Dental implant and subperiosteal implant comprising biocompatible graft

Abstract

The present invention provides a dental implant or subperiosteal implant having a porous polymer structure and its use in methods of treatment of periodontal diseases, conditions and symptoms.

Description

Background Art

[0001] The restoration of edentulous patients with or without atrophic jaws is a surgical challenge. Conventional endosseous implant-supported overdentures and immediate loading options remain clinically challenging. Many techniques have been described in the literature to overcome this problem, such as reconstructive procedures such as autologous bone grafting or guided bone regeneration. However, autologous bone grafting requires a second surgical site, implying additional morbidity, and immediate loading is not always recommended. Guided bone regeneration, especially vertical bone regeneration, is often limited in benefit and is also associated with possible complications in completely atrophic jaws. Both techniques require several months to wait for the graft to mature. After implantation, peri-implantitis may occur years after dental implant placement, requiring surgical intervention and sometimes even implant removal. The atrophic jaw is accompanied by anatomical changes that increase the risk of damage to important structures, thereby increasing the need for specific surgical skills during the surgery.

[0002] There is a need to provide a safe and reliable dental implant or subperiosteal implant that can provide a permanent solution for edentulous jaws, atrophic jaws and related diseases while avoiding the risks of inflammation, implant exposure and dislocation, peri-implantitis, infection and eventual implant loss and the need for secondary surgery. Summary of the invention

[0003] The present invention provides an effective and stable technical solution for implanting dental implants and subperiosteal implants, which are versatile on the one hand, making the surgical operation simple and easy, and are biostable and biocompatible on the other hand, have improved long-lasting effects, and provide effective integration with the jawbone and tooth tissue.

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

[0005] When referring to a "subperiosteal implant", it is understood to refer to a metal implant framework that rests directly on top of the bone, beneath the periosteum, and provides attachment posts that extend through the gingival tissue to achieve prosthetic anchorage.

[0006] When referring to a "dental implant", it should be understood to refer to a prosthesis that interfaces with the jawbone or skull to support a dental prosthesis such as a crown, bridge, denture or facial prosthesis, or to serve as an orthodontic anchor. Dental implants are typically made of materials such as titanium or zirconium oxide and form a tight bond with the bone in which they are implanted. The implant retainer is placed first to allow osseointegration to occur, and then the dental prosthesis is added. Osseointegration requires varying degrees of healing time before the dental prosthesis (tooth, bridge or denture) is attached to the implant, or before an abutment is placed to secure the dental prosthesis / crown. A prerequisite for the long-term success of osseointegrated dental implants is healthy bone and gums. Because both bone and gums shrink after tooth extraction, pre-prosthetic surgery such as a sinus lift or gum graft is sometimes required to re-establish ideal bone and gums.

[0007] Typical traditional implants (such as Figure 1 The dental implant (as shown) comprises a root implant part (103) in the form of a screw (similar to a tooth root) made of metal (usually made of titanium or a titanium alloy) with a rough or smooth surface, and a top part (101) similar to a tooth (or multiple teeth), for example made of zirconium oxide. The abutment (102) is connected between the implanted root part and the upper visible tooth part. The root implant part of the dental implant is mostly made of commercially pure titanium or a titanium alloy. Most modern dental implants also have a textured surface (by etching, anodizing or multimedia spraying) to increase the surface area and bone bonding potential of the implant. In Figure 2 In some embodiments of the implant of the present invention shown, the root implant portion is covered with said synthetic biocompatible graft (106), wherein the abutment (105) and the outer tooth portion (104) remain uncoated.

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

[0009] When referring to a "synthetic biocompatible implant", it is understood to refer to an implantable synthetic polymer material that is biocompatible with dental tissue (such as gingival tissue), wherein cell growth near the implant enables growth and integration within the implant at the jaw-gingival boundary. In some embodiments, the implant of the present invention is in sheet form.

[0010] In some embodiments, the at least one synthetic biocompatible graft covers, coats and / or coats substantially all of the metal framework (metal root implant portion) of the subperiosteal implant or any dental implant. In other embodiments, the at least one synthetic biocompatible graft covers, coats and / or coats at least a portion of the metal framework of the subperiosteal implant or any dental implant.

