BONE GRAFT SYSTEM

Abstract

The present invention relates to methods for bioresorbable and biodegradable casings having both micropores and macropores for providing shape, structure and containment to different bone grafting materials. Kits and methods of use are also described.

Claims

1. An implantable bone graft device comprising a bioresorbable casing comprising a cavity for receiving and containing a fill material, the bioresorbable casing comprising one or more seams configured to remain joined after trimming across them.

2. The implantable bone graft device of claim 1, wherein the one or more seams are sutured using a buttonhole stitch.

3. The implantable bone graft device of claim 1, wherein the one or more seams are joined by an adhesive.

4. The implantable device of claim 1, wherein the bioresorbable casing comprises a surface having both micropores and macropores, wherein the macropores are created in a sheet of bioresorbable material by mechanical, chemical, or thermal process and patterned and sized to prevent the fill material within the cavity from escaping therethrough while allowing osteogenic cells to pass through.

5. The implantable device of claim 1, wherein the bioresorbable casing comprises collagen.

6. The implantable device of claim 5, wherein the collagen casing contains demineralized bone matrix (DBM) in one or more formats selected from the group consisting of fibers, granules, paste, powder, chips, strips, and sponge.

7. The implantable device of claim 5, wherein the collagen casing contains biomaterials, bioceramics, bioglass, or calcium sulfate in one or more formats selected from the group consisting of fibers, granules, paste, powder, chips, strips, and sponge.

8. The implantable device of claim 5, wherein the collagen casing contains demineralized bone matrix (DBM) and bioceramics.

9. The implantable device of claim 1, wherein the micropores are random.

10. The implantable device of claim 2, wherein the sutures comprise a bioabsorbable material selected from the group consisting of polyglycolic acid, polylactic acid, and poly(lactic-co-glycolic acid).

11. The implantable device of claim 1, wherein the bioresorbable casing is formed from a single strip of folded collagen.

12. A method for preparing an implantable device, the method comprising: providing a bioresorbable casing comprising a cavity for receiving and containing a fill material, the bioresorbable casing comprising one or more sutured seams; trimming the bioresorbable casing to a desired size by cutting across one or more of the one or more sutured seams; closing the cavity of the trimmed bioresorbable casing.

13. The method of claim 12, wherein the provided bioresorbable casing cavity is empty, the method further comprising adding a fill material to the cavity before closing.

14. The method of claim 12, wherein closing the cavity comprises suturing.

15. The method of claim 12, wherein the sutured seams comprise buttonhole stitches.

16. The method of claim 12, wherein the one or more sutured seams comprise sutures comprising a bioabsorbable material selected from the group consisting of polyglycolic acid, polylactic acid, and poly(lactic-co-glycolic acid).

17. The method of claim 12, wherein the bioresorbable casing comprises collagen.

18. The method of claim 13, wherein the fill material comprises demineralized bone matrix (DBM) in one or more formats selected from the group consisting of fibers, granules, paste, powder, chips, strips, and sponge.

19. The method of claim 13, wherein the fill material comprises biomaterials, bioceramics, bioglass, or calcium sulfate in one or more formats selected from the group consisting of fibers, granules, paste, powder, chips, strips, and sponge.

20. The method of claim 12, wherein the bioresorbable casing comprises a surface having both micropores and macropores, wherein the macropores are created in a sheet of bioresorbable material by mechanical, chemical, or thermal process and patterned and sized to prevent the fill material within the cavity from escaping therethrough while allowing osteogenic cells to pass through.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 shows an open-ended bioresorbable casing according to certain embodiments.

[0028] FIG. 2 shows an exemplary closed bioresorbable casing.

[0029] FIG. 3 shows an exemplary open-ended bioresorbable casing with a fill tube inserted therein.

[0030] FIG. 4 shows an exemplary two-piece fill tube.

[0031] FIG. 5 shows an exemplary assembled fill tube.

[0032] FIG. 6 shows an exemplary plunger.

[0033] FIG. 7 shows an exemplary open-ended bioresorbable casing with a fill tube and plunger inserted therein.

[0034] FIG. 8 shows an exemplary holder.

[0035] FIG. 9 shows an open-ended bioresorbable casing in a body of an exemplary holder.

[0036] FIG. 10 shows an open-ended bioresorbable casing enclosed in an exemplary holder.

[0037] FIG. 11 shows an exemplary kit of the invention.

[0038] FIG. 12 shows an exemplary collagen strip.

[0039] FIG. 13 shows an exemplary collagen strip being folded and sutured into a casing.

[0040] FIG. 14 shows an exemplary collagen strip held in a tool for suturing into a casing.

