Dental and subperiosteal implants containing biocompatible grafts

Abstract

The present invention provides dental or subperiosteal implants having porous polymeric structures and their use in methods for treating periodontal diseases, conditions and symptoms.

Description

[Background technology]

[0001] Rehabilitating edentulous patients, whether their jaws are atrophied or not, is a surgical challenge. Traditional endosseous implant-supported overdentures and immediate loading protocols still present clinical challenges today. Many techniques have been described in the literature to overcome this problem. Reconstructive methods such as autogenous bone grafting or guided bone regeneration are often used. However, autogenous bone grafting requires a second surgical site, which implies additional morbidity, and immediate loading is not always recommended. Guided bone regeneration (especially vertically) has limited gain and is often associated with potential complications in completely atrophied jaws. Both of these techniques require several months for graft maturation. After implantation, dental implants can exhibit peri-implantitis many years after implantation, potentially requiring surgical intervention and sometimes implant removal. Atrophied jaws are associated with anatomical changes and a high risk of damaging intrinsic structures, thus increasing the need for specific surgical skills during surgery. Summary of the Invention [Problem to be solved by the invention]

[0002] There is a need to provide a safe and reliable dental implant or dental subperiosteal implant that can provide a permanent solution for edentulous and atrophic jaws and associated diseases and conditions without the risk of inflammation, implant exposure and extrusion, peri-implantitis, infection, and ultimately implant loss, and without the need for further surgery. [Means for solving the problem]

[0003] The present invention provides an effective and stable solution for placing dental and subperiosteal implants that, on the one hand, is versatile and simplifies the performance of the procedure, and, on the other hand, is biostable and biocompatible, has an improved long-lasting effect, and provides effective integration with the jaw and tooth tissues.

[0004] The present invention provides a dental or subperiosteal implant comprising at least one synthetic biocompatible graft having a porous polymeric structure with pores less than 5 microns.

[0005] Reference to a "subperiosteal implant" should be understood to refer to a metal-implanted framework that rests directly on the bone, beneath the periosteum, and provides attachment posts that extend through the gum tissue for prosthetic fixation.

[0006] When referring to a "dental implant," it should be understood to refer to a prosthesis that interfaces with the bone of the jaw or skull to support a dental prosthesis, such as a crown, bridge, denture, or facial prosthesis, or to act as an orthodontic anchor. Dental implants are typically formed from materials such as titanium or zirconia and form a tight bond with the bone into which they are implanted. The implant fixture is first positioned to facilitate osseointegration, and then the dental prosthesis is added. A variable amount of healing time is required for osseointegration before the dental prosthesis (tooth, bridge, or denture) is attached to the implant or before the abutment holding the dental prosthesis / crown is placed. Healthy bone and gums are a prerequisite for the long-term success of osseointegrated dental implants. Because both bone and gums can atrophy after tooth extraction, preprosthetic procedures such as sinus lifts or gum grafts may be required to recreate ideal bone and gum conditions.

[0007] A typical conventional implant (shown in FIG. 1 ) includes a root-implanted portion (103) made of metal (usually titanium or a titanium alloy) in the form of a thread (resembling a tooth root) with a roughened or smooth surface, and an upper portion (101) resembling a tooth (or teeth), for example, made of zirconia. An abutment (102) connects the implanted root portion to the visible tooth portion of the upper portion. Most root-implanted portions of the dental implant are made of commercially pure titanium or titanium alloys. Modern dental implants also have a textured surface (by etching, anodizing, or by-blasting with various media) to increase the implant's surface area and the likelihood of bone fusion. In some embodiments of the implant of the present invention, shown in FIG. 2 , the root-implanted portion is covered with the synthetic biocompatible implant (106), while the abutment (105) and the external tooth portion (104) remain uncovered.

[0008] Thus, the implant of the present invention provides advantageous bone integration.

[0009] When referring to a "synthetic biocompatible implant," it is understood that this term refers to an implantable synthetic polymeric material that is biocompatible with dental tissue, such as gingival tissue, and that cell growth adjacent to the implant can grow and integrate at the jawbone-gingival boundary within the implant. In some embodiments, the implants of the present invention are in the form of a sheet.

[0010] In some embodiments, the at least one synthetic biocompatible graft covers, encases, and / or coats substantially all of the metallic framework of the subperiosteal implant or any dental implant, while in other embodiments, the at least one synthetic biocompatible graft covers, encases, and / or coats at least a portion of the metallic framework of the subperiosteal implant and any dental implant.