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

[0012] In some embodiments, the synthetic biocompatible graft having a porous polymer structure has pores between about 0.01 microns and 5 microns. In some embodiments, the synthetic biocompatible 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, 5 microns.

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

[0014] In other embodiments, the synthetic biocompatible graft of the present invention is a non-degradable graft. In other embodiments, the synthetic biocompatible graft of the present invention is a permanent, intact, non-degradable graft.

[0015] In some embodiments, the thickness of the synthetic biocompatible implant of the present invention is between 100-1000 μm. In other embodiments, the thickness of the synthetic biocompatible implant of the present invention is between 10-100 μm. In other embodiments, the thickness of the synthetic biocompatible implant of the present invention is between 1000-2500 μm.

[0016] In some embodiments, the porous polymer structure comprises at least one polymer. In other embodiments, the porous polymer structure comprises nanofibers (in some embodiments, the nanofibers have a thickness of 500 nanometers to several micrometers).

[0017] 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 (eg, using a 3D printing device).

[0018] In some other embodiments, the porous polymer structure includes at least one polymer 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), polyvinylidene fluoride, polyacrylonitrile, polycaprolactone, polycarboxymethyl silane, polylactic acid, polystyrene, polyvinyl pyrrolidone, polyvinyl alcohol (PVA), polyethylene oxide (PEO), polyurethane (including aromatic polyurethane), polyvinyl chloride (PVC), hyaluronic acid (HA), chitosan, alginate, polyhydroxybutyrate and copolymers thereof, nylon 11, cellulose acetate, hydroxyapatite, poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid), poly(DL-lactide), polycaprolactone and poly(L-lactide) or any combination thereof.

[0019] Electrospun fibers are typically several orders of magnitude smaller than fibers produced using conventional spinning techniques. By optimizing parameters such as: i) the intrinsic properties of the solution, including the polarity and surface tension of the solvent, the molecular weight and conformation of the polymer chains, and the viscosity, elasticity, and conductivity of the solution; and ii) operating conditions, such as the strength of the electric field, the distance between the spinneret and the collector, and the feed rate of the solution, electrospinning is able to produce fibers with diameters as small as tens of nanometers. Other parameters that affect the properties of electrospun fibers include the molecular weight, molecular weight distribution, and structure (branching, linearity, etc.) of the polymer, solution properties (viscosity, conductivity, and surface tension), electromotive force, flow rate and concentration, the distance between the capillary and the collecting net, environmental parameters (temperature, humidity, and air flow rate in the chamber), and the motion of the target net (collector). The fabrication of highly porous fibers can be achieved by electrospinning the jet directly into a cryogenic liquid. Under freeze-drying conditions, well-defined pores are formed on the surface of each fiber due to temperature-induced phase separation between the polymer and the solvent and evaporation of the solvent.

[0020] A variety of methods have been developed to organize electrospun fibers into aligned arrays. For example, electrospun fibers can be aligned into uniaxial arrays by replacing a monolithic collector with a pair of conductive substrates separated by a gap. In this case, the nanofibers are stretched across the gaps oriented perpendicular to the electrode edges. It has also been shown that pairs of electrodes can be patterned on insulating substrates such as quartz or polystyrene so that uniaxially aligned fibers can be stacked layer by layer into a three-dimensional lattice. More complex architectures consisting of aligned nanofibers can also be generated by controlling the electrode pattern and / or the sequence in which the high voltage is applied.

[0021] Electrospun nanofibers can also be directly deposited on various objects to obtain nanofibrous structures with well-defined and controllable shapes. In addition, aligned or randomly oriented nanofibrous membranes can be manually processed into various types of structures after electrospinning: for example, tubes can be made by rolling up the fiber membranes, or disks with controllable diameters can be prepared by punching the fiber membranes.

[0022] The present invention relates to any electrospinning technology known in the art, including Electrospinning, J. Stanger, N. Tucker, and M. Staiger, I-Smithers Rapra publishing (UK), An Introduction to Electrospinning and Nanofibers, S. Ramakrishna, K. Fujihara, WE Teo, World Scientific Publishing Co. Pte Ltd (June 2005), 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, which are incorporated herein by reference in their entirety.

