Implantation tools and protocols for optimized solid matrices for promoting cell and tissue growth

Abstract

The invention provides a method for optimal implantation of a solid matrix that promotes cell or tissue growth or restoration of function in osteochondral, bone or cartilage tissue of a subject in need thereof. The method comprises selecting and preparing a solid matrix for implantation that promotes cell or tissue growth or restoration of function, the solid matrix having a length and width or promoting a close fit within the boundaries of the implantation site, and further characterized by having a sufficient height such that when a first end of the solid matrix is implanted within a bone in the implantation site, a second end of the solid matrix is at a height of at least 2 mm below the surface of the articular cartilage layer, or proximal to the tidemark region in the implantation site, and optionally applying a biocompatible polymer layer to the top surface of the implant, the height of the layer not exceeding the surface of the articular cartilage layer. Tools for implementing optimal positioning are described, including unique tools (5-120) for trimming cartilage at the implantation site.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 612,735, filed January 2, 2018, and U.S. Provisional Patent Application No. 62 / 783,221, filed December 21, 2018, both of which are incorporated herein by reference in their entirety. Background Technology

[0003] Tissue growth, regeneration, and repair are often necessary for restoring tissue function and reconstructing tissue morphology, for example, due to trauma exposure, tumor formation, abnormal tissue growth, aging, and other consequences.

[0004] Articular cartilage is a highly specialized tissue that covers the surface of long bones to allow for movement with minimal friction under heavy loads. In healthy bones, this joint function allows the bones to change their relative angular relationship with respect to the joint, as in the hip and knee joints. Due to the properties of the synovial fluid within the joint and the smooth morphology of the cartilage surface resulting in low friction on the mating joint surfaces, this function of the joint occurs painlessly and with almost no additional effort.

[0005] Many diseases / conditions are caused by cartilage damage, ranging from localized tears to loss of the underlying bone covering the affected area, to degenerative conditions such as osteoarthritis and rheumatoid arthritis, in which the entire cartilage layer and the underlying (subchondral) bone can be affected. Generalized or degenerative diseases, most commonly osteoarthritis, are usually treated with total joint replacement, where the cartilage surface and the underlying bone are completely replaced with artificial materials that allow for joint movement with minimal friction.

[0006] Synthetic materials have been used for many years as matrices to promote the assembly and repair of ex vivo tissues and similarly to restore and reconstruct such tissues (e.g., for bone), with mixed results.

[0007] Another possibility is autologous tissue transplantation, although the supply of autologous tissue is limited and tissue harvesting can be painful, with risks of infection, bleeding, cosmetic disability, nerve damage, and loss of function. Furthermore, significant morbidity is associated with the autologous graft harvesting site. These problems can be overcome by tissue engineering using solid matrices made from synthetic or natural biomaterials that promote the adhesion, migration, proliferation, and differentiation of stem cells, such as mesenchymal stem cells (MSCs).

[0008] Many diseases and conditions seeking treatment will benefit from the ability to promote cell and tissue growth in a site-specific manner, thereby promoting the growth and incorporation of new tissue within damaged or diseased sites.

[0009] In bone and cartilage applications, direct microenvironment and three-dimensional (3D) tissue organization are important factors in general differentiation as well as in chondrogenesis and osteogenic differentiation.

[0010] Some bone tissue engineering scaffolds are composed of natural polymers such as collagen, alginate, hyaluronic acid, and chitosan. Natural materials offer advantages such as specific cell interactions and ease of cell seeding due to their hydrophilic interactions, low toxicity, and low chronic inflammatory response. However, these scaffolds are often mechanically unstable and do not readily induce the formation of tissue structures with a specific, predetermined shape for transplantation. Chemical modification is required to achieve mechanical strength, which can lead to toxicity.

[0011] Defects and degeneration of the articular cartilage surface of a joint cause pain and stiffness. Damage to the cartilage that protects the joint can be caused by physical injury as a result of trauma, movement, or repetitive stress (e.g., osteochondral fracture, secondary injury due to cruciate ligament injury) or by disease (e.g., osteoarthritis, rheumatoid arthritis, aseptic necrosis, osteochondritis dissecans).

[0012] Osteoarthritis (OA) is caused by overall wear and tear and tearing of joints, most notably the hip and knee. While common in older adults, in fact, by age 40, most individuals have some inflammatory changes in their weight-bearing joints. Another emerging trend contributing to the increasing prevalence of osteoarthritis is the rise in obesity. The CDC estimates that 30% of American adults (or 60 million people) are obese. Obese adults are four times more likely to develop knee OA than adults of normal weight. Rheumatoid arthritis is an inflammatory condition that causes cartilage destruction. It is considered, at least in part, an autoimmune disease in which patients have a genetic predisposition to the disease.

[0013] Orthopedic prevention and repair of damaged joints is a heavy burden on the medical profession in terms of both cost and time spent treating patients. This is partly because cartilage lacks the ability to self-repair. Attempts to regenerate hyaline cartilage to repair cartilage defects have not yet been successful. Orthopedic surgery is feasible in efforts to prevent severe degenerative changes in joints, aiming to repair defects and prevent further joint damage. The use of surgical techniques typically requires the removal and donation of healthy tissue to replace damaged or diseased tissue. Techniques using donor tissue from autologous grafts, allogeneic grafts, or xenografts are entirely unsatisfactory, as autologous grafts introduce additional trauma to the subject, while allogeneic and xenografts are limited by the host subject's immune reactivity and the potential transfer of infectious agents. Surgical attempts to use materials other than human or animal tissues for cartilage regeneration have also been unsuccessful.

[0014] Because each joint is unique in terms of the geometry of its joint surface, another challenge for successful transplantation / implantation is considered to be the need for the most perfect morphological match that can be achieved.

[0015] To date, there is still a lack of ideal means and materials to restore the organizational function of such organizations and to promote the restructuring of their form. Summary of the Invention

[0016] In some embodiments, the present invention provides optimized processes / methods and tools / kits / means for implanting solid matrices to treat osteoarthritis of bone, cartilage, osteochondral or osteoarthritis.

[0017] In some embodiments, the present invention provides optimized processes / methods and tools / kits / means for implanting solid matrices to promote cell or tissue growth or functional restoration of osteochondral tissue.

[0018] In some embodiments, the present invention provides processes / methods and tools / kits / means for ensuring optimal cartilage regeneration in subjects suffering from osteochondral, bone, or cartilage diseases or disorders, particularly by providing grafts in the affected tissue sites.

[0019] In some embodiments, the present invention provides a process / method for optimally implanting a solid matrix in a subject as needed to promote cell or tissue growth or functional restoration of osteochondral, bone, or cartilage tissue.

[0020] In some embodiments, such a process / method for optimally implanting a solid matrix into the osteochondral, osteoarthritic joint, bone, or cartilage tissue of a subject in need includes the step of selecting and / or preparing a solid matrix for implantation, the solid matrix having a certain length and width or facilitating a close fit within the boundaries of the implantation site, and is further characterized by having sufficient height such that when the first end of the solid matrix is ​​implanted into the bone at the implantation site, the second end of the solid matrix is ​​at a height at least 2 mm below the surface of the articular cartilage layer or at the proximal end of the tide mark region in the implantation site.

[0021] In some embodiments, the process / method includes the step of implanting a solid matrix within the implantation site to span the long axis of the implantation site, wherein a first end of the implant is implanted into bone at the basal surface of the implantation site, and a second end is positioned such that the second end is at a height at least 2 mm lower than the outer surface layer of the articular cartilage in which the matrix is ​​implanted, or is located or substantially at the proximal end of a tidal marker region in the implantation site that separates the cartilage layer from the bone layer.

[0022] According to this aspect, and in some embodiments, implanting a region above the second distal end at a height at least 2 mm lower than the outer surface layer of the articular cartilage in which the matrix is ​​implanted results in a gap between the boundary of the distal end and the surface layer of the articular cartilage. In some embodiments, the method further includes applying a biocompatible polymer layer to the tip surface of the implant, the layer filling the gap region up to the level of the joint surface.

[0023] When a solid matrix, the optimal choice for cell and tissue growth and / or functional restoration, is specifically implanted within the tissue repair site, the present invention provides unexpectedly superior healing, whereby the solid matrix forms a substantial fight fit relative to the length and width of the implantation site, but the height of the solid matrix remains approximately 2 mm below the articular cartilage layer in the cartilage tissue proximal to the implantation site. Figure 3 specifically illustrates the improved healing and articular cartilage regeneration in the apical region above the implantation site as a result of the implantation method described and illustrated herein.

[0024] In particular, the present invention provides an unexpected application in which bone regeneration, repair and formation enhancement are optimal when the solid matrix is ​​characterized within the implanted tissue repair site, such that the solid matrix is ​​substantially press-fitted / close-fitted relative to the length and width of the implantation site, but the height of the solid matrix is ​​still about 2 mm below the articular cartilage layer in the cartilage tissue proximal to the implantation site.

[0025] In other embodiments, the present invention provides an unexpected advantage in terms of greater cartilage formation when the solid matrix is ​​characterized within the implanted tissue repair site, such that the solid matrix is ​​substantially press-fitted / close-fitted relative to the length and width of the implantation site, but the height of the solid matrix remains approximately 2 mm below the articular cartilage layer in the cartilage tissue proximal to the implantation site.

[0026] In some embodiments, the present invention provides a method for optimally implanting a solid matrix to promote cell or tissue growth or restore function, thereby treating osteoarthritis, bone disorders, osteochondral defects, or cartilage damage in a subject in need, the method comprising:

[0027] • Select and prepare a solid matrix for treatment or to promote cell or tissue growth or functional recovery to be stably implanted in a region of bone and cartilage in a subject. The solid matrix has a certain length and width or promotes close fit within the boundaries of the implantation site, and is characterized by having sufficient height such that when the first end of the solid matrix is ​​implanted into the bone of the implantation site, the second end of the solid matrix is ​​at a height at least 2 mm below the surface of the articular cartilage layer or at the proximal end of the tide mark region in the implantation site.

[0028] • The selected and prepared solid matrix is ​​implanted into the implantation site across the long axis from the base to the tip of the implantation site, wherein a first end of the implant is implanted into the bone at the base surface, and a second end is positioned such that the second end is at a height at least 2 mm below the surface of the articular cartilage layer, or proximal to the tide mark region in the implantation site, thereby creating a gap between the tip surface of the matrix and the articular cartilage layer; and optionally

[0029] • Apply a biocompatible polymer layer or hydrogel or therapeutic compound or cell population or combination thereof to the tip surface of the implant to fill the void formed between the second end and the articular cartilage layer.

[0030] In some embodiments, the present invention provides the use of a solid matrix for promoting cell or tissue growth or functional recovery in the preparation of products for treating osteoarthritis, bone disorders, osteochondral defects, or cartilage damage in subjects requiring treatment, wherein the solid matrix for treating or promoting cell or tissue growth or functional recovery is used to stably implant in a region of bone and cartilage in the subject, the solid matrix having a certain length and width or promoting a close fit within the boundaries of the implantation site, and is further characterized by having sufficient height such that when the first end of the solid matrix is ​​implanted into the bone at its basal surface, the apex of the second end of the solid matrix is ​​positioned at a height at least 2 mm below the surface of the articular cartilage layer or at the proximal end of the tide mark region in the implantation site, thereby forming a gap between the apex surface of the matrix and the articular cartilage layer.

[0031] In some embodiments, the substrate has a height of 1-18 mm, and in some embodiments, the solid substrate has a height of 5-10 mm. In some embodiments, the solid substrate has a diameter of approximately 1-35 mm.

[0032] In some embodiments, the method / use of the present invention includes implanting more than one solid matrix in a tissue site as described above, and in some aspects, carefully implanting two implanted matrices such that a first end is implanted into the bone and a second end of each matrix is ​​positioned at a height at least 2 mm lower than the outer surface layer of the articular cartilage in which such matrix is ​​implanted, or substantially at the proximal end of the tidal region in the implantation site, as described, wherein the distance between the two or more implanted matrices in the tissue sites is about 3-10 mm, so that each matrix is ​​completely confined by the bone.

[0033] In some embodiments, the solid matrix comprises coral or a coral derivative. In some embodiments, the coral or coral-derived solid matrix is ​​characterized by a specific fluid absorption capacity of at least 75%, or is characterized by a contact angle of less than 60 degrees when in contact with a fluid, or the solid matrix is ​​an allogeneic graft, autograft, or xenograft, and the solid matrix is ​​further characterized by a tapered side.

[0034] In some embodiments, determining the specific fluid absorption capacity of the solid matrix includes contacting the solid matrix with a fluid for 0.1-15 minutes, thereby allowing spontaneous fluid absorption of the fluid within the solid matrix to reach the spontaneous fluid absorption value. In some embodiments, determining the specific fluid absorption capacity of the solid matrix further includes contacting the solid matrix with a fluid and applying a negative pressure to the solid matrix to promote maximum absorption of the fluid within the solid matrix to reach the total fluid absorption value. In some embodiments, the fluid is a protein-containing, salt-containing, or carbohydrate-containing solution. In some embodiments, the fluid is a biological fluid or blood analog or synthetic blood analog. In some embodiments, the specific fluid absorption capacity is a function of the weight change of the marine organism skeleton derivative-based solid material.

[0035] In some embodiments, the specific fluid absorption capacity value is a function of the fluid volume change of the fluid applied to the marine organism bone-derived matrix solid material. In some embodiments, the biofluid is autologous relative to the subject's cells or tissue when the solid matrix comes into contact with the subject's cells or tissue. In some embodiments, the fluid is water.

[0036] In some embodiments, the solid matrix has a height between 1 and 20 mm, and in some embodiments, the solid matrix has a diameter of about 1 to 50 mm. In some embodiments, the solid matrix is ​​further characterized by sloping sides, and in some embodiments, the solid matrix is ​​further characterized by including sloping sides at an angle of about 0.75 to 4 degrees with respect to the longitudinal axis of the solid matrix. In some embodiments, the sloping sides form an angle of about 2 degrees with respect to the longitudinal axis of the solid matrix.

[0037] In some embodiments, the solid matrix is ​​characterized by a conical or pyramidal frustum shape, and optionally takes the general shape of a rod, plate, cube, cylinder, cone, or screw. In some embodiments, the solid matrix comprises coral or coral derivatives, primarily including aragonite, calcite, hydroxyapatite, or combinations thereof.

[0038] In some embodiments, the solid matrix used according to the method described herein is further characterized by at least one substantially flat cross-section and inclined side surface at an end of the solid matrix. In some embodiments, the solid matrix used according to the method described herein is further characterized by having a side surface at an angle of 0.75 to about 4 degrees with respect to the longitudinal axis of the solid matrix, and in some embodiments, at an angle of about 2 degrees with respect to the longitudinal axis of the solid matrix. In some embodiments, the solid matrix used according to the method described herein is further characterized by a conical or pyramidal frustum shape.

[0039] In some implementations, the solid substrate used according to the method described herein is an allogeneic graft, an autologous graft, or a xenograft.

[0040] In some embodiments, the solid matrix used according to the method described herein is further characterized by comprising a curved surface whose radius of curvature is close to the radius of curvature of the tissue in which the solid matrix is ​​applied or implanted.

[0041] In some embodiments, the solid matrix used according to the method described herein is coral or a coral derivative, which in some embodiments is aragonite, calcite, mixtures thereof, or other pleomorphs thereof. In some embodiments, the solid matrix is ​​isolated from species of the genera *Porites*, *Goniopora*, *Millepora*, or *Acropora*.

[0042] In some implementations, the solid matrix is ​​separated from the enriched coral.

[0043] In some embodiments, the term "enriched" in relation to solid implants described herein, particularly corals, may refer to materials coated or impregnated with bone and cartilage growth promoters or materials. Such enrichment can be introduced by applying the material directly to the implant, such as a surface treatment of a coral implant, or in some embodiments, by enriching the growth medium in which the coral grows in its natural or artificial habitat.

[0044] For example, U.S. Patent 7,008,450 discloses a method for influencing the coral surface by coating corals with silicon, magnesium, and phosphates through a hydrothermal process to obtain a hydroxyapatite surface with 0.6% by weight silicon, which is considered to be the specific “enriched coral” described herein. In some aspects, “enriched coral” includes modifications to the mineral structure and / or chemistry of corals in their habitat (e.g., natural habitats, artificial habitats) during their growth and mineralization, for example, as described in U.S. Patent 7,704,561 or Y. Uema et al., “Silicon-rich Coral Sand Improves Bone Metabolism and Bone Mechanical Properties in Mice,” 59 J. Japanese Soc'yof Nutritional Food Science 265-70 1138-49 (2006), which is expressly incorporated herein by reference in its entirety. In some respects, coral treatments as described in PCT International Application Publication No. WO / 2012 / 038962 are contemplated for use with the methods and materials according to the invention, and are included in the term "enriched corals" as used herein.

[0045] It should be understood that the use of any corals (whether in natural or artificial habitats) that are further enriched for certain desired properties / components is considered herein and is included in the term "enriched corals".

[0046] In some embodiments, the solid matrix includes one or more cavities along a Cartesian coordinate axis of the solid matrix. In some embodiments, the one or more cavities are along an axis that spans substantially from the second end to the first end. In some embodiments, the one or more cavities are along an axis that extends from the second end to the first end to half the height of the solid matrix. In some embodiments, the one or more cavities are along an axis that extends from the second end to the first end to 30% of the height of the solid matrix. In some embodiments, the biocompatible polymer is absorbed in a region proximal to the one or more cavities or within the one or more cavities. In some embodiments, the solid matrix is ​​an allogeneic graft, autologous graft, xenograft, allogeneic graft derivative, autologous graft derivative, or xenograft derivative. In some embodiments, the biocompatible polymer includes natural polymers comprising glycosaminoglycans, collagen, fibroin, elastin, silk, chitosan, calcium alginate, cross-linked calcium alginate, cross-linked chitosan, hyaluronic acid, sodium hyaluronate, cross-linked hyaluronic acid, and any combination thereof.

[0047] In some implementations, the solid matrix further comprises cytokines, growth factors, therapeutic compounds, drugs, cell populations, or any combination thereof.

[0048] In some embodiments, the solid matrix has an overall shape that is oval or elliptical. In some embodiments, the solid matrix includes an elliptical outline.

[0049] In some embodiments, implantation is performed at an implant angle of about 0.75 degrees to about 4 degrees with respect to an axis perpendicular to the surface of the tissue site so treated. In some embodiments, implantation is performed at an implant angle of about 2 degrees with respect to an axis perpendicular to the surface of the tissue site so treated. In some embodiments, the solid matrix further comprises a bone filler or bone substitute material or osteoconductive material. In some embodiments, the method further includes the step of contacting the solid matrix with cells or tissue before, during, or after surgery. In some embodiments, the cells consist of stem cells, chondrocytes, osteoblasts, bone marrow cells, stromal cells, embryonic cells, precursor cells, progenitor cells, or combinations thereof. In some embodiments, contact promotes adhesion, proliferation, or differentiation of cells within the cells or tissue, or combinations thereof.