[0011] In some embodiments, the at least one synthetic biocompatible graft covers at least a portion of the implant. In such embodiments, the at least one synthetic biocompatible graft covers at least the root-implanted portion of the dental implant. In other embodiments, the at least one synthetic biocompatible graft covers at least the metal-implanted framework of the subperiosteal implant of the present invention.

[0012] In some embodiments, the synthetic biocompatible implants having porous polymer structures have pores between about 0.01 microns and 5 microns, 0.01 microns, 0.05 microns, 0.1 microns, 0.5 microns, 1 micron, 1.5 microns, 2 microns, 2.5 microns, 3 microns, 3.5 microns, 4 microns, 4.5 microns, and 5 microns.

[0013] The present invention further provides a synthetic biocompatible implant having a porous polymer structure with pores between 5 microns and 20 microns, hi some embodiments, the synthetic biocompatible implant has a porous polymer structure with pores of 5 microns, 6 microns, 7 microns, 8 microns, 9 microns, 10 microns, 11 microns, 12 microns, 13 microns, 14 microns, 15 microns, 16 microns, 17 microns, 18 microns, 19 microns, or 20 microns.

[0014] In another embodiment, the synthetic biocompatible implant of the present invention is a non-degradable implant. In another embodiment, the synthetic biocompatible implant of the present invention is a permanent, one-piece, non-degradable implant.

[0015] In some embodiments, the synthetic biocompatible implants of the present invention have a thickness of 100 μm to 1000 μm. In other embodiments, the synthetic biocompatible implants of the present invention have a thickness of 10 μm to 100 μm. In other embodiments, the synthetic biocompatible implants of the present invention have a thickness of 1000 μm to 2500 μm.

[0016] 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 are between 500 nm and several microns thick).

[0017] In some embodiments, the porous polymer structure comprises at least one porous electrospun polymer. In some other embodiments, the porous polymer structure comprises at least one porous printed polymer (e.g., using a 3D printing device).

[0018] In some further embodiments, the porous polymer structure is made of polycarbonate, poly(DTE carbonate) polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactic acid (PLLA), poly(DL-lactide-co-caprolactone), poly(ethylene-co-vinyl acetate) vinyl acetate, poly(methyl methacrylate), poly(propylene carbonate), poly(vinylidene fluoride), polyacrylonitrile, polycaprolactone, polycarbomethylsilane, polylactic acid, polystyrene, polyvinylpyrrolyl The material comprises at least one polymer selected from the group consisting of polyvinyl alcohol (PVA), polyethylene oxide (PEO), polyurethane (including aromatic polyurethane), polyvinyl chloride (PVC), hyaluronic acid (HA), chitosan, alginate, polyhydroxybutyric acid and its copolymers, nylon 11, cellulose acetate, hydroxyapatite, poly(3-hydroxybutyrate-co-hydroxyvalerate), poly(DL-lactide), polycaprolactone, and poly(L-lactide), or any combination thereof.

[0019] Electrospun fibers are typically orders of magnitude smaller than those produced using conventional spinning techniques. By optimizing parameters such as (i) the polarity and surface tension of the solvent, the molecular weight and conformation of the polymer chains, and the intrinsic properties of the solution, including its viscosity, elasticity, and conductivity, and (ii) operational conditions such as the electric field strength, the distance between the spinneret and the collector, and the solution feed rate, electrospinning can produce fibers as thin as tens of nanometers in diameter. Additional parameters that affect the properties of electrospun fibers include the polymer's molecular weight, molecular weight distribution, and structure (branched, linear, etc.), solution properties (viscosity, conductivity, and surface tension), electric potential, flow rate, and concentration, the distance between the capillary and the collection screen, ambient parameters (temperature, humidity, and air velocity within the chamber), and the movement of the target screen (collector). The production of highly porous fibers can be achieved by electrospinning a jet directly into a cryogenic liquid. Well-defined pores appear on the surface of each fiber as a result of temperature-induced phase separation between the polymer and the solvent and evaporation of the solvent under freeze-drying conditions.

[0020] 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 monolithic collector with a pair of conductive substrates separated by an air gap. In this case, nanofibers tend to stretch across the gap oriented perpendicular to the edges of the electrodes. It has also been shown that a pair of electrodes can be patterned on an insulating substrate, such as quartz or polystyrene, thus stacking uniaxially aligned fibers layer by layer into a 3D lattice. By controlling the electrode pattern and / or the sequence for applying high voltages, it is also possible to generate more complex structures consisting of well-aligned nanofibers.