[0023] Suitable electrospinning technology is disclosed in, for example, International Patent Application Publication Nos. WO2002 / 049535, WO2002 / 049536, WO2002 / 049536, WO2002 / 049678, WO2002 / 074189, WO2002 / 074190, WO2002 / 074191, WO2005 / 032400 and WO2005 / 065578, the contents of which are incorporated by reference. It should be understood that, although electrospinning technology is particularly emphasized when describing according to the preferred embodiments of the present invention, it is not intended to limit the scope of the present invention to electrospinning technology. Representative examples of other spinning technologies suitable for embodiments of the present invention include, but are not limited to, wet spinning technology, dry spinning technology, gel spinning technology, disperse spinning technology, reactive spinning technology or viscose spinning technology. Such and other spinning techniques are well known in the art and are described, 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, which are incorporated by reference in their entireties.

[0024] In order to improve the bone bonding of the implant of the present invention, the outer surface of the at least one synthetic biocompatible implant coating the implant (i.e., the surface in contact with the bone or tissue of the implant site) is rough and granular (uneven), and particles (e.g., coral-like surface) are formed on its surface. In some embodiments, the surface of the at least one synthetic biocompatible implant is a rough granular surface. In some embodiments, the at least one synthetic biocompatible implant comprises an electrospun fiber having a coral-like rough surface. In some embodiments, the outer surface of the at least one synthetic biocompatible implant has a granular surface with a particle size of at least 50 μm. In some embodiments, the surface of the at least one synthetic biocompatible implant has a particle size of at most 50 μm. In some embodiments, the surface of the at least one synthetic biocompatible implant has a particle size of 1 to 50 μm. In some embodiments, the at least one synthetic biocompatible implant comprises an electrospun fiber that has been post-treated by cryogenic grinding.

[0025] In some embodiments, the synthetic biocompatible implant of the present invention further comprises at least one active agent. In some embodiments, the at least one active agent is selected from proteins, type I collagen, fibronectin or TGF-β2, heparin, growth factors, antibodies, antimetabolites, chemotherapeutic agents, anti-inflammatory agents, antibiotics and any combination thereof.

[0026] In some embodiments, the synthetic biocompatible graft of the present invention is cut into a specified shape (in some embodiments, the cutting is laser cutting, manual cutting, pressure cutting, 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 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.

[0028] When referring to a "non-porous layer", it is understood to include a membrane layer which is substantially free of pores and therefore cannot be penetrated by tissue, as compared to the porous layer of the biocompatible implant of the invention.

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

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

[0031] In some embodiments, the nonporous polymer structure comprises at least one polymer. In other embodiments, the nonporous polymer structure comprises nanofibers (in some embodiments, the nanofibers have a thickness of 500 nm to several microns).

[0032] In some other embodiments, the non-porous polymer structure includes at least one polymer 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), polyvinylidene fluoride, polyacrylonitrile, polycaprolactone, polycarboxymethyl silane, polylactic acid, polystyrene, polyvinyl pyrrolidone, polyvinyl alcohol (PVA), polyethylene oxide (PEO), polyurethane (including aromatic polyurethane), polyvinyl chloride (PVC), hyaluronic acid (HA), chitosan, alginate, polyhydroxybutyrate and copolymers thereof, nylon 11, cellulose acetate, hydroxyapatite, poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid), poly(DL-lactide), polycaprolactone and poly(L-lactide) or any combination thereof.

[0033] Reference to "periodontal disease, condition or symptom" is understood to include inflammation affecting the tissues surrounding the teeth, such as gum disease, gingivitis, periodontitis, tooth decay, tooth loss, bone loss, peri-implantitis, and any combination thereof.

[0034] In some embodiments, such periodontal diseases, disorders, or symptoms may result in the need for periodontal surgery.