[0050] In some embodiments, the solid matrix promotes cell or tissue growth or restoration of function in the tissues of a subject suffering from defects or impairments or diseases of cartilage or bone, or a combination thereof. In some embodiments, cartilage defects or impairments or diseases include complete or partial thickness articular cartilage defects; osteochondral defects; osteoarthritis, avascular necrosis; osteochondritis dissecans; bone cysts, non-union fractures, fractures, bone defects, bone edema, osteoporosis, joint defects, or defects caused by trauma, exercise, or repetitive stress. In some embodiments, the method is used to delay or eliminate the need for complete or partial joint replacement in an affected subject. In some embodiments, the method is used for surface resurfacing of the affected joint in a subject. In some embodiments, the method can be performed using an automated system for the preparation and implantation of the solid matrix. In some embodiments, the automated system may utilize a robotic system. In some embodiments, the method can provide optimal customized implants and implantation.

[0051] In some embodiments, the present invention provides the use of a solid matrix for promoting cell or tissue growth or functional recovery in treating osteoarthritis, bone disorders, osteochondral defects, or cartilage damage in a subject requiring treatment, wherein the solid matrix for treating or promoting cell or tissue growth or functional recovery is used for stable implantation in a region of bone and cartilage in the subject, the solid matrix having a certain length and width or promoting a close fit within the boundaries of the implantation site, and is further characterized by having sufficient height such that when the first end of the solid matrix is ​​implanted into the bone at its basal surface, the apex of the second end of the solid matrix is ​​positioned at a height at least 2 mm below the surface of the articular cartilage layer or at the proximal end of the tidal zone in the implantation site, thereby forming a gap between the apex surface of the matrix and the articular cartilage layer.

[0052] It should be understood that the specific aspects of the methods described above are also applicable to the uses described herein.

[0053] In some embodiments, the present invention provides a cartilage cutter comprising:

[0054] • Slender handle;

[0055] • A head region connected to the elongated handle, the head region further including

[0056] o The top portion connected to the elongated handle;

[0057] o The base portion inserted into the implantation site;

[0058] o First and second inclined side regions, which taper from the top portion to the base portion;

[0059] The first inclined side region further includes:

[0060] • Tapered blade surface

[0061] • A supporting tapered angled surface positioned relative to the surface of the tapered blade; and

[0062] • The hollow area located between the two,

[0063] Thus, the tissue cut in this way that comes into contact with the surface of the conical blade has a thickness suitable for insertion into the hollow region.

[0064] As described in this article, for example, relative to Figure 1A-1SBy specifically implanting the solid matrix into the tissue repair site with a press-fit / close fit relative to the length and width of the implantation site, but with the height of the solid matrix remaining approximately 2 mm below the articular cartilage layer in the proximal cartilage tissue of the implantation site, unexpectedly excellent healing and / or bone regeneration and / or greater cartilage formation were observed using an optimally selected solid matrix. Figure 3 specifically illustrates the improved healing and articular cartilage regeneration in the apical region above the implantation site as a result of the implantation method described and illustrated herein. In some respects, the tools and procedures used to accomplish this process are relatively superior to those used in other procedures. Figure 1A-1S The description illustrates by way of example, and in some respects, the cartilage cutter described herein is particularly suited to perfecting the method / use of the invention, thereby facilitating ideal cartilage trimming to achieve the ability to position the solid matrix in a press-fit / tight-fit manner and to position the solid matrix 2 mm below the articular cartilage layer in the cartilage tissue proximal to the implantation site.

[0065] In some aspects, and representing embodiments of the invention, the head region of the cartilage cutter is connected to an elongated handle portion for easy gripping, which is ergonomic in some respects. In some aspects, the basal portion of the head region of the cartilage cutter is inserted into the implantation site; and is angled by first and second inclined side regions of the head region, which taper from the apical portion to the basal portion; and this taper facilitates proper fit within the implantation site for inserting the tapering solid matrix therein.

[0066] It should be understood that the term "tapered" in relation to the components of a cartilage cutter refers to a gradual inclination or taper relative to the longitudinal axis through which the implantation site is located.

[0067] The first inclined side region of the cartilage cutter head region further includes a conical blade surface and a supporting conical inclined surface positioned opposite the conical blade surface; and a hollow region therebetween. As those skilled in the art will understand, this arrangement of the conical blade surface, the supporting conical inclined surface positioned opposite the conical blade surface, and the hollow region therebetween facilitates the insertion of tissue that contacts and is thereby cut within the conical blade surface, and further adjusts the thickness of the tissue thus cut for insertion within the hollow region.

[0068] In some embodiments, the internal region between the first and second inclined side regions is substantially hollow, or in some embodiments, the internal region between the first and second inclined side regions is substantially solid but contains a hollow region into which cut tissue can be inserted.

[0069] In some implementations, the basal surface of the cartilage cutter head region is substantially flat, or in some implementations, it is ensured that the insertion of the cartilage cutter into the implantation site is smooth so that the insertion of the cartilage cutter into the implantation site does not negatively affect the insertion of the solid matrix into the implantation site in any way.

[0070] In some embodiments, the cartilage cutter handle includes an elongated portion that is comfortably gripped by the user, and in some embodiments, the handle has a gripping surface, and in some embodiments, the elongated handle is ergonomically configured. In some embodiments, the elongated handle can be removably attached to the head region. For example, see reference to... Figure 5F The handle can be removed by connecting the handle and the head area.

[0071] Those skilled in the art will understand that various arrangements / schemes can be designed to removably connect the head region and the handle, and the connection point can be at any suitable location, such as adjacent to the head region or at a reasonable distance from the base of the head region.

[0072] In some implementations, the head region is expandable to accommodate the size range of tissue sites requiring cartilage cutting.

[0073] In some embodiments, the present invention provides a component kit including a cartilage cutter as described herein. For example, and in some embodiments, Figure 1A-1S The tools described can all be provided as a single package, or from... Figure 1A-1S The tools selected from the components of the tools described herein may be provided as part of a kit and are considered a specific aspect of this application.

[0074] In some embodiments, the present invention provides a method for optimal implantation of a solid matrix for promoting cell or tissue growth or restoring function, thereby treating osteoarthritis, bone disorders, osteochondral defects, or cartilage damage in a subject in need, the method comprising:

[0075] • Select and prepare a solid matrix for treatment or to promote cell or tissue growth or functional recovery to be stably implanted in a region of bone and cartilage in a subject. The solid matrix has a certain length and width or promotes close fit within the boundaries of the implantation site, and is characterized by having sufficient height such that when the first end of the solid matrix is ​​implanted into the bone of the implantation site, the second end of the solid matrix is ​​at a height at least 2 mm below the surface of the articular cartilage layer or at the proximal end of the tide mark region in the implantation site.

[0076] • The selected and prepared solid matrix is ​​implanted into the implantation site across the long axis from the base to the tip of the implantation site, wherein a first end of the implant is embedded in the bone at the base surface, and a second end is positioned such that the second end is at a height at least 2 mm below the surface of the articular cartilage layer, or proximal to the tide mark region in the implantation site, thereby creating a gap between the tip surface of the matrix and the articular cartilage layer; wherein the implantation site is prepared for insertion of the solid matrix by creating a gap having the desired dimensions in terms of depth, length, and width, and the sidewalls of the implantation site are formed to include a taper, and the cartilage tissue within the implantation site is removed by means of a cartilage cutter as described herein, and optionally

[0077] • A biocompatible polymer layer or hydrogel or therapeutic compound or cell population or combination thereof is applied to the tip surface of the implant to fill the gap formed between the second end and the surface of the articular cartilage layer.

[0078] All publications, patents, and patent applications mentioned in this invention are incorporated herein by reference in their entirety, as if specifically and individually indicated by reference to each individual publication or patent. In the event of any conflict between this specification and the incorporated references, this specification shall prevail. When a numerical range is given herein, the range includes the endpoints. Moreover, it should be understood that, unless otherwise stated or demonstrated by context and knowledge of a person skilled in the art, a value expressed as a range may be assumed to be any specific value or subrange within that specified range, optionally including or excluding any one or both endpoints in different embodiments of the invention, up to one-tenth of the lower limit unit of the range, unless the context explicitly indicates otherwise. When a percentage is used to refer to a value that itself has an integer unit, any resulting fraction may be rounded to the nearest integer. Attached Figure Description

[0079] Figure 1A-1T The general procedure for preparing a defective site for implantation is illustrated schematically. Figure 1A-1E The procedure depicts the application of implantation alignment tools 1-10 at an angle substantially 90 degrees to / perpendicular to the tissue surface, with rod-shaped structures 1-20 inserted through them. Figure 1A-1C This rod-like structure drills into the subchondral bone 1-30 below. Figure 1D The alignment tool may include markings 1-50 (which serve as indicators of the depth in which the rod-like structure can be drilled / advanced). Figure 1E ), and then remove the alignment tool. Figure 1F-1H The drilling / expansion site for implant insertion is depicted. The drill sleeve 1-60 is positioned on the rod-shaped structure 1-20. Figure 1F-1GThe sleeve potentially / optionally includes an end adapted for stable insertion into the underlying tissue, and a special drill bit can be adapted to facilitate / assist rotation of the drill bit 1-70 when placed on a rod-like structure but within the drill bit sleeve 1-60. Figure 1H Then remove the drill bit and drill sleeve. Figure 1I Meanwhile, the rod-shaped structure remains in place and is embedded in the subchondral bone.

[0080] Figures 1J to 1L The use of the tissue reamer 1-80 is described, which can be used as follows: Figure 1J As shown, the reamer's end modifies and expands / enlarges the walls of the cartilage and subchondral bone implantation site, and the reamer is subsequently removed. Figure 1K-1L Afterwards, clean the tissue area, such as... Figure 1M As shown. Figure 1N-1Q The use of a tissue shaper is described. Tissue shapers 1-110 can be used to further process the tissue wall of the implant, and the shaper can be removed from the site after tissue shaping is complete. Figure 1R As shown, the tissue area was then cleaned, as follows. Figure 1S As shown, the tissue site can be accessed using a cartilage cutter (such as...) as further described herein. Figure 1T (As shown) or a scalpel or other suitable tool 1-120 to shape / smooth / expand or further shape / smooth / expand.

[0081] Figure 2A-2L This schematically depicts the initial introduction of an implant at a site requiring osteochondral repair, bone repair, or cartilage repair. Implant 2-130 ( Figure 2A Manually insert into the prepared tissue site, such as Figure 2B As shown, and as Figure 2C As shown, it is pressed in to fit within, so that the implant is initially introduced / placed within the repair site, as... Figure 2D As shown. Then, as Figure 2E and Figure 2F The tamper 2-140 shown is used to further advance the implant into the desired repair site, to further advance the implant to form a press-fit, for example... Figure 2H The depiction facilitates the insertion of the implant into the bone at the defect site, wherein the upper boundary of the implant is no longer flush with the articular cartilage layer, but rather about 2 mm below the articular cartilage surface. Figure 2J-2K The application of a biocompatible / therapeutic polymer composition to the tip of an implant 2-160 using a syringe 2-170 is described. Figure 2I An insertion of more than one solid matrix 2-130 as described is depicted. Figure 2L It shows crossing Figure 2GA cross-section of the area where the intraosseous matrix is ​​implanted, with the tip of the implant extending to an area approximately 2 mm below the surface of the articular cartilage.

[0082] Figures 3A-3C The MRI results of human patients participating in the clinical trial are described, showing full-thickness regeneration of the articular cartilage surface in the subjects after treatment with the specific method of the present invention.

[0083] Figures 4A-4H Comparative results of two patients who underwent implantation of a solid matrix are described, and unexpectedly excellent results are demonstrated in patients treated with the specific method according to the invention. (Compared to...) Figure 4E-4H compared to, Figures 4A-4D The defect site showed healing, but there was no sign of healing or full cartilage thickness reformation in the area proximal to the implantation site.

[0084] Figure 5A-5I The cartilage cutter is described, and some of its key features are highlighted. Detailed Implementation

[0085] In particular, this invention provides an optimized method for implanting solid matrices to promote cell or tissue growth or restore function.

[0086] In some embodiments, the present invention provides optimized methods and means for implanting a solid matrix to promote cell or tissue growth or functional recovery of osteochondral tissue.

[0087] In some embodiments, the present invention provides means and methods for ensuring optimal cartilage regeneration in subjects suffering from osteoarthritis or osteochondral, bone or cartilage diseases or disorders, particularly by providing implants in the affected tissue sites.

[0088] In some embodiments, the present invention provides a method for optimally implanting a solid matrix to promote cell or tissue growth or functional restoration in osteoarthritis, osteochondral, bone or cartilage tissue of a subject in need.

[0089] In some respects, the method of the present invention facilitates the treatment of osteoarthritis or diseases or disorders of bone, cartilage, or osteochondrium.

[0090] When used in conjunction with a disease or condition, the terms "treatment" and "management" refer to the implementation of a protocol that may include cartilage, bone, and / or osteochondral repair procedures in an attempt to alleviate the signs or symptoms of a disease or condition or an immune response. Relief can occur before and after the signs or symptoms of a disease or condition appear. Therefore, treatment or management includes prevention or avoidance of a disease or undesirable condition. Furthermore, treatment, management, prevention, or avoidance does not require complete relief of signs or symptoms, does not require a cure, and particularly includes protocols with only a borderline effect on the patient. In some implementations, bone, cartilage, and / or osteochondral repair implants may be used to treat subchondral, osteochondral, or cartilage defects.

[0091] The term "subchondral" refers to the region beneath the articular cartilage. The term "subchondral bone" refers to the layer of bone located just beneath the cartilaginous region. "Osteochondral" refers to a combined area of ​​cartilage and bone in which one or more injuries may be present. "Osteochondral defect" refers to an injury that is a combination of damage to cartilage and subchondral bone. "Cartilage" includes cartilage containing groups of homologous chondrocytes located within lacunae cavities scattered throughout the extracellular collagen matrix.

[0092] Methods / uses / tools / kits for improving bone, cartilage, and / or osteochondral repair are provided. The methods described herein for implanting the matrix can promote the growth of bone, cartilage, and / or related tissues, particularly in repairing bone, cartilage, and / or osteochondral defects.

[0093] In some implementations, a solid matrix implantation method is provided for treating bone, cartilage, and / or osteochondral repair, including a tissue scaffold configured to allow the growth of at least bone and / or cartilage.

[0094] Tissue scaffolds provide a matrix for cells to guide the process of three-dimensional tissue formation in vivo. The morphology of the scaffold guides cell migration, and cells can migrate individually into or onto the scaffold. Furthermore, the creation of discrete voids in the cartilage layer on a solid matrix, for example for the application of hydrogels or the addition of therapeutic solutions, reduces inflammation / irritation at the implantation site and / or otherwise promotes implant incorporation, regeneration of cartilage and / or bone tissue, and / or healing of the site.

[0095] In some embodiments, a method for optimally implanting a solid matrix for promoting cell or tissue growth or functional restoration in the osteochondral, bone, or cartilage tissue of a subject in need includes the steps of selecting and / or preparing a solid matrix for implantation that promotes cell or tissue growth or functional restoration, the solid matrix having a certain length and width or promoting a close fit within the length and width boundaries of the implantation site, and further characterized by having sufficient height such that when a first end of the solid matrix is ​​implanted into the bone at the implantation site, a second end of the solid matrix is ​​at a height at least 2 mm below the surface of the articular cartilage layer, or at the proximal end of the tidal region of the implantation site.

[0096] In some embodiments, the method includes the step of implanting a solid matrix within the implantation site to span the long axis of the implantation site, wherein a first end of the implant is implanted into bone, and a second end is positioned such that the second end is at a height at least 2 mm below the surface of the articular cartilage layer or proximal to the tide mark region of the implantation site.

[0097] It should be understood that the term "tide mark" is used to express its common and conventional meaning. For example, and in some embodiments, the term "tide mark" includes the calcified cartilage layer that separates hyaline cartilage from bone in a joint. In some aspects, the term "tide mark" refers to the calcified cartilage layer that attaches hyaline cartilage to bone. In some aspects, the term "tide mark" refers to the boundary line between calcified cartilage and hyaline cartilage. In some aspects, the term "tide mark" broadly refers to the entire tissue region bridging cartilage and bone tissue in a joint.

[0098] It should be further understood that the methods / uses and means of the present invention are intended for the implantation of a solid matrix as described above, wherein the top surface of the matrix reaches the lower 1 / 3 of the cartilage layer in which the matrix is ​​implanted.

[0099] For example, and in some embodiments, if the cartilage layer is thick, the implantation can be performed such that the apical region of the matrix is ​​more than 2 mm from the articular cartilage surface. In some embodiments, the implantation occurs at or near the tide mark, and in some embodiments, the implant is located within the lower third of the cartilage layer, and the upper two-thirds of the cartilage layer is open to the environment, and its height can exceed 2 mm. For example, and in some embodiments, if the cartilage layer is thin, the implantation can be performed such that the apical region of the matrix is ​​less than 2 mm from the articular cartilage surface. In some embodiments, the implantation occurs at or near the tide mark, and in some embodiments, the implant is located within the lower third of the cartilage layer, and the upper two-thirds of the cartilage layer is open to the environment, and its height can be less than 2 mm.

[0100] It should be understood that the present invention contemplates methods / uses and means of implanting a solid matrix into bone extending upwards to the cartilage layer, wherein the apex of the implant is: 1) at least 2 mm below the articular cartilage layer; or 2) at or near the tidal marker; or 3) within the lower third of the total cartilage tissue proximal to the implantation site, and all of the above are considered to be contemplated embodiments of the present invention.

[0101] In some embodiments, as described, the method / use and means include implanting a first end of a solid matrix into bone tissue at the implantation site.

[0102] According to this aspect, and in some embodiments, the implant in the bone facilitates access to basal cells involved in bone and / or cartilage healing and / or regeneration. In other embodiments, the implant in the bone provides a scaffold, thereby allowing cells and / or factors involved in bone and / or cartilage healing and / or regeneration to enter the implantation site and / or solid matrix, and promoting cartilage and / or bone healing and / or regeneration.

[0103] In some implementations, intraosseous implantation allows for careful avoidance of implantation into the growth plate of the subject's bone.

[0104] In some embodiments, intraosseous implantation allows the solid matrix to penetrate into the underlying bone tissue to a certain depth and / or level, thereby promoting stable scaffold integration, and as those skilled in the art will understand, considerations relating to the nature of the solid matrix and its mechanical stability requirements and / or the nature of the bone in which the solid matrix is ​​implanted and / or the age and fragility of the bone tissue are taken into account.

[0105] Any suitable matrix that promotes the repair or regeneration of cartilage, bone, or osteochondral is contemplated for use in the method according to the invention.

[0106] In some respects, the implant is as described in, for example, U.S. Patent Application Publication Nos. 2007029951, 20040192605, 20100049322, 20070276506 and U.S. Patent Nos. 8518433, 9168140 and 7931687 and others, each of which is incorporated herein by reference in its entirety.

[0107] In some respects, the implant is as described in, for example, European Patent No. EP1447104B1, PCT International Application Publication Nos. WO2012063201A1, WO2011064724A1 and U.S. Patent Application Publication Nos. US20140134258A1, US20130129634A1, WO / 2012 / 038962, etc.

[0108] In some implementations, the implant is any implant recognized in the prior art. For example, and representing a contemplated embodiment of the invention, various commercially available implants and well-described implants can be used according to the invention, and representing an embodiment of the invention, including, in particular, US 9211126, US 20100191245, US 20100268239, US7029479, US 8864827, US 20170311983, US 20120271417, US 20120191187, US20150250602, US 20170360566, US 20160022280, US 20160022279, US 20160106444, US7896885, US 20170303934, US 8540717, US 20150250475, US 20110152870, US20170119528, US 20100312342, US 9204873, US 20140012267, US 20150250594, US9510840, US 20140309689, US 9572587, US 8177841, US 20140012389, US 20080033443, US7713305, US 9358029, US 7896883, US 20080172125, US 9055955, US 20080183174, US9668757, US 20110152869、US US 20140288561, US 8556902, US 7914545, US 20170100251, US20170128085, US 20090192516, US 20090216285, US 9283076, US 6610067, US 7901408, US20080195113, US 20120253365, and US 9468448 are all incorporated herein by reference in their entirety and elsewhere.