[0021] Electrospun nanofibers can also be directly deposited onto various objects to obtain nanofiber-based constructs with well-defined and controllable shapes. Furthermore, after electrospinning, the aligned or randomly oriented nanofiber membranes can be manually processed into various types of constructs (e.g., rolling up the fiber membrane to produce tubes or punching out the fiber membrane to create disks with controllable diameters).

[0022] The present invention relates to any electrospinning technique known in the art, including Electrospinning (J. Stanger, N. Thucker, and M. Staiger, I-Smithers Rapra Publishing, UK); An Introduction to Electrospinning and Nanofibers (S. Ramakrishna, K. Fujihara, W. E. Teo, World Scientific Publishing Co. Pte Ltd, June 2005); Electrospinning of micro- and nanofibers: fundamentals and applications in separation and filtration process (Y. Fillatov, A. Budyka, and V. Kirichenko, Trans. D. Letterman, Begell House Inc., New York, USA, 2007), the entire contents of all of which are incorporated herein by reference.

[0023] Suitable electrospinning techniques are disclosed, for example, in International Patent Application Publication Nos. 2002 / 049535, 2002 / 049536, 2002 / 049536, 2002 / 049678, 2002 / 074189, 2002 / 074190, 2002 / 074191, 2005 / 032400, and 2005 / 065578, the contents of which are incorporated herein by reference. While particular emphasis has been placed on electrospinning techniques in accordance with presently preferred embodiments of the present invention, it will be understood that it is not intended that the scope of the present invention be limited to electrospinning techniques. Representative examples of other spinning techniques suitable for embodiments of the present invention include, but are not limited to, wet spinning, dry spinning, gel spinning, dispersion spinning, reaction spinning, or tuck spinning. Such and other spinning techniques are known in the art and are disclosed, for example, in U.S. Pat. Nos. 3,737,508, 3,950,478, 3,996,321, 4,189,336, 4,402,900, 4,421,707, 4,431,602, 4,557,732, 4,643,657, 4,804,511, 5,002,474, 5,122,329, 5,387,387, 5,667,743, 6,248,273, and 6,252,031, the contents of which are incorporated herein by reference.

[0024] To enhance bone integration of the implants of the present invention, the at least one synthetic biocompatible graft coating the implant has an outer surface (in contact with the bone or tissue at the implantation site) that is rough and grainy (uneven) with grain formation on its surface (e.g., a coral-like surface). In some embodiments, the at least one synthetic biocompatible graft has a surface that is a rough and grainy surface. In some embodiments, the at least one synthetic biocompatible graft comprises electrospun fibers with a coral-like rough surface. In some embodiments, the outer surface of the at least one synthetic biocompatible graft has a grained surface with a grain size of at least 50 μm. In some embodiments, the surface of the at least one synthetic biocompatible graft has a grain size of up to 50 μm. In some embodiments, the surface of the at least one synthetic biocompatible graft has a grain size of 1 μm to 50 μm. In some embodiments, the at least one synthetic biocompatible graft comprises electrospun fibers that have been post-treated with cryogenic grinding.

[0025] In some embodiments, the synthetic biocompatible implant of the present invention further comprises at least one active agent, which in some embodiments is 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.

[0026] In some embodiments, the synthetic biocompatible implants of the present invention are cut to a specified shape (in some embodiments, the cutting is laser cut, manual cut, pressure cut, etc.).

[0027] In some embodiments, the synthetic biocompatible implant of the present invention further comprises at least one non-porous layer. In some embodiments, the at least one non-porous layer is in the form of a film. When used as a tissue substitute in periodontal surgery, the at least one non-porous layer or film is placed on the bone side of the cavity to be filled.

[0028] Reference to a "non-porous layer" should be understood to encompass a film layer that is substantially free of pores and therefore cannot be penetrated by tissue and is impermeable compared to the porous layer of the biocompatible implant of the present invention.

[0029] In some embodiments, the non-porous layer is a biocompatible implant, hi other embodiments, the non-porous layer is a non-degradable implant.

[0030] In some embodiments, the non-porous layer has a thickness of 100 μm to 1000 μm. In other embodiments, the non-porous layer has a thickness of 10 μm to 100 μm. In other embodiments, the non-porous layer has a thickness of 1000 μm to 2500 μm.

[0031] In some embodiments, the non-porous polymer structure comprises at least one polymer, while in other embodiments, the non-porous polymer structure comprises nanofibers (in some embodiments, the nanofibers are between 500 nm and several microns thick).

