Multilayered biomimetic osteochondral grafts

Abstract

Provided herein is a biomimetic osteochondral graft (100) generally useful for at least partially reconstructing damaged cartilage tissue within a joint. The graft is configured to have a modular layered structure in which the physical properties (e.g., stiffness and lubricity) or dimensions of each layer can be tailored (e.g., by using appropriate materials and controlling the thickness of the materials) based on the anatomical structure to be replaced. For example, the material and / or thickness of the layers can be selected to approximate the physical properties and / or dimensions of cartilage tissue (and, optionally, cartilage and subchondral bone).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. patent application Ser. No. 17 / 365,135, filed July 1, 2021, entitled "Multilayered Biomimetic Osteochondral Grafts and Methods of Use Thereof," the entire contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Many different injuries or constant stresses can wear away articular cartilage, the sliding surface of joints. Cartilage damage, especially in weight-bearing joints, often does not heal naturally and can be associated with long-term complications such as pain, loss of joint function, and osteoarthritis. In the United States, 1.2 million patients are diagnosed with knee cartilage damage annually, while only 550,000 patients undergo knee cartilage repair surgery annually. Nevertheless, there is a large disparity in satisfaction among patients diagnosed with cartilage damage, and they reject the current surgical standard of care due to poor outcomes, with more than 30% of microfracture procedures failing, and long rehabilitation periods. Furthermore, some believe that osteochondral damage cannot be reversed by current treatment parameters, either naturally or therapeutically. Poor quality of repair is common, and stable regeneration of hyaline cartilage is a rare outcome. Thus, unmet needs in cartilage tissue injury repair include improved joint function and reduced pain, greater efficacy of therapeutic interventions, faster return to weight-bearing daily activities, reduced rehabilitation time, long-term implant efficacy, applicability to a wide range of patients and injuries, single-operative repair, and rapid adoption of effective techniques by surgeons.

[0003] Several tissue regeneration techniques for cartilage defects range from simple microfracture (where multiple holes are drilled through the cartilage defect into the subchondral bone) to multi-stage cartilage transplantation surgery. Regenerative approaches have several drawbacks. For example, they require a long recovery period before the patient can return to full weight bearing and activity levels, the results are highly variable depending on individual patient factors such as age and body mass index, and they are generally not suitable for middle-aged and older patients because they have a poor ability to regenerate hyaline cartilage tissue and often result in the production of poorly characterized fibrocartilage tissue. Furthermore, regenerative approaches have not demonstrated a viable method for successful integration or fixation of regenerated cartilage tissue to bone. Many attempts have been made in cartilage regeneration and repair, or bone regeneration and repair, but have not addressed the osteochondral complex associated with solid clinical outcomes. Moreover, even for patients who initially benefit, long-term performance is often unclear. The availability of tissue supplies, high costs, and the need for multiple surgeries are all additional challenges for regenerative approaches. The shortcomings of tissue regeneration techniques have prompted investigations into the use of synthetic grafts.

[0004] Although synthetic materials such as metals and most polymers are usually more durable than cartilage tissue, they do not mimic the properties of native tissue closely enough, and tend to adversely affect the health of the surrounding tissue and damage the opposing cartilage surface at the articulation, thereby limiting the lifespan of such implants and accelerating the failure of the opposing cartilage surface. Other materials are ineffective because, compared to cartilage tissue, they have too low tear strength, poor mechanical properties, and often cannot be adequately fixed to the patient's bone to provide a stable long-term solution. Thus, there is a need for new osteochondral implants with improved properties and techniques to repair localized cartilage defects. Summary of the Invention

[0005] Disclosed herein are methods for repairing articular cartilage defects, as well as osteochondral mimetic grafts and systems suitable for use therein. Provided herein are biomimetic osteochondral grafts that are layered constructs that mimic the properties (e.g., stiffness) of articular cartilage and, in some implementations, the underlying subchondral bone throughout their thickness. The underlying multi-layered structure is achieved by multiple zones that are linked together by mechanical connections, chemical bonds, biological adhesion, and / or other linking mechanisms. Mimicking the properties of the cartilage or other tissue to be replaced as closely as possible can provide benefits such as improved stress transfer from the articulating surface to the subchondral bone, and preservation of the opposing cartilage surface in the case of unilateral repair of the joint. The disclosure relates, in part, to observing the response of tissue to applied loads and resulting stresses through remodeling. If the osteochondral graft is formed from a material with mechanical properties significantly different from those of the surrounding tissue, the shape and / or amount of tissue surrounding the implant site may change, thereby compromising the long-term success of the implant. Thus, an advantage of the technology described herein is to provide an osteochondral graft that provides similar properties to the surrounding natural cartilage and bone, allowing the graft to better respond to physiological loads without compromising the health of the natural cartilage and bone. In an illustrative example, the graft comprises three sections: an articulation zone, a base zone, and a mid zone, the mid zone having a first surface that connects to the underside of the articulation zone, a second surface that connects to the base zone, and a thickness and stiffness between the first and second surfaces that allows the mid zone to absorb a portion of the articulation loads. In some implementations, the mid zone mimics that of natural cartilage in stiffness, but is hydrophobic and stronger than fibrocartilage.

[0006] In a first aspect, a biomimetic osteochondral graft is provided herein, the graft having a support zone, a base zone configured to be coupled to bone (e.g., subchondral, cancellous, scleral bone) upon implantation of the graft, and a hydrophobic intermediate zone disposed between the support zone and the base zone. The support zone comprises a conforming surface configured for articulation in a diarthrodial joint or other joint, a lower surface, a first thickness extending between the conforming surface and the lower surface, and a first compressibility having a first stiffness. The intermediate zone has a shaped first surface, a second surface, and a second thickness extending between the first surface and the second surface, the shaped first surface including a periphery and an exterior surface spaced apart within the periphery and coupled to the lower surface of the support zone, the lower surface of the support zone conforming in shape to the surface, and the intermediate zone further comprises a second compressibility having a second stiffness greater than the first stiffness. The base region has an outer base surface connected to the second surface of the intermediate region, an inner base surface configured to connect to a bone, a third thickness extending between the inner base surface and the outer base surface, and has a third compressibility having a third stiffness greater than the second stiffness.

[0007] In some implementations, the support region includes a two-phase polymer. The two-phase polymer may have a water composition of at least 10%, at least 20%, at least 30%, at least 40%, or more. In some implementations, the two-phase polymer has a water composition gradient between the conforming surface and the lower surface. For example, the water composition gradient has a water composition of less than 10%, less than 5%, or less than 1% at the lower surface. For example, the water composition gradient has a water composition of greater than 30%, greater than 40%, greater than 50%, about 40%, about 45%, or about 50% at the conforming surface. For example, the water gradient provides a water composition of about 5% water at the lower surface and 40%-50% water at the conforming surface. In some implementations, the conforming surface is smooth. In some implementations, the lower surface is not smooth. In some implementations, the support region includes urethane. In some implementations, the support region comprises a water-swellable interpenetrating polymer network (IPN) or semi-IPN, the base region comprises porous metal, and the intermediate region comprises a copolymer of urethane dimethacrylate monomers and monomers selected from methyl methacrylate, acrylamide, and dimethylacrylamide.

[0008] In some implementations, the contact interface is formed between the front surface and the underside and extends across at least 50% of the surface, e.g., the contact interface extends across at least 50%, at least 75%, at least 85%, or at least 95% of the surface.

[0009] In some implementations, the implant has at least one pile structure in the support region, intermediate region, or base region. The at least one pile structure may have multiple piles in the intermediate region. For example, the at least one pile structure is disposed on the molded first surface or second surface.

[0010] In some implementations, the implant includes a central axis extending through the support region, the intermediate region, and the base region, the support region, the intermediate region, and the base region each having an axis and aligned coaxially along the central axis. In some implementations, the second thickness is variable by a first height extending between the second surface and the first surface at a first location along the first surface, and a second height extending between the second surface and the first surface at a second location along the first surface. For example, the first height is greatest at a location along the perimeter, and the second height is greatest at a location within the surface. The second height may be aligned coaxially with the axis of the base region. In some implementations, the intermediate region is plano-convex or plano-concave. In some implementations, the implant has a tapered region extending along the surface from a maximum second height toward the perimeter. In some implementations, the maximum first height is greater than the maximum second height. For example, the tapered region forms a concave curve. In some implementations, the maximum first height is less than the maximum second height. For example, the tapered region forms a convex curved surface.

[0011] In some implementations, the periphery includes a curved edge extending circumferentially around the central axis. In some implementations, the raised regions extend radially across the surface. In some implementations, a plurality of ridges protrude into the lower surface. In some implementations, the surface includes a plurality of regions each having a different radius of curvature.

[0012] In some implementations, the second thickness at the location along the perimeter has a boundary height of 0.01 mm to 10 mm, 0.2 mm to 5 mm, or about 1 mm. The second thickness of the intermediate region may taper toward the perimeter such that the boundary height is less than 0.1 mm. In some implementations, the support region and intermediate region extend axially from the outer base surface to the conforming surface over an axial length of 2 mm to 10 mm or 4 mm to 4.5 mm. In some implementations, the perimeter encompasses a region having a width of 5 mm to 15 mm (if the region is circular and the width is the diameter of the circle). In some implementations, the first thickness is 1 mm to 5 mm.