[0109] In some embodiments, implants that can be used according to the present invention and represent embodiments of the present invention include, in particular, US 8012206, US 8162947, US 5895425, US 20140350688, US 9603712, WO / 2013 / 153435A1, US 9510951, US 20140379089, US 20150134066, US 20160166301, US 7264634, US20170367827, WO / 2004 / 014303A2, US 8211112, WO / 2016 / 099620A1, US 20150142052, US8961538, US 20130150885, US 9216090, US 8430909, US 20130245775, US 7820638, WO / 2014 / 202494A1, WO / 2004 / 014303, US 7959636, US 8591592, US 7160305, US 20010053934, US 20130338792, US 20170304076, US 20150010606, US 7862567, US 6623524, US20170367741, US 9610167, US 9216091, US 8512410、US20130238099、US US 8663279, US20170360569, US 8512411, US 8876900, US 8409209, US 8888785, US 7967823, US7993369, US 20090187216, US 8540777, US 8167951 and US 20160095709, each of which is incorporated herein by reference in its entirety and elsewhere.

[0110] In some embodiments, implants that can be used according to the present invention and represent embodiments of the present invention include, in particular, US 20070202084, US 20020071855, WO / 2002 / 009792, US 5443473, US 6548081, US20020128512, US 20170326271, US 20170312385, US 8865964, US 20110312912, US20160082038, US 20110196328, US 20050222083, US 20040038934, WO / 2002 / 068383, US20130045945, US 6620927、WO / 2013 / 156547、US 8124120、US 20070203095、US 5621093、US20050136122、US 8323617、US 6884788、US 8901202、WO / 2007 / 070546、WO / 2007 / 070546、WO / 2007 / 070617、US 5356883、US 6096727、US 5502081、US 6537979、US 6013679, WO / 2005 / 067994, WO / 2017 / 189723, WO / 2017 / 189733, WO / 2007 / 070547, WO / 2007 / 070547, US7722616, US 20040044416, US 20070196342, US 7842487, US 6482231, US 20080317808, US20110104284, WO / 1994 / 002517, US 20100136081, US 7968111, US 20080097605 and US20070110819, each of which is incorporated herein by reference in its entirety or otherwise.

[0111] In some embodiments, implants that can be used according to the present invention and represent embodiments of the present invention include, in particular, US 20160287407, US 9155543, WO / 2016 / 161026, US 20130006368, US 20160287392, US9526632, WO / 2016 / 161025, US 20160038308, US 9737294, US 20150351815, US20140214080, WO / 2014 / 117107, US 20170165074, US 20160302930, WO / 2016 / 168363, WO / 2012 / 162552, US 20130211451 and US20050278025 are each incorporated herein by reference in their entirety or otherwise.

[0112] In some embodiments, implants that can be used according to the present invention and represent embodiments of the present invention include, in particular, US 8071083, WO / 2003 / 020117, US 7942934, US 7132110, US 8460685, US 7205337, US6309659, US 7241813, US 6623748, 7811608, US 4772284, US 6180606, US 6180605, US20060251729, US20020034531, US20040022858, US 6311690, WO / 2004 / 060430, WO / 2003 / 055933, US 8497236, US20060136068, US 8945535, US20110307010, WO / 2011 / 009635, US20080306610, US20100003304, US 4472840, US20090054906, US20110293584, US20050037978, US 4394370, US 7147846, US20020082697, US20040081704, US20120263683, US20080269895, US 8173162, US 6679918, US 4772284, US RE43714, WO / 2007 / 094672, WO / 2006 / 115398, US 20010014667, WO / 2008 / 154149, WO / 2008 / 154149, US20080294270, US 20120021008, US 6511510, US 20030044445, US20100034865 and US20110020419, each of which is incorporated herein by reference in its entirety or otherwise.

[0113] In some implementations, any commercially available implant product is envisioned for use according to the invention.

[0114] In some respects, the implant is an implant such as that described in, for example, U.S. Patent Nos. 8,932,581, 8,808,725; 8,802,115; 8,790,681 or 9,770,531; or U.S. Patent Application Publication Nos. 2015-0134065, 2015-0147397, 2015-0289889, 2016-0000969; or PCT Application Publication No. WO / 2016 / 178226, each of which is fully incorporated herein by reference.

[0115] In some embodiments, the present invention provides an optimized solid matrix for promoting cell or tissue growth or functional restoration, the solid matrix comprising coral or coral derivatives, characterized by a specific fluid absorption capacity of at least 75%, or characterized by a contact angle of less than 60 degrees when in contact with a fluid, and optionally further characterized by an inclined side.

[0116] In some embodiments, the present invention more generally provides an optimized solid matrix for promoting cell or tissue growth or functional restoration, the solid matrix comprising a porous natural matrix, such as an allogeneic or autologous graft, or other suitable marine, plant or animal-derived material, the porous solid matrix being absorbent to biological fluids when implanted in situ, having sufficient strength and stiffness, and being usable to stimulate bone and / or cartilage repair, and the matrix optionally further characterized by a sloping side.

[0117] In some embodiments, the present invention more generally provides an optimized solid matrix for promoting cell or tissue growth or restoring function, the solid matrix comprising any matrix suitable for implantation, such as metals, any suitable alloys, bioactive glass, PLGA, PGA, any suitable carbon composite implant material, ceramic materials, alginate-based implants, coral-based implants, including cultured or otherwise enriched coral-based implants, alcohols, etc., which, as those skilled in the art will understand, have sufficient strength and rigidity when implanted in situ and can be used to stimulate bone and / or cartilage repair, or bone and / or cartilage therapy, and the matrix optionally further features a sloping side.

[0118] In some embodiments, the present invention provides an optimized solid matrix for promoting cell or tissue growth or functional recovery, the solid matrix being characterized by a specific fluid absorption capacity of at least 75%, or a contact angle of less than 60 degrees when in contact with a fluid, and optionally further characterized by at least one surface of the matrix having a radius of curvature substantially similar to that of the tissue surface in which the solid matrix is ​​applied / implanted.

[0119] In some embodiments, the present invention provides an optimized solid matrix for the treatment or restoration of bone and / or cartilage function, the solid matrix being characterized in that at least one surface of the matrix has a radius of curvature substantially similar to that of a tissue surface.

[0120] According to these aspects and in some embodiments, any solid matrix described herein may comprise coral or any other similar naturally porous material derived from plants or animals. In some aspects, such a matrix may comprise allogeneic, autologous, or xenografts. In some aspects, such a matrix may comprise plant material, such as bamboo.

[0121] In some respects, porous natural matrices can be cell-free or further processed to be suitable for implantation into human hosts.

[0122] In some aspects, the solid matrix as described herein may be characterized by including an inclined side. In some embodiments, the term "inclined side" refers to an angle of 0.75 to about 4 degrees between the side of the solid implant and the longitudinal axis of the solid matrix.

[0123] In some aspects, the solid matrix is ​​characterized by having at least one substantially flat cross-section at its ends, and in some embodiments, the solid matrix includes a series of pores, channels, or voids in the region of the matrix adjacent to the cartilage tissue treated by the method of the present invention. In some aspects, this solid matrix is ​​also characterized by being solid and optionally including a porous phase, but without channels in the region of the matrix adjacent to bone when implanted according to the method of the present invention.

[0124] In some aspects, mentioning the substantially flat cross-section of the solid matrix does not preclude the possibility of rounded edges of the solid matrix, or, in some embodiments, slightly rounded top or bottom surfaces. In some embodiments, according to this aspect, the solid matrix may have a slight bulge or other notch at either end. In some embodiments, according to this aspect, the solid matrix is ​​slightly rounded without end points or one or more sharp points. In some embodiments, one end may appear more rounded than the other. In some embodiments, the end may also be characterized by the presence of a series of longitudinal channels or voids formed therein; however, the top surface can still be considered substantially flat because the surface is substantially flat in its overall appearance.

[0125] In some respects, the solid matrix has a generally conical shape.

[0126] In some respects, the term "substantially conical" refers to a solid matrix as characterized above, whose shape approximates a cone because it has a circular cross-section and sloping sides at each end of the matrix. In other respects, the term "substantially conical" excludes the presence of pointed ends in the matrix, but does include shapes approximating a cone, where the tips are scraped or removed, leaving a circular cross-section in place of its conical ends.

[0127] According to this aspect, and in some embodiments, the solid matrix is ​​characterized by a conical truncated shape.

[0128] According to this aspect, and in some embodiments, the solid matrix is ​​characterized by a conical frustum shape, i.e., a portion of a solid cone located between two parallel planes cutting the solid matrix. In some aspects, the two parallel planes cutting the solid cone have different diameters, one larger and one smaller. In some embodiments, the solid matrix characterized by the conical frustum shape is further characterized in that the solid matrix is ​​inserted into the osteochondral defect such that the plane characterized by the smaller diameter is inserted first, thereby positioning the apex of the plane characterized by the larger diameter within the implantation site.

[0129] In some respects, the solid matrix has a substantially pyramidal shape.

[0130] In some respects, in terms of shape, the term "generally pyramidal" refers to a solid matrix as characterized above, whose shape approximates a pyramid shape because it has a flat cross-section and sloping sides at each end of the matrix. In other respects, the term "generally pyramidal" excludes the presence of pointed ends in the matrix, but does include shapes approximating a pyramid shape where the tips are scraped or removed, leaving a flat cross-section in place of the tapered ends.

[0131] According to this aspect, and in some embodiments, the solid matrix is ​​characterized by a pyramidal frustum shape.

[0132] According to this aspect, and in some embodiments, the solid matrix is ​​characterized by a pyramidal frustum shape, i.e., a portion of a solid pyramid located between two parallel planes cutting the solid matrix. In some aspects, the two parallel planes cutting the solid pyramid have different lengths / widths, such that one is larger and the other smaller. In some embodiments, the solid matrix characterized by the pyramidal frustum shape is further characterized in that the solid matrix is ​​inserted into the osteochondral defect such that the plane characterized by the smaller length / width is inserted first, thereby positioning the apex of the plane characterized by the larger length / width within the implantation site.

[0133] In some implementations, when referring to the shape of the matrix's boundaries or outer contours, the solid matrix is ​​characterized by a substantially oval shape.

[0134] In some respects, the solid matrix is ​​characterized by allowing any shape of inclined sides and, in some embodiments, substantially flat ends, which can be adapted to ideally and optimally fit within the defect site. In some respects, the solid matrix presents any suitable geometry with inclined sides, approximating a rod, cube, ellipse, i.e., a solid shape substantially similar to, for example, a rod, plate, cube, or ellipse, cut by two parallel planes.

[0135] In some respects, the solid matrix is ​​characterized by a shape having inclined sides, as described above, which, as those skilled in the art will understand, can approximate the overall shape of the talus, big toe, shoulder, condyle, ankle, patella, trochlea, pelvis, vertebrae, hip bones, and others, or approximate smaller blocks that can be easily inserted into such structures in an optimized press-fit manner.

[0136] In some aspects, the solid matrix may be characterized in that the diameter of the first end varies between about 50-97% of the second diameter at the second end of the matrix, or in some embodiments, the solid matrix may be characterized in that the diameter of the first end varies between about 50-65% of the second diameter at the second end of the matrix, or the diameter of the first end varies between about 55-75% of the second diameter at the second end of the matrix, the diameter of the first end varies between about 70-85% of the second diameter at the second end of the matrix, the diameter of the first end varies between about 75-97% of the second diameter at the second end of the matrix, the diameter of the first end varies between about 60-95% of the second diameter at the second end of the matrix, the diameter of the first end varies between about 65-97% of the second diameter at the second end of the matrix, the diameter of the first end varies between about 80-98% of the second diameter at the second end of the matrix, or the diameter of the first end varies between about 70-85% of the second diameter at the second end of the matrix.

[0137] In some respects, the inclined side forms an angle of two degrees with the longitudinal axis along the solid matrix.

[0138] In some aspects, the inclined side forms an angle of 0.5 to 6.5 degrees with respect to the longitudinal axis of the solid matrix. In some aspects, the inclined side forms an angle of 0.5 to 4 degrees with respect to the longitudinal axis of the solid matrix. In some aspects, the inclined side forms an angle of 0.75 to 3.5 degrees with respect to the longitudinal axis of the solid matrix, or in some embodiments, the inclined side forms an angle of 1 to 3.25 degrees with respect to the longitudinal axis of the solid matrix, or in some embodiments, the inclined side forms an angle of 1.5 to 2.75 degrees with respect to the longitudinal axis of the solid matrix, or in some embodiments, the inclined side forms an angle of 1.75 to 4 degrees with respect to the longitudinal axis of the solid matrix. See also Figure 1B The specific solid matrix of the present invention is shown, whereby the narrowing of the lateral sides is evident when viewed along the longitudinal axis depicted by the black bar spanning the implant.

[0139] The solid matrix of the present invention may be characterized by a specific fluid absorption capacity of at least 75%, which is determined by establishing a spontaneous fluid absorption value divided by the total fluid absorption value, or by a contact angle of less than 60 degrees when in contact with a fluid. For example, a method for determining specific fluid absorption and contact angle values ​​is described in PCT International Application Publication No. WO2014125478, which is incorporated herein by reference in its entirety.

[0140] In some aspects, the solid matrix is ​​characterized by a curved cross-section at its ends. According to this aspect, and in some embodiments, this curvature is more typical at the tip surface of the solid matrix as described herein, to accommodate a proper fit of the implant, thereby facilitating correction of defects involving curved surfaces. In some aspects, the curved surface at the defect site is substantially symmetrical, and therefore the tip surface of the implant comprises a substantially symmetrically curved surface. In some aspects, the curved surface at the defect site is substantially asymmetrical, and therefore the tip surface of the implant comprises a substantially asymmetrically curved surface.

[0141] In some embodiments, the curved surface or curved cross section at the end of the solid substrate of the present invention includes the radius of curvature of the substrate, wherein the radius may vary along the X-axis of the plane of the substrate surface, or in some embodiments, the radius may vary along the Z-axis of the plane of the substrate surface, or in some embodiments, the radius may vary along both the X-axis and Z-axis of the plane of the substrate surface.

[0142] Similarly, as described herein, the curved surface or curved cross section at the end of the solid matrix of the present invention includes the radius of curvature of the matrix, wherein the radius may vary along the coronal or sagittal plane of the matrix surface, or in some embodiments, the radius may vary along the transverse or anterior / posterior plane of the matrix surface, or in some embodiments, the radius may vary along the matrix surface described herein, along any axis defined herein.

[0143] In some embodiments, the solid matrix of the present invention comprises a coral-based material. Corals, composed of CaCO3 in the form of aragonite or calcite crystals, have been shown to have advantages in supporting rapid cellular invasion, adhesion, and proliferation. Corals have been shown to be an effective matrix for promoting the adhesion, proliferation, and differentiation of mesenchymal stem cells and their eventual introduction into cartilage and / or bone tissue. Corals have also been shown to act as an excellent matrix for promoting the adhesion and proliferation of many other cell types, thus serving as an excellent support for cell and tissue growth.

[0144] The terms “coral”, “aragonite”, and “calcite” are used interchangeably in this document.

[0145] In some embodiments, as used herein, references to “implant,” “plug,” or “solid matrix” refer to any embodiment or combination thereof as described herein with respect to a solid matrix and considered to be included in the aspects described herein. For example, as used herein, references to “solid matrix” should be understood to refer to any embodiment of a solid matrix suitable for the illustrated purpose or containing the illustrated properties, etc., as described herein.

[0146] In one embodiment, "solid matrix" refers to a shaping platform for cell and / or tissue repair and / or restoration functions, wherein the shaping platform provides sites for such repair and / or restoration functions. In one embodiment, the solid matrix is ​​a temporary platform. In one embodiment, "temporary platform" refers to the natural degradation of the coral of the present invention over time during such repair process, wherein the natural complete or partial degradation of the coral can lead to changes in the shape and / or size of the solid matrix over time.

[0147] In some implementations, the solid implant is cannulated, while in others, it is not cannulated.

[0148] It should be understood that different species of coral vary in their average pore size and pore volume, and the present invention contemplates the use of any such coral as a starting material for preparing a solid matrix as described herein, wherein the solid matrix is ​​characterized by a specific fluid uptake value of at least 75%. As used herein, the term “pore volume” refers to the volume or open space within the porous scaffold of the present invention. Pore volume is determined by any means known in the art. Porosity can be calculated by standard methods, one example of which is further provided below, see, for example, Karageorgiou V, Kaplan D. (2005) "Porosity of 3D biomaterial scaffolds and osteogenesis" Biomaterials.;26(27):5474-91, which is incorporated herein by reference in its entirety.

[0149] It should be understood that the term "coral" refers to the starting material from which aragonite, calcium carbonate, calcite, or hydroxyapatite can be separated.

[0150] It should also be further understood that any matrix mentioned herein, particularly any coral matrix, is contemplated as encompassing known existing forms of matrix, modifications of the matrix, etc. For example, and representing a specific contemplated embodiment, if the solid matrix is ​​coral-derived, then in some respects such coral can grow in enriched media or aquatic environments, and in some embodiments such coral can be further processed, including surface modification, for example by cold plasma processing, as known in the art and described in the various patents and patent applications cited herein, all of which are fully incorporated herein by reference.

[0151] In some embodiments, the applicant has particular consideration of the preparation method described in PCT International Application Publication No. WO2014125478 and its description of cold plasma processing of coral-based implants, in order to include it in the method of the present invention.

[0152] It should be understood that any known cold plasma treatment method or surface modification method for implants suitable for use according to the method of the present invention is considered herein and is regarded as part of the invention.

[0153] In one embodiment, the use, method, and / or kit of the solid matrix of the present invention utilizes the use of coral. In one embodiment, the coral includes any species, particularly including *Porphyra*, *Stachys*, *Hylocereus*, *Porphyra*, or combinations thereof. In another embodiment, the solid matrix, method, and / or kit of the present invention utilizes the use of nacre, mollusc shells, or bone fragments.

[0154] In one embodiment, the coral belongs to the genus *Periflora*. In one embodiment, the coral is *Periflora* (…). Porites lutea In one embodiment, the coral is from the genus *Staphyllum*. In one embodiment, the coral is *Giant Staghorn Coral* (*Staphyllum giganteum*). Acropora grandis In one embodiment, it is very common, grows rapidly, and is easy to grow in culture. Therefore, in one embodiment, staghorn coral samples can be easily collected in sheltered areas of coral reefs, and collection from coral reefs can be avoided by using cultured coral material.

[0155] In another embodiment, the coral belongs to the genus *Millettia*. In one embodiment, the coral is *Millettia bifida* (…). Millepora dichotoma In one embodiment, the coral has a pore size of 150 μm and can be cloned and cultured, making the genus *Ceratops* usable as a framework for the solid matrix, methods, and / or kits of the present invention.

