Gum graft

Abstract

The present invention provides a synthetic gingival patch graft having a porous polymeric structure and relates to its use in methods for treating periodontal disease, its symptoms and its signs.

Description

[Background technology]

[0001] Gingival recession, also called gingival recession, is the manifestation of loss of gingival tissue and / or exposure of the root of the tooth caused by recession of the gingival margin from the crown, first exposing the neck and eventually exposing part of the root. Gingival recession is most common in adults over the age of 40, but can also occur in teenagers or as early as the age of 10. Gingival recession may or may not be accompanied by a loss of crown-to-root ratio (alveolar bone recession). In most cases, gingival recession is a progressive condition that occurs gradually over many years. The classification of the condition is based on the location of the interdental papillae, as well as the buccal, lingual and palatal recession.

[0002] Gingival recession can have many causes, including (i) gum disease (periodontal disease), which is the most common cause, (ii) excessive brushing or improper flossing (e.g., rough or aggressive) that cuts the gums, (iii) genetic predisposition to gingival recession due to thin, weak, or insufficient gum tissue, (iv) consumption of tobacco products that affect the mucous membranes of the mouth, (v) self-inflicted trauma, such as digging fingernails or pencils into the gums or lip or tongue piercings, (vi) diseases such as scurvy (dietary deficiency of vitamin C) or acute necrotizing ulcerative gingivitis, (vii) irregular tooth position, such as crowding, or inadequate coverage of one or more teeth by the jaw bone, and (viii) intentional gingival recession during dental and oral surgery.

[0003] The following signs and symptoms may indicate gum recession, such as loose teeth, dentin sensitivity, changes in the appearance of the teeth (teeth appearing longer, roots appearing exposed, teeth feel like they are notched at the gum line, changes in tooth color, spaces between teeth), and cavities below the gum line. If gum recession is caused by gingivitis, the following symptoms may also be present: swollen, red, or thickened gums (inflammation), bleeding gums while brushing or flossing, and bad breath (halitosis). In some cases, treating gingivitis may reveal a gum recession problem that was previously hidden by swollen gums.

[0004] Solutions to the symptoms of gingival recession vary depending on the appearance of the recession and the level of bone surrounding the tooth. Such solutions include regeneration of the recessed area with new gingival tissue using various gingival grafting procedures. These procedures include covering the recession by repositioning adjacent gingival tissue (called a pedicle graft), or using a free gingival graft with or without a connective tissue graft taken from the roof of the mouth (collectively called a free gingival graft or subepithelial connective tissue graft). Alternatively, a material called acellular dermal matrix (processed from donated human skin allograft) may be used in place of connective tissue taken from the patient's own palate.

[0005] Recent advances have introduced bone graft materials infused with platelet-derived growth factor (PDGF). This material is usually combined with a cellular matrix to form a soft bone paste, which is then covered by an allograft. The development of this type of cellular matrix of bone and tissue (also known as orthofiller) results in better osseointegration with the patient's healthy bone and soft tissue. The results are evaluated after several months, and in some cases, further shaping of the new tissue is required to achieve optimal results.