[0035] The term "periodontal surgery" is intended to include dental procedures, maxillofacial procedures, and any combination thereof, that prevent, correct, or reconstruct anatomical, traumatic, developmental, age-related, or plaque-induced defects in the bone, gingiva, or alveolar mucosa. The objectives of such procedures include: accessing instruments to root surfaces, eliminating inflammation, creating an oral environment for plaque control, controlling periodontal disease, maintaining oral hygiene, maintaining an adequate diastema, addressing gingival-alveolar mucosal problems, and improving aesthetics. Surgical procedures include crown lengthening, frenectomy, gingival-mucosal flap surgery, gingivectomy, apicoradial flap (APF), apicoradial flap (APF) combined with bone revision (osteoplasty / osteotomy), and any combination thereof.

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

[0037] The present invention further provides a synthetic biocompatible implant as described above and below for use in treating a periodontal injury, disease, disorder or condition.

[0038] The present invention also provides a device comprising the dental implant or subperiosteal implant of the present invention.

[0039] The present invention also provides a kit comprising the dental implant or subperiosteal implant of the present invention, tools for implanting / placing the dental implant or subperiosteal implant into the gingival tissue of a subject, and instructions for use.

[0040] In some embodiments, the instructions for use may include instructing a caregiver on how to custom cut the implants of the present invention and how to place the implants of the present invention, for example, on teeth and gum tissue. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The subject matter regarded as the invention has been particularly pointed out and distinctly claimed in the concluding portion of the specification. However, the organization and method of operation of the invention, together with objects, features, and advantages thereof, may be best understood by reference to the following detailed description when read in connection with the accompanying drawings, in which:

[0042] Figure 1 A typical dental crown implant is shown.

[0043] Figure 2A typical dental crown implant covered with a biocompatible graft is shown.

[0044] Figure 3A-3B The surgical site at the end of Example 1 (3 weeks post-surgery) is shown.

[0045] Figure 4A-4C Shown are histological sections (H&E) of untreated sites at 6 weeks post-surgery in Example 2 (B-bone tissue; CT-connective tissue; Ep-epithelial cells).

[0046] Figure 5A-5D Shown is a histological section (H&E) of the implantation site of the patch of the present invention at 3 weeks after surgery in Example 3 (asterisk-marked patch).

[0047] Figure 6A-6F Shown are histological sections (H&E) of the surgical site at 10 weeks post-surgery in Example 4 (asterisk - synthetic biocompatible graft).

[0048] Figure 7 The test model of Example 5 is shown.

[0049] Figure 8A-8D Shown is a histological section of the implantation site of the patch of the present invention in a Sinclair MiniPig 1 month after implantation.

[0050] Figure 9A-9B Shown are scanning electron microscope images of particles post-processed with electrospun fibers to create a coral-like rough surface.

[0051] It is understood that, in order to make the illustrations simple and clear, the elements shown in the drawings are not necessarily drawn to scale. For example, for the sake of clarity, the size of some elements may be exaggerated relative to other elements. In addition, where appropriate, reference numerals may be repeated in multiple drawings to indicate corresponding or similar elements. DETAILED DESCRIPTION

[0052] In the following detailed description, many specific details are listed to provide a thorough understanding of the present invention. However, those skilled in the art will appreciate that the present invention can be implemented without these specific details. In other cases, in order to avoid obscuring the present invention, well-known methods, procedures and components are not described in detail.

[0053] Figure 1 A typical dental implant is shown with an outer crown and a metal implant inserted into the jawbone. Figure 2 A dental crown implant is shown in which a metal implant inserted into the jawbone is covered / capped / coated with a biocompatible graft.

[0054] Example 1 - Evaluation of the oral implantation of the present invention in a rat model to assess its integration with gingival and bone tissue.

[0055] Experimental Model: A single rat was selected as an animal model to evaluate the feasibility and performance of synthetic biocompatible implants in the oral environment. A synthetic biocompatible implant measuring 2×2 mm was implanted into the gums on the right side of the rat's maxilla. During the subsequent three-week observation period, the rat showed normal eating habits, indicating no discomfort or damage.

[0056] Results: When examined at the end of the study, the gingival tissue at the implant sites showed signs of complete healing, similar to that of untreated areas.