[0041] FIG. 15 shows an exemplary stitching for use in forming a casing seam capable of being trimmed.

[0042] FIG. 16 shows an exemplary seam of a trimmable casing.

[0043] FIG. 17 shows an exemplary finishing knot for a trimmable casing seam.

DETAILED DESCRIPTION

[0044] Systems and methods of the invention relate to bioresorbable casings for providing containment and shape to bone graft particles. Such casings can be preferentially made of collagen or other bio-compatible and/or natural materials. They may be formed of a mesh comprising micro, macro, and/or nanopores. The pores should be sized based on the graft material contained therein to prevent the material from escaping and while allowing osteogenic cells and other biological fluids and materials to pass through, providing access to the graft material. Casings may be provided pre-filled, closed, and ready for use or may be provided open to be filled by a user before use. The open casing may be provided as part of a kit along with fill material and means for filling and closing the casing.

[0045] Casings may include one or more seams joining two edges of casing material together to form cavity in which to contain a fill material. In order to permit trimming of casings to fit a particular defect or other grafting application, such seams may be formed using a method that will prevent unraveling or further separation of the seam after trimming across it. In certain embodiments, such seams may be formed using an adhesive or application of heat (e.g., laser welding) to bond two sections of material together. In some embodiments, the seams may be formed via sutures and a buttonhole or locking stitch may be used in order to maintain the seam's integrity after trimming. A tool or fixture may be provided to aid in suturing the seam of a casing by holding the casing in the preferred size and shape and providing indicators for suture placement. Methods of preparing and using casings of the invention are also described herein.

[0046] FIGS. 1 and 2 show exemplary bioresorbable casings 101 of the invention. The casing 101 may be made of synthetic materials such as polyesters, polyamides, or polyolefins. Preferred synthetic materials include biodegradable polymers such as polyglycolide (PGA) and poly(lactic-co-glycolic acid) (PLGA). In preferred embodiments, the casing is made of a natural material such as collagen.

[0047] Casings preferably have both micropores and macropores. Macropores generally refer to pores between 100 m to 1000 m. Micropores generally refer to pores less than about 1 m to 100 m and, in certain embodiments, between about 1 m and about 10 m. In certain embodiments, the casing material may comprise nanopores, generally referring to pores 1 m or smaller.

[0048] Any of the above pores may be distributed randomly or patterned across the casing's surface. The pores may be distributed in a pattern based on the application of the final implant. For example, the macropores may be concentrated based on the anatomical location of the casing 101 once implanted to provide better access to osteogenic cells, fluids, or other biological material. Micro and macropores may be randomly distributed or patterned based on other considerations. FIG. 11 shows an exemplary collagen strip for use in preparing a casing having an exemplary pattern of pores across the surface of the material.

[0049] Pores may be formed via molding of the casing material wherein the size and distribution of the pores are dictated by the surface features of the mold. Casing materials may comprise solid sheets in which pores are created via known mechanical, chemical, or thermal processes. In certain embodiments, laser processing is used to form the desired size and pattern of pores in the casing material. In some embodiments, pores may be punched into the casing.

[0050] Casings 101 may be formed into the final desired size and shape through any known technique including injection or other molding techniques. Casings 101 are preferably prepared with a cavity therein to receive and contain the graft material. In initial preparation, an opening 105 should left by which the graft material can be inserted into the casing 101.

[0051] The open end 105 may be closed after filling either at a remote manufacturing site or by a user such as a surgeon or other medical professional before implantation using sutures 203 (FIG. 2). Sutures may be any biocompatible material including the natural and synthetic materials used to form the casing 101. In preferred embodiments, the sutures 203 comprise PGA or PLGA or collagen. Sutures may also include non-resorbable materials such as polypropylene and polyethylene. Other sealing methods are contemplated including adhesives, heat, and pressure, depending upon the nature of the casing material and intended use.

[0052] In certain embodiments, the casing 101 may be prepared from one or more sheets of the porous casing material. For example, a tube-shaped casing 101 may be prepared from two sheets of collagen or other material by laying the sheets together and suturing or otherwise sealing the sides 103 and bottom 107 to form a casing 101 with an opening 105 through which to add graft material. In some embodiments, a single sheet of porous material may be folded along an edge to form the bottom 107 of the casing 101 and then sutured or otherwise joined along the sides 103 to create the open-ended casing 101.