[0013] In some implementations, the second stiffness is between 50 MPa and 500 MPa. In some implementations, the first stiffness is between 40 MPa and 150 MPa, and the third stiffness is between 1.5 GPa and 11 GPa. In some implementations, the support region has a stiffness gradient of 1 kPa / mm or more extending from the lower surface to the conforming surface. In some implementations, the intermediate region is configured to be capable of deforming between 1% and 20% under physiological load (e.g., a stress of about 3 MPa) and repeatedly recovering 70% or more of the deformation upon removal of the physiological load. In some implementations, the support region has the ability to deform between 1% and 40% under physiological load and repeatedly recover more than 70% of the deformation upon removal of the load. In some implementations, when the support layer and intermediate layer are coupled, the implant has the ability to deform between 5% and 20% under physiological load and repeatedly recover 80% or more or 95% or more.

[0014] In some implementations, the base region includes at least one of a porous metal, a polymer, a ceramic, bone, or a synthetic bone, For example, the porous metal includes one or more of titanium, tantalum, stainless steel, cobalt chromium, nickel titanium alloy, or zirconium alloy, and the polymer includes one or more of a porous polymer, polyetheretherketone (PEEK), polyethylene, polysulfone, polyester, polyetherimide, polypropylene, or any other suitable engineering or porous polymer.

[0015] In some implementations, the medial base surface is configured to couple to the distal femur. In some implementations, the medial base surface is configured to couple to the proximal tibia. The implant may be adapted to repair or replace cartilage tissue, or cartilage tissue and bone, within a diarthrodial joint or other joint within the body, such as a knee joint (e.g., condyles, patellofemoral joint, total knee joint, meniscus, patella, or tibial plateau), ankle joint (e.g., talus surface or tibial surface), elbow joint (e.g., proximal ulna, distal humerus, or radial head), shoulder joint (e.g., labrum, glenoid cavity, humeral head, or any portion thereof), wrist joint (e.g., metacarpal joint, knuckle, thumb joint, or base of thumb), hip joint (e.g., acetabular surface, femoral head, or part of either surface), foot joint (e.g., metatarsal joint or toe joint), temporomandibular joint (e.g., temporomandibular joint), wrist joint, and spinal joint (e.g., facet joint). In some implementations, the support and intermediate zones are disposed on an outer base surface, the base zone being metallic or polymeric and configured with a preformed coupling mechanism (e.g., screw, peg, finger, or other component) at one end (e.g., distal femur or proximal femur) that can be mechanically coupled to the bone, e.g., by screwing, pegging, interfitting, or otherwise. In other applications, the implant is placed by integration into an existing joint replacement component, e.g., a metallic or polymeric femoral head in a hip joint repair. In such cases, an existing metallic or polymeric implant (e.g., femoral head) that has already been coupled to the bone (e.g., proximal femur) in a previous surgery serves as the base zone, and an implant (as disclosed herein) having a preformed support and intermediate zone is directly coupled to the existing metallic or polymeric base zone.

[0016] In another aspect, provided herein is a method of repairing a cartilage injury at an articulating surface in an orthopedic joint (e.g., a diarthrodial joint) that includes subchondral or other bone, the injury being at least partially surrounded at the articulating surface by external cartilage, a portion of which provides an area with a native tissue line for articulation. The method includes the steps of: (i) preparing a surgical site in the external cartilage region by removing at least a portion of the cartilage surrounding the defect, leaving an external cartilage hole having an inner diameter extending through the external cartilage region into the bone; (ii) providing a biomimetic osteochondral graft including a support area having a lower surface, a conforming surface having an outer surface and a first outer circumference having an outer diameter, and a base construct, the conforming surface configured to change shape upon articulation in the joint such that the outer surface conforms to a shape of an opposing surface of the orthopedic joint; (iii) threading the graft into the hole and into the bone such that the base construct directly bonds with the bone; and (iv) fixing the graft to the bone such that the outer surface of the conforming surface is offset in height relative to the natural tissue line of the external cartilage. It should be understood that the graft may be fixed such that the offset is zero at one or more locations along the conforming surface. The graft may be a graft according to any of the implementations of the first or second aspect.

[0017] In some implementations, the support region includes a two-phase polymer. The two-phase polymer may have a water composition of at least 10%, at least 20%, at least 30%, or more. In some implementations, the two-phase polymer has a water composition gradient between the conforming surface and the lower surface. The composition gradient is configured such that the water composition changes along the thickness of the two-phase polymer from its outer conforming surface at one end to its inner lower surface with a bulk region therebetween to provide proper connection of the hydrophobic intermediate layer and the hydrophilic articulating surface. The gradient comprises a water composition at the conforming surface, a water composition at the lower surface, and a bulk water composition extending between the conforming surface and the lower surface. In some implementations, the water composition is highest at the conforming surface and lowest (e.g., close to 0) at the lower surface, forming an essentially hydrophobic interface with the intermediate layer of the composition, and the bulk water composition is at a level intermediate between the two surfaces. The water composition at the conforming surface can be adjusted as needed in combination with adjustment of the remaining gradients. In some implementations, the water composition at the conforming surface is at least 25% and may be higher, while the water composition at the underside is low (e.g., less than 10%, less than 5%, or less than 1% (or near or at 0)). The bulk water composition is distributed at an operating condition that provides an optimal water balance and transition between the hydrophilic conforming surface and the hydrophobic underside. In implementations, the bulk water composition is within a range of 25%-41% (e.g., 27%-34%) and may be distributed as a gradient between that range to provide a smooth transition between the conforming surface and the underside, or may be distributed at a generally constant level at some point within that range (e.g., 27% or 34%). In some implementations, the conforming surface is smooth. In some implementations, the underside is not smooth. In some implementations, the support region comprises polyurethane. In some implementations, the implant is plano-convex (flat on one side and convex on the other) or plano-concave (flat on one side and concave on the other). In some implementations, the base construct comprises porous metal. In some implementations, the support zone comprises a stiffness gradient between the conforming surface and the lower surface, e.g., the stiffness gradient comprises a stiffness at the conforming surface that is less than a stiffness at the lower surface, the stiffness varying between the conforming surface and the lower surface.

[0018] In some implementations, the support zone is a first polymer layer disposed between the conforming surface and the lower surface, and the base construct includes a porous layer configured to directly couple to the bone, and a second polymer layer, the second polymer layer coupled to the first polymer layer at an intermediate interface between the lower surface and a molded surface of the second polymer layer such that the second layer is disposed between the intermediate interface and the porous layer. In some implementations, the first polymer layer has a first stiffness and the second polymer layer has a second stiffness, the second stiffness being greater than the first stiffness. The porous layer may have a third stiffness greater than the second stiffness. In some implementations, the second polymer layer includes a copolymer of urethane dimethacrylate monomers and methyl methacrylate monomers comprising hard and soft segments. For example, the hard segment of the urethane dimethacrylate of the first polymer adhesive is formed from one or more of 1,5-naphthalene diisocyanate (NDI), 2,6-toluene diisocyanate or 2,4-toluene diisocyanate (TDI), 3,3-bitoluene diisocyanate (TODI), cyclohexyl diisocyanate (CHDI), hexamethyl diisocyanate (HDI), isophorone diisocyanate (IPDI), methylene bis(p-phenyl)isocyanate, methylene diphenyl isocyanate (MDI), and methylene bis(p-cyclohexyl)isocyanate (HMDI). For example, the soft segment of the urethane dimethacrylate monomer is formed from one or more of polybutadiene, polyethylene oxide (PEO), hydroxy-terminated butadiene, hydroxybutyl-terminated polydimethylsiloxane (PDMS), hydroxyl-terminated polyisobutylene, poly(1,6-hexyl-1,2-ethyl carbonate), polycaprolactone, polycarbonate, polyethylene adipate, polyhexamethylene carbonate glycol, polypropylene oxide (PPO), polytetramethylene adipate, poly(dimethylsiloxane), and poly(tetramethylene oxide) (PTMO).In some implementations, the first polymer layer is a water-swellable interpenetrating polymer network (IPN) or semi-IPN that includes a first polymer network and a second polymer network of a thermoplastic polymer.

[0019] In some implementations, the surgical site is at the distal femur, proximal tibia, patella, distal tibia, distal fibula, calcaneus, talus, tibiofibular joint, proximal humerus, glenoid fossa, proximal femur, pelvis, distal humerus, proximal ulna, proximal radius, distal radius, distal ulna, carpal bones, distal metacarpal bones, proximal phalanges, metatarsals, or other articular surfaces having articular cartilage tissue. In some implementations, the injury is partially or completely surrounded by tissue.

[0020] In some implementations, step (i) includes using at least one of an awl, a surgical drill, a bur, a reamer, an alignment guide, a pin, a cutting tooth, a cutter, or a wire. Step (i) may include inserting a wire or pin into the injury via the guide, placing a drill, bur, or reamer over the wire or pin, and forming a hole with the drill, bur, or reamer. In some implementations, step (i) is performed with a single instrument, such as a self-guiding surgical drill with a reamer function, to minimize instrument changes during surgery. In some implementations, step (i) includes remodeling the bone in the hole. In some implementations, the method further includes verifying the depth of the hole prior to step (iii). For example, verifying the depth includes inserting a test graft that mimics the graft into the hole. In some implementations, step (iii) includes using an graft insertion device that releasably holds the graft. In some implementations, step (iv) includes using a mallet and a tamp to fully seat the graft into the hole. In some implementations, one or more of steps (i)-(iv) are performed through an arthroscope. In some implementations, the method further comprises closing the surgical site.