[0057] It is noteworthy that the synthetic biocompatible graft was clearly present beneath the gingival tissue, indicating successful implantation. However, during tissue dissection, it could be observed that the synthetic biocompatible graft was more tightly integrated with the adjacent bone tissue than with the soft tissue. Although it was not completely integrated into the gingival tissue, it was difficult to remove it, indicating that it was well integrated with the bone. Figure 3A and Figure 3B The surgical site at the end of the surgery (3 weeks post-surgery) is shown. Figure 3A The maxilla (surgical site) before dissection is shown, with no macroscopic adverse effects noted. This is evident from the similarity in tissue appearance compared to the unoperated contralateral side. Figure 3B The surgical site is shown immediately after tissue dissection. The synthetic biocompatible graft, indicated by the arrow, is clearly visible and appears to be firmly attached to the bone beneath the gums.

[0058] Conclusion: The synthetic biocompatible graft showed excellent wound healing and integration with bone tissue. However, the integration with soft tissue was relatively low.

[0059] Example 2 - Evaluation of the effectiveness of synthetic biocompatible implants in a gingival recession model and assessment of acute healing of both soft and bone tissues.

[0060] Experimental model: This study involved six SD rats, equally divided, terminated at 3 and 6 weeks after surgery. Each rat received a test device implantation surgery in a gingival pouch formed on the right side of the maxilla. This required the creation of a 3 mm wide and 3 mm deep pocket in front of the upper right molar using a 15c blade. Subsequently, a 2×2 mm patch was placed on the buccal side of the pocket, and the defect was then closed with Vicryl 5-0 sutures.

[0061] Results: All animals showed signs of successful healing except for one rat that had patch exposure at both the 3-week and 6-week checkpoints. Histological analysis provided significant evidence of cellular infiltration of adjacent bone tissue, indicating a robust bond between the implanted synthetic biocompatible graft and bone tissue. This suggests that synthetic biocompatible grafts show promise for integration into bone tissue and may be a viable option for similar applications. Figure 4A-4C Shown are histological sections (H&E) of untreated sites 6 weeks after surgery (B - bone tissue; CT - connective tissue; Ep - epithelial cells). Figure 4B The patch was clearly discernible and was shown to engage the soft tissue. Of note, there was a clear lack of inflammatory cell response, indicating biocompatibility. Figure 4C The patch is shown in contact with bone tissue. Figure 4B Similarly, there was no inflammatory cell response. In addition, the figure also highlights the infiltration of cells from both soft and bone tissue into the porous matrix, with a discernible increase in cell infiltration at the junction with bone tissue, indicating a more secure cell association in this area.

[0062] Conclusions: In conclusion, histological analysis provided convincing evidence of extensive cellular infiltration originating from adjacent bone tissue, indicating strong integration of the implanted patch into the bone matrix. This finding supports the potential applicability of synthetic biocompatible grafts in applications involving integration into bone tissue.

[0063] Example 3 - Rat skull defect - model validation

[0064] Experimental Model: Three rats were involved, each of which received a subperiosteal implant of an oversized rectangular synthetic biocompatible graft in a 5 mm bone defect in the skull. The animals were observed for 3 weeks after implantation.

[0065] Results: During the three-week treatment, no adverse effects were observed and all animals showed normal weight gain. Macroscopic examination at termination showed that the position and orientation of two of the three patches were well maintained, while one patch seemed to be partially displaced toward the nasal area. Histological evaluation showed moderate cellular infiltration of the patches, mainly in the part facing the bone tissue. Osteogenesis was observed in the defect site of all animals, with significant osteogenesis observed in the patch of the animal with graft dislocation. Figure 5A-5D Shown are histological sections (H&E) of the implantation site of the patch of the present invention 3 weeks after surgery (asterisk-marks patch). Figure 5A and Figure 5BExtracted from the tissue section of the implantation site of animal No. 1, both low (5A) and high (5B) magnifications are provided. The patch is clearly visible, showing no signs of inflammatory response. 501 marks the bone defect. 502 marks the old bone and 503 marks the new bone formed. It is noteworthy that there is obvious new bone formation at the periphery of the bone defect and obvious cellular infiltration in the porous matrix. Figure 5C and Figure 5D Histological section of the implant site from animal 2, where the implant appears to be partially displaced. This is seen at both low (5C) and high (5D) magnification. In this case, there is significant bone formation above the patch and bone formation extends into the patch itself, indicating that the patch has the potential to promote bone formation. 504 marks new bone formation above the patch and 505 marks new bone formation within the patch.