[0032] In some further embodiments, the non-porous polymer structure is selected from the group consisting of polycarbonate, poly(DTE carbonate), polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactic acid (PLLA), poly(DL-lactide-co-caprolactone), poly(ethylene-co-vinyl acetate), vinyl acetate, poly(methyl methacrylate), poly(propylene carbonate), poly(vinylidene fluoride), polyacrylonitrile, polycaprolactone, polycarbomethylsilane, polylactic acid, polystyrene, polyvinylpyrrolyl The material comprises at least one polymer selected from the group consisting of polyvinyl alcohol (PVA), polyethylene oxide (PEO), polyurethane (including aromatic polyurethane), polyvinyl chloride (PVC), hyaluronic acid (HA), chitosan, alginate, polyhydroxybutyric acid and its copolymers, nylon 11, cellulose acetate, hydroxyapatite, poly(3-hydroxybutyrate-co-hydroxyvalerate), poly(DL-lactide), polycaprolactone, and poly(L-lactide), or any combination thereof.

[0033] Reference to "periodontal diseases, conditions or symptoms" should be understood to include, for example, inflammatory conditions affecting the tissues surrounding the teeth, such as gum disease, gingivitis, periodontitis, dental caries, tooth loss, bone loss, peri-implantitis and any combination thereof.

[0034] In some embodiments, such periodontal diseases, conditions or symptoms may lead to the need for periodontal surgery.

[0035] The term "periodontal surgery" is meant to encompass forms of dental surgery, maxillofacial surgery, and any combination thereof that prevent, correct, or reconstruct anatomical, traumatic, developmental, age-related, or plaque-related defects in bone, gingiva, or alveolar mucosa. The goals of this surgery include instrument accessibility to the tooth root surface, removal of inflammation, creating an oral environment for plaque control, controlling periodontal disease, maintaining oral hygiene, maintaining adequate interdental space, addressing gingival-alveolar mucosal problems, and aesthetic improvement. Surgical procedures include, among others, crown lengthening, frenectomy, mucogingival flap surgery, gingivectomy, apical flap (APF) surgery, apical flap (APF) with bone reduction (osteogenesis / osteectomy), and any combination thereof.

[0036] The present invention further provides a synthetic biocompatible implant as disclosed herein above and below for use in periodontal and / or dental surgery.

[0037] The present invention further provides a synthetic biocompatible implant as disclosed hereinabove and below for use in treating periodontal injuries, diseases, conditions or symptoms.

[0038] The present invention further provides an appliance comprising a dental or subperiosteal implant of the present invention.

[0039] The present invention further provides a kit comprising a dental or subperiosteal implant of the present invention, means for its periodontal implantation / placement in the gum tissue of a subject, and instructions for use.

[0040] In some embodiments, the instructions for use may include instructions for the caregiver on how to custom cut the implant of the present invention, for example, how to place the implant invention over the teeth and on the gum tissue.

[0041] 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, together with its objects, features, and advantages, both as to organization and method of operation, may best be understood by reference to the following detailed description when read in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0042] [Figure 1] FIG. 1 illustrates a typical crown implant. [Figure 2] FIG. 1 shows a typical crown implant covered with a biocompatible graft. [Figure 3A-3B] FIG. 1 shows the surgical site at the end of Example 1 (3 weeks after surgery). [Figures 4A-4C] FIG. 1 shows a histological slide (H&E) of the untreated site 6 weeks after surgery in Example 2 (B indicates bone tissue, CT indicates connective tissue, and Ep indicates epithelium). [Figures 5A-5D] FIG. 1 shows a histological slide (H&E) of the site where the patch of the present invention was implanted 3 weeks after surgery in Example 3 (the asterisk indicates the patch). [Figures 6A-6F] FIG. 1 shows a histological slide (H&E) of the surgical site from Example 4, 10 weeks after surgery (asterisk indicates synthetic biocompatible implant). [Figure 7] FIG. 1 shows the test model of Example 5. [Figures 8A-8D] FIG. 1 shows a histological slide (Sincair miniature pig) of the implantation site of a patch of the present invention one month after implantation. [Figure 9A-9B] 10 is an SEM image of particles obtained by post-treatment of electrospun fibers onto a coral-like rough surface. DETAILED DESCRIPTION OF THE INVENTION

[0043] 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 elements may be exaggerated relative to other elements for clarity. Further, where necessary, reference numerals may be repeated among the figures to indicate corresponding or similar elements.

[0044] 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.

[0045] Figure 1 shows a typical dental implant with an external crown and a metal implant inserted into the jawbone. Figure 2 shows a crown implant in which the metal implant inserted into the jawbone is covered / encased / coated by a biocompatible graft.