[0006] Available solutions for gingival recession have many drawbacks. They require at least two painful, technically challenging and time-consuming dental procedures and are also limited by the thickness and length of the potential implants. Current solutions are tissue-based and therefore biodegradable, which limits their long-term efficiency and stability according to current expert literature. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2002 / 049535 [Patent Document 2] International Publication No. 2002 / 049536 [Patent Document 3] International Publication No. 2002 / 049678 [Patent Document 4] International Publication No. 2002 / 074189 [Patent Document 5] International Publication No. 2002 / 074190 [Patent Document 6] International Publication No. 2002 / 074191 [Patent Document 7] International Publication No. 2005 / 032400 [Patent Document 8] International Publication No. 2005 / 065578 [Patent Document 9] U.S. Pat. No. 3,737,508 [Patent Document 10] U.S. Pat. No. 3,950,478 [Patent Document 11] U.S. Pat. No. 3,996,321 [Patent Document 12] U.S. Pat. No. 4,189,336 [Patent Document 13] U.S. Patent No. 4,402,900 [Patent Document 14] U.S. Pat. No. 4,421,707 [Patent Document 15] U.S. Pat. No. 4,431,602 [Patent Document 16] U.S. Pat. No. 4,557,732 [Patent Document 17] U.S. Pat. No. 4,643,657 [Patent Document 18] U.S. Pat. No. 4,804,511 [Patent Document 19] U.S. Patent No. 5,002,474 [Patent Document 20] U.S. Pat. No. 5,122,329 [Patent Document 21] U.S. Pat. No. 5,387,387 [Patent Document 22] U.S. Pat. No. 5,667,743 [Patent Document 23] U.S. Patent No. 6,248,273 [Patent Document 24] U.S. Patent No. 6,252,031 [Non-patent literature]

[0008] [Non-Patent Document 1] A review of recent advances in the field of keratoprosthesis, Salvador-Culla et al. Journal of Functional Biomaterial. 2016, 7, 13. [Non-Patent Document 2] Electrospinning, J. Stanger, N. Tucker, and M. Staiger, I-Smithers Rapra publishing (UK). [Non-Patent Document 3] An introduction to Electrospinning and Nanofibers, S. Ramakrishna, K. Fujihara, WE Teo, World Scientific Publishing Co. Re Ltd (Jun 2005). [Non-Patent Document 4] Electrospinning of micro- and nanofibers: fundamentals and applications in separation and filtration processes, Y. Fillatov, A. Budyka, and V. Kirichenko (Trans. D. Letterman), Begell House Inc., New York, USA, 2007. Summary of the Invention [Means for solving the problem]

[0009] There is therefore a need to provide an effective and stable solution for gingival recession which, on the one hand, is versatile and easy to treat, and on the other hand, is biostable and has an improved and long-lasting effect.

[0010] It is to be understood that reference to a "synthetic gingival patch graft" refers to an implant of a synthetic polymeric material used to repair defects in a subject's gingival tissue. In some embodiments, the patch graft of the present invention has the form of a sheet.

[0011] In some embodiments, the synthetic gingival patch graft having a porous polymer structure has pores between about 0.01 μm and 5 μm. In some embodiments, the synthetic gingival patch graft having a porous polymer structure has pores of 0.01, 0.05, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 μm.

[0012] The present invention further provides a synthetic gingival patch graft having a porous polymer structure with pores of 5 to 20 μm, in some embodiments configured to be a synthetic gingival patch graft having a porous polymer structure with pores of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 μm.

[0013] In some embodiments, the synthetic gingival patch graft is configured to be a biocompatible patch. In other embodiments, the synthetic gingival patch graft of the present invention is configured to be a non-degradable patch.

[0014] In some embodiments, the synthetic gingival patch graft of the present invention has a thickness of 100-1000 μm. In other embodiments, the synthetic gingival patch graft of the present invention has a thickness of 10-100 μm. In other embodiments, the synthetic gingival patch graft of the present invention has a thickness of 1000-2500 μm.

[0015] In some embodiments, the porous polymer structure comprises at least one polymer, while in other embodiments, the porous polymer structure comprises nanofibers (in some embodiments, the nanofibers have a thickness of from 500 nm to several microns).

[0016] In some embodiments, the porous polymer structure comprises at least one porous electrospun polymer. In other embodiments, the porous polymer structure comprises at least one porous printed polymer (e.g., using a 3D printer).