[0021] The hole may be shaped such that the implant will be a press fit into the hole when secured. In some implementations, at least a portion of the conforming surface is offset from the natural tissue line in a direction distal to the bone. In some implementations, at least a portion of the conforming surface is offset from the natural tissue line in a direction proximal to the bone. In some implementations, the support zone is aligned laterally with the external cartilage tissue along a first perimeter such that the support zone abuts the external cartilage tissue. [Brief description of the drawings]

[0022] The above and other objects and advantages will become apparent from a consideration of the following detailed description when taken in conjunction with the accompanying drawings in which like reference characters refer to like parts throughout. [Figure 1A] 1 illustrates a longitudinal section of a three-layered biomimetic osteochondral graft according to an exemplary implementation. [Figure 1B] FIG. 1B shows an exploded view of the cross section of FIG. 1A. [Figure 1C] 1 shows a longitudinal section of a three-layered biomimetic osteochondral graft according to another exemplary implementation. [Figure 2A] 1 illustrates a two-layer biomimetic osteochondral graft (exterior view) according to an exemplary implementation. [Figure 2B] FIG. 2B is a cross-sectional view of the bilayered biomimetic osteochondral graft of FIG. 2A. [Figure 3A] 1 shows a three-layer biomimetic osteochondral graft (exterior view) according to an exemplary implementation. [Figure 3B] FIG. 3B is a cross-sectional view of the three-layered biomimetic osteochondral graft of FIG. 3A. [Figure 4A] 1 shows an exemplary implementation of a biomimetic osteochondral graft after insertion into an implantation site having a convex joint surface. In this implementation, the edges of the fitting surface are offset from the plane of the cartilage tissue, while the center of the graft extends outward from the plane of the natural joint such that the offset varies across the fitting surface. The dotted line represents the natural joint surface. [Figure 4B]FIG. 4B shows an exemplary implementation of a biomimetic osteochondral graft after insertion into an implantation site with a convex joint surface. In this implementation, the edges of the fitting surface are offset from the plane of the cartilage tissue while the center of the graft projects outward from the plane of the natural joint such that the offset varies across the fitting surface. The dotted line represents the natural joint surface. FIG. 4B shows the ideal curvature of the graft after loading, where the fit of the graft with the natural joint surface has been improved and now closely approximates the natural joint line (dotted line). [Figure 5A] 5A shows an exemplary implementation of a biomimetic osteochondral graft after insertion into an implantation site having a concave joint surface. FIG. 5A shows the biomimetic osteochondral graft after implantation and prior to physiological loading, in which the outer edge of the fitting surface is in or offset from the plane of the cartilage tissue while the center of the graft is thicker, creating a mismatch in fit with the opposing side of the joint. [Figure 5B] 5A and 5B show an exemplary implementation of a biomimetic osteochondral graft after insertion into an implantation site having a concave joint surface, and FIG. 5B shows the ideal curvature of the graft after loading, where the surface of the graft conforms to the line of the original joint, allowing the graft to articulate closely with the opposing joint surface. [Figure 6A] 6A-6C show a biomimetic osteochondral graft according to an exemplary implementation inserted into a surgical site: Fig. 6A shows the graft with a circular matching surface implanted onto a representative convex joint surface; [Figure 6B] 6A and 6B show a biomimetic osteochondral graft according to an exemplary implementation inserted into a surgical site, and FIG. 6B shows the graft with an elongated oval conforming surface grafted onto a representative convex joint surface. [Figure 7A] 1 illustrates an example implementation of an implant shape (or the shape of a portion of an implant, such as a smooth top surface) that can be selected based on the needs of different sizes of joints or injuries. [Figure 7B] 1 illustrates an example implementation of an implant shape (or the shape of a portion of an implant, such as a smooth top surface) that can be selected based on the needs of different sizes of joints or injuries. [Figure 7C]1 illustrates an example implementation of an implant shape (or the shape of a portion of an implant, such as a smooth top surface) that can be selected based on the needs of different sizes of joints or injuries. [Figure 7D] 1 illustrates an example implementation of an implant shape (or the shape of a portion of an implant, such as a smooth top surface) that can be selected based on the needs of different sizes of joints or injuries. [Figure 8A] 1 illustrates various connection mechanisms according to example implementations. The connection mechanisms may be used to connect layers of the implant to one another and may be used to connect the implant to bone. [Figure 8B] 1 illustrates various connection mechanisms according to example implementations. The connection mechanisms may be used to connect layers of the implant to one another and may be used to connect the implant to bone. [Figure 8C] 1 illustrates various connection mechanisms according to example implementations. The connection mechanisms may be used to connect layers of the implant to one another and may be used to connect the implant to bone. [Figure 8D] 1 illustrates various connection mechanisms according to example implementations. The connection mechanisms may be used to connect layers of the implant to one another and may be used to connect the implant to bone. [Figure 8E] 1 illustrates various connection mechanisms according to example implementations. The connection mechanisms may be used to connect layers of the implant to one another and may be used to connect the implant to bone. [Figure 8F] 1 illustrates various connection mechanisms according to example implementations. The connection mechanisms may be used to connect layers of the implant to one another and may be used to connect the implant to bone. [Figure 8G] 1 illustrates various connection mechanisms according to example implementations. The connection mechanisms may be used to connect layers of the implant to one another and may be used to connect the implant to bone. [Figure 8H] 1 illustrates various connection mechanisms according to example implementations. The connection mechanisms may be used to connect layers of the implant to one another and may be used to connect the implant to bone. [Figure 8I]1 illustrates various connection mechanisms according to example implementations. The connection mechanisms may be used to connect layers of the implant to one another and may be used to connect the implant to bone. [Figure 9A] 1 illustrates various surface geometries of a biomimetic osteochondral implant according to an exemplary implementation. [Figure 9B] 1 illustrates various surface geometries of a biomimetic osteochondral implant according to an exemplary implementation. [Figure 9C] 1 illustrates various surface geometries of a biomimetic osteochondral implant according to an exemplary implementation. [Figure 9D] 1 illustrates various surface geometries of a biomimetic osteochondral implant according to an exemplary implementation. [Figure 9E] 1 illustrates various surface geometries of a biomimetic osteochondral implant according to an exemplary implementation. [Figure 9F] 1 illustrates various surface geometries of a biomimetic osteochondral implant according to an exemplary implementation. [Figure 9G] 1 illustrates various surface geometries of a biomimetic osteochondral implant according to an exemplary implementation. [Figure 9H] 1 illustrates various surface geometries of a biomimetic osteochondral implant according to an exemplary implementation. [Figure 9I] 1 illustrates various surface geometries of a biomimetic osteochondral implant according to an exemplary implementation. [Figure 9J] 1 illustrates various surface geometries of a biomimetic osteochondral implant according to an exemplary implementation. [Figure 10] 1 shows a graph of peak contact pressure of various implants against a cartilage defect at the medial femoral condyle, where the native knee results are with no defect or implant in place, the tri-layer implant results are pressures after implantation with a tri-layer biomimetic osteochondral implant according to an exemplary implementation of the present disclosure, and the CoCr results are after implantation of an implant with a CoCr articular surface of the same shape as the tri-layer biomimetic osteochondral implant. [Figure 11A] 1 is a plot of the creep and relaxation behavior of a semi-IPN polymer. [Figure 11B] 1 is a plot of the creep and relaxation behavior of UDMA-MMA copolymers. [Figure 11C] 1 is a plot of creep and relaxation behavior of a composite of a semi-IPN polymer layer, a UDMA-MMA copolymer layer, and a porous titanium layer. [Figure 12] 1 illustrates a flowchart of a method for repairing damaged cartilage tissue at an articulating surface in an orthopedic joint, according to an example implementation. [Figure 13A] 1 illustrates a method of repairing damaged cartilage tissue at an articulating surface in an orthopedic joint, according to an exemplary implementation. [Figure 13B] 1 illustrates a method of repairing damaged cartilage tissue at an articulating surface in an orthopedic joint, according to an exemplary implementation. [Figure 13C] 1 illustrates a method of repairing damaged cartilage tissue at an articulating surface in an orthopedic joint, according to an exemplary implementation. [Figure 13D] 1 illustrates a method of repairing damaged cartilage tissue at an articulating surface in an orthopedic joint, according to an exemplary implementation. [Figure 14A] Photograph of a biomimetic osteochondral graft seated on the medial femoral condyle of a goat. [Figure 14B] 14B is a photograph of the biomimetic osteochondral graft of FIG. 14A with aluminum foil pressed onto the surface of the graft during surgery to outline the surface of the graft site. [Figure 14C] Photographs of explants showing overall implant compatibility with surrounding tissue. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] In order to provide an overall understanding of the systems, methods, and devices described herein, some exemplary embodiments are described. Although the embodiments and features described herein are specifically described for application in connection with repairing cartilage tissue damage, it should be understood that all components and other features outlined below may be combined with each other in any suitable manner and may be adapted and applied to other types of medical treatments, patient health conditions, and material configurations.

[0024] Certain terms are used herein to describe various aspects of the present disclosure. Some definitions are provided for ease of reference, while others are provided by use of the terms in context throughout the application. The scope of a term should be understood to include all species known to those of skill in the art, whether or not specifically recited.

[0025] As used herein, "carboxylic acid groups" can refer to both the non-ionized (protonated) and ionized (carboxylated) forms of these groups. For purposes of this application, "sulfonic acid groups" can refer to both the non-ionized (protonated) and ionized (sulfonated) forms of these groups.

[0026] As used herein, an "interpenetrating polymer network" or "IPN" is a material that includes two or more polymer networks that are at least partially entangled at the molecular level, but are not covalently bonded to each other and cannot be separated without breaking chemical bonds. A "semi-interpenetrating polymer network" or "semi-IPN" is a material that includes one or more polymer networks and one or more linear or branched polymers, characterized by the molecular-level penetration of at least one of the networks by at least some of the linear or branched polymers. Semi-interpenetrating polymer networks are distinguished from interpenetrating polymer networks because the constituent linear or branched polymers can, in principle, be separated from the constituent polymer networks without breaking chemical bonds, and they are polymer blends.