[0066] Conclusion: The synthetic biocompatible graft showed overall safety and potential to induce bone regeneration.

[0067] Example 4 - Evaluation of bone regeneration using a rat skull defect model

[0068] Experimental Model: This study involved a larger cohort of 10 rats divided into the following three experimental groups:

[0069] Group 1 - received synthetic biocompatible implants implanted directly on the skull.

[0070] Group 2 - received synthetic biocompatible grafts implanted in the skull defect.

[0071] Group 3 - served as a control group with bone defects but without the implantation of a synthetic biocompatible graft.

[0072] The animals were observed for 10 weeks after implantation.

[0073] Results: No systemic or local reactions were observed during the 10-week follow-up. Macroscopic evaluation after termination showed that all patches remained in place. Histological analysis showed extensive cell growth in the patch pores and even slight osteogenesis in the patches. Group 2 showed new bone formation above the patches, indicating that the synthetic biocompatible grafts have the potential to promote bone regeneration compared with untreated bone defects. Figure 6A-6F Shown are histological sections (H&E) of the surgical site 10 weeks post-surgery (asterisk - synthetic biocompatible graft).

[0074] Fig. 6A and Figure 6BBoth low (6A) and high (6B) magnifications are provided from tissue sections extracted from animal No. 1 in Group 1. The synthetic biocompatible graft is clearly visible with no signs of inflammatory response. Notably, new bone formation is observed growing into the synthetic biocompatible graft. Additionally, note the tares in the patch, which are artifacts of the histological processing and indicate a solid connection to the underlying bone. 601 marks the new bone formed. Figure 6C and Fig.6D Tissue sections obtained from animal No. 2 in Group 2 provide both low (6C) and high (6D) magnifications. Of note, significant bone regeneration is evident, starting at the edge of the bone defect, extending through the synthetic biocompatible graft, and even above it. At the edge of the defect, tissue discoloration can be observed, which may indicate thermal osteonecrosis, most likely caused by overheating of the drill hole. 602 marks the suture line and 603 marks the bone defect. 604 marks new bone growing through and on the patch, and 605 marks suspected thermal osteonecrosis, which may be caused by overheating of the drill hole.

[0075] Fig. 6E and Fig. 6F Histological section from animal number 1 in group 3, showing both low (6E) and high (6F) magnifications. In this case, minimal bone formation was observed, while soft tissue filled the bone defect. 606 marks soft tissue filling the void, no new bone formation. 607 marks suspected thermal osteonecrosis (due to drilling). 608 marks minimal new bone formation.

[0076] Conclusion: This study suggests that the described synthetic biocompatible graft has the potential to induce bone regeneration and may offer advantages over untreated defects.

[0077] Example 5 - Minipig mandibular defect model

[0078] Experimental Model: This study involved a more complex animal model utilizing miniature pigs to evaluate the efficacy of synthetic biocompatible grafts for the treatment of mandibular defects. The study combined ante-mortem and post-mortem evaluations to assess osseointegration and new bone growth. The study included 3 Sinclair miniature pigs, all of which initially had 6 mandibular premolars extracted. After a 10-week healing period, three (3) approximately 7×8×10 mm ridges were created in each mandibular hemi-mandible. 3 After the defects were created, they were filled with commercial bone fillers (Bio-Oss, Geistlich) and Figure 7 The regimen in the present invention was covered with a test article (CorNeat gPatch) or a reference article (Ossix Plus) or left untreated.