[0046] Example 1 - Oral placement of implants of the present invention in a rat model is evaluated to assess integration with gingival and bone tissue.

[0047] Experimental Model: A rat was selected as an animal model to assess the feasibility of implanting a synthetic biocompatible implant in the oral environment and its performance. A 2x2mm synthetic biocompatible implant was implanted into the right maxillary gingiva of the rat. Over the subsequent 3-week observation period, the rat exhibited normal feeding habits and showed no discomfort or functional impairment.

[0048] Results: When examined at the end of the study, the gingival tissue at the implant sites showed signs of complete healing similar to the untreated areas.

[0049] Notably, the synthetic biocompatible implant was visibly present beneath the gingival tissue, indicating successful implantation. However, during tissue dissection, it was observed that the synthetic biocompatible implant was more integrated with the adjacent bone tissue than with the soft tissue. Although the synthetic biocompatible implant did not completely integrate with the gingival tissue, it was difficult to remove, indicating strong integration with the bone. Figures 3A and 3B show the surgical site at completion (3 weeks postoperatively). Figure 3A shows the maxilla (surgical site) before dissection and shows no visible adverse events. This is evident from the similarity of tissue appearance compared to the unoperated contralateral side. Figure 3B shows the surgical site immediately after tissue dissection. The synthetic biocompatible implant, as indicated by the arrow, is clearly visible and appears firmly attached to the bone beneath the gingival tissue.

[0050] Conclusions: The synthetic biocompatible implant showed excellent wound healing and integration with bone tissue, but relatively poor integration with soft tissue.

[0051] Example 2 - Evaluate the efficacy of a synthetic biocompatible implant in a gingival recession model to assess acute healing of both soft and bone tissue.

[0052] Experimental Model: This study utilized six SD rats, equally distributed for termination at 3 and 6 weeks postoperatively. Each rat underwent implantation of the test device into a gingival pocket prepared on the right side of the maxilla. This required the creation of a 3 mm wide, 3 mm deep pocket anterior to the upper right molar using a 15c blade. A 2 x 2 mm patch was then placed on the buccal surface of the prepared pocket, and the defect was subsequently closed using Vicryl 5-0 sutures.

[0053] Results: At both the 3-week and 6-week checkpoints, all animals showed signs of successful healing, except for one rat in which the patch was exposed. Histological analysis showed significant evidence of cellular infiltration from adjacent bone tissue, indicating robust integration between the implanted synthetic biocompatible implant and bone tissue. This indicates that synthetic biocompatible implants are promising for integration into bone tissue and may be a viable option for similar applications. Figures 4A-4C show histological slides (H&E) of the untreated site 6 weeks postoperatively (B indicates bone tissue, CT indicates connective tissue, and Ep indicates epithelium). Figure 4B shows that the patch is clearly identified and in interfacial contact with the soft tissue. Notably, there is a notable absence of inflammatory cell response, indicating biocompatibility. Figure 4C shows that the patch is in contact with bone tissue. As in Figure 4B, there is no inflammatory cell response. Furthermore, the figure clearly shows cell infiltration into the porous matrix from both soft and bone tissue, with a discernible increase in cell infiltration at the interface with the bone tissue, indicating a more robust cell fusion in this region.

[0054] Conclusion: In conclusion, histological analysis provided strong evidence of substantial cellular infiltration originating from adjacent bone tissue, demonstrating strong integration between the implanted patch and the bone matrix. This finding supports the potential suitability of synthetic biocompatible implants for applications involving integration into bone tissue.

[0055] Example 3 - Rat calvarial bone defect - model validation

[0056] Experimental model: Three rats were used, each of which received a large rectangular synthetic biocompatible implant subperiosteally implanted into a 5 mm bone defect in the calvaria. The animals were observed for a period of 3 weeks after implantation.