[0027] A "polymer" is a material having a single type of repeating unit, including homopolymers (polymers derived from one type of monomer) and copolymers (polymers derived from two or more types of monomers). A "hydrophobic polymer" can be a preformed polymer network that has at least one of the following two properties: (1) a surface water contact angle of at least 45°, and (2) a water absorption rate of 2.5% or less after 24 hours at room temperature according to ASTM test standard D570. A "hydrophilic polymer" can be a polymer network that has a surface water contact angle of less than 45° and a water absorption rate of more than 2.5% after 24 hours at room temperature according to ASTM test standard D570. An "ionic polymer" is a polymer that contains ionic monomers (e.g., monomers having carboxylate groups, sulfonic acid groups, or both), ionizable monomers (e.g., monomers having protonated carboxyl groups, protonated sulfonic acid groups, or both), or both ionic and ionizable monomers, regardless of their nature and arrangement, and generally consists of at least 2% by weight of ionic or ionizable monomers (or both). A "thermoplastic polymer" is one that melts or flows when heated and can be repeatedly remelted to form other shapes or products, unlike a thermoset polymer, which can be heated and formed only once. Thermoplastic polymers may be covalently (chemically) crosslinked. "Phase separation" is defined as the conversion of a single-phase system to a multiphase system. For example, the separation of two immiscible blocks of a block copolymer into two phases, where there may be a small interphase that allows some intermixing.

[0028] "About" may be understood to mean plus or minus 20% of a value, for example "about 20 mm" would encompass the range from 16 mm to 24 mm.

[0029] Aspects of the present disclosure include biomimetic osteochondral grafts, kits, or systems comprising the grafts and one or more tools for implanting the grafts, and methods of manufacturing and implanting the grafts. Biomimetic osteochondral grafts

[0030] Provided herein are biomimetic osteochondral grafts that are generally useful for replacing damaged cartilage tissue and / or partially or completely regenerating cartilage tissue in joints. The grafts are configured to have a modular layered structure, where the physical properties (e.g., stiffness and lubricity) and dimensions of each layer can be tailored (e.g., by using appropriate materials and controlling their thickness and stiffness) based on the anatomical structure to be replaced or repaired. For example, the material and / or thickness of the layers can be selected to approximate the physical properties, function, and dimensions of cartilage tissue (and, optionally, cartilage and subchondral bone) such that the graft mimics cartilage tissue. Also provided herein are methods of treatment involving the use of biomimetic osteochondral grafts to repair osteochondral defects in joints.

[0031] The biomimetic osteochondral grafts herein can be made in a variety of shapes and sizes depending on the particular joint in which the graft is to be placed. The grafts may be adapted to repair or replace cartilage tissue, or cartilage tissue and bone, within a joint in the body, such as a knee joint (e.g., condyles, patellofemoral joint, total knee joint, meniscus, patella, or tibial plateau), ankle joint (e.g., talus surface or tibial surface), elbow joint (e.g., proximal ulna, distal humerus, or radial head), shoulder joint (e.g., labrum, glenoid cavity, humeral head, or any portion thereof), wrist joint (e.g., metacarpal joint, knuckle, thumb joint, or base of thumb), hip joint (e.g., acetabular surface, femoral head, or part of either surface), foot joint (e.g., metatarsal joint or toe joint), temporomandibular joint (e.g., temporomandibular joint), wrist joint, or spinal joint (e.g., facet joint). In some applications, the implants described herein can be placed by integration into an existing joint replacement component, such as a metal or polymer femoral head that may have been installed in a previous hip joint repair. In such cases, an existing metal or polymer implant (e.g., a femoral head joined to a femoral stem by itself) that has already been connected to a bone (e.g., a proximal femur) in a previous operation serves as a base zone, and an implant (as disclosed herein) having a support zone and an intermediate zone is directly connected to the existing metal or polymer base zone. In some implementations, the base zone is configured as a metal or polymer with a preformed connection mechanism (e.g., a screw, a peg, a finger, or other component) at one end (e.g., a distal femur or a proximal femur) and configured to mechanically connect to the bone, for example, by screwing, pegging, interdigitation, or another method. One or more surfaces of the base zone and intermediate zone can also be provided with a plasma coating or other porous layer. The base region may be suitably configured as a sphere, disk, cylinder, or other shape suitable for providing adequate fixation to the base (eg, bone), such as a triangle or quadrilateral.Although the examples provided herein describe the use of the implant in the repair of diarthrodial joints, it should be understood that the implant can also be used for the repair of other tissues and joints, including, but not limited to, the spine, meniscus, and other bone or cartilage tissue structures. The implant can articulate against native tissue or against other implants, such as implants according to the present disclosure, ceramic implants, metal (such as CoCr) implants, or polymeric implants, such as PEEK or ultra-high molecular weight polyethylene (UHMWPE) implants. For example, a joint defect can be repaired by implanting two biomimetic osteochondral implants on opposing sides of the joint. One or both of the opposing sides can be replaced in their entirety. Pictorial representations of example implants are shown in Figures 1-5.

[0032] In some implementations, the biomimetic osteochondral graft or a portion thereof (such as the smooth top surface of FIG. 6A) exhibits a circular profile. In some implementations, the biomimetic osteochondral graft or a portion thereof (such as the smooth top surface of FIG. 6B) exhibits, for example, an elongated oval profile. Other non-limiting examples of shapes that the biomimetic osteochondral graft (or a portion thereof) may have are shown in FIGS. 7A-7D and 9A-9J.

[0033] In some implementations, the biomimetic osteochondral graft is shaped as a plug (e.g., a cylindrical plug) for partial reconstruction of the articular surface. In some implementations, the biomimetic osteochondral graft comprises a stem portion formed on or connected to the bone-contacting surface of the graft (i.e., the bottom surface of the base) adapted for insertion into a hole or opening in the bone. In some implementations, the stem is press-fit into the hole or opening in the bone, exposing a smooth upper surface of the graft to function as an artificial cartilage tissue.

[0034] In some implementations, the biomimetic osteochondral graft is axially symmetrical or symmetrical along one or more vertical planes. For example, the graft can be cylindrical with a hemispherical shape on the outer surface with a single radius of curvature. Alternatively, it can have two or more radii of curvature. For example, the graft can have a radius of curvature in one plane and a larger radius of curvature in a perpendicular plane, making it more "tilted" in one direction and less tiling in the perpendicular plane. In a natural articular surface, such as the condyles of the knee, there may be two major planes of curvature, one along the flexion / extension axis of the knee (referred to herein as the "long radius") and the other perpendicular to this plane and with a smaller radius of curvature (referred to herein as the "short radius"). There may be three or more radii of curvature. These radii of curvature can also vary depending on the exact location of the articular surface. For example, the graft can be placed in an osteochondral defect that approximates the curvature of the surrounding articular surface. Over time within the joint, the conforming surface reshapes under physiological loads such that the smooth upper surface assumes the radius of curvature of the surrounding articular surface (FIGS. 4A, 4B, 5A, and 5B). The biomimetic osteochondral grafts herein can conform to any joint shape, including generally convex articular surfaces, generally concave articular surfaces, generally flat articular surfaces, or articular surfaces with both convex and concave curvatures. Thus, the graft can, for example, start out convex and become more convex, flat, or concave, start flat and become concave or convex, or start concave and become even more concave (more steeply curved), depending on the shape of the surrounding articular surface.

[0035] In some implementations, an axisymmetric graft having a single radius of curvature is inserted into an implantation site where the native cartilage has a different radius of curvature than the graft. After implantation, the conforming surface of the graft reshapes under physiological loads, and the radius of curvature of the graft substantially matches that of the native cartilage, providing a smooth continuity of curvature in the repaired joint over and around the graft.

[0036] In some implementations, an axisymmetric graft having a single radius of curvature is inserted into an implantation site where the native cartilage has two different radii of curvature than the graft. After implantation, the conforming surface of the graft reshapes under physiological loads, outlining two radii of curvature that match those of the native cartilage, providing a smooth continuity of curvature in the repaired joint over and around the graft.

[0037] In some implementations, a graft having two different (e.g., perpendicular) radii of curvature is inserted into an implantation site where the native cartilage has two different radii of curvature than the graft. After implantation, the conforming surface of the graft reshapes under physiological loads, outlining two radii of curvature that match those of the native cartilage, providing a smooth continuity of curvature in the repaired joint over and around the graft.

[0038] FIG. 1A shows a longitudinal section of a three-layered biomimetic osteochondral graft 100 according to an illustrative example. The graft 100 includes a support region 102, an intermediate region 106, and a base region 112. Each of the support region 102, intermediate region 106, and base region 112 has distinct physical / mechanical properties. Each of the support region 102, intermediate region 106, and base region 112 has multiple surfaces that can form distinct interfaces and / or edges between the regions. For example, the support region 102, intermediate region 106, and base region 112 can be separately compounded such that they can be joined together at one or more surfaces (as described below) using one or more of the connection techniques described herein. The support region 102 has a conforming surface 104, a lower surface 105 opposite the conforming surface 104, a first thickness 103 extending between the conforming surface 104 and the lower surface 105, and a first compressibility with a first stiffness. The intermediate region 106 has a shaped first side 108, a second side 109 opposite the first side 108, a second thickness 107 extending between the first side 108 and the second side 109, and a second compressibility having a second stiffness greater than the first stiffness. The shaped first side 108 includes a perimeter 110 and an exterior surface 111 spaced apart within the perimeter 110. The exterior surface 111 and the lower surface 105 are coupled (e.g., mechanically connected, chemically bonded, biologically bonded, or otherwise linked). In some implementations, the support region 102 and the intermediate region 106 do not form a single polymer network, but are joined together at their edges via non-covalent, covalent, and / or mechanical bonds of the distinct materials that comprise the support region 102 and the intermediate region 106. Non-covalent bonds include hydrogen bonds, ionic interactions, van der Waals interactions, and / or hydrophobic bonds. In some implementations, the support region 102 and the intermediate region 106 are joined via polymer entanglement, such as entanglement of poly(methyl methacrylate) (PMMA) and / or polyurethane present in the intermediate region 106 with a polymer (e.g., polyurethane) present in the support region 102.In some implementations, the exterior surface 111 and the underside 105 are connected such that when the support area 102 and the intermediate area 106 each include one polymer network, the two polymer networks in the support area 102 and the intermediate area 106, respectively, do not form a (continuous) interpenetrating polymer network.