[0079] Results: Abnormalities associated with synthetic biocompatible grafts were observed in both animals, including membrane exposure and possible infection, leading to difficulty in eating and weight loss. Findings after autopsy supported the clinical observations, indicating enlarged and reactive lymph nodes in the hemi-mandible implanted with synthetic biocompatible grafts. Ultimately, the study was terminated early due to safety concerns, and the safety of synthetic biocompatible grafts under these specific conditions was not confirmed. The adverse events observed in this study may be attributed to a combination of factors. First, the thickness (250 μm) and shape memory of the synthetic biocompatible graft may have resulted in a mismatch with the mandibular implant surface, which could have hampered integration with the surrounding tissue and led to implant exposure. In addition, the surgical technique used during implantation may have influenced the results, as some techniques, especially those using non-degradable membranes, have been associated with an increased risk of wound edge separation (dehiscence) and subsequent implant exposure. The use of improved surgical techniques could improve implant stability and integration, thereby reducing the likelihood of adverse events. Finally, the choice of minipigs as an animal model may have led to the observed results. Differences between the minipig and the more commonly used canine model may affect device performance in the oral environment, especially with regard to daily oral hygiene practices, which are not feasible in this animal model and may affect implant response and integration with oral tissues.

[0080] The collected jawbone samples were processed and evaluated histologically. Although macroscopic cracking of the soft tissue was observed during the examination, the histological analysis showed that the synthetic biocompatible graft was firmly fixed to the internal soft and bone tissue. This finding suggests that synthetic biocompatible grafts have the potential to be a good solution for guided bone regeneration (GBR) and guided tissue regeneration (GTR) indications. Figure 8A-8D Shown is a histological section of a Sinclair MiniPig at the site of implantation of the patch of the present invention 1 month after implantation.

[0081] Fig. 8A and Figure 8B H&E low and medium magnification images are shown, respectively. Cross section of porous polymer (blue asterisk). Figure 8C H&E at very high magnification showing a patch of the invention (blue asterisk) is shown. Fibroblasts were observed to be present within the porous polymer, indicating that tissue incorporation occurred. Fig.8D Shown is a high-magnification H&E image showing the boundary of the bone defect (red dashed line) and the bone formation process inside it.

[0082] Conclusion: Although adverse events were observed during the study observation period, the positive histological findings suggest that the synthetic biocompatible graft has promising potential for guided bone regeneration (GBR) and guided tissue regeneration (GTR) applications. These results further highlight its continued development as a valuable solution in the fields of dentistry and regenerative medicine, offering great promise for improving patient outcomes in surgeries requiring tissue regeneration and augmentation.

[0083] Example 6 - Post-treatment of electrospun fibers into coral-like rough surfaces

[0084] Cell attachment to different surfaces is influenced by several properties of the surface, such as topography (rough vs. smooth), charge, chemistry, porosity, etc. When working with orthopedic and dental implants made of titanium or other metal alloys, there is a need to improve the adhesion of bone or connective tissue to such implants, making them more resistant to peri-implantitis or other failure factors associated with such implants. There are many known methods to improve / modify the surface properties of titanium implants by physical or chemical methods, but these methods still do not provide a completely reliable solution for successful implant retention. Biomaterial coatings of implants can enhance the adhesion of implants to adjacent tissues. Such biomaterials can be mineral based to increase bone growth, antimicrobial or other materials that inhibit bacterial colonization.

[0085] Post-processed electrospun fibers can be used to provide coral-like structures that provide increased surface roughness while maintaining the fibrous architecture and mechanical support. In addition, the synthetic nature of the biomaterial allows it to be further processed and impregnated with different functional molecules as needed. The biomaterial can be easily (end-)bound to the implant surface and cross-linked, resulting in a long-term functional coating of the implant.

[0086] Fibroblasts have been documented to prefer to adhere to smooth surfaces due to the increased focal adhesion points. However, such smooth surfaces on implants have been shown to promote scar tissue formation (fibroblast differentiation into myofibroblast type cells). In addition, rough surfaces have a higher surface to volume ratio which, combined with other material features, can balance the reduced adhesion pattern of fibroblasts on such surfaces. Osteoblasts have been documented to prefer to bind to rough surfaces and such surface topography has been shown to be beneficial in promoting bone formation. In fact, coral materials have been and are still being used as bone formation matrix materials.