[0156] In one embodiment, the coral belongs to the genus *Hylocereus*. In some embodiments, the coral is... Goniopora albiconus , Goniopora burgosi , Goniopora cellulosa Ceylon hornhole coral ( Goniopora ceylon ), Goniopora ciliatus Cylindrical hornhole coral ( Goniopora columna ), Goniopora djiboutiensis , Goniopora eclipsensis , Goniopora fruticosa Fine-toothed coral ( Goniopora gracilis ), Goniopora klunzingeri , horn-porphyrin corals ( Goniopora lobata ), Goniopora mauritiensis , Goniopora minor , Goniopora norfolkensis , Goniopora palmensis , Goniopora pandoraensis , Goniopora parvistella , Goniopora pearsoni , Goniopora pendulus , Goniopora planulata Polymorphous horn-porous coral ( Goniopora polyformis ), Goniopora reptans , Goniopora savignyi , Goniopora somaliensis , Goniopora stokes , Scots's horn-porphyrin ( Goniopora stutchburyi ), Sudanese hornhole coral ( Goniopora sultani ), tender horn-hole coral ( Goniopora tenella ), Goniopora tenuidens Or emerald green horn-hole coral ( Goniopora viridis ).

[0157] In another embodiment, the coral is from any one or more of the following species: Cape beehive coral ( Favites halicora ); Reticulated Chrysanthemum Coral ( Goniastrea retiformis ); Spiny coral ( Acanthastrea echinata ); Acanthastrea hemprichi ; Acanthastrea ishigakiensis Rough staghorn coral ( Acropora aspera Simple axial-hole corals ( Acropora austera ); Coral genus " brown digitate ”; Thorny Staghorn Coral ( Acropora carduus ); Staghorn coral ( Acropora cerealis ); Deep-sea staghorn coral ( Acropora suharsonoi Staghorn coral ( Acropora chesterfieldensis ); checkered staghorn coral ( Acropora clathrata ); Acropora cophodactyla Coral genus fund-like "; Two-pronged axial-porous coral ( Acropora divaricata ); Tong's axial-porous coral ( Acropora donei ); Spiny staghorn coral ( Acropora echinata Blue-flowered coral ( Acropora efflorescens ); Acropora buds ( Acropora gemmifera Staghorn coral ( Acropora globiceps ); Granular staghorn coral ( Acropora granulosa ); Acropora cf hemprichi ; Acropora kosurini ; Acropora cf loisettae ; Acropora longicyathus ; Lolita axial porcini ( Acropora loripes Corals with short, coarse shafts ( ); Acropora cf lutkeni ); Acropora paniculata ; Acropora proximalis ; Acropora rudis ; Lycopodium Acropora ( Acropora selago ); Individual staghorn coral ( Acropora solitaryensis ); Acropora cf spicifera as per Veron ; Acropora cf spicifera as per Wallace ; Soft-branched axial-porous coral ( Acropora tenuis ); Warren's axial hole coral ( Acropora valenciennesi ); Giant cone-shaped coral ( Acropora vaughani ); Spiral axial-porous coral ( Acropora vermiculata ); warty star-hole coral ( Astreopora gracilis ); Multiporous coral ( Astreopora myriophthalma ); Landell Star-shaped Coral ( Astreopora randalli ); Astreopora suggesta Australian coral ( Australomussa rowleyensis ); cylindrical sieve coral ( Coscinaraea columna ); shell-like sieve coral ( Coscinaraea crassa ); Spiny coral ( Cynarina lacrymalis Purple lateral coral ( Distichopora violacea ); Thorny-leaved coral ( Echinophyllia echinata ); Coral family ( Echinophyllia cf echinoporoides ); gem punctured coral ( Echinopora gemmacea Rough spiny coral ( ); Echinopora hirsutism ); Hammer coral ( Euphyllia ancora ); Coral in a vase ( Euphyllia divisa ); Euphyllia yaeyamensis ; Circular horned coral ( Favia rotundata ); Favia truncatus ; Favorites acuticollis ; Pentagonal honeycomb coral ( Pentagon Favourites ); Granular stone coral ( Fungia granulosa ); Fungia klunzingeri ; Mollusc fungi ; Galaxea achrelia Ai's Chrysanthemum Coral ( Goniastrea edwardsi ); Goniastea minuta ; Hydnophora pilosa Ringed coral ( Leptoseris explanata ); shell-like soft-textured coral ( Leptoseris incrustans ); Soft-textured coral ( ) Leptoseris mycetoseroides ); Textured coral ( Leptoseris scabra Leaf-shaped soft-textured coral ( Leptoseris yabei ); wavy stony coral ( Lithophyllon undulate ); Hector's leaf coral ( Lobophyllia hemprichii ); Rough-ribbed coral ( Merulina scabricula ); Two-pronged thousand-hole coral ( Millepora dichotoma ); Millepora exaesa ; The tangled thousand-hole coral ( Millipora intricata ); Millepora murrayensis ; *Platycladus orientalis* ( Millipora platyphylla ); Brief Garden Chrysanthemum Coral ( Short monastic robe ); Coleman's Monastery Coral with curved surface pores ( Montipora caliculata ); warty coral ( Montipora capitata ); Shallow-nest rose coral ( Montipora foveolata ); Montipora meandering ; nodular rose coral ( Montipora tuberculosa ); Montipora cf. vietnamensis ; Oulophyllia laevis ; Oxypora crassispinosa ; Tear-spined coral ( Oxypora lacera ); Peacock two-part ; vein knot peony coral ( Venous peacock ); Lettuce comb-shaped coral ( Alcicorn scallop ); Peony comb coral ( Peony scallop ); Sharp-edged flat-headed coral ( Sharp-nosed platygyra ); Microcerebral coral ( Platygyra pine trees ); Flat-brained coral green ";Vibrio ceratops ( Platygyra verweyi ); Podabacia cf. from Lanka Wart coral ( Porites anna ); refers to surface-porous coral ( Porites cylindrical ); Porites Evermann ; Porites monticulosa Finger-shaped perforated coral ( Psammocora digitata ); Psammocora explained Blood red sand coral ( Psammocora haimeana ); shallow sand coral ( Psammocora superficial ); Serrated coral ( Sandalolitha dentata Shallow cup coral with perforated surface ( Seriatopora calendula ); Armored column corals ( Stylocoeniella armata ); Columnar corals ( Stylocoeniella Guenther ); Pillar coral ( Stylaster sp. ); Sheng Coral ( Tubipora musica ); Little Star Gyro Coral ( Starry Turbinaria ); or any coral or combination thereof known in the art.

[0158] In another embodiment, marine animal derivatives—such as corals, sponges, mollusc shells, and other related organisms—can be used in the solid matrix, method, and / or kit of the present invention, and may be from the orders Scleractinidae, Helioporidae, genus *Helioporidae*, genus *Helioporidae*, or other species known in the art. In some embodiments, the corals used in the matrix, method, and / or kit of the present invention may include reef-building corals, and in some embodiments, *Helioporidae* and others. In some embodiments, the corals used in the matrix, method, and / or kit of the present invention may include *Alveoppora*. In some embodiments, the corals used in the matrix, method, and / or kit of the present invention may include bamboo corals, and in some embodiments, include corals from the family Isididae, genus *Keratoisis*, *Isidella*, and others.

[0159] In one embodiment of the invention, the term "coral" refers to coral cut from a single piece of coral.

[0160] In one embodiment, the coral can be machined into a prescribed configuration, and is envisioned to be substantially conical, but may be further modified, for example, to include or be shaped into a fairly complex shape including a threaded structure, and it can be formed by suitable machinery or other processing such as chemical processing.

[0161] In some implementations, the size / dimensional scaling of the solid matrix is ​​adapted to best fit the site of desired tissue growth or repair in terms of its width and length, while its height results in the implant being at least 2 mm lower than the surface of the articular cartilage layer or located proximal to the tidal zone of the implantation site when implanted within the underlying bone / cartilage interface.

[0162] In some embodiments, the solid matrix contains one or more cavities along the Cartesian coordinate axis of the solid matrix, and the solid matrix is ​​made of any suitable material.

[0163] In one embodiment, the length and / or width of the solid matrix can be any length and / or width suitable for the purposes of this invention, as known to those skilled in the art for the purpose. For example, in one embodiment, the solid matrix can be substantially the same length and / or width as the structure to be replaced, while in another embodiment, the solid matrix or a portion thereof can be the length and / or width of a defect, crack, or fracture, such that it can be placed therein to enhance / replace tissue formation / function in discrete locations. Based on these aspects, it is understood that the sides of such an implant can have a taper relative to the longitudinal axis of such implant, and the height of such implant is approximately 2 mm lower than the articular cartilage surface proximal to the treated tissue site.

[0164] In one embodiment, the solid matrix of the present invention comprises an average void diameter, an average pore size, or a combination thereof suitable for cell seeding and / or vascular system development.

[0165] In one embodiment, when the substrate used is coral, the coral is washed, bleached, frozen, dried, and exposed to electricity, magnetism, ultrasound, microwave, electromagnetic radiation, or high pressure, or a combination thereof, before its use.

[0166] For example, and in some embodiments, the solid matrix used for osteochondral treatment or repair may use a matrix with a diameter of about 5-15 mm and a height of about 5-25 mm; however, the implantation of this matrix ensures that its height does not reach the articular surface layer near the tissue site to be treated, and in some aspects, the height is at least about 2 mm lower than the articular surface. In some embodiments, the solid matrix has a diameter of about 1-35 mm and a height of about 1-45 mm; however, the implantation of this solid matrix ensures that its height does not reach the articular surface layer near the tissue site to be treated, and in some aspects, the height is at least about 2 mm lower than the articular surface. In some embodiments, the solid matrix has a diameter of about 5-40 mm, such as 5, 10, 15, 20, 25, 30, 35 or 40 mm, and a height of about 5-60 mm, such as 5, 10, 15, 20, 25, 30, 35, 49, 45, 50, 55 or 60 mm, or a diameter of about 5-15 mm and a height of about 5-45 mm. However, the implantation of the solid matrix ensures that its height does not reach close to the articular surface layer of the treated tissue site, and in some respects, the height is at least about 2 mm lower than this articular surface.

[0167] Those skilled in the art will understand that the size of the matrix can be selected to suit a specific application; for example, when used as a scaffold material for bone repair, its size can approximate the size of the long bones in the subject. Therefore, the present invention should not be limited by the size of the solid matrix.

[0168] Those skilled in the art will understand that the overall shape of the matrix can be chosen to suit a particular application; for example, when used as a scaffold material for condylar repair, its shape may be additionally curved beyond the dimensions of the condylar region being repaired in the subject. Therefore, the present invention should not be limited by the shape of the solid matrix.

[0169] In some embodiments, the corals used according to the invention can be prepared as described in PCT International Application Publication No. WO 2009 / 066283, PCT International Application Publication No. WO 2010 / 058400, PCT International Application Publication No. WO 2010 / 146574 and PCT International Application Publication No. WO 2010 / 146574 (each of which is incorporated herein by reference in its entirety).

[0170] The solid matrix of the present invention is characterized by, for example, a specific fluid absorption capacity value of at least 75% as required for a particular application, said specific fluid absorption capacity value being determined by establishing a spontaneous fluid absorption value divided by the total fluid absorption value.

[0171] In some embodiments, the fluid is a biological fluid, which in some embodiments is blood, and in some embodiments, the biological fluid is water. In some embodiments, the biological fluid is hydrophilic. In some embodiments, the fluid is plasma or a plasma-containing solution. In some embodiments, the fluid is a protein-containing or carbohydrate-containing solution. In some embodiments, the fluid is a saline solution. In some embodiments, the solution is a glycoprotein-containing solution.

[0172] In some embodiments, when the solid matrix comes into contact with such cells or tissues of the subject, the biofluid is autologous relative to the subject's cells or tissues.

[0173] In some implementations, the biological fluid is a blood analogue as defined herein.

[0174] In some embodiments, surprisingly, a solution containing 40% glycerol and 1 g / L glucose in physiological saline has been found to be a useful fluid for assessing the specific fluid uptake capacity of the solid matrix described herein. In some embodiments, such a solution is referred to as a "blood analog" because its biocompatibility and other desired properties (such as viscosity) for the purpose of assessing the specific fluid uptake capacity of the solid matrix described herein provide values ​​consistent with those obtained using autologous or allogeneic blood or water, and therefore it can be used as an analog for such screening protocols.

[0175] In some respects, the blood analogues mentioned in this article should be understood to specifically refer to any solution containing approximately 20% to approximately 60% glycerol and 1 g / L glucose in physiological saline.

[0176] In some aspects, as those skilled in the art will understand, such blood analogs may further comprise color indicators or dyes, such as FD&C Blue #2 aluminum lake dye or FD&C Blue #2 dye, or any other suitable color indicator. In some embodiments, the blood analog comprises 1 g / L FD&C Blue #2 aluminum lake dye, or in some embodiments, the blood analog further comprises 0.075 g / L FD&C Blue #2 dye, as these are appropriate concentrations of color indicator. Those skilled in the art will understand that color indicators can be provided at any appropriate concentration to provide the desired detectable signal.

[0177] Those skilled in the art will understand that the fluid used to determine the specific fluid absorption capacity value of the solid matrix described herein may include any suitable fluid, such as a salt-based solution, such as physiological saline (0.9% sodium chloride), or in some embodiments, a carbohydrate-based solution, such as 1 g / L glucose in saline, or in some embodiments, 1 g / L glucose in WFI, or in some embodiments, 10 g / L glucose in WFI, or in some embodiments, a protein-based solution, such as 50 g / L BSA in saline, or in some embodiments, 5 g / L BSA in WFI, or in some embodiments, 0.5 g / L BSA in WFI, or in some embodiments, a glycerol-based solution, such as 22% glycerol in saline, or in some embodiments, 22% glycerol in WFI, or in some embodiments, 30% glycerol in WFI, or 44% glycerol in WFI, or in some embodiments, xanthan gum & glycerol solution, such as 0.025% xanthan gum + 30% glycerol, or in some embodiments, combinations of the above, such as glycerol / glucose / BSA / saline / skim milk, or in some embodiments, 0.1 g / dL glucose + 5 g / dL BSA in saline, or in some embodiments, 5 g / dL skim milk in saline, or in some embodiments, 22% glycerol + 50 g / L skim milk in saline, or in some embodiments, 22% glycerol + 10 g / L glucose in saline, or in some embodiments, 30% glycerol + 1 g / L glucose in saline, or in some embodiments, 30% glycerol + 10 g / L glucose in saline, or in some embodiments, 32.5% glycerol + 1 g / L glucose in saline, or in some embodiments, 35% glycerol + 1 g / L glucose in saline, or in some embodiments, 35% glycerol + 1 g / L glucose in saline, or in some embodiments, 40% glycerol + 1 g / L glucose in saline, or in some embodiments, PEG / Tween20 / gelatin, for example, 40% glycerol + 1 g / L glucose in saline. 40% glycerol + 1% PEG in a saline solution, or in some embodiments, 40% glycerol + 1 g / L glucose + 1% PEG in a saline solution, or in some embodiments, 40% glycerol + 1 g / L glucose + 0.1% PEG + 0.1% Tween 20 in a saline solution, or in some embodiments, 40% glycerol + 1 g / L glucose + 0.1% PEG + 0.1% gelatin in a saline solution, and others, as understood by those skilled in the art.

[0178] Those skilled in the art will also understand that any such fluid used to determine the specific fluid absorption capacity value of the solid matrix described herein can also be considered as representing the contemplated "blood analogue" described herein.

[0179] It should be understood that any of the foregoing is considered for determining the specific fluid absorbance value of the solid matrix described herein, and may be used in part as a type of blood analogue for such assay purposes. In some aspects, as a preferred embodiment of the blood analogue referred to herein, such analogue comprises 40% glycerol and 1 g / L glucose in physiological saline, and optionally also comprises the color indicator described herein.

[0180] In some respects, the blood analogues described herein are further characterized by having a density of about 1.12 g / mL and a viscosity of about 4.57 mPa / sec at 25°C.

[0181] It should be understood that the biofluid is suitable for introduction into a solid matrix for the desired application.

[0182] In some embodiments, the method further includes contacting the material with a fluid for 2-15 minutes to promote spontaneous fluid absorption of the fluid within the coral-based solid material to achieve the spontaneous fluid absorption value. In some embodiments, the method may allow the material to be contacted with the fluid for 0.5-15 minutes, or 0.5-5 minutes, or 10-60 minutes, or 60-90 minutes, or other time intervals to promote spontaneous fluid absorption. Those skilled in the art will appreciate that the time for applying the fluid to determine spontaneous absorption can be extended or shortened depending on variations in the size and geometry of the sample matrix being evaluated. In some embodiments, when evaluating larger samples, the method further includes contacting the material with a fluid for 2-24 hours to promote spontaneous fluid absorption of the fluid within the coral-based solid material to achieve the spontaneous fluid absorption value.

[0183] In some embodiments, the method further includes the step of contacting the solid material with a fluid and applying negative pressure to the solid implant material to promote maximum absorption of the fluid in the coral-based solid material to achieve the total fluid absorption value. In some embodiments, the application of positive pressure promotes fluid entry into the matrix by applying a vacuum to the matrix impregnated in the fluid.

[0184] In some embodiments, the method may further include the step of contacting the solid implant material with a fluid and applying positive pressure to the solid implant material to promote maximum absorption of the fluid in the solid implant material to achieve the total fluid absorption value. According to this aspect, and in some embodiments, care should be taken to ensure that the application of pressure does not in any way impair the structural integrity of the solid matrix.

[0185] In some embodiments, positive pressure is applied via any manual method, such as by using any applicator, syringe, gravity pressure, and others, as understood by those skilled in the art. In some embodiments, positive pressure is applied via forced permeation, centrifugation, etc. In some embodiments, combinations of the methods are contemplated.

[0186] In some embodiments, the solid matrix used to promote cell or tissue growth or functional recovery comprises coral or coral derivatives, or other suitable solid implant materials, characterized by having a contact angle value of less than 60 degrees when in contact with a fluid.

[0187] Methods for determining the contact angle are well known, and any suitable method can be used.

[0188] In some respects, the sample is further dried under vacuum and / or heated, pressurized, or steam-treated.

[0189] In some implementations, for aspects involving specific fluid absorption values, this value is a function of the weight change of the solid implant material.

[0190] According to this aspect and in some implementations, the dry weight of each sample is recorded, and the fluid as described herein is added to the measuring container.

[0191] According to this aspect and in some embodiments, a sample size in mm is applied to a container at a ratio of at least 1:1 to the volume of added fluid in ml. In some embodiments, the amount of fluid applied is excessive compared to the sample size.

[0192] According to this aspect and in some embodiments, once the initial fluid absorption is evaluated, the solid matrix sample is subsequently contacted with the fluid, and the weight of the solid matrix sample is evaluated. In other embodiments, the specific gravity is evaluated by gradient centrifugation according to Archimedes' principle.

[0193] According to this aspect and in some implementations, spontaneous fluid absorption is evaluated and the spontaneous fluid absorption value is determined based on the weight change of the sample.

[0194] According to this aspect and in some embodiments, the specific fluid absorption capacity value is a function of the fluid volume change of the fluid applied to the solid material based on marine organism skeleton derivatives. According to this aspect, spontaneous fluid absorption is evaluated and a spontaneous fluid absorption value is determined based on the total absorption applied to the volume of the sample.

[0195] According to this aspect and in some embodiments, the method then further includes contacting a significantly increased amount of fluid with the sample and applying pressure thereto to promote maximum fluid absorption to the sample’s total fluid absorption capacity.