[0017] In some further embodiments, the porous polymer structure comprises at least one polymer selected from polycarbonate, poly(DTE carbonate), polycaprolactone, (DL-lactide-co-caprolactone) copolymer, ethylene vinyl acetate copolymer, polymethyl methacrylate, polypropylene carbonate, polyvinylidene fluoride, polyacrylonitrile, polycarbomethylsilane, polystyrene, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide, polyurethanes (including aromatic polyurethanes), polyvinyl chloride, chitosan, alginates, polyhydroxybutyrate and its copolymers, nylon 11, cellulose acetate, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly-DL-lactide, and poly-L-lactide, or any combination thereof.

[0018] Electrospun fibers are typically several orders of magnitude smaller than those produced using conventional spinning techniques. By optimizing parameters such as: i) solvent polarity and surface tension, molecular weight and conformation of the polymer chains, viscosity, elasticity and conductivity of the solution, and intrinsic properties of the solution; and ii) operational conditions such as electric field strength, distance between the spinneret and the collector, and the solution feed rate, it is possible to produce thin fibers with diameters of tens of nanometers by electrospinning. Additional parameters that affect the properties of electrospun fibers include the polymer molecular weight, molecular weight distribution and structure (branched or linear, etc.), solution properties (viscosity, conductivity and surface tension), electric potential, flow rate and concentration, distance between the capillary and the collection screen, ambient parameters (temperature, viscosity and air velocity in the chamber), and the movement of the target screen (collector). The production of highly porous fibers can be achieved by electrospinning the jet directly into a cryogenic liquid. As a result of temperature-driven phase separation between the polymer and the solvent, and evaporation of the solvent under freeze-drying conditions, well-defined pores develop on the surface of each fiber.

[0019] Several approaches have been developed to organize electrospun fibers into aligned arrays. For example, electrospun fibers can be aligned into uniaxial arrays by replacing the single collector with a pair of conducting substrates separated by a void gap. In this case, the nanofibers stretch across the gap oriented perpendicular to the ends of the electrodes. It has also been shown that uniaxially aligned fibers can be stacked into a three-dimensional lattice by patterning a pair of electrodes onto an insulating substrate such as quartz or polystyrene. By controlling the electrode pattern and / or the sequence of high voltage applications, it is also possible to generate complex structures containing aligned nanofibers.

[0020] By directly depositing electrospun nanofibers onto various objects, nanofiber-based structures with well-defined and controllable shapes can be obtained. Furthermore, after electrospinning, aligned or randomly aligned nanofiber membranes can be manually processed to obtain various kinds of structures. For example, the fiber membrane can be rolled up to make tubes, or punched out to prepare disks with controllable diameters.

[0021] In some embodiments, the synthetic gingival patch graft of the present invention further comprises at least one active agent selected from proteins, type I collagen, fibronectin, or TGF-β2, heparin, growth factors, antibodies, antimetabolites, chemotherapeutic agents, anti-inflammatory agents, antibiotic agents, and any combination thereof.

[0022] In some embodiments, the synthetic gingival patch graft of the present invention is cut to a specified shape (in some embodiments, such cutting is by laser cutting, manual cutting, pressure cutting, etc.).

[0023] In some embodiments, the synthetic gingival patch graft of the present invention further comprises at least one non-porous layer. In some embodiments, the at least one non-porous layer is configured to be in the form of a membrane. When used as a tissue substitute in periodontal surgery, the at least one non-porous layer or membrane is placed on the bone side of the cavity to be filled.

[0024] Reference to a "non-porous layer" should be understood to encompass a membrane layer that is substantially free of pores and therefore impermeable and impermeable, as compared to the porous layer of the gingival patch graft of the present invention.

[0025] In some embodiments, the non-porous layer is configured to be a biocompatible patch, hi other embodiments, the non-porous layer is configured to be a non-degradable patch.

[0026] In some embodiments, the non-porous layer has a thickness of 100 to 1000 μm. In other embodiments, the non-porous layer has a thickness of 10 to 100 μm. In other embodiments, the non-porous layer has a thickness of 1000 to 2500 μm.