[0039] The support region 102 can be coupled to the intermediate region 106 via chemical, mechanical, or physical means (e.g., those of Figures 8A-8H). As shown, the lower surface 105 conforms to the outer surface 111. In some implementations, the lower surface 105 and the molded first surface 108, or portions thereof, are coupled such that loads can be transferred from the lower surface 105 to the molded first surface 108 via chemical or mechanical coupling means. The intermediate region 106 can be or include a liquid, such as a curable liquid and / or a thermoplastic material, and can be formed by machining, casting, and / or injection molding. In some implementations, the intermediate region 106 is a photocurable polymer. In some implementations, the outer surface 111 is a liquid surface upon implantation. In some implementations, the lower surface 105 of the support region 102 is or includes a polyurethane. In some implementations, the intermediate region 106 is or includes a polyurethane. In some implementations, the support region 102 includes a polyurethane on the lower surface 105, which forms a polymer network with the polyurethane of the intermediate region 106. The base region 112 has an outer base surface 114 coupled to the second surface 109, an inner base surface 115 opposite the outer base surface 114 and configured to couple to the bone 116, a third thickness 113 extending between the outer base surface 114 and the inner base surface 115, and a third compressibility having a third stiffness greater than the second stiffness. In some implementations, the intermediate region 106 and the base region 112 do not form a single polymer network. In some implementations, the outer base surface 114 and the second surface 109 are coupled such that when the intermediate region 106 and the base region 112 each include a single polymer network, the two polymer networks of the intermediate region 106 and the base region 112 do not intertwine at a molecular level (at least when implanted). As shown, the second surface 109 conforms to the outer base surface 114 .In some implementations, the second surface 109 and the outer base surface 114, or a portion of the second surface 109 and the outer base surface 114, are coupled via chemical or mechanical coupling means such that loads can be transferred from the second surface 109 to the outer base surface 114. The intermediate region 106 and the base region 112 are joined together at their edges via chemical, mechanical, or (other) physical means (e.g., those of Figures 8A-8H). In some implementations, the edges between the intermediate region 106 and the base region 112 include interdigitation of the material of the intermediate region 106 (e.g., a polymer) with the material of the base region 112 (e.g., a metal such as a porous metal). Figure 1B shows an exploded view of the layers of the implant 100. Although the surfaces of the implant are shown as having a convex shape, with a certain shape curving or bulging outward, it should be understood that any of the surfaces may be flat, concave (with an inwardly bulging shape, as shown in the alternative form of implant 100 in FIG. 1C), or any combination of flat, convex, or concave surface areas. It is understood that any of the convex and concave surfaces as shown in FIGs. 1A and 1B, or elsewhere herein, may be asymmetric or symmetric.

[0040] A variety of materials can be used to construct each layer of the implant 100. Suitable materials include polymers, ceramics, metals, synthetic bone, regenerated tissue, or other suitable materials, or combinations thereof. In particular, suitable materials for the support region 102 include materials that have a smooth nature. For example, the support region 102 is constructed from a material that provides a smooth conforming surface 104 and a non-smooth underside surface 105.

[0041] In some implementations, one of the layers, such as the support area 102, includes a two-phase polymer comprising a polymer and water. For example, the two-phase polymer can have a water composition of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60%. The two-phase polymer can have a water composition that is consistently distributed throughout the support area 102, or the water can be distributed within the support area, for example, in a gradient that extends from one side to the other, or in a gradient that extends only partially within the support area. The water composition gradient is configured such that the water composition changes along the thickness of the area from its exterior conforming surface (conforming surface 104) at one end to its interior lower surface 105, with a bulk region in between, to provide proper connection between the hydrophobic intermediate layer (intermediate area 106) and the hydrophilic articulating surface (conforming surface 104). More specifically, the gradient comprises a first water composition at the conforming surface 104, a second water composition at the lower surface 105, and a bulk water composition extending between the two surfaces. In some implementations, for example those useful for repairing diarthrodial joints, the water is distributed in the support area 102 such that the water composition is highest at the conforming surface 104 and lowest (e.g., at or near zero) at the lower surface 105, providing an essentially hydrophobic non-smooth interface with the intermediate layer (intermediate area 106) of the construct, with the bulk water distributed at a composition between the respective water compositions of the two surfaces. The arrangement provides one side of the support area 102 with a smooth interface for articulation, and the other side with a hydrophobic non-smooth connection surface to the intermediate layer (intermediate area 106). The water composition at the conforming surface can be adjusted as needed in combination with adjustments of the remaining gradients. For example, the water gradient can extend between the conforming surface 104 and the lower surface 105. The water gradient can range from less than 1% at one site of the two-phase polymer to at least 20%, at least 30%, or at least 40% at another site of the two-phase polymer.For example, the gradient can have a water composition that is less than 1% on the hydrophobic side (e.g., on the lower surface 105, which may be located just proximal to the interface with the intermediate region 106 in a distal femoral implant) and at least 20%, at least 30%, at least 40%, or at least 50% on the opposing, more hydrophilic side (e.g., on the conforming surface 104, which is the articulating surface of the support region 102 in a distal femoral implant). In some implementations, the water composition on the conforming surface 104 is at least 25% and can be higher (e.g., 40%-50%, e.g., 40%, 45%, or 50%, or even 60%-80%), resulting in a lubricious character, while the water composition on the lower surface 105 is lower (e.g., less than 10%, less than 5%, or less than 1% (or approaching or being 0)), resulting in a non-lubricious character. In the bulk region, the bulk water composition is distributed at operating conditions that provides an optimal water balance and transition between the hydrophilic conforming surface 104 and the hydrophobic undersurface 105. In some implementations, the bulk water composition is within a range of 25%-41% (e.g., 27%-34%) and may be distributed as a gradient between that range to provide a smooth transition between the conforming surface 104 and the undersurface 105, or may be distributed at a generally constant level between the two surfaces, for example at some point within that range (e.g., 27% or 34%).

[0042] The two-phase polymer can be a water-swellable interpenetrating polymer network (IPN) or semi-IPN including a first polymer network of a thermoplastic polymer and a second polymer network of a polymer having carboxylic acid groups or derivatives thereof, the IPN or semi-IPN having a maximum concentration of carboxylic acid groups or derivatives thereof at the conforming surface 104 and decreasing to zero or substantially zero in the bulk of the IPN or semi-IPN. The carboxylic acid groups or derivatives thereof can include underivatized carboxylic acid groups, sulfonic acid derivatized carboxylic acid groups, or mixtures thereof. For example, the polymer having carboxylic acid groups or derivatives thereof is formed from one or more monomers selected from acrylic acid, methacrylic acid, crotonic acid, linoleic acid, maleic acid, fumaric acid, and derivatives thereof. The carboxylic acid groups can be fully underivatized or can include sulfonic acid derivatized carboxylic acid groups (a mixture of underivatized and derivatized groups, or fully derivatized groups). The sulfonic acid derivatized carboxylic acid groups can be taurine derivatized carboxylic acid groups. In some implementations, the thermoplastic polymer is not water-based, but is functionally conformable to the articular geometry and sufficiently biocompatible to be used in place of two-phase polymers, e.g., polyurethanes such as polyether urethanes and other forms of polyurethanes, in the support areas of the construct.

[0043] In some implementations, a layer such as the intermediate region 106 includes a urethane or urethane-based material. In some implementations, the urethane-based material is a copolymer of urethane dimethacrylate monomers with hard and soft segments and methyl methacrylate monomers. For example, the intermediate region 106 can be formed from a copolymer of about 60% (w / w) to about 99% (w / w) (e.g., about 60% (w / w) to about 80% (w / w)) urethane dimethacrylate monomers and about 1% (w / w) to about 40% (w / w) (20% (w / w) to about 40% (w / w)) methyl methacrylate monomers. In some implementations, the hard segment of the urethane dimethacrylate of the first polymer adhesive is formed from one or more of 1,5-naphthalene diisocyanate (NDI), 2,6-toluene diisocyanate or 2,4-toluene diisocyanate (TDI), 3,3-bitoluene diisocyanate (TODI), cyclohexyl diisocyanate (CHDI), hexamethyl diisocyanate (HDI), isophorone diisocyanate (IPDI), methylene bis(p-phenyl)isocyanate, methylene diphenyl isocyanate (MDI), and methylene bis(p-cyclohexyl isocyanate) (HMDI). In some implementations, the soft segment of the urethane dimethacrylate monomer is formed from one or more of polybutadiene, polyethylene oxide (PEO), hydroxy-terminated butadiene, hydroxybutyl-terminated polydimethylsiloxane (PDMS), hydroxyl-terminated polyisobutylene, poly(1,6-hexyl-1,2-ethyl carbonate), polycaprolactone, polycarbonate, polyethylene adipate, polyhexamethylene carbonate glycol, polypropylene oxide (PPO), polytetramethylene adipate, poly(dimethylsiloxane), and poly(tetramethylene oxide) (PTMO). For example, the hard segment of the urethane dimethacrylate monomer may be formed from MDI and the soft segment of the urethane dimethacrylate can be formed from PTMO.In some implementations, the urethane dimethacrylate soft segment of the polymer adhesive layer can be formed from a mixture of PTMOs having different molecular weights, for example, ranging from about 500 Da to about 1250 Da.