[0196] According to this aspect and in some embodiments, as shown above, this pressure can be positive or negative, and the application time is sufficient to ensure that the applied fluid is absorbed to the marine organism skeleton derivative sample for a period of time.

[0197] According to this aspect and in some embodiments, this time may include a time interval of 0.5-60 minutes, or in some embodiments, when evaluating larger samples, this time may include a time interval of 2-24 hours to reach the spontaneous fluid absorption value. It should be understood that the time intervals described herein apply to any embodiment as described herein. Those skilled in the art will appreciate that the amount of time required to apply the fluid to determine the full capacity fluid absorption can be extended or shortened depending on variations in the size and geometry of the sample matrix being evaluated.

[0198] Based on these aspects, the total fluid absorption capacity is evaluated, and then the specific fluid absorption capacity value is determined.

[0199] In some embodiments, the invention specifically considers solid matrices with a specific fluid uptake capacity value exceeding 75% of the cutoff value, and it should be noted that such solid matrices are optimized for promoting cell or tissue growth in this sample. It should be understood that the cutoff value is considered to be a reasonable value for promoting a reduction in the presence of significant false positives (i.e., solid matrices that are not best suited for the indicated applications).

[0200] In some embodiments, the invention specifically considers solid matrices having a contact angle value of less than 60 degrees when in contact with a fluid, and it should be noted that such solid matrices are optimized for promoting cell or tissue growth in this sample. It should be understood that the invention considers the cutoff values ​​as reasonable values ​​for promoting a reduction in the presence of significant false positives (i.e., solid matrices that are not best suited for the indicated applications).

[0201] In some embodiments, a specific selection of a solid matrix based on a biological skeletal derivative, characterized by a specific absorbability value of at least 75% or a contact angle value of less than 60 degrees when in contact with a fluid, is then used to isolate a proximal region from which such a sample is obtained. This sample can then be reliably used and is considered optimized according to the method of the invention. In some embodiments, with respect to coral-based samples, this region may include the entire annual growth ring region within the coral from which the sample is derived.

[0202] In some implementations, a solid matrix based on a biological skeletal derivative, which is processed and found to be characterized by a specific fluid absorbability value of at least 75% or a contact angle value of less than 60 degrees when in contact with a fluid, may then be completely dried and used for implantation in a subject or as an ex vivo matrix for subsequent implantation for cell or tissue growth, and is then mechanically processed into a substantially conical shape as characterized herein.

[0203] In some implementations, when the sample is used in vivo for subsequent applications, in some aspects, prior to implantation, the sample is first contacted with an autologous biological fluid or material from the host, validating the observed enhanced fluid absorption phenotype as described herein.

[0204] In one embodiment of the invention, the solid matrix may further contain additional materials.

[0205] In some implementations, this additional material may include polymers, viscosupplements, hydrogels, etc.

[0206] In some embodiments, the polymer can be top-applied to an in-situ solid matrix, and in some embodiments, the polymer can form a top layer on the solid matrix to fill the void created by the matrix being approximately 2 mm below the articular cartilage layer proximal to the implantation site.

[0207] In some embodiments, the term "polymer" refers to the presence of a polymeric material layer bonded to at least a portion of the solid matrix material. In some embodiments, this polymeric layer is a coating for the solid matrix material.

[0208] In some embodiments, the coating may cover the entire solid matrix, and in some embodiments, the coating may penetrate into the voids and / or pores and / or voids of the solid matrix. In some embodiments, the coating may be selectively applied to specific areas of the solid matrix such that it creates a separate phase on the solid matrix, and in some embodiments, the polymer may be applied such that a thick polymer layer or phase is bonded to a portion of the solid matrix, thereby creating a separate polymer phase bonded to the solid matrix described herein.

[0209] In one embodiment, the polymer coating provides enhanced characteristics to the solid matrix as described herein, such as increased tensile strength, increased flexibility, reduced brittleness, and other properties for the solid matrix. In some embodiments, the polymer coating results in greater cell attraction and adhesion to the solid matrix as described herein, which in turn leads to enhanced repair in terms of quantity, quality, and timing. In some embodiments, the polymer coating enhances cell proliferation and / or differentiation into desired mature tissue, which in turn leads to enhanced repair in terms of quantity, quality, and timing.

[0210] In one embodiment of the invention, the polymer coating is permeable. In one embodiment, the permeable polymer coating comprises a special porous membrane. In one embodiment, the term "permeable" refers to having pores and openings. In one embodiment, the permeable polymer coating of the present invention has pores and openings that allow nutrients, therapeutic compounds, cell populations, chelating agents, or combinations thereof to enter. In one embodiment, the permeable polymer coating of the present invention has pores and openings that allow nutrients, therapeutic compounds, cell populations, chelating agents, or combinations thereof to leave / release.

[0211] In one embodiment, the polymer coating of the present invention is discontinuous. In another embodiment, one or more sub-regions of the coral of the present invention lack the polymer coating, thereby allowing direct contact between the coral and the environment.

[0212] In some embodiments, the solid matrix incorporates a biocompatible polymer, which is bound to the aragonite or calcite component via any physical or chemical association. In some embodiments, the polymer is part of a hydrogel incorporated into the solid matrix of the invention. In some embodiments, such a hydrogel-containing solid matrix may then be freeze-dried or dried and subsequently reconstituted.

[0213] In some embodiments of the solid matrix of the present invention, the polymer may be applied to the solid matrix to form a separate phase, or in some embodiments, the polymer may be applied as a layer on the solid matrix, or in some embodiments, the solid matrix may contain a polymer as an inner or outer related layer and a separate phase containing the same or different polymer materials attached thereto.

[0214] Such polymer-containing solid matrices are particularly suitable for cartilage repair, regeneration, or enhancement of its formation. In some embodiments, according to this aspect, for example, in the treatment of osteochondral defects, the solid matrix has a size suitable for incorporation into the affected bone and further comprises a polymer-containing phase, which, when inserted into the affected defect site, is proximal to the affected cartilage. In another aspect, and representing an embodiment of the invention, the solid matrix comprises a polymer that permeates into the voids and pores of the solid matrix, which is inserted into the cartilage repair site and the polymer facilitates cartilage growth, regeneration, or healing of the defect site.

[0215] This polymer-containing solid matrix is ​​particularly suitable for bone repair, regeneration, or reinforcement of its formation. In some embodiments, according to this aspect, for example, in the treatment of bone edema, bone breakage or fracture, nonunion fractures, dental and maxillofacial applications, conditions or defects, the coral-based solid matrix is ​​sized to be incorporated into the affected bone and further comprises a polymer that permeates into the voids and pores of the solid matrix, the solid matrix being inserted into the bone and the polymer facilitating bone growth, regeneration, or healing of defect sites.

[0216] In one embodiment, the polymer coating of the present invention comprises natural polymers including collagen, fibroin, elastin, silk, hyaluronic acid, sodium hyaluronate, cross-linked hyaluronic acid, chitosan, cross-linked chitosan, alginate, calcium alginate, cross-linked calcium alginate, and any combination thereof.

[0217] In one embodiment, the polymer comprises a synthetically modified natural polymer and may include cellulose derivatives such as alkyl cellulose, hydroxyalkyl cellulose, cellulose ethers, cellulose esters, and nitrocellulose. Examples of suitable cellulose derivatives include methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, and sodium cellulose sulfate.

[0218] In one embodiment of the invention, the polymer comprises a synthetic biodegradable polymer. In another embodiment of the invention, the synthetic biodegradable polymer comprises α-hydroxy acids, including polylactic acid, polyglycolic acid, their enantiomers, copolymers, polyorthoesters, and combinations thereof.

[0219] In one embodiment, the polymers of the present invention include poly(cyanoacrylate), poly(alkyl-cyanoacrylate), poly(ketal), poly(caprolactone), poly(acetal), poly(α-hydroxy-ester), poly(α-hydroxy-ester), poly(hydroxy-alkanoate), poly(propylene glycol fumarate), poly(imino-carbonate), poly(ester), poly(ether), poly(carbonate), poly(amide), poly(siloxane), poly(silane), poly(thioether), poly(imide), poly(urea), poly(amide-enamine), poly(organic acid), poly(electrolyte), poly(p-dioxanone), poly(olefin), poloxamer, inorganic or organometallic polymers, elastomers, or any derivatives thereof, or copolymers obtained from combinations thereof.

[0220] In one embodiment, the polymer of the present invention comprises poly(D,L-lactide-co-glycolic acid) (PLGA). In another embodiment, the polymer comprises poly(D,L-lactide) (PLA). In yet another embodiment, the polymer comprises poly(D,L-glycolic acid) (PGA). In one embodiment, the polymer comprises glycosaminoglycans.

[0221] In one embodiment, the polymer comprises a synthetic biodegradable polymer, which may include, but is not limited to, polyhydroxy acids, such as poly(lactide), poly(glycolic acid), and copolymers thereof; poly(ethylene terephthalate); poly(hydroxybutyric acid); poly(hydroxyvalerate); poly[lactide-co-(ε-caprolactone)]; poly[glycolic acid-co-(ε-caprolactone)]; poly(carbonate), poly(pseudoamino acid); poly(amino acid); poly(hydroxyalkanoate); poly(anhydride); poly(orthoester); and blends and copolymers thereof.

[0222] In one embodiment of the invention, the polymer includes proteins such as corn protein, modified corn protein, casein, gelatin, gluten, serum albumin, collagen, actin, alpha-fetoprotein, globulin, macroglobulin, cohesin, laminin, fibronectin, fibrinogen, osteocalcin, osteopontin, osteoprotegerin, or other proteins as understood by those skilled in the art. In another embodiment, the polymer may include cyclic sugars, cyclodextrins, synthetic derivatives of cyclodextrins, glycolipids, glycosaminoglycans, oligosaccharides, polysaccharides such as alginates, carrageenan (χ, λ, μ, k), chitosan, cellulose, chondroitin sulfate, curdlan, dextran, elsinan, furcellran, galactomannan, gellan, glycogen, gum arabic, hemicellulose, inulin, ebony gum, fructan, pectin, amylopectin, pyrogallol, prophyran, stearyl glucan, starch, tragacanth gum, welan, xanthan gum, xylan, hyaluronic acid, chitin, or poly(3-hydroxyalkanoates), such as poly(β-hydroxybutyrate), poly(3-hydroxyoctanoate), or poly(3-hydroxyfatty acid), or any combination thereof.

[0223] In one embodiment, the polymer comprises biodegradable polymers such as poly(lactide-co-glycoli), poly(anhydride), and poly(orthoester), which have carboxyl groups exposed on the outer surface as the smooth surface of the polymer is eroded; these may also be used. In one embodiment, the polymer contains unstable bonds, such as polyanhydrides and polyesters.

[0224] In one embodiment, the polymer may comprise its chemical derivatives (substitution, addition, and elimination of chemical groups such as alkyl and alkylene groups; hydroxylation; oxidation, and other modifications conventionally performed by those skilled in the art), such as blends of proteins or carbohydrates alone or in combination with the synthetic polymer.

[0225] In one embodiment of the invention, the polymer is biodegradable. In one embodiment, the term "biodegradable" or its grammatical form refers to the material of the invention that degrades in the biological environment in which it is present. In one embodiment, the biodegradable material undergoes degradation, during which acidic products are released, or in another embodiment, basic products are released. In one embodiment, biodegradation includes the material being degraded into its constituent subunits, for example, via digestion through a biochemical process. In one embodiment, biodegradation may include, for example, the cleavage of bonds (whether covalent or other) in the polymer backbone of the invention. In another embodiment, biodegradation may include the cleavage of bonds within the side chains or bonds (whether covalent or other) that connect the side chains to, for example, the polymer backbone.

[0226] In one embodiment, the solid matrix of the present invention is covalently bonded to a polymer coating using a crosslinking agent. In one embodiment, the phrase "crosslinking agent" refers to a reagent that promotes the formation of covalent bonds between two atoms. In one embodiment, the crosslinking agent is a zero-length crosslinking agent.

[0227] In one embodiment, the crosslinking agent is (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), N-sulfonylhydroxysuccinamide (sulfon-NHS), 5-iodopyrimidine, N-alkoxycarbonyl dihydroquinoline, pyrroloquinolinequinone, genipin, or a combination thereof.

[0228] In one embodiment, the crosslinking agent is a homobifunctional crosslinking agent, such as, for example, N-hydroxysuccinimide esters (e.g., disuccinimide octanoate or dithiobis(succinimide propionate), homobifunctional imine esters (e.g., dimethylhexamethyleneimine ester or heptamethine dimethyl ester), thiol-reactive crosslinking agents (e.g., 1,4-di-[3'-(2'-pyridinedithio)propionylamino]butane), difluorobenzene derivatives (e.g., 1,5-difluoro-2,4-dinitrobenzene), aldehydes (e.g., formaldehyde, glutaraldehyde), bis-epoxides (e.g., 1,4-butanediol diglycidyl ether), acylhydrazides (e.g., adipate dihydrazides), bis-diazo derivatives (e.g., o-toluidine), bis-alkyl halides, or combinations thereof.

[0229] In one embodiment, the crosslinking agent is a heterobifunctional crosslinking agent, such as, for example, amine-reactive and thiol-reactive crosslinking agents (e.g., N-succinimide 3-(2-pyridinedithio)propionate, carbonyl-reactive and thiol-reactive crosslinking agents (e.g., 4-(4-N-maleimide-phenyl)butyric acid hydrazide), or combinations thereof.

[0230] In some embodiments, the crosslinking agent is a trifunctional crosslinking agent, such as, for example, 4-azido-2-nitrophenyl biocytin-4-nitrophenyl ester, sulfosuccinimide-2-[6-biotinamide]-2-(p-azidobenzamido)hexanamido]ethyl-1,3'-dithiopropionate (sulfon-SBED), or a combination thereof.

[0231] In another embodiment, the cross-linking agent is an enzyme. In one embodiment of the invention, the cross-linking agent includes transglutaminase, peroxidase, xanthine oxidase, polymerase or ligase, or a combination thereof.

[0232] In a given application, the choice of crosslinking agent concentration for activity will vary depending on the volume, reagent, and polymer selected, as understood by those skilled in the art.

[0233] In one embodiment, the bonding of the solid matrix of the present invention with the polymer coating of the present invention comprises physical and / or mechanical bonding. For example, in one embodiment, physical and / or mechanical bonding may include imbibing, air drying, using a crosslinking agent, applying heat, applying vacuum, applying a freeze-drying method, freezing, applying mechanical force, or any combination thereof, to promote the physical bonding between the coral and the polymer coating described in the present invention.

[0234] In some embodiments, the selection of the polymer or the application of the polymer to the solid matrix as described herein can be chosen to increase the ability to enhance fluid absorption. Similarly, the surface of the solid matrix can be treated to increase fluid absorption therewith. In some embodiments, such surface treatment may include applying plasma to the solid matrix.

[0235] It will be clear to those skilled in the art that the physical and / or chemical properties of the polymer applied to the solid matrix and its components of the present invention can affect the methods or uses of the present invention and their kits for inducing or enhancing cartilage and / or bone repair.

[0236] In one embodiment, the thickness of the polymer applied to the solid matrix of the present invention is from 2.0 μm to 0.1 μm. In one embodiment, the thickness of the polymer coating is about 1.0 μm. In one embodiment, the thickness of the polymer coating of the present invention is from 10 μm to 50 μm. In one embodiment, the thickness of the polymer coating applied to the solid matrix of the present invention is about 10-25, or about 15-30, or about 25-50 μm. In one embodiment, the thickness of the polymer coating applied to the solid matrix of the present invention is about 0.0001-0.1 μm. In one embodiment, the thickness of the polymer coating applied to the solid matrix of the present invention is about 20-200 μm. In one embodiment, the thickness of the polymer coating applied to the solid matrix of the present invention is about 100-1500 μm. In one embodiment, the thickness of the polymer coating applied to the solid matrix of the present invention is about 0.1-1.5 mm, or 1-3 mm, or 2-7 mm.

[0237] In some embodiments, such as when the polymer applied to the solid matrix of the present invention is a thin coating that is bonded to the solid matrix of the present invention and has the thickness indicated above.

[0238] In some embodiments, the polymer used in the solid matrix of the present invention is applied to the entire solid matrix of the present invention, such that in some embodiments, the pores and voids within the solid matrix of the present invention are filled with the polymer described herein, and the thickness of such polymer layer as applied can be about 60-900 μm.

[0239] In some embodiments, as part of the implantation procedure of the present invention, the polymer is applied in situ to the tip surface of the implant.

[0240] In some embodiments, the polymer applied to the solid matrix of the present invention is applied to the end of the solid matrix of the present invention or a portion of the coating to form an additional polymer phase on the solid matrix of the present invention. According to this aspect and in some embodiments, the thickness of the applied polymer layer is about 0.1-10 mm.

[0241] In some embodiments, multiple solid matrices comprising polymer additives are implanted into a desired implantation site, wherein the polymer thickness of the first solid matrix applied to the desired implantation site may vary compared to the polymer thickness of the second solid matrix. This variation in thickness may reflect the scope described in this invention.

[0242] In one embodiment, the thickness of the polymer applied to the solid matrix of the present invention affects the physical properties of the solid matrix of the present invention. For example, the thickness of the polymer application can affect the elasticity, tensile strength, adhesiveness, or retention force of the solid matrix of the present invention, or any combination thereof. In one embodiment, the polymer application increases the elasticity of the solid matrix of the present invention. In one embodiment, the polymer application increases the tensile strength of the solid matrix of the present invention. In one embodiment, the adhesiveness of the polymer application relates to the adhesion to mesenchymal stem cells, blood vessels, tissue at the desired repair site (including cartilage repair), cartilage tissue, or bone tissue, or combinations thereof. In one embodiment, the polymer application reduces the adhesiveness of the solid matrix of the present invention. In one embodiment, the polymer application increases the adhesiveness of the solid matrix of the present invention. Those skilled in the art will understand that the polymer application can increase adhesiveness for one item while decreasing adhesiveness for another item. For example, in one embodiment, the polymer application increases adhesiveness to mesenchymal stem cells while decreasing adhesiveness to infectious agents. In one embodiment, the retention force of the polymer application relates to the retention of cell populations. In one embodiment, the cell populations retained within the polymer coating are mesenchymal stem cell populations, chondrocyte populations, osteoblast populations, etc. In one embodiment, the retention force of the polymer application relates to the retention of effector compounds.

[0243] In one embodiment, the thickness of the polymer application affects the proliferation and / or differentiation of cells applied to the solid matrix of the present invention, or affects the activation or migration of cells associated with the cell or tissue growth / recovery function of the matrix of the present invention, or a combination thereof.

[0244] Incorporation of biocompatible polymers (such as hyaluronic acid) into the solid matrix of the present invention can be achieved by any means, including pressure-driven applications in some embodiments, such as application under vacuum, centrifugal force, or mechanical pressure. In some embodiments, gravity is sufficient to allow hyaluronic acid to penetrate appropriately and relatively uniformly into the desired depth of the implant. According to this aspect, in one embodiment, visual examination of the implant, for example using Fast Green / Safranin O staining, indicates that hyaluronic acid is uniformly distributed through the matrix to the desired depth over time and under varying conditions of application.

[0245] In one embodiment, the solid matrix of the present invention may further comprise an effect compound, which in some embodiments may be directly bonded to the solid matrix of the present invention, or in some embodiments may be bonded to and applied in combination with a polymer.