[0087] It has been shown that grinding polyurethane electrospun webs using cryogenic conditions (liquid nitrogen) can provide particles of about 50 microns in size with a rough surface texture. The raw material is first cooled using liquid nitrogen. Details of the process can be found in the attached RETCH report. The process has shown that the average particle size of the polyurethane web can be reduced to 50 microns. These particles can also be further reduced in size by different screening methods to obtain smaller particles. In addition, the raw material itself (i.e. thickness) can be varied, making it possible to obtain dispersions of different particle sizes. Figure 9A-9B SEM images of the particles obtained by this method are shown. Fig. 9A and Fig. 9B The low magnification of electrospun fibers after grinding is shown ( Fig. 9A ) and high power ( Fig. 9B ) shows the roughness of the substrate after grinding, and the fiber structure is in a semi-intact state. The particle raw material is a promising candidate to be tested as a coating material. The free space between particles and the primary pores between particles enable high porosity.

[0088] Principle of coating dental implants with polyurethane particles: It is assumed that the particles are activated by plasma treatment to enhance the hydrophilicity of the particles by adding carboxyl or hydroxyl groups (COOH / OH). Metal implants can be processed in a similar manner or by alkali / acid treatment. The particles are soluble in aqueous media and adhere to the implant surface by van der Waals interactions or hydrogen bonds. The particles should be further crosslinked and one possible crosslinking mechanism could be solvent-based gas crosslinking (exposing the coated implant to solvent vapors to achieve time-dependent crosslinking), which is carried out at room temperature and has many advantages over other heat-based or chemical crosslinking methods. It is important to understand that other functional groups can be added to the particle material or implant material as needed to promote other attachment mechanisms, such as silane-based covalent crosslinking or others. This process allows high flexibility in the manufacturing process.

[0089] Although some features of the present invention have been illustrated and described herein, those skilled in the art will now be able to conceive of many modifications, substitutions, changes and equivalents. Therefore, it should be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the present invention.

Claims

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

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

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

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

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

6. The dental implant or subperiosteal implant according to any of the preceding claims, wherein the at least one synthetic biocompatible graft covers at least a portion of the implant.

7. The dental implant or subperiosteal implant according to any one of the preceding claims, wherein the thickness of the synthetic biocompatible graft is between 10 microns and 100 microns.

8. The dental implant or subperiosteal implant according to any one of the preceding claims, wherein the thickness of the synthetic biocompatible graft is between 100 microns and 1000 microns.

9. The dental implant or subperiosteal implant according to any one of the preceding claims, wherein the thickness of the synthetic biocompatible graft is between 1000 microns and 2500 microns.

10. The dental implant or subperiosteal implant according to any one of the preceding claims, wherein the porous polymer structure comprises at least one polymer.

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

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

13. A dental implant or subperiosteal implant according to any one of the preceding claims, wherein the porous polymer structure comprises at least one polymer 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), polyvinylidene fluoride, polyacrylonitrile, polycaprolactone, polycarboxymethyl silane, polylactic acid, polystyrene, polyvinyl pyrrolidone, polyvinyl alcohol (PVA), polyethylene oxide (PEO), polyurethane, polyvinyl chloride (PVC), hyaluronic acid (HA), chitosan, alginate, polyhydroxybutyrate and copolymers thereof, nylon 11, cellulose acetate, hydroxyapatite, poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid), poly(DL-lactide), polycaprolactone and poly(L-lactide) or any combination thereof.

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

15. The dental implant or subperiosteal implant according to claim 13, wherein the at least one active agent is selected from proteins, type I collagen, fibronectin or TGF-β2, heparin, growth factors, antibodies, antimetabolites, chemotherapeutic agents, anti-inflammatory agents, antibiotics and any combination thereof.

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

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

18. A device comprising at least one dental implant or subperiosteal implant as defined in any one of the preceding claims.

19. A kit comprising at least one dental implant or subperiosteal implant as defined in any one of the preceding claims, tools for implanting / placing said dental implant or subperiosteal implant in the subperiosteal space of a subject and instructions for use.

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