[0044] In some implementations, layers such as the base region 112 of the implant 100 include metals (e.g., titanium, tantalum, stainless steel, cobalt chrome, nickel titanium, zirconium, or alloys thereof), polymers (e.g., PEEK, PE, PS, or PP), ceramics, bone, or synthetic bone, or combinations thereof. The base region 112 can be coupled to the bone 116 via mechanical or physical means (e.g., those of Figures 8A-8H) immediately after implantation. At some time after implantation, new bone can already grow from the bone 116 into the base region 112, securing the implant 100 in place.

[0045] The exterior surface 111 of the shaped first surface 108 has one shape (i.e., topography or surface contour) and the underside surface 105 conforms to that shape of the exterior surface 111. The conforming shape of the underside surface 105 may then be transformed through the support area 102 into the conforming shape of the conforming surface 104 such that the conforming surface 104 also reflects the shape of the exterior surface 111. Thus, the exterior surface 111 may be shaped in a specific manner (e.g., convex as shown in Figures 1A and 1B, concave as shown in Figure 1C, or any of the shapes shown in Figures 9A-9J) to impart to the conforming surface 104 a shape that approximates the surface shape of the natural cartilage tissue at the site where the implant 100 is inserted. The shape of the conforming surface 104 may be offset from the surface of the surrounding natural cartilage tissue at the site such that physiological loads imposed on the implant 100 through the conforming surface 104 cause the conforming surface 104 to approximate the surface shape of the natural cartilage tissue. In some implementations, a contact interface is formed between the exterior surface 111 and the underside 105. In some implementations, the intermediate region 106 is or includes an adhesive. In some implementations, the intermediate region 106 is or includes an injectable adhesive. The injectable adhesive can be light curable. In some implementations, there is no chemical bonding or polymer entanglement at the contact interface between the exterior base surface 114 and the second surface 109 unless provided by an intermediate adhesive or other bonding layer between the base surface 114 and the second surface 109. The contact interface between the exterior surface 111 and the underside 105 can extend over at least 50%, at least 75%, at least 90%, at least 95%, or 100% of the exterior surface 111 or the underside 105. The contact interface between the exterior base surface 114 and the second surface 109 can extend over at least 50%, at least 75%, at least 90%, at least 95%, or 100% of the exterior base surface 114 and the second surface 109.

[0046] A variety of connection mechanisms (e.g., mechanical, chemical, or biological) can be used to connect each of the support region 102, intermediate region 106, and base region 112 to one another or to the surrounding native cartilage tissue or bone (e.g., bone 116 below the base region 112). Any of the connection mechanisms described and illustrated with respect to Figures 8A-8H can be used with the implant 100. Suitable connections include stake structures (e.g., a single stake or multiple stakes on the molded first side 108 or second side 109 of the intermediate region 106), spikes, hooks, screws, adhesives, chemical cements, sutures, barbs, plugs, or other forms of interdigitation or mechanisms known to those skilled in the art. The connection mechanisms can be integrally formed in any of the sections of the implant 100 or can include separate materials.

[0047] Any of the first thickness 103, second thickness 107, or third thickness 113 can have a height of 1 mm to 10 mm, 1 mm to 9 mm, 1 mm to 8 mm, 1 mm to 7 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, 1 mm to 2 mm, about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, or about 10 mm.

[0048] The implant 100 and each layer can have a particular shape. For example, the shape of the implant 100 or a section can be created during manufacturing or can result from conforming to the shape of an adjacent section or native tissue / bone. In some implementations, the implant 100 includes a central axis that extends through the support region 102, the intermediate region 106, and the base region 112, and the support region 102, the intermediate region 106, and the base region 112 each have an axis and are coaxially aligned along the central axis.

[0049] In some implementations, the second thickness 107 is variable by a first height extending between the second surface 109 and the first surface 108 at a first location along the first surface 108, and a second height extending between the second surface 109 and the first surface 108 at a second location along the first surface 108. The first height can be greatest at a location along the perimeter 110, and the second height is greatest at a location within the exterior surface 111. For example, the second height, which is greatest at a location within the exterior surface 111, can be coaxially aligned with the axis of the support region 102, the axis of the intermediate region 106, or the axis of the base region 112. As discussed above, the exterior surface 111 can be convex or concave, while the second surface 109 can be flat, such that the intermediate region 106 is plano-convex (e.g., as shown in FIGS. 3B, 4A, and 4B) or plano-concave (e.g., as shown in FIGS. 6A and 6B), respectively. There may be a tapered region extending along the exterior surface 111 from the maximum second height toward the periphery 110. The maximum first height may be greater than the maximum second height such that the tapered region forms a concave contour / curve. Alternatively, the maximum first height is less than the maximum second height such that the tapered region forms a convex contour / curve. The exterior surface 111 may include a ridge region extending radially across the exterior surface 111. Multiple ridges may protrude into the lower surface 105. In some implementations, the exterior surface 111 includes multiple regions each having a different radius of curvature. For example, the regions may include a combination of two or more of flat, concave, convex, angled, raised, or pointed surfaces.

[0050] The implant 100 and periphery 110 can have a variety of shapes. The shape may be selected to surround or encase a damaged area of ​​cartilage tissue in an articular area, such as a diarthrodial joint. Suitable shapes for the implant 100 and periphery 110 are shown in Figures 7A-7D and 9A-9J. However, other shapes may be used as needed to accommodate the size and shape of a given injury or area to be repaired using the implant 100. The periphery 110 can include a curvilinear edge that extends circumferentially around a central axis of the implant 100.

[0051] The implant 100 may also be of various sizes, and individual regions may vary in size accordingly according to different implementations. For example, the first thickness 103, the second thickness 107, or the third thickness 113 may each have a height of one or more of between 0.01 mm and 25 mm, between 1 mm and 20 mm, between 5 mm and 15 mm, between 3 mm and 4.5 mm, between 5 mm and 10 mm, about 1 mm, about 5 mm, about 10 mm, or about 15 mm. As explained above, the second thickness 107 or other thicknesses may also vary in height. The first thickness 103, the second thickness 107, or the third thickness 113 may each have a border height of between 0.01 mm and 10 mm at a location along the perimeter 110. The border height may be 0.1 mm to 5 mm, 0.2 mm to 5 mm, 1 mm to 5 mm, about 1 mm, about 2 mm, about 3 mm, about 4 mm, or about 5 mm. In some implementations, the first height is about 1 mm. In some implementations, the first thickness 103, the second thickness 107, or the third thickness 113 tapers toward the outer periphery 110 such that the border height is less than 0.1 mm, but the implant 100 has a thickness located within the border away from the outer periphery that is even higher than the border height, for example, between 2 and 10 times higher than the border height. Alternatively, the thickness can taper inward such that the border height is higher than the height of the interior thickness within the border. The support region 102 and the intermediate region 106 can extend axially from the outer base surface 114 to the conforming surface 104 over an axial length of 1 mm to 10 mm, 2 mm to 8 mm, 4 mm to 6 mm, or about 5 mm. The width of the implant 100 (or the area that its periphery 110 can encompass) can be between 5 mm and 25 mm, between 5 mm and 15 mm, or about 10 mm, and the implant 100 can be aligned perpendicular to and across the central axis.

[0052] As discussed above, the stiffness of the intermediate zone 106 is greater than that of the support zone 102, and the stiffness of the base zone 112 is greater than that of the intermediate zone, thereby providing an increasing stiffness gradient from the support zone to the base zone similar to that found in normal cartilage and osteochondral units. The change in stiffness between the zones can be quite high (e.g., stiffness can vary from 20% to 2,000% or more). In some implementations, the stiffness of the support zone is between 40 MPa and 150 MPa. In some implementations, the stiffness of the intermediate zone is between 50 MPa and 500 MPa, while in some implementations, the stiffness of the base zone is between 1.5 GPa and 11 GPa. In some implementations, the stiffness of the intermediate region is at least 1x-20x, 1x-15x, 1x-10x, 1x-5x, 5x-10x, 10x-15x, 15x-20x, about 1.25x, about 2x, about 5x, about 10x, about 15x, or about 20x the stiffness of the support region. In some implementations, the stiffness of the base region is at least 3x-25x, 5x-20x, 5x-15x, 5x-10x, 10x-15x, 15x-20x, 20x-25x, about 3x, about 5x, about 10x, about 15x, about 20x, or about 25x the second stiffness. Any of the first stiffness, second stiffness, and third stiffness can have a stiffness gradient extending through the first stiffness, second stiffness, and third stiffness. For example, the support zone 102 can have a stiffness gradient of 1 kPa / mm or more extending from the lower surface 103 to the conforming surface 104. The stiffness gradient can be less than or equal to 0.1 kPa / mm, 1 kPa / mm, 5 kPa / mm, or 10 kPa / mm, or more. A high relative difference in stiffness between the zones can lead to poor distribution of physiological loads as they are applied by the opposing articular surfaces to the implant 100 (see FIG. 10), increasing the risk of damage to the implant 100 or the surrounding native tissue. By creating a more gradual stiffness gradient across the layers, and one that matches the surrounding tissue, loads can be better distributed throughout the implant 100, interfacing with the native tissue to create a smooth transition between the implant and the surrounding tissue, and can distribute forces laterally within the implant to stabilize the axial structure of the implant.In a particular implementation, the support region 102 has an average stiffness of about 100 MPa, the intermediate region 106 has an average stiffness of about 250 MPa, and the base region 112 has an average stiffness of about 5 GPa.