[0246] In one embodiment, the effector compound may include silver ions, copper ions, or other metals, or combinations thereof. In another embodiment, the release of the compound may be facilitated by applying a charge.

[0247] In another embodiment, the first implant may be coated with a metal such as silver, and the second implant may be coated with a second metal such as gold. The application of an electric field or battery drive can cause charge to flow between the implant materials, resulting in sterilization of the area due to the discharge of silver ions. This implementation can, for example, be used to treat osteomyelitis.

[0248] In some respects, coatings with any osteoconductive material are envisioned, such as hydroxyapatite, titanium, calcium phosphate biomaterials, or coatings as described in Goodman SB et al., Biomaterials. 2013 Apr; 34(13): 3174-3183 or Zhang, BGX et al., Int J Mol Sci. 2014 Jul; 15(7): 11878-11921, both of which are incorporated herein by reference in their entirety.

[0249] In one embodiment, the effect compound comprises components for incorporation into the solid matrix of the invention as described herein.

[0250] In one embodiment of the invention, the effector compound includes cytokines, bone morphogenetic proteins (BMPs), growth factors, chelating agents, cell populations, adhesive supplements, platelet-rich plasma (PRP), stem cells, therapeutic compounds, or antibiotics, or any combination thereof.

[0251] In one embodiment of the invention, the phrase "therapeutic compound" refers to a peptide, protein, or nucleic acid, or a combination thereof. In another embodiment, the therapeutic compound is an antibacterial, antiviral, antifungal, or antiparasitic compound. In another embodiment, the therapeutic compound has cytotoxic or anticancer activity. In another embodiment, the therapeutic compound is an enzyme, receptor, channel protein, hormone, cytokine, or growth factor. In another embodiment, the therapeutic compound is immunostimulatory. In another embodiment, the therapeutic compound inhibits inflammatory or immune responses. In one embodiment, the therapeutic compound includes angiogenic factors.

[0252] In one embodiment, the effector compound includes antiparasitic agents, antihistamines, immunomodulators, anticoagulants, surfactants, antibodies, β-adrenergic receptor inhibitors, calcium channel blockers, ACE inhibitors, growth factors, hormones, DNA, siRNA or vectors, or any combination thereof.

[0253] In one embodiment, the phrase "effect compound" refers to any agent or compound, when applied to the solid matrix, kit, and / or method of the present invention, having a specific purpose or application for treating, preventing, stopping, inhibiting, delaying, or reducing the incidence of infection, disease, disorder, or ailment. In one embodiment, the effect compound of the present invention will produce the intended effect of imaging solely for the purpose of using the compound. In some embodiments, the effect compound can be used to image the site where the compound is present; however, this ability is secondary to the purpose or choice of using the compound.

[0254] In one embodiment of the invention, when referred to herein, the term "effect compound" should be understood to also include "pharmaceutical" and "agent," and represents a molecule that is desired to be incorporated into the solid matrix and / or package of the invention or for which its use is required. In one embodiment, the agent is directly incorporated into the solid matrix and / or package of the invention. In another embodiment, the agent is incorporated into the solid matrix and / or package of the invention through physical interaction with or in combination with the polymer coating of the invention, coral or coral particles, and / or the package of the invention.

[0255] In one implementation, the "effect compound" is a therapeutic compound.

[0256] In one embodiment, the phrase "therapeutic compound" refers to a molecule that provides a beneficial effect when administered to a subject in need. In some cases, the molecule is therapeutic because it serves to replace the absence or reduced presence of such a molecule in the subject. In one embodiment, the molecule is a nucleic acid encoding the expression of a protein that is not present, such as in the case of an endogenous null mutant, compensated by the expression of a heterologous protein. In other embodiments, an endogenous protein is mutated and produces a nonfunctional protein, which is compensated by the expression of a heterologous functional protein. In other embodiments, the expression of a heterologous protein is an addition to low endogenous levels, resulting in a cumulative enhanced expression of a given protein. In other embodiments, the molecule stimulates the expression or secretion of key elements or other aspects of signaling cascades for cellular or host function.

[0257] In another embodiment, the therapeutic compound may be natural or non-natural insulin, amylase, protease, lipase, kinase, phosphatase, glycosyltransferase, trypsinogen, chymotrypsinogen, carboxypeptidase, hormone, ribonuclease, deoxyribonuclease, triglyceride lipase, phospholipase A2, elastase, amylase, coagulation factor, UDP-glucuronyltransferase, ornithine carbamate transferase, cytochrome p450 enzyme, adenosine deaminase, serum thymic factor, thymic humoral factor, thymopoietin, growth hormone, somatostatin, co-stimulatory factor, antibody, colony-stimulating factor, erythropoietin, epidermal growth factor, hepatic erythropoietin (hepatocyte-stimulating factor), hepatocyte growth factor, interleukin, interferon, negative growth factor, fibroblast growth factor, α-family transforming growth factor, β-family transforming growth factor, gastrin, secretin, cholecystokinin, somatostatin, serotonin, substance P, transcription factor, or combinations thereof.

[0258] In any embodiment of this document, the solid matrix and its use in the methods of the invention may also include, or be implanted with, other compounds, such as, for example, antioxidants, growth factors, cytokines, antibiotics, anti-inflammatory agents, immunosuppressants, antiseptics, analgesics, other therapeutic agents, and excipients. In one embodiment, examples of growth factors that may be applied, in addition to HMG-CoA reductase inhibitors, include, but are not limited to, epidermal growth factor (EGF), transforming growth factor-α (TGF-α), transforming growth factor-β (TGF-β), human endothelial growth factor (ECGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), bone morphogenetic protein (BMP), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), chondrocyte-derived morphogenetic protein (CDMP), platelet-derived growth factor (PDGF), or any combination thereof. Examples of antibiotics include antimicrobial agents and antibacterial agents.

[0259] In any embodiment of this invention, the solid matrix and its use in the method of the invention may further include plasma, platelet-rich plasma, any growth factor (as applicable), any glycosaminoglycan, particularly hyaluronic acid and any useful form thereof, or any combination thereof, or implanted together with it.

[0260] In one embodiment, the effector compound used in the solid matrix and / or kit and / or method of the present invention may particularly include antibodies or antibody fragments, peptides, oligonucleotides, ligands of biological targets, immunoconjugates, chemically analogous functional groups, glycolipids, labeling reagents, enzymes, metal ion chelators, enzyme cofactors, cytotoxic compounds, bactericidal compounds, bacteriostatic compounds, fungicidal compounds, antifungal compounds, chemotherapeutic agents, growth factors, hormones, cytokines, toxins, prodrugs, antimetabolites, microtubule inhibitors, radioactive materials or targeting portions, or any combination thereof.

[0261] In one embodiment, the solid matrix and / or kit of the present invention and / or the method of the present invention comprise or utilize oligonucleotides, nucleic acids, or carriers. In some embodiments, the term "oligonucleotide" is used interchangeably with the term "nucleic acid" and can refer to molecules including, but not limited to, prokaryotic sequences, eukaryotic mRNA, cDNA derived from eukaryotic mRNA, genomic DNA derived from eukaryotic (e.g., mammalian) DNA, and even synthetic DNA sequences. The term also refers to sequences comprising any known base analogues of DNA and RNA.

[0262] In one embodiment, the solid matrix and / or kit of the present invention and / or the method of use of the present invention may include nucleic acids, or in another embodiment, the solid matrix and / or kit of the present invention and / or the method of use of the present invention may include delivery of nucleic acids as part of a specific vector. In one embodiment, a polynucleotide fragment encoding a target sequence may be ligated into a commercially available expression vector system suitable for transducing / transforming mammalian cells and suitable for directing the expression of recombinant products within transduced cells. It should be understood that such commercially available vector systems can be readily modified via common recombination techniques to replace, duplicate, or mutate existing promoter or enhancer sequences and / or introduce any additional polynucleotide sequences, such as, for example, sequences encoding additional selectable markers or sequences encoding reporter peptides.

[0263] In one embodiment, the effector compounds used in the solid matrix and / or package of the present invention and / or the methods of the present invention may particularly include cytokines, bone morphogenetic proteins (BMPs), growth factors, chelating agents, cell populations, therapeutic compounds, anti-inflammatory compounds, pro-angiogenic compounds, or antibiotics, or any combination thereof.

[0264] It should be understood that any specific added / combined solid matrix described herein and included herein refers to such a matrix having the inclined sides described herein, or in some embodiments, being specifically shaped as generally oval, and optionally further including the taper described herein.

[0265] In some embodiments, the solid matrix of the present invention can be inoculated with cells, cell populations or tissues before, during or after surgery.

[0266] In some implementations, the cell or tissue comprises stem cells or progenitor cells or a combination thereof.

[0267] It should be understood that this refers to any suitable stem cell or progenitor cell obtained from any source or through any protocol.

[0268] In some embodiments, adipose tissue-derived stem cells are specifically envisioned for use in the methods of the present invention and for integration with the solid matrix of the present invention or the kit of the present invention.

[0269] In one embodiment of the invention, cells or tissues used in accordance with the matrix, method of use, or kit of the invention are engineered to express the desired product.

[0270] In one embodiment, the phrase "cell population" refers to a transfected cell population, a transduced cell population, a transformed cell population, or a cell population isolated from a subject, or a combination thereof. In some embodiments, transfected, transduced, or transformed cells may be seeded on a solid matrix, or in some embodiments, may be incorporated into a polymer application of a solid matrix, or a combination thereof.

[0271] In one embodiment, the cell population of the present invention comprises mesenchymal stem cells. In one embodiment, the mesenchymal stem cells are transformed.

[0272] In one embodiment, the cell population comprises cells that facilitate the repair of tissues into which the solid matrix of the present invention is desired to be implanted.

[0273] In some embodiments, the cells facilitate and / or promote cartilage and / or bone formation and / or repair. Such cells may include chondrocytes or chondrocytes; fibrochondrocytes; osteocytes; osteoblasts; osteoclasts; synovial cells; bone marrow cells; stromal cells; stem cells; embryonic stem cells; precursor cells derived from adipose tissue; peripheral blood progenitor cells; stem cells isolated from adult tissues; genetically transformed cells; or combinations thereof. In another embodiment, precursor cells may refer to combinations of chondrocytes and other cells; combinations of osteocytes and other cells; combinations of synovial cells and other cells; combinations of bone marrow cells and other cells; combinations of mesenchymal cells and other cells; combinations of stromal cells and other cells; combinations of stem cells and other cells; combinations of embryonic stem cells and other cells; combinations of precursor cells isolated from adult tissues and other cells; combinations of peripheral blood progenitor cells and other cells; combinations of stem cells isolated from adult tissues and other cells; and combinations of genetically transformed cells and other cells. Precursor cells used in the methods of the present invention are prepared from organ tissues of recipient mammals (i.e., autologous) or from syngeneic mammals. In another embodiment, allogeneic and xenogeneic precursor cells may be used.

[0274] In one embodiment, the solid matrix of the present invention incorporates stem cells, progenitor cells, or precursor cells. These cells can be obtained directly from a mammalian donor (e.g., the patient's own cells), a cell culture from the donor, or an established cultured cell line. In some embodiments, the mammal is a mouse, rat, rabbit, guinea pig, hamster, cow, pig, horse, goat, sheep, dog, cat, monkey, ape, or human. Cells of the same species and / or with the same immune characteristics can be obtained from the patient or a close relative via biopsy. Using standard cell culture techniques and conditions, the cells are then grown in a culture medium until they converge and are ready for use when needed. Cells can be cultured until a sufficient number of cells are obtained for a specific application.

[0275] In one embodiment, the solid matrix of the present invention incorporates any cells that can participate in tissue repair, such as cartilage and / or bone formation or repair. In some embodiments, such cells represent autologous grafts because the cells are cultured in vitro to seed the cells onto the solid matrix of the present invention, and this seeded solid matrix is ​​implanted into the subject.

[0276] In some embodiments, such cells may represent allogeneic or xenografts that can be incorporated into the solid matrix of the present invention and implanted into the repair site.

[0277] In one embodiment, the implant of the present invention comprises a cell population derived from a culture sufficient for seeding the implant with cells for a period of time before / during or after surgery. In one embodiment, the cell population is a population of mesenchymal stem cells; chondrocytes; fibrochondrocytes; osteocytes; osteoblasts; osteoclasts; synovial cells; bone marrow cells; stromal cells; stem cells; embryonic stem cells; precursor or stem cells derived from adipose tissue; peripheral blood progenitor cells; stem cells isolated from adult tissue; genetically transformed cells; or combinations thereof. In one embodiment, in vitro seeded mesenchymal stem cells; chondrocytes; fibrochondrocytes; osteocytes; osteoblasts; osteoclasts; synovial cells; bone marrow cells; stromal cells; stem cells; embryonic stem cells; precursor cells derived from adipose tissue; peripheral blood progenitor cells; stem cells isolated from adult tissue; genetically transformed cells; or combinations thereof are transformed. In one embodiment, the cell population comprises a cell population beneficial for cartilage repair. In one embodiment, the culture contains a chelating agent. In one embodiment of the present invention, the chelating agent in the culture comprises a calcium chelating agent.

[0278] In some embodiments, the solid matrix may further serve as a bone substitute or bone void filler. In some embodiments, the solid matrix may further incorporate a bone substitute or bone void filler. In some embodiments, this bone-containing material may comprise autologous or allogeneic bone. In some embodiments, this bone-containing material may comprise animal bone.

[0279] When a solid matrix, the best choice for cell and tissue growth and / or functional restoration, is specifically implanted into the tissue repair site, such that the solid matrix is ​​substantially press-fitted / close-fitted relative to the length and width of the implantation site, but the height of the solid matrix remains approximately 2 mm below the articular cartilage layer in the cartilage tissue proximal to the implantation site, the present invention provides unexpectedly excellent healing. Figure 3A-3C Specifically, it demonstrates improved healing and articular cartilage regeneration in the apical region above the implantation site as a result of the implantation methods described and illustrated herein.

[0280] In particular, the present invention provides an unexpected application where bone regeneration, repair and enhancement are optimal when the solid matrix is ​​characterized within the implanted tissue repair site, such that the solid matrix is ​​substantially press-fitted / close-fitted relative to the length and width of the implantation site, but the height of the solid matrix is ​​approximately 2 mm below the articular cartilage layer in the cartilage tissue proximal to the implantation site.

[0281] In other embodiments, when the solid matrix is ​​characterized within the implanted tissue repair site, such that the solid matrix is ​​substantially press-fitted / tightly fitted relative to the length and width of the implantation site, but the height of the solid matrix is ​​approximately 2 mm below the articular cartilage layer in the cartilage tissue proximal to the implantation site, the present invention provides an unexpected advantage in terms of greater cartilage formation.

[0282] In some embodiments, the solid matrix of the present invention can be applied to subjects with bone defects requiring repair, wherein proximity to the bone defect leads to the formation of a defect in the overlying cartilage, and the solid matrix of the present invention allows for ideal healing of the affected bone or bone and cartilage tissue when the solid matrix for repairing the affected bone or bone and cartilage tissue is implanted into the tissue repair site, whereby the solid matrix is ​​substantially press-fitted / tight-fitted relative to the length and width of the implantation site, but the height of the solid matrix remains approximately 2 mm below the articular cartilage layer in the cartilage tissue, or flush with the proximal tidal marker of the implantation site.

[0283] In other embodiments, such solid matrix can be applied to subjects with cartilage defects requiring repair, wherein optimal insertion of the solid matrix to stimulate cartilage repair requires anchoring the scaffold in the underlying bone, for example by creating a minimal gap in the underlying bone to insert the solid matrix, and is further characterized by such implantation within the tissue repair site, whereby the solid matrix is ​​substantially press-fitted / tightly fitted relative to the length and width of the implantation site, however, the height of the solid matrix is ​​approximately 2 mm below the articular cartilage layer in the cartilage tissue proximal to the implantation site.

[0284] In other embodiments, this solid matrix can be applied to subjects suffering from osteochondral defects, where both bone and cartilage tissue require repair as part of the disease pathogenesis. The methods / matrix used in this regard are particularly suitable for this application in some embodiments.

[0285] Those skilled in the art should understand that applications particularly involving bone therapy may include the use of a solid matrix incorporating any additional elements as described herein, including, for example, bone xenografts, bone autografts, bone substitutes, known bone void fillers, therapeutic compounds, etc.

[0286] In some embodiments, the solid matrix of the present invention can be used in combination with other known and / or available materials to stimulate / enhance cell and / or tissue growth and / or restore function, for example by promoting bone and / or cartilage repair, and the implantation method utilizes the solid matrix incorporating thereof.

[0287] It should be understood that when the implantation method is characterized by the implantation of a solid matrix in a press-fit / close-fit manner relative to the length and width of the implantation site within the tissue repair site, but the height of the solid matrix is ​​still about 2 mm below the articular cartilage layer in the cartilage tissue, or flush with the tide mark proximal to the implantation site, any use of the solid matrix of the present invention, alone or in combination with other suitable materials, for the treatment, repair or stimulation of cell or tissue growth or restoration of function is considered part of the present invention.

[0288] It should be understood that the solid matrix of the present invention can have any suitable size to suit its application according to the method of the present invention. For example, and in some embodiments, for the application of the solid matrix of the present invention in the long bone of a subject, the size of the solid matrix is ​​scaled to approximate the size of the site in which the scaffold is implanted, and can be scaled to the order of millimeters to centimeters as needed, characterized in that the matrix is ​​implanted within the tissue repair site, whereby the solid matrix is ​​substantially press-fitted / tight-fitted relative to the length and width of the implantation site, however, the height of the solid matrix is ​​approximately 2 mm below the articular cartilage layer in the cartilage tissue proximal to the implantation site.

[0289] In some embodiments, the present invention provides a solid matrix for repairing cartilage and / or bone tissue defects in a subject that are associated with physical trauma or with a disease or condition.

[0290] In some respects, particularly, the methods, solid matrices, kits, tools, and systems of the present invention are applicable to hip replacement, big toe fusion, arthrodesis, ankle replacement or fusion, and total or partial knee replacement surgery, including any or all of the foregoing.

[0291] In some embodiments, the plurality of solid matrices described herein are inserted to maximally occupy the defect site, thereby being suitably inserted into the desired area within the desired implantation site in terms of length and width, and further characterized in that the solid matrices are inserted into the tissue repair site such that the length and width of the implantation site are substantially press-fit / close fit, however the height of the solid matrices is about 2 mm below the articular cartilage layer in the cartilage tissue, or flush with the tide mark proximal to the implantation site.

[0292] In some embodiments, the present invention provides a method for optimally implanting a solid matrix to promote cell or tissue growth or functional restoration in osteochondral, bone, or cartilage tissue of a desired subject, the method comprising:

[0293] • Select and prepare a solid matrix for implantation to promote cell or tissue growth or functional recovery, the solid matrix having a certain length and width or promoting close fit within the boundaries of the implantation site, and characterized in that it has sufficient height such that when the first end of the solid matrix is ​​implanted at or substantially proximal to the tide mark in the bone of the implantation site, the second end of the solid matrix is ​​at a height of about 2 mm below the surface of the articular cartilage layer, or is flush with the tide mark.