[0057] Results: Over the three weeks, no adverse events were observed, and all animals showed normal weight gain. Visual examination at the end of the study revealed that two of the three patches remained well positioned and in place, but one patch appeared to have partially shifted toward the nasal cavity area. Histological evaluation revealed moderate cellular infiltration into the patch, primarily on the surface facing the bone tissue. Bone formation at the defect site was noted in all animals, with significant bone formation throughout the patch in animals with misplaced implants. Figures 5A-5D show histological slides (H&E) of the implanted site of the inventive patch three weeks postoperatively (asterisks indicate the patch). Figures 5A and 5B are extracted from histological slides of the implanted site of Animal #1, at low (5A) and high (5B) magnifications. The patch was clearly visible and showed no signs of an inflammatory response. 501 indicates the bone defect. 502 indicates old bone, and 503 indicates new bone formation. In particular, there is observable new bone formation around the bone defect and significant infiltration of cells into the porous matrix. Figures 5C and 5D are from histological slides of the implantation site of Animal #2, in which the implant appeared to have partially migrated. Both low (5C) and high (5D) magnifications were observed. In this case, bone formation was evident above the patch and extended into the patch itself, indicating the patch's potential to promote bone formation. 504 shows new bone formation above the patch, and 505 shows new bone formation within the patch.

[0058] Conclusions: The synthetic biocompatible implant demonstrated overall safety and potential for inducing bone regeneration.

[0059] Example 4 - Assessment of bone regeneration using a rat calvarial bone defect model

[0060] Experimental Model: This study used a larger cohort of 10 rats, which were divided into three test groups as follows: Group 1 - A synthetic biocompatible implant was placed directly on the calvarial bone. Group 2 - A synthetic biocompatible implant was placed over the calvarial bone defect. Group 3 - A control group with bone defects but without the synthetic biocompatible implant.

[0061] The animals were observed for 10 weeks after implantation.

[0062] Results: No systemic or local reactions were observed over the 10-week follow-up period. Macroscopic evaluation at the end of the study showed that all patches remained in place. Histological analysis revealed significant cell proliferation into the patch pores, as well as mild bone formation into the patches. Group 2 demonstrated new bone formation above the patches, demonstrating that the synthetic biocompatible implant has the potential to promote bone regeneration compared to untreated bone defects. Figures 6A-6F show histological slides (H&E) of the surgical site 10 weeks postoperatively (asterisks indicate synthetic biocompatible implants).

[0063] Figures 6A and 6B are low-magnification (6A) and high-magnification (6B) views from a histological slide of Animal #1 in Group #1. The synthetic biocompatible implant is prominently visible without any signs of an inflammatory response. Notably, new bone formation is observed growing into the synthetic biocompatible implant. Furthermore, note that the tares within the patch are an artifact of histological processing and indicate strong integration with the underlying bone. 601 indicates new bone formation. Figures 6C and 6D are low-magnification (6C) and high-magnification (6D) views from a histological slide of Animal #2 in Group #2. Significant bone regeneration is evident, particularly beginning at the margins of the bone defect and extending through and above the synthetic biocompatible implant. At the defect margins, there is observable tissue discoloration, potentially indicating thermal osteonecrosis, possibly the result of overheating the drill. 602 shows the suture, 603 shows the bone defect, 604 shows new bone growing through and on top of the patch, and 605 shows suspected thermal osteonecrosis, possibly due to overheating of the drill.

[0064] Figures 6E and 6F are low (6E) and high (6F) magnification views from histological slides of Animal #1 in Group #3. In this case, minimal bone formation is evident, but soft tissue fills the bone defect. 606 shows soft tissue filling the gap without new bone formation. 607 indicates suspected thermal osteonecrosis (due to the drill). 608 shows minimal new bone formation.

[0065] Conclusions: This study suggests that synthetic biocompatible implants hold promise for inducing bone regeneration and may offer benefits over untreated defects.

[0066] Example 5 - Mandibular defect model in miniature pigs

[0067] Experimental Model: This study used a more complex animal model utilizing minipigs to evaluate the therapeutic effects of synthetic biocompatible implants on mandibular defects. The study incorporated in-life and post-mortem assessments to assess bone fusion and new bone growth. The study consisted of three Sinclair minipigs that initially underwent extraction of six mandibular premolars. After a 10-week healing period, three approximately 7 x 8 x 10 mm implants were obtained per hemi-mandible. 3 Alveolar bone defects were created in 1000 x g of 1000 x ...

[0068] Results: Synthetic biocompatible implant-related abnormalities, including membrane exposure and potential infection, leading to feeding difficulties and weight loss, were observed in both animals. Postmortem findings confirmed clinical observations showing enlarged, reactive mandibular lymph nodes in hemimandibles implanted with the synthetic biocompatible implant. Ultimately, the study was terminated early due to safety concerns, and the safety of the synthetic biocompatible implant was not demonstrated under these specific conditions. The adverse events observed in the study may be attributable to a combination of factors. First, the thickness (250 microns) and shape memory of the synthetic biocompatible implant led to incompatibility with the mandibular implant surface, potentially preventing integration with surrounding tissue and resulting in implant exposure. Furthermore, the surgical technique used during implantation may have influenced the results, as certain techniques, particularly those using nondegradable membranes, are associated with an increased risk of wound edge separation (dehiscence) and subsequent implant exposure. Improved surgical techniques can improve implant stability and integration, thereby reducing the potential for adverse events. Finally, the choice of the minipig as an animal model may have contributed to the observed results: differences between the minipig and the more commonly used canine model may have affected device performance in the oral environment, particularly in terms of daily oral hygiene practices, which are not feasible in this animal model and may have influenced implant response and integration with oral tissues.