[0027] In some embodiments, the non-porous polymer structure comprises at least one polymer, hi other embodiments, the non-porous polymer structure comprises nanofibers (in some embodiments, the nanofibers are between 500 nm and several microns thick).

[0028] In some further embodiments, the porous polymer structure comprises at least one polymer selected from polycarbonate, poly(DTE carbonate), (DL-lactide-co-caprolactone) copolymer, ethylene vinyl acetate copolymer, polymethyl methacrylate, polypropylene carbonate, polyvinylidene fluoride, polyacrylonitrile, polycarbomethylsilane, polystyrene, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide, polyurethanes (including aromatic polyurethanes), polyvinyl chloride, chitosan, alginates, polyhydroxybutyrate and its copolymers, nylon 11, cellulose acetate, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly-DL-lactide, and poly-L-lactide, or any combination thereof.

[0029] Reference to "periodontal disease, symptoms or signs thereof" should be understood to include inflammatory conditions affecting the tissues surrounding the teeth, such as periodontal disease, gingivitis, periodontitis, tooth decay, tooth loss, bone loss and any combination thereof.

[0030] In some embodiments, such periodontal disease, symptoms thereof or signs thereof may require periodontal surgery.

[0031] The term "periodontal surgery" encompasses any form of dental surgery that prevents or corrects anatomical, traumatic, developmental, or plaque-induced defects of bone, gingiva, or alveolar mucosa. The purpose of surgery is to provide access to the tooth roots, eliminate inflammation, establish a plaque-controlling oral environment, control periodontal disease, maintain oral hygiene, maintain adequate interdental space, address gingival and alveolar problems, and improve esthetics. Surgical procedures include, among others, crown lengthening, frenectomy, gingival and alveolar flap, gingivectomy, apical position flap (APF), apical position flap (APF) with bone reduction (osteoplasty / osteectomy), and any combination thereof.

[0032] The invention further provides a synthetic gingival patch graft as disclosed herein above and below for use in periodontal and / or dental surgery.

[0033] The invention further provides a synthetic gingival patch graft as disclosed hereinabove and hereinafter for use in the treatment of periodontal disease, its symptoms or its signs.

[0034] The invention further provides a synthetic gingival patch graft as disclosed hereinabove and below for use in the treatment of gingival recession.

[0035] The invention further provides a synthetic gingival patch graft as disclosed hereinabove and below for use in root coverage procedures.

[0036] The invention further provides a synthetic gingival patch graft as disclosed herein above and below for use in treating root disease, its symptoms or its signs.

[0037] In some embodiments, the synthetic gingival patch graft of the present invention is configured to be a periodontal tissue replacement patch.

[0038] In other embodiments, the synthetic gum patch graft of the present invention is configured to be a periodontal tissue supplement patch.

[0039] In a further embodiment, the synthetic gingival patch graft of the present invention is configured to be a periodontal tissue reconstruction / regeneration patch.

[0040] The present invention further provides a device comprising at least one synthetic gingival patch graft of the present invention. In some embodiments, the device is configured to be a dental implant comprising at least one synthetic gingival patch graft of the present invention (e.g., covered by at least one synthetic gingival patch graft of the present invention).

[0041] The present invention further provides kits comprising at least one synthetic gingival patch graft of the present invention, means for its periodontal implantation / placement into the gingival tissue of a subject, and instructions for use.

[0042] In some embodiments, the instructions for use may include a step instructing a caregiver how to custom cut the patch graft of the present invention, e.g., how to place the patch graft invention over the teeth and over the gum tissue (see, e.g., 110 in FIG. 1). [Brief description of the drawings]

[0043] The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of this specification, however the invention, both as to organization and method of operation, together with its objects, features, and advantages, may best be understood by reference to the following detailed description when read in conjunction with the accompanying drawings.