[0294] • The selected and prepared solid matrix is ​​implanted into the implantation site across the long axis from the base to the tip of the implantation site, wherein the first end of the implant is implanted into the bone at the base surface, and the tip of the second end is positioned such that the second end is at a height at least 2 mm below the surface of the articular cartilage layer, or proximal to the tide mark region in the implantation site; and optionally

[0295] • Apply a biocompatible polymer layer to the top surface of the implant to fill the empty voids, reaching the level of the articular cartilage surface in height.

[0296] In some embodiments, the substrate has a height of 1-18 mm, and in some embodiments, the solid substrate has a height of 5-10 mm. In some embodiments, the solid substrate has a diameter of approximately 1-35 mm.

[0297] In some embodiments, the method of the present invention includes implanting more than one solid matrix in a tissue site as described above, and in some aspects, carefully implanting two implanted matrices such that a first end is implanted into the bone and a second end of each matrix is ​​positioned at a height at least 2 mm below the surface of the articular cartilage layer or at the proximal end of the tidal region in the implantation site, as described, wherein there is at least a 2 mm distance between the two matrices implanted in the tissue site such that each implant is completely surrounded by bone.

[0298] In some embodiments, the method / solid matrix used according to the invention promotes cell or tissue growth or functional restoration in the tissues of a subject suffering from defects or impairments or diseases of cartilage or bone, or a combination thereof. In some embodiments, cartilage defects or impairments or diseases include total or partial thickness articular cartilage defects; osteochondral defects; osteoarthritis; avascular necrosis; osteochondritis dissecans; bone cysts; nonunion fractures; joint defects or defects caused by trauma, exercise, or repetitive stress. In some embodiments, bone defects or impairments or diseases include fractures, bone defects, bone edema, osteoporosis, or defects caused by trauma, exercise, or repetitive stress. In some embodiments, the method reduces the incidence, duration, or need for joint replacement in affected subjects. In some embodiments, the method is used for surface reconstruction of affected joints in subjects.

[0299] In one embodiment, the phrase "cartilage repair" refers to restoring a cartilage defect to a healthier state. In one embodiment, cartilage repair results in the regeneration of cartilage tissue. In one embodiment, cartilage repair results in the regeneration of articular cartilage defects of complete or partial thickness. In one embodiment, cartilage repair results in complete or partial regeneration of cartilage tissue at the cartilage repair site. In one embodiment, cartilage repair can result in the restoration / repair of missing or defective bone tissue, wherein the repair of cartilage defects requires the removal of bone tissue at the cartilage repair site. In one embodiment, cartilage repair results in the regeneration of osteochondral defects. In one embodiment, cartilage repair includes the restoration of cartilage defects in joints (e.g., knee, elbow, wrist, ankle, toes, fingers, hip, shoulder), ears, nose or trachea (wind pipe), and lumbar intervertebral discs.

[0300] In one embodiment, the phrase "bone repair" refers to restoring a bone defect to a healthier state. In one embodiment, bone repair results in the regeneration of bone tissue. In one embodiment, bone repair results in the filling of any fractures or voids within the bone tissue. In one embodiment, bone repair results in complete or partial regeneration of bone tissue at the site of bone repair. In one embodiment, bone repair can result in the restoration / repair of missing or defective bone tissue. In one embodiment, bone repair includes restoring any bone defect as needed, treating bone edema, avascular necrosis, osteochondritis dissecans, bone cysts, nonunion fractures, and other bone disorders.

[0301] In some embodiments, the phrase "bone repair" refers to treating a subject suffering from osteoporosis, Paget's disease, fibrous dysplasia, bone edema, or bone dystrophy. In another embodiment, the subject suffers from bone and / or cartilage weakness. In yet another embodiment, the subject suffers from other bone remodeling disorders, including osteomalacia, rickets, rheumatoid arthritis, achondroplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecum, congenital hypophospholipid syndrome, fibromatosis, multiple myeloma, abnormal bone turnover, osteolytic bone disease, periodontitis, or combinations thereof. In one embodiment, bone remodeling disorders include metabolic bone diseases characterized by disturbances in the organic matrix, bone mineralization, bone remodeling, endocrine, nutritional, and other factors regulating the homeostasis of bone and inorganic matter, or combinations thereof. These disorders may be hereditary or acquired, and in one embodiment, are systemic and affect the entire skeletal system.

[0302] In other respects, the present invention particularly contemplates the use of the solid matrix described herein and methods for treating bone and / or cartilage defects caused by tumors or avascular necrosis using the solid matrix.

[0303] The solid matrix and / or the kit and method of the present invention can also be used to enhance bone and / or cartilage formation in conditions where bone and / or cartilage defects are caused by factors other than impaired bone remodeling. Such bone defects include fractures, bone trauma, and conditions related to traumatic bone surgery, joint repair surgery, osteopathic surgery, bone chemotherapy, dental surgery, and bone radiation therapy. Fractures include all types of microscopic and macroscopic fractures. In one embodiment, some examples of fractures include avulsion fractures, comminuted fractures, transverse fractures, oblique fractures, torsion fractures, segmental fractures, displaced fractures, impacted fractures, greenwood fractures, ridge fractures, stress fractures, intra-articular fractures (epithelial fractures), closed fractures (simple fractures), open fractures (invasive fractures), and occult fractures. In one embodiment, the fracture intended to be treated using the method of the present invention is a nonunion fracture.

[0304] In one embodiment, the solid matrix and / or the kit and method of the present invention can also be used to induce or enhance the repair of cartilage and / or bone defects or disorders or diseases. In one embodiment, the cartilage defect is caused by trauma, tear, sports injury, full-thickness articular cartilage defect, joint defect, or repetitive stress injury (e.g., osteochondral fracture, secondary injury due to cruciate ligament injury). In one embodiment, the cartilage disorder includes cartilage disease. In one embodiment, the method of the present invention induces or enhances the repair of cartilage in osteoarthritis, rheumatoid arthritis, avascular necrosis, osteochondritis (including osteochondritis dissecans), articular cartilage injury, patellar chondromalacia, chondrosarcoma, head and neck chondrosarcoma, costochondritis, enchondroma, hallux stiffness, acetabular labral tear, osteochondritis dissecans, meniscus tear, recurrent polychondritis, canine arthritis, fourth branchial arch defect, or wrinkled ear. In one embodiment, the method of the present invention induces or enhances cartilage repair in degenerative cartilage diseases, said diseases comprising at least in part disorders characterized by degeneration or metabolic disturbances of the body's connective tissue, which includes not only joints or related structures (including muscles, bursae (synovium), tendons, and fibrous tissue), but also growth plates, the meniscus system, and intervertebral discs.

[0305] In one embodiment, the methods, materials, and kits of the present invention are used for surface reconstruction of joints, and in some embodiments, the methods, materials, and kits of the present invention prevent joint replacement, reduce its need, delay its need, or eliminate its need in the purposes described herein.

[0306] In one embodiment, the solid matrix, kit, and method of the present invention can also be used to enhance the repair of long bone fractures; generate bone in segmental defects; provide bone graft substitutes for fractures; promote tumor remodeling or spinal fusion; provide local treatment (by injection) for weak or osteoporotic bone in osteoporosis of the hip, vertebra, or wrist, or combinations thereof. In another embodiment, the solid matrix, kit, and method of the present invention can also be used to accelerate the repair of long bone fractures; treat delayed healing or nonunion of long bone fractures or pseudoarthrosis of spinal fusion; induce new bone formation in avascular necrosis of the hip or knee, or combinations thereof.

[0307] In some embodiments, the solid matrix, kit, and method of the present invention may also be used as a substitute for any bone described herein (e.g., hip, knee, shoulder, elbow, ankle, and other bones that a person skilled in the art will understand), or to delay complete or partial joint replacement.

[0308] In one embodiment, the method of the present invention evaluates cartilage and / or bone tissue repair sites by examining them, wherein the evaluation is performed by histological, histochemical, palpation, biopsy, endoscopy, arthroscopy, or imaging techniques including X-ray photography, computerized X-ray densitography, computerized fluorescence densitography, CT, MRI, or other methods known in the art, or any combination thereof.

[0309] In one embodiment, the method of the present invention includes inducing and enhancing cartilage and / or bone repair, wherein the solid matrix of the present invention is implanted into the cartilage and / or bone repair site to influence and improve cartilage and / or bone repair.

[0310] In one embodiment, the method of the present invention induces or enhances cartilage and / or bone repair, wherein the solid matrix attracts cell populations to the solid matrix, thereby influencing or improving cartilage and / or bone repair.

[0311] Clinicians in the art will recognize that the present invention’s method, which requires the implantation of a solid matrix into a cartilage and / or bone repair site, may require preparation of the cartilage and / or bone repair site to enable, as described herein, insertion into the bone, ensuring that the height of the implanted matrix is ​​at least 2 mm less than the surface of the articular cartilage layer, or proximal to the tidal region of the implantation site.

[0312] These preparations can occur before or simultaneously with the implantation of the coral solid matrix. For example, cartilage and / or bone tissue and / or other tissues proximal to the cartilage and / or bone repair site can initially be drilled to create a channel sized suitable for the coral solid matrix used in the method of the present invention. The coral solid matrix is ​​then implanted into the site such that a region of the coral solid matrix penetrates the drilled cartilage and / or bone tissue. Alternatively, the coral solid matrix can be attached to a tool capable of penetrating cartilage and / or bone or other tissues or combinations thereof. In this case, the attached coral solid matrix is ​​implanted simultaneously as the tool penetrates the cartilage and / or bone tissue.

[0313] In some embodiments, after the solid matrix is ​​implanted at the repair site or within several solid matrix implantation sites, the solid matrix is ​​processed to optimize incorporation and best cartilage and / or bone repair. In some embodiments, this processing may include cutting, polishing, or otherwise smoothing the surface of the solid matrix or coral solid matrix to optimize repair. According to this aspect and in some embodiments, the processed portion ensures that the matrix region located in the cartilaginous phase still has a maximum height at least 2 mm below the surface layer of the articular cartilage, or is flush with the tide mark proximal to the implantation site.

[0314] It should be understood that any method and / or use of the present invention and / or implant substrate and / or tool used with the present invention as described herein may be used for human or veterinary purposes.

[0315] In some embodiments, the present invention provides a method for implanting an optimized solid matrix to promote cell or tissue growth or functional restoration in a desired subject, the method comprising:

[0316] • Isolate or prepare an optimized solid matrix for promoting cell or tissue growth or restoring function, the solid matrix comprising coral or coral derivative, characterized by a specific fluid absorption capacity value of at least 75%, or characterized by a contact angle value of less than 60 degrees, and further characterized by being substantially conical in shape, having a circular cross-section and inclined sides at each end of the solid matrix.

[0317] • Establish the specific fluid absorption capacity value of the solid matrix, which is determined by establishing a spontaneous fluid absorption value divided by the total fluid absorption value;

[0318] • Select a solid matrix characterized by a specific fluid absorption capacity of at least 75% or a contact angle of less than 60 degrees; and

[0319] • Implantation in the desired site of the subject is characterized by a specific fluid absorption capacity value of at least 75% or is characterized by having a contact angle value of less than 60 degrees, wherein the implantation is performed at an implant angle of 2 degrees with respect to the axis perpendicular to the surface of the tissue site so treated, and wherein the implantation is performed such that a gap is created between the articular cartilage layers on either side of the implanted matrix, such that the apex of the solid matrix is ​​approximately 2 mm below the articular cartilage layer.

[0320] In some embodiments of the methods described herein, the invention provides a kit comprising one or more implants described herein, and in other embodiments, the kit may include a full complement to the implants described herein, as well as tools for implanting the implants as needed / desired.

[0321] In some embodiments, these kits contain any supplements to the solid matrix described herein, and optionally, may further contain any biocompatible polymers described herein, with hyaluronic acid particularly envisioned in this case.

[0322] This invention specifically considers customized applications, wherein a solid matrix for implantation is specially prepared in a customized manner to best fit the defect site of the subject who needs to implant the solid matrix, such that the height of the implant constructed is about 2 mm below the surface of the articular cartilage, or level with the tide mark of the tissue proximal to the implantation site.

[0323] In some respects, the present invention particularly considers customized (particularly implantation procedures relative to the subject's curved tissue sites) procedures that ideally include the preparation of a solid matrix for implantation, for example, by compiling information from multiple sources, such as MRI and / or CT scans, to obtain multiple medical images of the bone region with the defective area and convert them into three-dimensional data.

[0324] In some respects, this three-dimensional data is then used by automated systems to specifically engineer suitable and ideal implants.

[0325] In some implementations, this 3D data is then used to facilitate the selection of implants from a variety of standard implants of different sizes and shapes, in order to facilitate the selection of the best implant option from a range of available implants.

[0326] In some implementations, in any case, the thus truly optimized implant is specifically and custom-machined to ideally fit the subject, or an optimized implant reflecting the best fit is selected from a wide variety of criteria. The implant may further include the inclined sides as described herein and / or the circular surface as described herein, while ensuring that the implant height is approximately 2 mm below the articular cartilage layer of the tissue proximal to the implantation site.

[0327] In some implementations, the method of the present invention is suitable for use with automated systems.

[0328] In some respects, these automated systems are adapted to robotic components to generate the movements required for surgical site preparation and implantation.

[0329] In some respects, these automated systems are adapted to robotic components to generate the desired movements for preparing the implantation site, and in some embodiments, for implanting the solid matrix described herein.

[0330] In some respects, these automated systems have been well established and allow for greater precision and control in surgical implantation procedures, and can be further combined with customized methods, implants, and tools described herein and in other patents / applications fully incorporated herein by reference to provide ideal implantation and optimal outcomes in subjects who require such methods, implants, and tools.

[0331] In some embodiments, the present invention provides a solid matrix and tools for the solid matrix, the solid matrix further comprising / containing a surface characterized by a radius of curvature, which in some embodiments may be substantially similar to the radius of curvature of a tissue surface to which the tools and / or solid matrix described herein are applied.

[0332] In some embodiments, this radius of curvature of the tool or solid substrate described herein may vary along the X-axis of the surface plane of the tool or solid substrate.

[0333] It should be understood that references to the symmetry or asymmetry of the radius of curvature of the solid matrix and / or its inclusion in the kit of the present invention and / or its use and / or method of implementation may reflect the selection of an approximate curved tissue structure that the solid matrix and / or the kit of the present invention containing it and / or its use and / or method of implementation are intended to present. In some aspects, this selection is particularly derived from sagittal and / or coronal sectional imaging of the defect site, and the same dimensions and features determined from this image are applied to obtain the optimal implant / matrix.

[0334] In some respects, the symmetry or asymmetry of the radius of curvature of the solid matrix surface of the present invention, or in the case of the invention and / or the method according to the invention, will reflect the sagittal and / or coronal variations of the identified corresponding tissue sites.

[0335] Similarly, it should be understood here that the X-axis and / or Z-axis mentioned in this article refer to the sagittal and / or coronal planes, and include consideration of them.

[0336] In some embodiments, the radius of curvature of the tool or solid substrate described herein may vary along the Z-axis of the surface plane of the tool or solid substrate, and in some embodiments, the radius of curvature of the tool or solid substrate described herein may vary along both the X-axis and the Z-axis of the surface plane of the tool or solid substrate.

[0337] In some respects, the radius of curvature of the tools and / or solid matrices described herein is specifically tailored to fit a defined radius of curvature along the X-axis or Z-axis or a combination thereof along the tissue surface to which the tool or matrix is ​​applied, as obtained from a topological assessment of the tissue surface performed.

[0338] In some embodiments, the radius of curvature of the tool or solid substrate described herein may vary along the Z-axis of the surface plane of the tool or solid substrate, and in some embodiments, the radius of curvature of the tool or solid substrate described herein may vary along both the X-axis and the Z-axis of the surface plane of the tool or solid substrate.

[0339] In some respects, the radius of curvature of the tools and / or solid matrices described herein is specifically tailored to fit a defined radius of curvature along the X-axis or Z-axis or a combination thereof along the tissue surface to which the tool or matrix is ​​applied, as obtained from a topological assessment of the tissue surface performed.

[0340] In some aspects, the tools used for the implants / solid matrix and methods / uses of the present invention include those described in PCT International Patent Application Publication No. 2014 / 072982, which is incorporated herein by reference in its entirety. In some aspects, such tools can be modified to include / accommodate a surface characterized by a radius of curvature, which in some embodiments may substantially resemble the radius of curvature of the tissue surface to which the tools and / or solid matrix described herein are applied. In some aspects, and referring to FIG1, the tool may include an implant alignment tool 1-10 placed on the desired implantation site to facilitate the insertion of a rod-like structure through it at a substantially 90-degree angle / perpendicular to the tissue surface into the repair tissue site, which may then be attached to a drill bit and thereby drill into the underlying subchondral bone. A specialized drill bit, such as that described in WO 2014 / 072982, may be adapted to facilitate / facilitate rotation of the drill bit when placed on the rod-like structure but within the drill bit sleeve. A tissue reamer may be further applied and applied to the K-line and rotated to expand / enlarge the walls of the implantation site within the cartilage and subchondral bone. The tissue wall of the implant can be further processed, for example, by using a tissue cone shaper to smooth it further, which can then be inserted into the rod structure and rotated to smooth the tissue wall at the implantation site.

[0341] With the aid of a cartilage cutter 1-120, a scalpel, or other suitable tool, tissue sites can be shaped / smoothed / expanded, or further shaped / smoothed / expanded. The cartilage cutter of this invention includes a head region and an elongated body connected thereto, whereby the elongated body facilitates proper gripping of the cartilage cutter tool.

[0342] In some implementations, the cartilage cutter includes:

[0343] • Slender handle;

[0344] • A head region connected to the elongated handle, the head region further including

[0345] o The top portion connected to the elongated handle;

[0346] o The base portion inserted into the implantation site;

[0347] o First and second inclined side regions, which taper from the top portion to the base portion;

[0348] The first inclined side region further includes:

[0349] • Conical blade surface,

[0350] • A supporting tapered inclined surface positioned relative to the surface of the tapered blade; and

[0351] • The hollow area located in between,

[0352] Thus, the tissue cut in this way that comes into contact with the surface of the conical blade has a thickness suitable for insertion into the hollow region.

[0353] According to this aspect and in some embodiments, the basal surface is substantially flat. In some embodiments, the internal region between the first and second inclined side regions is substantially hollow, or in some embodiments, the internal region between the first and second inclined side regions is substantially solid, but includes a hollow region into which cut tissue can be inserted.

[0354] In some embodiments, the elongated handle has a gripping surface, and in some embodiments, the elongated handle is configured to be ergonomic. In some embodiments, the elongated handle can be removably attached to the head region.

[0355] In some implementations, the head region is expandable to accommodate the size range of tissue sites where cartilage cutting is required.

[0356] therefore, Figure 1A-1S Specific methods and tools for preparing tissue sites for implantation in sites requiring osteochondral repair are described. Importantly, as described in the methods herein, tissue site preparation includes forming a smooth insertion site that facilitates the insertion of a therapeutic implant that penetrates to the underlying bone.

[0357] In some embodiments, the term "comprising" or its grammatical form means comprising the specified ingredients of the invention, as well as comprising other active agents and pharmaceutically acceptable carriers, excipients, emollients, stabilizers, etc., as known in the pharmaceutical industry.

[0358] In one implementation, the term “about” means a change of 1-10% compared to the indicated value, or in another implementation, a change of 5-15%, or in yet another implementation, a change of up to 10%, or in yet another implementation, a change of up to 25%, unless the context indicates that the change should not result in a value exceeding 100%.