[0069] Histological processing and evaluation were performed on the collected jaw samples. Despite gross soft tissue dehiscence observed during the examination, histological analysis revealed that the synthetic biocompatible implant was strongly fixed to the internal soft and bony tissues. This finding indicates that the synthetic biocompatible implant may serve as a good solution for guided bone regeneration (GBR) and guided tissue regeneration (GTR). Figures 8A-8D show histological slides (Sincair minipig) of the implanted site of the patch of the present invention one month after implantation.

[0070] Figures 8A and 8B are low- and medium-magnification H&E images, respectively. Figure 8C shows a cross-section of the porous polymer (blue asterisk) and a very high-magnification H&E showing a patch of the present invention (blue asterisk). Note the presence of fibroblasts within the porous polymer, indicating tissue integration. Figure 8D is a high-magnification H&E showing the border of the bone defect (dashed red line) and the bone formation process within it.

[0071] Conclusion: Although adverse events were observed during the observation period of the study, the positive histological findings offer promising prospects for the potential effectiveness of synthetic biocompatible implants in guided bone regeneration (GBR) and guided tissue regeneration (GTR) applications. These results further underscore the importance of their continued development as a valuable solution in regenerative dentistry, holding great promise for improved patient outcomes in procedures requiring tissue regeneration and augmentation.

[0072] Example 6 - Post-treatment of electrospun fibers onto a coral-like rough surface

[0073] Cell attachment to different surfaces is influenced by multiple surface characteristics, such as surface topography (roughness vs. smoothness), charge, chemistry, and porosity. When examining orthopedic and dental implants made of titanium or other metal alloys, there is a need to improve bone or connective tissue adhesion to such implants to enhance resistance to peri-implantitis or other failure factors associated with such implants. While many methods are known to physically or chemically improve / alter the surface properties of titanium implants, such methods have yet to be shown to provide a completely reliable solution for successful implant retention. Biomaterial coatings on implants can improve implant integration with adjacent tissues. Such biomaterials can be mineral-based to promote bone growth, antibacterial to inhibit bacterial colonization, or other biomaterials.

[0074] Electrospun fibers with post-treatment can be used to provide a coral-like structure that increases surface roughness while maintaining a fiber-like structure and mechanical support. Furthermore, the synthetic nature of the biomaterial allows it to be further processed and impregnated with different functional molecules, depending on demand. Biomaterials can be easily incorporated (end-wise) into the implant surface and cross-linked, allowing for long-term functional coverage of the implant.

[0075] It has previously been demonstrated that fibroblasts prefer to adhere to smooth surfaces due to the increased number of focal adhesions on these surfaces. However, such smooth surfaces on implants have been shown to promote scar tissue formation (differentiation of fibroblasts into myofibroblast-type cells). Furthermore, rough surfaces provide a higher surface area-to-volume ratio, which, along with other functionalities of the material, can offset the reduced adhesion pattern of fibroblasts on such surfaces. Osteoblasts have previously been demonstrated to prefer to attach to rough surfaces, and this surface topography has been shown to be beneficial for promoting bone formation. In fact, coral materials have been used as osteogenic matrix materials.

[0076] The applicability of cryogenic (liquid nitrogen) milling of polyurethane electrospun mesh to form particles of approximately 50 μm with a rough surface structure was demonstrated. First, liquid nitrogen was used to cool the feedstock. Details of this process are described in the accompanying report by RETCH. This process demonstrates that polyurethane mesh can be reduced to an average particle size of 50 μm. The particles can be further reduced by different screening methods to obtain smaller particles. It is also possible to obtain different particle size distributions by modifying the feedstock itself (changing its thickness). Figures 9A-9B show SEM images of particles obtained by this method. Figures 9A and 9B show low-magnification (9A) and high-magnification (9B) views of electrospun fibers after milling, demonstrating the roughness of the substrate after milling, while the fiber structure is semi-intact. This particle feedstock is a promising candidate for testing as a coating material. High porosity is achieved due to the free space between particles, as well as the natural pores between them.