[0053] Casings 101 can be prepared and used in any size and shape depending on the intended application. Casings are contemplated for use in medical procedures such as orthopedic surgery and maxillofacial procedures. In certain embodiments, casings of the invention may be sized and shaped for use in spinal fusion procedures. For example, casings and implants made therefrom may be configured for placement in a posterolateral gutter for spinal fusion. They may be offered in various sizes depending on the number and position of the vertebrae to be fused and based on the age and/or size of the patient.

[0054] Methods of the invention can include obtaining a casing and optionally filling with a graft material if it is not prefilled. Filling may comprise the use of kit components as described below including one or more of a holder, a casing, a fill material, a plunger, and a fill tube. A user may then close the casing if it was not prefilled using the methods described above. Methods can include then implanting the filled casing to repair a bone defect, treat a traumatic injury, perform a spinal fusion, or any other osteogenic treatment calling for a graft prosthesis. Fill material such as those described below, including DBM and/or bioceramics may be obtained in dry form and can be wetted prior to filling. The bioceramics particles may include, for example, HA, tricalcium phosphate, monetite, brushite, or mono-calcium phosphate monohydrate (MCPM). Additional fill materials may include bioglass, collagen-ceramic mixtures, cell-based products, autografts, and growth factor containing products.

[0055] In certain embodiments, bioresorbable casing may be provided in kit form. Kits may include one or more of a casing, a fill material, a holder, a fill tube, and a plunger to facilitate filling of the casing by a user. Additional materials such as syringes and fluids for wetting and preparing fill material and/or the casing may also be included.

[0056] An exemplary kit is shown in FIG. 11. The kit includes a holder 801, a casing 101, and a fill tube 301, all shown assembled ready for filling. A plunger 601 is included as well as fill material 1101 shown in a dish for wetting and preparation as well as a syringe 1103 of fluid for wetting and preparing the fill material 1101.

[0057] A fill tube 301 is depicted in FIGS. 3-5. The fill tube 301 should have at least one end sized to fit within the opening 105 of the casing 101. The tube 301 comprises a lumen through which fill material may be passed into the casing 101 through the opening 105. The casing material may generally offer little material support such that maintaining the opening 105 during filling is difficult. The fill tube 301 can be rigid enough to then maintain the opening 105 for filling. The outer surface of the fill tube 301 is preferably sized to fit snugly within the opening 105 and the inner lumen of the fill tube 301 is preferably sized to allow the passage of fill material therethrough and into the casing 101. The outer surface and lumen of the fill tube 301 may be enlarged at the end not inserted into the opening 105 to ease loading of material. For example, the fill tube 301 may include a funnel 303 at one end providing a large opening for material to be added followed by a gradual reduction in cross-sectional profile to fit within the casing 101. The fill tube 301 may comprise multiple parts to ease in packaging or to provide different funnel 303 options. For example, the fill tube 301 may be made up of two components including a casing insertion portion 307 and a funnel portion 305 which can be assembled prior to filling. Funnel portions 305 of different sizes may be selected based on the fill material.

[0058] Fill tubes 301 may be made of any known material including, for example, metal, glass, plastic, and composite materials. In certain embodiments, kits may include a plunger 601 for aiding in casing filling as shown in FIG. 6. The plunger 601 is sized to fit within the lumen of the fill tube as sized at the end inserted into the casing 101. The plunger 601 may have a single size and shape or may have a smaller handle portion 603 and a larger plunging portion 605 to provide a large cross-sectional area for forcing fill material into the casing 101.

[0059] The plunger 601 preferably has a cross-sectional profile sized just smaller than the lumen of the fill tube 301 and the opening 105 in the casing 101 so that fill material cannot readily pass between the inside of the fill tube 301 lumen and the edges of the plunger 601. Filling action using the plunger 601 to force fill material through a fill tube 301 into the opening 105 of a casing 101 is shown in FIG. 7. The plunger may include features such as serrations or openings in the plunging portion 605 to physically process the fill material during insertion including separating granules and avoiding clumping.

[0060] Kits may include a holder 801 for supporting and positioning a casing 101 for fill. An exemplary holder 801 is shown in FIG. 8. The holder 801 can comprise a body 803 sized to accept the casing 101 and align the opening 105 of the casing 101 with an inlet 805 in the body 803 of the holder 801. As noted above with respect to the fill tube 301, the casing material has little rigidity and, therefore filling the casing 101 can be difficult, even with the use of the fill tube 301. The holder 801 can work alone or in conjunction with the fill tube 301 to support the outside of the casing 101 during fill. The holder 801, like the fill tube 301, and the plunger 601 may be made out of any known material including, for example, metal, glass, plastic, and composite materials. The holder 801 can be operable to fully enclose the casing 101 only providing access to the opening 105 of the casing 101 through an inlet 805 in the holder 801. Accordingly, the holder can assist in maintaining sterility of the casing 101 and minimizing the potential for damage through repeated handling of the casing 101 directly.