[0044] [Figure 1A] FIG. 1 illustrates an embodiment of a synthetic gingival patch graft of the present invention. [Figure 1B] FIG. 1 illustrates an embodiment of a synthetic gingival patch graft of the present invention. [Figure 1C] FIG. 1 illustrates an embodiment of a synthetic gingival patch graft of the present invention. [Figure 1D] FIG. 1 illustrates an embodiment of a synthetic gingival patch graft of the present invention. [Figure 1E] FIG. 1 illustrates an embodiment of a synthetic gingival patch graft of the present invention. [Figure 2A] FIG. 1 illustrates an embodiment of a synthetic gingival patch graft of the present invention. [Figure 2B] FIG. 1 illustrates an embodiment of a synthetic gingival patch graft of the present invention.

[0045] It will be understood that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity of illustration. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0046] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0047] Figure 1A shows a synthetic gingival patch graft (100) of the present invention. Figure 1B shows a synthetic gingival patch graft (101) of the present invention with a groove (102) cut to a shape for periodontal placement. Figures 1C and 1D show embodiments of synthetic gingival patch grafts (103) and (105) of the present invention with holes (104) and (106) cut to a shape for periodontal placement. Figure 1E shows a synthetic gingival patch graft (107) of the present invention placed on a typical periodontal segment (109), with holes (108) cut in the patch to allow for placement over the teeth and gingival tissue (110).

[0048] Figure 2A shows a synthetic gingival patch graft of the present invention (200 and 201, cross sections AA of 200) that includes a non-porous (membrane) layer (203) in addition to the porous layer (202). Figure 2B shows a synthetic gingival patch graft of the present invention (300 and 301, cross sections AA of 300) that includes two porous layers (302 and 303) with one non-porous (membrane) layer (304) between them.

Claims

1. A tissue-replacement synthetic gingival patch graft that has a porous polymer structure with pores less than 5 μm and is non-degradable.

2. 10. The synthetic gingival patch graft of claim 1, which has a porous polymer structure with pores of about 0.01 μm to about 5 μm and is non-degradable.

3. The synthetic gingival patch graft of claim 1 or 2, which is a biocompatible patch.

4. The synthetic gingival patch graft according to any one of claims 1 to 3, having a thickness of 10 to 100 μm.

5. The synthetic gingival patch graft according to any one of claims 1 to 3, having a thickness of 100 to 1000 μm.

6. The synthetic gingival patch graft according to any one of claims 1 to 3, having a thickness of 1000 to 2500 μm.

7. The synthetic gingival patch graft according to any one of claims 1 to 6, wherein the porous polymer structure comprises at least one polymer.

8. The synthetic gingival patch graft of any one of claims 1 to 7, wherein the porous polymer structure comprises nanofibers.

9. The synthetic gingival patch graft according to any one of claims 1 to 8, wherein the porous polymer structure comprises at least one porous electrospun polymer.

10. The synthetic gingival patch graft of any one of claims 1 to 9, further comprising at least one active agent.

11. 11. The synthetic gingival patch graft of claim 10, wherein the at least one active agent is selected from a protein, type I collagen, fibronectin, or TGF-β2, heparin, a growth factor, an antibody, an antimetabolite, a chemotherapeutic agent, an anti-inflammatory agent, an antibiotic agent, and any combination thereof.

12. The synthetic gingival patch graft of any one of claims 1 to 11, further comprising at least one non-porous layer.

13. A synthetic gingival patch graft according to any one of claims 1 to 12 for use in the treatment of periodontal disease, its symptoms or its signs.

14. A synthetic gingival patch graft according to any one of claims 1 to 13 for use in the treatment of gingival recession.

15. A synthetic gingival patch graft according to any one of claims 1 to 14 for use in the treatment of root disease, its symptoms or its signs.

16. A device comprising at least one synthetic gingival patch graft as defined in any one of claims 1 to 15.

17. A kit comprising at least one synthetic gingival patch graft as defined in any one of claims 1 to 15, means for its implantation / placement into the gingival tissue of a subject, and instructions for use.

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