[0077] The principle of coating dental implants with polyurethane particles: The particles are activated by plasma treatment, which is thought to increase their hydrophilicity through the addition of carboxylic acid or hydroxyl groups (COOH / OH). Metal implants can be treated in a similar manner, or by alkaline / acid treatment. The particles are soluble in aqueous media and adhere to the implant surface through van der Waals interactions or hydrogen bonding. The particles must then be crosslinked. One possible crosslinking mechanism is solvent-based gas crosslinking (exposing the coated implant to solvent vapor for time-dependent crosslinking). This crosslinking occurs at room temperature and offers many advantages over other thermal-based or chemical crosslinking methods. It is important to understand that other functional groups can be added to the particle or implant material as needed to promote other attachment mechanisms, such as silane-based covalent crosslinking. This process offers great flexibility in the manufacturing process.

[0078] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will occur to those skilled in the art, and it is therefore to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the invention.

Claims

1. A dental or subperiosteal implant comprising at least one synthetic biocompatible graft having a porous polymer structure with pores less than 5 microns.

2. A dental or subperiosteal implant comprising at least one synthetic biocompatible graft having a porous polymeric structure with pores of about 0.01 microns to about 5 microns.

3. A dental or subperiosteal implant comprising at least one synthetic biocompatible graft having a porous polymer structure with pores between 5 microns and 20 microns.

4. 3. A dental or subperiosteal implant according to claim 1 or claim 2, wherein the synthetic biocompatible graft is a biocompatible graft.

5. 3. A dental or subperiosteal implant according to claim 1 or claim 2, wherein the synthetic biocompatible graft is a non-degradable graft.

6. Dental or subperiosteal implant according to any one of claims 1 to 5, wherein said at least one synthetic biocompatible graft covers at least a part of said implant.

7. Dental or subperiosteal implant according to any one of claims 1 to 6, wherein the synthetic biocompatible graft has a thickness of between 10 μm and 100 μm.

8. Dental or subperiosteal implant according to any one of claims 1 to 7, wherein the synthetic biocompatible graft has a thickness of between 100 μm and 1000 μm.

9. A dental or subperiosteal implant according to any one of claims 1 to 8, wherein the synthetic biocompatible graft has a thickness of between 1000 μm and 2500 μm.

10. A dental or subperiosteal implant according to any one of claims 1 to 9, wherein said porous polymer structure comprises at least one polymer.

11. A dental or subperiosteal implant according to any one of claims 1 to 10, wherein the porous polymer structure comprises nanofibers.

12. A dental or subperiosteal implant according to any one of claims 1 to 11, wherein the porous polymer structure comprises at least one porous electrospun polymer.

13. The porous polymer structure may be made of polycarbonate, poly(DTE carbonate), polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactic acid (PLLA), poly(DL-lactide-co-caprolactone), poly(ethylene-co-vinyl acetate), vinyl acetate, poly(methyl methacrylate), poly(propylene carbonate), poly(vinylidene fluoride), polyacrylonitrile, polycaprolactone, polycarbomethylsilane, polylactic acid, polystyrene, polyvinylpyrrolidone, polyvinyl alcohol (PVA), poly 13. The dental or subperiosteal implant of any one of claims 1 to 12, comprising at least one polymer selected from polyethylene oxide (PEO), polyurethane, polyvinyl chloride (PVC), hyaluronic acid (HA), chitosan, alginic acid, polyhydroxybutyric acid and its copolymers, nylon 11, cellulose acetate, hydroxyapatite, poly(3-hydroxybutyrate-co-hydroxyvalerate), poly(DL-lactide), polycaprolactone, and poly(L-lactide), or any combination thereof.

14. The dental or subperiosteal implant according to any one of claims 1 to 13, wherein the synthetic biocompatible graft further comprises at least one active agent.

15. 14. The dental or subperiosteal implant of claim 13, 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.

16. The dental or subperiosteal implant according to any one of claims 1 to 15, wherein the synthetic biocompatible graft further comprises at least one non-porous layer.

17. A subperiosteal implant according to any one of claims 1 to 16 for use in the treatment of jawbone deficiency, jawbone fractures, edentulous patients with partial jawbone resorption, and any similar conditions or symptoms.

18. An appliance comprising at least one dental or subperiosteal implant according to any one of claims 1 to 17.

19. A kit comprising at least one dental or subperiosteal implant according to any one of claims 1 to 18, means for its implantation / positioning in the subperiosteal space of a subject, and instructions for use.

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