed for weight-bearing long bone repair (FIGs. 1A-1C) was used. The MST device comprised two parts: osteoinductive hydrogel filament and osteoconductive porous scaffold (FIGs. 6A-6B). The surgery was successful, and the horse recovered (FIGs. 7A-7B). Radiographs at six months post-operation showed complete regeneration of new bone in the defect, with no difference in mineral density between the regenerated bone and the surrounding native bone (FIG. 7B).

[0278] A CT scan imaging comparison (FIGs. 8A-8B) shows that the growing bone cyst before operation, and the regenerating bone 18 months after treatment. In FIG. 8A, the growing bone cyst exhibits more than a threefold increase in width compared to the contralateral bone. In FIG. 8B, the regenerating bone has filled the previous defect following surgical removal of the bone cyst. This regeneration has significantly reduced the lesion width, bringing it much closer to that of the contralateral bone. The presence of regenerated cortical and trabecular bone suggests successful structural recovery post-treatment.

[0279] Example 5: Exemplary MST Designs

[0280] This example further illustrates the customizability of the MST device described herein by exemplifying various designs of the MST device. The example demonstrates the effectiveness of the MST device for the regenerative treatment for a wide range of bone defects ranging from simple to complex morphologies and different defect conditions.

[0281] Design 1 : Custom-Made MST Device

[0282] FIG. 9 shows a customized, patient specific MST device. The osteoconductive porous scaffold is composed of FDA cleared biodegradable composite of polycaprolactone and P-tricalcium phosphate PCL / p-TCP. A set of modular osteoinductive inserts are inserted into the osteoconductive porous scaffold which enables easy surgical handling as a unified structure.

[0283] Design 2: Flat Design

[0284] FIGs. 10A-10B show a flat MST design. This design is useful as flat bone grafts (e.g. treatment of ankle defects). The design incorporates a flat osteoconductive porous scaffold together with osteoinductive inserts.

[0285] Design 3 : Circular Design

[0286] FIG. 11 shows a circular MST design. The circular MST design includes an osteoconductive porous scaffold with single osteoinductive hydrogel filament.

[0287] From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without deviating from the scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

CLAIMS1. An osteoinductive material, comprising: a) a scaffold filament; b) a hydrogel layer cross-linked with the scaffold filament, and c) an osteoinductive growth factor, wherein the hydrogel layer comprises the osteoinductive growth factor, a covalent crosslinking polymer, a covalent cross-linking monomer, and a physical cross-linking polymer.

2. The osteoinductive material of claim 1, wherein the scaffold filament comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP).

3. The osteoinductive material of claim 1, wherein the scaffold filament comprises polycaprolactone-beta-tricalcium phosphate (PCL-TCP) in a weight ratio of about 4: 1.

4. The osteoinductive material of claim 1, wherein the scaffold filament comprises calcium sulfate microparticles deposited onto the scaffold filament.

5. The osteoinductive material of claim 1, wherein the surface of the scaffold filament is modified to provide a rough and microporous surface.

6. The osteoinductive material of claim 1 , wherein the scaffold filament has pores ranging from 10 nm to 50 mm.

7. The osteoinductive material of claim 1, wherein the osteoinductive growth factor comprises BMP-2.

8. The osteoinductive material of claim 1, wherein a concentration of the osteoinductive growth factor in the hydrogel layer is about 0.1 mg / ml to 3 mg / ml.

9. The osteoinductive material of claim 1, wherein the osteoinductive material releases the osteoinductive growth factor for at least 21 days after insertion into a patient in need thereof.10 The osteoinductive material of claim 1, wherein the osteoinductive material releases 10 pg / mL to 3 mg / mL per day of the osteoinductive growth factor for about 21 days following insertion into a patient in need thereof.

11. The osteoinductive material of claim 1, wherein the covalent cross-linking polymer comprises gelatin methacrylate, gelatin, collagen, collagen methacrylate, and combinations thereof.

12. The osteoinductive material of claim 1, wherein the covalent cross-linking monomer comprises polyethylene glycol dimethacrylate, polyethylene glycol diacrylate (PEG- DA), and combinations thereof.

13. The osteoinductive material of claim 1, wherein the physical cross-linking polymer comprises alginate.

14. The osteoinductive material of claim 1, wherein the tensile modulus of the osteoinductive material is about 100 MPa to aboutl,000 MPa.

15. The osteoinductive material of claim 1, wherein the material is sterilized.

16. The osteoinductive material of claim 1, wherein the material is shaped in a rod.

17. The osteoinductive material of claim 16, wherein the diameter of the rod is 1 mm to 20 mm.

18. The osteoinductive material of claim 16, wherein the length of the rod is 10 mm to 100 mm.

19. An osteoinductive material prepared by a process comprising: a) providing a scaffold filament; b) treating the scaffold filament to increase roughness and porosity; c) depositing microparticles on the treated scaffold filament; and d) cross-linking a hydrogel layer with the scaffold filament of step c), wherein the hydrogel layer comprises an osteoinductive growth factor.

20. A kit comprising: a) the osteoinductive material; and b) an osteoconductive porous scaffold comprising a central channel and one or more peripheral channels, wherein the osteoinductive material is shaped for insertion into the one or more peripheral channels of the osteoconductive porous scaffold.

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