[0359] In one embodiment, the present invention provides a combination formulation. In one embodiment, the term "combination formulation" is specifically defined as a "set of components," meaning that the combination of components as defined above can be used alone or in different combinations, i.e., simultaneously, together, alone, or successively.

[0360] While the invention has been described in conjunction with the illustrated embodiments, it should be understood that they are not intended to limit the invention to these embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents that may be included in the invention as defined by the appended claims.

[0361] Example

[0362] Example 1

[0363] Optimization methods for solid matrix implantation

[0364] Various tools and implants are envisioned for use in osteochondral defects and are considered equivalents in the methods / processes of this invention.

[0365] Figure 1A-1S A general procedure for preparing defect sites 1-05 is described. In this specific procedure, osteochondral defects in the condyle are treated. As a first step, the area requiring osteochondral repair is exposed in a conventional manner. The implantation site is prepared before implantation of the osteochondral-inducing implant. First, and as described in WO 2014 / 072982, which is fully incorporated herein by reference, an implantation alignment tool 1-10 is placed over the desired implantation site. This tool facilitates the insertion of a rod-like structure (e.g., K-lines 1-20) through it into the tissue repair site at a substantially 90-degree angle / perpendicular to the tissue surface. Figure 1B The ability to attach rod-like structures within a drill bit for insertion into the lumen 1-40 of an implantation calibration tool is described. Figure 1C The rod-like structure drills into the subchondral bone 1-30 below. Figure 1D The alignment tool may include markings 1-50. Figure 1D It serves as an indicator of the depth in which a rod-like structure can be drilled / advanced.

[0366] Once the rod-shaped structures 1-20 are secured, the implant alignment tools 1-10 can be removed, allowing the rod-shaped structures to embed through the cartilage and into the subchondral bone of the site to be repaired. For proper insertion of the therapeutic implant, the tissue area in which the implant will be inserted needs to be cleared and properly prepared for insertion. This can be done by drilling / expanding the implant insertion site to properly expose the implantation site.

[0367] Figure 1F The text describes placing a drill sleeve 1-60 onto a rod-shaped structure 1-20, the drill sleeve potentially / optionally including an end suitable for stable insertion into underlying tissue. Specialized drill bits, such as those described in WO 2014 / 072982, may be adapted to facilitate / advantage the placement of drill bits 1-70 onto the rod-shaped structure. Figure 1E However, rotate within 1-60 degrees of the drill sleeve. Then remove the drill bit and drill sleeve. Figure 1H At the same time, the rod-shaped structure is kept in place and embedded in the subchondral bone.

[0368] Therefore, the expanded insertion site is formed / drilled within the bone through the cartilage in the defective area below, thereby forming the insertion area within the bone. While drilling alone may be sufficient, additional treatment / smoothing of the tissue periphery around the implantation site may be necessary / desirable. For this purpose, and also as described in WO 2014 / 072982, it may be desirable to apply, as Figure 1I-1L The tissue expander 1-80 is depicted in the text.

[0369] The reamer 1-80 is used on K-lines, such as... Figure 1I As described, and when housed within the exposed repair area of ​​the borehole, the reamer can... Figure 1J The rotation depicted, with end modification of the reamer, expands / enlarges the wall of the cartilage and subchondral bone implantation site. The reamer may also include indicator lines 1-85, which provide depth measurement for tissue insertion and preparation. For example, and as... Figure 1K As depicted, when implanted within a central trochlear lesion, the guide line reaches the articular surface level of the sulcus for optimal insertion. After tissue modification, the reamer is removed. Figure 1L ), and can be achieved by using a syringe 1-100, for example, to clean the tissue site with saline, such as Figure 1M shown.

[0370] The tissue wall of the implant can be further processed, for example, by using a tissue cone shaper 1-110 to further smooth it, which can also be inserted onto the rod-shaped structure. Figure 1N Similar to that achieved using a tissue expander, the rotation of the tissue shaper ( Figure 10 This can smooth the tissue wall at the implantation site, and the shaping device can also have indicator lines 1-115 to inform the user of the appropriate insertion depth. Figure 1P Once the tissue shaping is complete, the shaping device can be removed from the area, as shown in Figure IQ.

[0371] The tissue site can be washed again using a syringe (1-100 ml), for example, with saline solution. Figure 1R As shown, the tissue site can be shaped / smoothed / expanded or further shaped / smoothed / expanded by means of a cartilage cutter 1-120, or in some embodiments by means of a scalpel or other suitable tool.

[0372] therefore, Figure 1A-1S Specific methods and tools for preparing tissue sites for implantation in sites requiring osteochondral repair are described. Importantly, as described in the methods herein, tissue site preparation involves forming a smooth insertion site that facilitates the insertion of the therapeutic implant, penetrating to the underlying bone.

[0373] It should be understood that any tool can be constructed to allow a common handle to be attached to it, for example, suitable for screw-in or snap-fit ​​connections. In some respects, such a handle can be ergonomically designed to facilitate ideal operation of the tool.

[0374] Figures 5A-5E It shows Figure 1S The enlarged view of the cartilage cutter 1-120 depicted in the image highlights its additional features. The cartilage cutter 5-120 comprises an elongated body including a handle portion 5-230 and a head portion 5-220. In some aspects, the cutter handle may include a knerling surface to prevent fingers from slipping when gripping the tool. Those skilled in the art will understand that any suitable material may be used to construct the elongated body and / or hand portion of the device.

[0375] The cartilage cutter 5-120 head portion 5-220 is constructed to provide an angled insertion area to facilitate insertion of the head into the implantation site. Figure 5A-5I The head portion 5-220 is also adapted to include a blade 5-250, which enhances the ability to trim cartilage around the formed hole / implantation site as the blade rotates within this portion. This ensures that any protruding cartilage remnants in the implantation site can be cut away safely and with precision. The head region containing the blade 5-250 is configured to include an insertion area 5-240 through which the cartilage cut during the cutting process can pass. Essentially, the width between the support portion 5-260 and the blade 5-250 provides a hollow groove through which the cut cartilage is inserted into 5-240 and advanced (circumferentially in some embodiments) as the trimming is completed. The support portion 5-260 is positioned relative to the blade edge 5-250, as... Figure 5B , 5E As clearly stated in the document.

[0376] A second inclined surface 5-270 is shown, which in some embodiments may be smooth to ensure smooth trimming when the tool rotates in the implantation site, and is inclined at an angle comparable to that of the component containing the blade.

[0377] In some respects, the second inclined surface 5-270 is flat, but this is optional. The second inclined surface and the overall dimensions and geometry of the cartilage cutter are chosen / constructed in such a way as to ensure ideal positioning of the cutter, thereby allowing the blade surface to be optimally positioned to trim the periphery of the implantation site for ideal insertion of the implant.

[0378] In some respects, the inner 5-280 of the cartilage cutter is hollow, and in other respects, the inner 5-280 is filled. In some embodiments, the hollow inner 5-280 facilitates easier and cleaner trimming of cartilage, and it can be rotatably inserted therein during use. In some embodiments, the hollow inner 5-280 facilitates convenient observation of the implantation site from the side during trimming (see...). Figure 5B and Figure 5E Presented in Figure 5B (Rotated view).

[0379] The cutter head 5-220 can be adapted to accommodate a component containing a replaceable blade, or in some embodiments, the cutter head itself 5-220 can be replaceable. Figure 5F ). refer to Figure 5C and Figure 5D The cutter head 5-220 is adaptable such that the edge component 5-250 containing the blade is assembled onto the cutter head 5-220 to increase the blade surface 5-250. The head portion connected to the handle portion 5-230 includes opposing support surfaces 5-260 and recesses 5-240 into which trimmed cartilage is inserted. A second beveled edge 5-270 can engage with a similar beveled edge on the cutter head 5-220, thereby allowing only the blade-containing component to be replaced or exchanged. It will be apparent to those skilled in the art that other methods of blade-specific replacement are contemplated, such as blade replacement similar to that on a scalpel handle, and other configurations.

[0380] In some respects, the cutter head 5-220 can be attached to the cutter handle 5-230, for example, as... Figure 5F As shown, and any connection system is envisioned, such as snap-fit ​​connectors, screw configurations, etc.

[0381] Figure 5G 5I describes various implantation sites whose size can vary, for example, in terms of their depth and width, and the size of the cartilage cutter 5-120, and especially the cartilage cutter head 5-220, can be varied / adjusted in terms of overall size to suit application to a given implantation site for optimal cartilage trimming.

[0382] Figures 2A-2D It describes the first introduction of an implant in a site requiring osteochondral repair or bone repair or cartilage repair.

[0383] The implant 2-130 can be manually inserted into the prepared tissue site, such as... Figure 2B As shown, and pressed to fit within, as Figure 2C As shown, this allows for the initial introduction / placement of the implant within the repair site, such as... Figure 2DAs shown, the upper boundary of the implant is basically flush with or slightly higher than the surface of the articular cartilage.

[0384] While the use of any suitable implant is envisioned, in this particular aspect, the use of the implant described in WO 2016 / 178226 is particularly considered. The tools for preparing the implantation site described in WO 2016 / 178226 can also be used to prepare the implantation site; however, according to the method of the invention, care is taken to ensure that the site preparation includes the ability to implant a therapeutic solid matrix within the repair site, whereby the top of the implant abuts or reaches the moisture mark, as described herein.

[0385] Similarly, the use of any therapeutic implants, such as those described in US 8,932,581 or US 8,808,725 or US 8,790,681 or WO 2014 / 125478, is envisioned and is incorporated herein by reference in its entirety.

[0386] Further uses such as Figure 2E and 2F The rammer 2-140 shown includes a modified end 2-150 that mitigates any damage to the implant when used to further advance the implant into the desired repair site. For example, the end may be made of durable silicone, thus providing a non-adhesive protective surface when applied to the implant, thereby applying force 2-170 to the rammer to further advance the implant in a press-fit manner, for example... Figure 2H The method shown promotes the insertion of the implant into the bone at the defect site, wherein the upper boundary of the implant is no longer flush with the articular cartilage layer, but is about 2 mm below the articular cartilage surface.

[0387] Furthermore, when more than one therapeutic implant is introduced, each implant is similarly inserted to reach and advance into the bone at each repair site, such that the upper boundary of each implant is approximately 2 mm below the surface of the articular cartilage layer at the respective defect site. In this case, the two implants should not be adjacent to each other, but rather a tissue distance of approximately 5 mm should be maintained between the implant boundary sites, such as... Figure 2I As shown.

[0388] Figure 2J Another specific aspect of the optimization method is described, wherein the upper boundary of the therapeutic implant is approximately 2 mm below the surface of the articular cartilage in the defect site, and a biocompatible / therapeutic polymer composition can be applied to the tip of the implant, such as... Figure 2J As shown. For example, hyaluronic acid solution or hyaluronic acid hydrogel can be applied to site 2-160 using syringe 2-170, thereby achieving the desired effect. Figure 2K As shown, the cartilage layer has a narrow region of about 2 mm 2-180 that is not filled by the implant. Figure 2L It shows crossing Figure 2J The matrix in the region is implanted in the cross section of the bone below 2-210, and the tip of the implant extends to region 2-230, which is about 2 mm lower than the articular cartilage surface layer 2-220.

[0389] Example 2

[0390] An improved solid matrix, adapted to the method of the invention, is incorporated according to the location variation of the coral-based solid matrix.

[0391] A coral plug is prepared as described in PCT International Patent Application Publication No. WO2010058400, and an implant is introduced into the defect site prepared therein.

[0392] Patients were assessed at 6, 12, 18, and 24 months post-implantation using the validated Knee Injury and Osteoarthritis Outcome Score (KOOS) and the International Knee Documentation Committee (IKDC) scale (0 = worst, 100 = best) to evaluate pain levels, function, activities of daily living (ADL), quality of life (QOL), and extent / ease of participation in movement. Additionally, MRI and X-ray images were acquired to assess the quality and overall appearance of the repaired tissue.

[0393] Obtained 3 months after implantation Figure 3A As shown, implant 3-10 is specifically positioned below the articular cartilage surface at 3-200. The depression of the implant manifests as an area on the implant lacking articular cartilage, as indicated by point 3-210 in the figure. Over time, cartilage regeneration occurs, and the implant is also reabsorbed / decomposed. Figure 3B The results showed that cartilage growth 3-200 readily occurred in the implantation area as early as 6 months post-implantation. By 12 months post-implantation, full-thickness articular cartilage 3-200 regenerated on the implant 3-10, subsequently fully integrating with the underlying subchondral bone.

[0394] The images in Figure 3 are representative, and in all cases, full-thickness articular cartilage regeneration and reabsorption / incorporation of the implant in the underlying subchondral bone were clearly observed in more than 200 patients who received coral-based implants using the method described.

[0395] To further highlight the unexpectedly improved outcomes resulting from the implantation procedure described in this article, we conducted paired comparisons of patients who underwent the procedure at approximately the same time in the same hospital.

[0396] Figures 4A-4HA representative comparison was provided. Two male patients of similar age, exhibiting similar cartilage defects and having previously undergone ligament repair (ACL), were treated with implants of the same size (10 mm in the medial condyle of the left knee in the first patient, and 10 mm in the medial condyle in the second patient). Both patients had excellent clinical outcomes, as they were completely pain-free and able to perform all activities, including vigorous exercise, at 2 years.

[0397] Excellent cartilage repair was observed in both cases. Nevertheless, patients in which the implant was specifically inserted across the bone and into the cartilage layer but below the surface of the articular cartilage exhibited superior cartilage thickness when repair was performed and a precise tidal marker was formed between the regenerated cartilage and regenerated bone. Figures 4A-4D Images depicting the patient's progress after implantation of the implant described herein. Figure 4A It is a photograph of the implantation site, in which the implant (4-10) spans the bone and cartilage, thereby filling the implantation site and being placed flush with the articular cartilage surface (4-200). Figure 4B This refers to X-rays taken at the implantation site after implantation, with the top of the implant (4-10) crossing the tide mark and reaching the joint surface at a level of 4-200. Two years post-implantation, X-rays were taken at a lower magnification. Figure 4C ) and higher magnification ( Figure 4D The acquired MRI images showed reconstruction of the joint surface 4-195, and the repaired cartilage was similar to natural cartilage in signal intensity. However, the repaired cartilage proximal to the implantation site was thinner than the natural cartilage and did not show obvious tidal marker reconstruction.

[0398] The table below provides an assessment of patient progression from baseline to 2 years post-implantation. [See...] www.aaos.org / uploadedFiles / PreProduction / Quality / Mesaures / IKDCEnglishUS.pdf ; www.koos.nu / ].

[0399]

[0400] As can be seen from the table, patients showed complete recovery and functional restoration of quality of life through treatment.

[0401] Figure 4E-4H Images depicting patient progression following implantation of an implant as described herein, using a specific method according to the invention. Figure 4E The image shows the implantation site, where the implant (4-10) spans the bone and cartilage, filling the implantation site and positioned at the level of the articular cartilage marker (4-200) 2 mm below the surface of the articular cartilage. Figure 4F This is an X-ray of the implantation site after implantation, where the top of implant 4-10 is now level with the tide marker 4-200. Two years post-implantation, at a lower magnification... Figure 4G ) and higher magnification ( Figure 4HThe acquired MRI images showed that the reconstructed and repaired cartilage at the joint surface 4-195 was similar to the natural cartilage in signal and thickness, and the complete reconstruction of the tidal marker was obvious at 4-200.

[0402] The table below provides an assessment of the patient's progression from baseline to 2 years post-implantation.

[0403]

[0404] Therefore, in similar implantation methods, where the implant is placed substantially flush with the surface of the articular cartilage, healing of osteochondral defects is provided for patients treated in this way. However, surprisingly, when the method specifically implemented in this paper is used, the timing, amount, and quality of articular cartilage regeneration are significantly improved compared to similar methods, especially when assessing the thickness and tidal marker formation of the regenerated cartilage.

[0405] Those skilled in the art will understand that various changes in form and detail may be made without departing from the spirit and scope of the invention as set forth in the appended claims. Those skilled in the art will recognize or be able to determine many equivalents of specific embodiments of the invention described herein using only conventional experimentation. Such equivalents are intended to be included within the scope of the claims.

[0406] In one embodiment of the invention, "about" refers to a quantity that satisfies a specific need; for example, the size may be primarily, but not exactly, the specified size, but it meets the specific needs of cartilage repair at the cartilage repair site. In one embodiment, "about" means adjacent to or close to, but not exactly. A small margin of error exists. This margin of error will not exceed a positive or negative integer value. For example, about 0.1 micrometers would mean not less than 0 but not more than 0.2. In some embodiments, the term "about" with respect to a reference value includes a deviation of no more than 5%, no more than 10%, or no more than 20% above or below the specified value.

[0407] In the claims, articles such as “a,” “an,” and “the” refer to one or more members unless stated otherwise or clearly from the context. Claims and descriptions including “or” or “and / or” among members of a group are considered to satisfy the presence, use, or additional relation of one, more than one, or all members of the group to a given product or method, unless stated otherwise or clearly from the context. The invention includes embodiments in which exactly one member of the group is present, used, or additionally related to a given product or method. The invention also includes embodiments in which more than one or all members of the group are present, used, or additionally related to a given product or method. Furthermore, it should be understood that in various embodiments, the invention provides all variations, combinations, and arrangements, wherein one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the listed claims are incorporated into another claim deriving from the same basic claim, unless otherwise stated or unless this would appear contradictory or inconsistent to a person skilled in the art. When elements are given in a list form, e.g., Markush combination form, it should be understood that subgroups of said elements are also disclosed, and any element may be removed from that group. It should be understood that, generally, when an invention or aspect thereof is referred to as including specific elements, features, etc., certain embodiments of the invention or aspect thereof consist of or are substantially composed of these elements, features. For the sake of simplicity, these terms are not specifically listed in every instance herein. For convenience, some claims exist in a dependent form, but the applicant reserves the right to rewrite any dependent claim into an independent form to include elements or limitations of the independent claim referenced by that claim or any other claim, and such rewritten claim is considered equivalent in all respects to the dependent claim, regardless of what form the claim was in before being rewritten into an independent form (modified or unmodified).

Claims

1. A cartilage cutter, comprising: Slender handle; A head region connected to the elongated handle, the head region further comprising... The top portion connected to the elongated handle; The basal portion is inserted into the implantation site, wherein the basal surface is flat; The first inclined side region and the second inclined side region taper from the top portion to the base portion; The first inclined side region further includes: Conical blade surface, A supporting tapered inclined surface positioned relative to the surface of the tapered blade; and The hollow area located between the two, Thus, the tissue cut in this way that comes into contact with the surface of the conical blade has a thickness suitable for insertion into the hollow region.

2. The cartilage cutter according to claim 1, wherein the internal region between the first inclined side region and the second inclined side region is hollow.

3. The cartilage cutter of claim 1, wherein the inner region between the first inclined side region and the second inclined side region is solid, but contains a hollow region into which the cut tissue can be inserted.

4. The cartilage cutter of claim 1, wherein the elongated handle has a gripping surface.

5. The cartilage cutter of claim 1, wherein the elongated handle is configured to be ergonomic.

6. The cartilage cutter of claim 1, wherein the elongated handle is removably attached to the head region.

7. The cartilage cutter of claim 1, wherein the head region is expandable to accommodate a range of sizes of tissue sites requiring cartilage cutting.

8. A component kit comprising the cartilage cutter of claim 1.

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