[0053] The implant 100 is suitable for repairing cartilage tissue at various sites within the body, such as articular cartilage tissue within diarthrodial joints (e.g., knee, hip, ankle, toe, thumb, wrist, elbow, shoulder). Suitable sites include the distal femur, proximal tibia, patella, distal tibia, distal fibula, calcaneus, talus, tibiofibular joint, proximal humerus, glenoid cavity, proximal femur, pelvis, distal humerus, proximal ulna, proximal radius, distal radius, distal ulna, carpal bones, distal metacarpal bones, proximal phalanges, and other cartilage tissues known to those skilled in the art. Other articulating joint surfaces that can be repaired with the techniques disclosed herein include the spinal disc (nucleus pulposus), spinal facets, and meniscus of the knee. The implant 100 is suitable for implantation into humans as well as other organisms that have cartilage tissue, particularly articular cartilage tissue.

[0054] The implant 100 can be designed to deform a certain amount under physiological load by adjusting the compressibility of any or all of the regions. For example, the support region 102 can be configured to have the ability to deform between 2% and 25% under physiological load and repeatedly recover more than 70% of the deformation upon removal of the load. The intermediate region 106 may be configured to deform between 2% and 10% under physiological load and repeatedly recover 70% or more of the deformation upon removal of the physiological load. When the support layer and intermediate layer are coupled, the implant 100 can have the ability to deform between 5% and 20% under physiological load and repeatedly recover 80% or more. In some implementations, the repeatable recovery is 95% or more. For the knee specifically, the standard maximum physiological loads through the knee joint are 2-4 times body weight during walking (e.g., 3.1 BW), 4-6 times body weight during jogging (e.g., 5.5 BW), 2-5 times body weight during sit-stand-sit, 4-6 times body weight during stair climbing, and 7-12 times body weight during running. See, for example, Bergmann G, Bender A, Graichen F, et al. Standardized loads acting in knee implants. PLoS One. 2014;9(1) (doi:10.1371 / journal.pone.0086035) and the Standard Guide for Total Knee Replacement Loading Profiles (ASTM F3141-17a Standard Guide for Total Knee Replacement Loading Profiles). Thus, when implanted in a knee joint, the implant 100 undergoes the above-described deformations under these maximum physiological loads on the knee joint.

[0055] The implant can be axially symmetrical or symmetrical along one or more vertical planes. For example, the implant can be cylindrical with a hemispherical shape on the outer surface with a single radius of curvature. Alternatively, it can have two or more radii of curvature. In some implementations, the implant can have a radius of curvature in one plane and a larger radius of curvature in a perpendicular plane, making it more "tilted" in one direction and less tiling in the perpendicular plane. In a natural articular surface, such as the condyles of the knee, there can be two major planes of curvature: one along the flexion / extension axis of the knee (referred to as the "long radius") and the other perpendicular to this plane and with a smaller radius of curvature (referred to as the "short radius"). These radii of curvature can also vary depending on the exact location of the articular surface. For example, the implant can be placed in an osteochondral defect that approximates the curvature of the surrounding articular surface. Over time within the joint, the conforming surface or support area reshapes under physiological loads. For example, the conforming surface or support area reshapes so that the smooth upper surface assumes the radius of curvature of the surrounding articular surface (FIGS. 4A / 4B and 5A / 5B). The biomimetic osteochondral graft of the present disclosure can conform to any joint shape, including a generally convex articular surface, a generally concave articular surface, a generally flat articular surface, or an articular surface with both convex and concave curvatures. Thus, the graft can, for example, start convex and become more convex, flat, or concave, or start flat and become concave or convex, or start concave and become even more concave (more steeply curved), depending on the shape of the surrounding articular surface. By any method, the graft can be designed such that the contour of the graft surface matches the contour of the native surface when physiological loads are applied.

[0056] An axisymmetric graft having a single radius of curvature can be inserted into an implantation site where the native cartilage has a different radius of curvature than the graft. After implantation, the conforming surface or support area of ​​the graft will assume a new shape under physiological loads, with the radius of curvature of the graft substantially matching that of the native cartilage, providing a smooth continuity of curvature in the repaired joint in all directions over and around the graft.

[0057] In some implementations, an axisymmetric graft having a single radius of curvature is inserted into an implantation site where the native cartilage has two different radii of curvature than the graft. After implantation, the conforming surface or support area of ​​the graft reshapes under physiological loads, exhibiting contours of two radii of curvature that match those of the native cartilage, providing a smooth continuity of curvature in the repaired joint over and around the graft.

[0058] In some implementations, a graft having two different, perpendicular radii of curvature is inserted into an implantation site where the native cartilage has two different radii of curvature than the graft. After implantation, the conforming surface or support area of ​​the graft reshapes under physiological loads, outlining the two radii of curvature that match those of the native cartilage, providing a smooth continuity of curvature in the repaired joint over and around the graft.

[0059] Although shown in Figures 1A-1C have three sections, it should be understood that the multi-layered grafts provided herein may have fewer or more than three layers. Figure 2A shows a bi-layered biomimetic osteochondral graft 200 (exterior view) according to an exemplary implementation of the graft 100 described above, and Figure 2B shows a cross-sectional view of the bi-layered biomimetic osteochondral graft 200 of Figure 2A. The graft 200 includes a support region 202 and a base region 206. The support region 202 has a first thickness 203, a conforming surface 204, and a lower surface 205. The base region 206 has a second thickness 207, an outer base surface 208, and an inner base surface 209. 2A and 2B show the conforming surface 204, underside surface 205, and outer base surface 208 as convex, giving the implant 200 an overall plano-convex shape, it should be understood that the implant 200 can also be formed with concave or flat surfaces, such that the implant 200 is plano-concave or planar, respectively. Each of the areas and surfaces of the implant 200 can have any of the elements or characteristics of the areas and surfaces of the implant 100 described above. Although the implant 200 appears to have a cylindrical or elliptical cylindrical shape, it should be understood that the implant 200 can have other shapes, including, but not limited to, any of the shapes shown in FIGS. 7A-7D and 9A-9J.

[0060] FIG. 3A shows a three-layered biomimetic osteochondral graft 300 (exterior view) according to an exemplary implementation of the graft 100 described above, and FIG. 3B shows a cross-sectional view of the graft 300. The graft 300 includes a support region 302, an intermediate region 306, and a base region 312. The support region 302 has a first thickness 303, a conforming surface 304 configured to couple with an opposing articular surface, and an underside 305. The intermediate region 306 has a second thickness 307, a shaped first surface 308 connected to the underside 305, and a second surface 309. The base region 312 has a third thickness 313, an outer base surface 314 connected to the second surface 309, and an inner base surface 315 configured to couple with bone. The underside 305 mates with a molded first surface 308 having a convex shape such that the support area 302 and the conforming surface 304 have a convex shape. Although Figures 3A and 3B show the conforming surface 304, underside 305, and molded first surface 308 as convex shapes, giving the implant 300 an overall plano-convex shape, it should be understood that the implant 300 can also be formed with concave or flat surfaces, respectively, such that the implant 300 is plano-concave or planar. Each of the areas and surfaces of the implant 300 can have any of the elements or characteristics of the areas and surfaces of the implant 100 described above. Although the implant 300 appears to have a cylindrical or elliptical cylindrical shape, it should be understood that the implant 300 can have other shapes, including, but not limited to, any of the shapes shown in Figures 7A-7D and 9A-9J.

[0061] 4A and 4B show a three-layered biomimetic osteochondral graft 400 according to an exemplary implementation of the graft 100 described above, implanted in an osteochondral site consisting of native tissue 418 (e.g., articular cartilage tissue) and bone 416. The graft 400 includes a support region 402, an intermediate region 406, and a base region 412. The support region 402 has a first thickness 403, a conforming surface 404, and a lower surface 405. The intermediate region 406 has a second thickness 407, a shaped first surface 408, and a second surface 409. The base region 412 has a third thickness 413, an outer base surface 414, and an inner base surface 415 fixed to the bone 416. The native tissue 418 has a native tissue surface line 419 represented by a dashed line in FIGS. 4A and 4B. Each of the areas and surfaces of implant 400 can have any of the elements or features of the areas and surfaces of implant 100 described above. Although implant 400 appears to be shown in two dimensions, it should be understood that implant 400 can have any of a variety of three-dimensional shapes, including, but not limited to, any of the shapes shown in Figures 7A-7D and 9A-9J.

[0062] 4A shows the implant 400, after it has been implanted and secured to the bone 416, offset from the natural tissue plane line 419. At the edges of the implant 400, the conforming surface 404 is below the natural tissue plane line 419, and at the center of the implant 400, the conforming surface 404 extends above the natural tissue plane line 419. This offset creates a conforming mismatch with the natural tissue 418 when articulated with the opposing joint surface.

[0063] This mismatch strategically allows the implant 400 to approximate the natural tissue plane 419 during and after physiological loading. In this manner, the implant 400 articulates intimately with the opposing articular surface in a continuous manner with the surrounding native tissue 418, providing an advantageous mimicking effect that minimizes long-term damage to the implant 400 or the surrounding native tissue 418. Figure 4B shows the ideal curvature of the implant after loading, where the implant 400's improved fit with the natural articular surface now closely approximates the natural tissue plane 419.