[0061] A casing 101 inserted into the body 803 of a holder 801 is depicted in FIG. 9. The body 803 and the casing 101 are similarly sized and shaped to aid in positioning of the casing opening 105 and the holder inlet 805. The holder inlet 805 may also be sized and shaped along with the fill tube 301 such that the fill tube can be passed through the inlet 805 into the casing 101 within the body 803. The components can be sized such that the outer surface of the fill tube 301 contacts the inner edges of the inlet 805 and may even form a seal, protecting the outside of the casing 101 such that the lumen of the fill tube 301 provides the only access and point of exposure to the casing 101.

[0062] In order to facilitate casing 101 placement in and retrieval from the body 803 of the holder 801, the holder may comprise multiple components including a lid 1003 as shown in FIG. At least a portion of the body 803 may be formed in a base 1005 of the holder 801 such that the casing 101 can be positioned therein. The fill tube 301 may be inserted into the opening 105 of the casing 101 before or after the casing 101 is placed in the body 803. Once positioned, the lid 1003 or other component of the holder 801 may then be coupled to the base 1005 to form the complete, enclosed body 803 and inlet 805 of the holder 801 with the casing inside. Once filled, the lid 1003 may be removed and the filled casing 101 can be taken from the body 803, closed, and implanted.

[0063] In various embodiments, casing disclosed herein may be pre-filled with a bone-grafting material. Preferably the material is provided in particulate form to provide increased surface area for infiltration by host cells and osteogenesis. Materials may include bone material which may be obtained from the patient before or during the implantation procedure. In certain embodiments, DBM may be used to fill the casing. DBM is bone that has had the inorganic mineral removed, leaving behind the organic matrix. Removal of the bone mineral exposes more biologically active bone morphogenetic proteins which aid in bone and cartilage formation. DBM is more biologically active than standard bone grafts but the mechanical properties of the bone are lost. Accordingly, casings of the invention are particularly useful in containing DBM and providing the mechanical support and shape desired for particular bone graft prostheses. Any combination of graft materials may be provided in the form of fibers, granules, paste, powder, chips, strips, sponge, or any other available particle type and any combination of these particle types.

[0064] In various embodiments, fill material may comprise metals, like titanium or tantalum, polymers like polylactides, hydrogel-based materials, or bioceramics. Bioceramics may include biphasic calcium phosphate which may be processed to produce osteoinductive surface morphologies as described below. Additional osteoinductive fill materials as well as prosthesis applications are described in U.S. Pat. Nos. 9,364,583; 4,430,760; and 9,801,978, incorporated by reference herein. Fill material may include bioglass, collagen-ceramic mixtures, as well as cell based products and growth factor containing products. See V. Krishnan and T. Lakshmi, 2013, Bioglass: A novel biocompatible innovation, J Adv Pharm Technol Res. 4(2): 78-83. Example of materials and agents which may be added to a fill material in a casing of the invention include, for example, osteogenic or chondrogenic proteins or peptides; DBM powder; collagen, insoluble collagen derivatives, etc., and soluble solids and/or liquids dissolved therein; anti-AIDS substances; anti-cancer substances; antimicrobials and/or antibiotics such as erythromycin, bacitracin, neomycin, penicillin, polymycin B, tetracyclines, biomycin, chloromycetin, and streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamycin, etc.; immunosuppressants; anti-viral substances such as substances effective against hepatitis; enzyme inhibitors; hormones; neurotoxins; opioids; hypnotics; anti-histamines; lubricants; tranquilizers; anti-convulsants; muscle relaxants and anti-Parkinson substances; anti-spasmodics and muscle contractants including channel blockers; miotics and anti-cholinergics; anti-glaucoma compounds; anti-parasite and/or anti-protozoal compounds; modulators of cell-extracellular matrix interactions including cell growth inhibitors and antiadhesion molecules; vasodilating agents; inhibitors of DNA, RNA, or protein synthesis; anti-hypertensives; analgesics; anti-pyretics; steroidal and non-steroidal anti-inflammatory agents; anti-angiogenic factors; angiogenic factors and polymeric carriers containing such factors; anti-secretory factors; anticoagulants and/or antithrombotic agents; local anesthetics; ophthalmics; prostaglandins; anti-depressants; anti-psychotic substances; anti-emetics; imaging agents; biocidal/biostatic sugars such as dextran, glucose, etc.; amino acids; peptides; vitamins; inorganic elements; co-factors for protein synthesis; endocrine tissue or tissue fragments; synthesizers; enzymes such as alkaline phosphatase, collagenase, peptidases, oxidases, etc.; polymer cell scaffolds with parenchymal cells; collagen lattices; antigenic agents; cytoskeletal agents; cartilage fragments; living cells such as chondrocytes, bone marrow cells, mesenchymal stem cells; natural extracts; genetically engineered living cells or otherwise modified living cells; expanded or cultured cells; DNA delivered by plasmid, viral vectors, or other member; tissue transplants; autogenous tissues such as blood, serum, soft tissue, bone marrow, etc.; bioadhesives; bone morphogenic proteins (BMPs); osteoinductive factor (IFO); fibronectin (FN); endothelial cell growth factor (ECGF); vascular endothelial growth factor (VEGF); cementum attachment extracts (CAE); ketanserin; human growth hormone (HGH); animal growth hormones; epidermal growth factor (EGF); interleukins, e.g., interleukin-1 (IL-1), interleukin-2 (IL-2); human alpha thrombin; transforming growth factor (TGF-beta); insulin-like growth factors (IGF-1, IGF-2); parathyroid hormone (PTH); platelet derived growth factors (PDGF); fibroblast growth factors (FGF, BFGF, etc.); periodontal ligament chemotactic factor (PDLGF); enamel matrix proteins; growth and differentiation factors (GDF); hedgehog family of proteins; protein receptor molecules; small peptides derived from growth factors above; bone promoters; cytokines; somatotropin; bone digesters; antitumor agents; cellular attractants and attachment agents; immuno-suppressants; permeation enhancers, e.g., fatty acid esters such as laureate, myristate and stearate monoesters of polyethylene glycol, enamine derivatives, alpha-keto aldehydes, etc.; and nucleic acids.

[0065] Fill materials may include biphasic calcium phosphate with modified surface morphologies prepared using hydrothermal and/or chemical treatment such as those described, for example, in U.S. patent application Ser. No. 16/828,583.

EXAMPLES

Example 1Casing Suture Procedure

[0066] A rectangular sheet of perforated collagen is provided. The procedure should be performed in a controlled, dry environment. If the collagen becomes wet, it should be discarded. the collagen sheet is folded in half along the center of its longest dimension. Using a traditional square knot, the end of the suture is knotted with a knot large enough so that the knot cannot pull through (approximately 3). Using a suture holder, the suture needle with suture is picked up and a first pass is made through the collagen sheet at the edge of the fold. If any tearing occurs in the collagen sheet, it should be discarded. The suture is pulled all the way through the collagen sheet 101 to the knot as shown in FIG. 13 and the knot is tucked underneath the fold so that it is not visible.

[0067] A fixture 1401 may be provided for holding and aligning the folded collagen sheet 101 to aid in suturing and may have scallops or other indications for suture 1403 placement as shown in FIG. 14. The edge of the fixture 1401 is aligned with the edge of the collagen sheet 101 by mating the fold of the collagen sheet 101 with the closed end of the fixture 1401. The edge of the fixture 1401 is lined up with the solid border of the collagen sheet 101 and the stitch is started in the end where the knot was placed.

[0068] Using a buttonhole stitch, described below, one can sew along the long edge of the collagen sheet 101 as shown in FIG. 15. Each 1403 stitch should create a purl or lock at the top. The fixture 1401 can be used as a distance guide and with sutures 1403 placed inside of each scallop. A buttonhole stitch may be made as follows. The needle is inserted through both sides of the collagen sheet and pulled until a loop is created. The needle can then be inserted through the loop from the back so that the needle is coming back toward the user. The suture can then be pulled straight up or towards the user until tight, making sure not to tear the collagen and ensuring that the purl is formed. If the purl loosens when the suture is not being pulled, then the stitch may not be locked and direction of the suture should be verified.

[0069] Once the entire length of the seam of the collagen sheet 101 is sutured 1403 (as shown in FIG. 16), the suture can be locked in place by going through the last loop (of the buttonhole stitch as described above) twice to form a double knot. That step can be repeated twice to form a second double knot sitting on top of the collagen sheet 101. A collagen sheet 101 with locked sutures 1403 in a fixture 1403 is shown in FIG. 17. The suture can then be clipped near the knot and the same needle and remaining length of suture material can be used to suture the other side(s) of the sheet 101 to form a casing.

[0070] If not immediately used in a bone grafting procedure, the casing may be placed in a vacuum chamber and/or packed in a moisture barrier pouch with nitrogen to preserve the casing(s) until use.

INCORPORATION BY REFERENCE

[0071] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.

EQUIVALENTS

[0072] Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.