[0064] 5A and 5B show how the same effect can be achieved using a concave biomimetic osteochondral graft 500 according to the exemplary implementation of the graft 100 described above. The graft 500 includes a support area 502, an intermediate area 506, and a base area 512. The support area 502 has a thickness 503, a conforming surface 504, and a lower surface 505. The intermediate area 506 has a thickness 507, a shaped first surface 508, and a second surface 509. The base area 512 has a thickness 513, an outer base surface 514, and an inner base surface 515 fixed to the bone 516. An opposing articular surface 520, which is concave in shape, is placed on the conforming surface 504. Each of the areas and surfaces of the graft 500 can have any of the elements or features of the areas and surfaces of the graft 400 described above. Although the implant 500 is shown in two dimensions, it should be understood that the implant 500 can have any of a variety of three-dimensional shapes, including, but not limited to, any of the shapes shown in Figures 7A-7D and 9A-9J.

[0065] 5A, the implant 500 has been implanted and has not yet been subjected to physiological loading of the opposing articular surface 520. Prior to loading, at the outer edges of the implant 500, the conforming surface 504 is at or below the plane of the native tissue 516, and at the center of the implant 500, the conforming surface 504 is thicker, creating a similar mismatch in conformance with the opposing surface 520, as described above.

[0066] 5B shows how the implant 500 conforms to the native tissue lines of the native tissue 518 when physiological loads are applied through the opposing articular surface 520, allowing the implant 500 to articulate closely with the opposing articular surface 520. This has the advantage of minimizing long-term damage to the implant 500 and surrounding cartilage tissue during physiological loads. For example, the two-phase polymer forming the support zone can have multiple structural molecules (e.g., polymer chains) and water composition that redistribute into the support zone upon compression (i.e., by the opposing articular surface) such that mechanical loads are evenly distributed across the implant.

[0067] 6A and 6B show examples of the three-dimensional shape of the implant 600 (or the shape of a portion of the implant 600, such as the conforming surface 604) according to the exemplary implementation of the implant 100 described above. In each example, the implant 604 has a conforming surface 604 and is implanted at an osteochondral site. Native tissue 618 at least partially surrounds (e.g., surrounds, forms a contact interface along the perimeter, or wraps around the edge of) the implant 600 secured to the bone 616. The implant 600 is multi-layered, for example, bi-layered or tri-layered as described above. The implant 600 can have any of the sections or characteristics of any of the implants described in any of the examples above (such as the implant 100 of FIG. 1). The implant 600 is shown with a representative convex articular surface 618, but can be adjusted to match any curvature of the native tissue.

[0068] 6A illustrates a circular implant 600 (or at least a circular conforming surface 604). The circular implant 600 may be particularly useful for repairing point defects in articular cartilage tissue. The circular implant 600 may have a concave, flat, convex, or any combination of these shaped surfaces as needed to fit a particular situation (e.g., a particular joint or surface of the joint).

[0069] FIG. 6B illustrates an oval or elliptical implant 600 (or at least an oval or elliptical conforming surface 604). The oval or elliptical implant 600 may be particularly useful for repairing defects in articular cartilage tissue that extend across the surface of the cartilage tissue in one or more directions. The oval or elliptical implant 600 may have a concave, flat, convex, or any combination of shaped surfaces as needed to fit a particular situation (e.g., a particular joint or surface of the joint). The joint repair implants and procedures disclosed herein may be applied as partial joint repair procedures (e.g., a "single" model that replaces or reshapes a portion (e.g., one condylar surface)), composite joint repair procedures (e.g., multiple condylar surfaces), or complete repair procedures on one or both sides of a joint (e.g., total knee replacement procedures) in which the implant is applied to both adjacent articulating surfaces. In some implementations, the implant (such as 600) may be useful for repairing large defects extending radially across a majority of the surface of a joint, for example, greater than 5%, greater than 10%, greater than 20%, or even at least 50% or more of the area of ​​the articulating surface of the joint.

[0070] 7A-7D depict additional shapes of osteochondral grafts provided herein. Each of FIGS. 7A-7D is a top-down view of the conforming surface 704 of graft 700, showing a two-dimensional view of the circumference. Each shape may be selected based on the needs of different joints or defects. Any of the grafts provided above may be tailored to these shapes. For example, an area of ​​injury may span over native cartilage tissue, and the shape of graft 700 may be selected to completely surround the area of ​​injury.

[0071] FIG. 7A shows a circular implant 700. FIG. 7B shows an elliptical implant 700. FIG. 7C shows an oval implant 700. FIG. 7D shows a "cloverleaf" shaped implant 700. A cloverleaf shape can be formed from two overlapping ovals or ovals. Other suitable shapes include polygonal, regular polygonal, or amorphous. Other implant shapes will be apparent to one of ordinary skill in the art upon review of this disclosure.

[0072] 8A-8I show cross-sectional views of various examples of connection mechanisms 822 for use in the implants provided herein. In each example, the connection mechanism 822 connects the first layer 802 to the second layer 806, which may be a mechanical connection, a chemical bond, a biological bond, or a combination thereof, or any other suitable connection. The first layer 802 or the second layer 806 may be any of the support zones, intermediate zones, base zones, base constructs, or bones described herein (i.e., any layer / section of FIGS. 1A-5B). For example, the connecting mechanism 822 can connect the support region 102 to the intermediate region 106 (i.e., between the lower surface 105 and the molded first surface 108 (or outer surface 111)), the intermediate region 106 to the base region 112 (i.e., between the second surface 109 and the outer base surface 114), or the base region 112 to the bone 116 (i.e., between the inner base surface 115 and the bone 116). Any of the connecting mechanisms 822 can be combined to connect two or more layers in the implant. Some connecting mechanisms include multiple features (e.g., multiple stakes, twines, spikes, overhangs, barbs, screws, hooks, glue spots, or other connecting units). It should be understood that the interlocking mechanism 822 can comprise at least 1, at least 2, at least 5, at least 10, at least 20, at least 30, at least 50, at least 100, at least 200, at least 500, or at least 1000 features (e.g., stakes, twines, spikes, overhangs, barbs, screws, hooks, other forms of interdigitation, or adhesive spots, or combinations thereof). The features can be distributed in a regular pattern across the second layer 806 or the first layer 802, or may be randomly positioned to provide increased surface area for mechanical or biological interlocking. The features can have picoscale, nanoscale, microscale, or milliscale dimensions. For example, the interlocking mechanism 822 may have a height, width, or length of 1 pm to 1000 pm, 1 nm to 1000 nm, 1 μm to 1000 μm, or 1 mm to 20 mm. The coupling mechanism 822 may be integrally formed with the second layer 806 or may be constructed as a separate component.

[0073] FIG. 8A illustrates a connection mechanism 822 including a peg structure having multiple pegs extending from the second layer 806 into the first layer 802 (or vice versa). For example, the second layer 806 is the base region 112 of FIG. 1 and has pegs extending from the inner base surface 115 into the bone 116, the first layer 802, upon implantation and fixation. In some implementations, the pegs extend into prefabricated cavities in the first layer 802 using a press fit. Alternatively, the pegs can be configured to penetrate into the first layer 802 to form cavities. The pegs can include spikes, overhangs, barbs, threads, or hooks, as shown and detailed in FIGS. 8C-8G. The pegs can extend straight into the first layer 802 or can have a curvature or angle. For example, the pegs may be interdigitated within the first layer 802 such that each peg interdigitates with at least one other peg (eg, like interdigitating fingers between two hands).

[0074] FIG. 8B shows a connecting mechanism 822 comprising a twine or wire connecting the first layer 802 to the second layer 806. Any suitable type of twine, wire, or suture can be used, such as surgical sutures or shape memory wires. The twine or wire can be sutured between the first layer 802 and the second layer 806, for example, using a surgical needle or other suitable suturing mechanism. In some implementations, the twine or wire is introduced during manufacture or implantation of the implant and then removed after the layers are bonded or connected to each other. For example, when the second layer 806 is bone and the first layer 802 is a porous base area, the connecting mechanism 822 holds the layers together during implantation. After implantation, once bone grows into the porous base area such that new growth secures the implant, the connecting mechanism 822 is no longer needed and can be removed.

[0075] 8C illustrates a linkage 822 comprising a number of spikes extending from the second layer 806 into the first layer 802. The spikes can have a conical, pyramidal, or other suitable shape. Although the spikes are shown extending straight, the spikes can also be curved or flexible to penetrate and secure within the first layer 802. In some implementations, the spikes include flares, barbs, threads, or hooks (as shown in FIGS. 8D-8G).

[0076] 8D shows a linkage 822 that includes a number of stakes with overhangs that extend from the second layer 806 into the first layer 802. The overhanging stakes can be shaped like mushrooms with a "cap" that extends radially outward from a "stalk." The overhangs serve to insert the second layer 806 into the first layer 802.

[0077] 8E shows a linkage 822 comprising a plurality of barbed stakes extending from the second layer 806 into the first layer 802. Although the barbed stake shown has two or more barbs, it should be understood that the barbed stake can comprise at least one barb, at least two barbs, at least three barbs, at least four barbs, at least five barbs, or more.

[0078] 8F shows a connection mechanism 822 comprising a plurality of threaded posts or screws extending from the second layer 806 into the first layer 802. The screws can be machine threads (having a uniform diameter, not shown) or tapered threads (having a sharp tip as shown in FIG. 8F). The connection 822 can further include a threaded cavity for receiving the screws.

[0079] 8G shows a coupling mechanism 822 comprising multiple hooks extending from the second layer 806 into the first layer 802. The hooks are shown with one hook tip, but can be configured with multiple hook tips. The first layer 802 can be configured with receiving mechanisms, such as multiple sockets or loops, that receive the hooks of the coupling mechanism 822 during manufacture of the implant.

[0080] FIG. 8H illustrates a coupling mechanism 822 comprising an adhesive or bonding layer between the first layer 802 and the second layer 806. The adhesive (layer) does not comprise the previously described areas such as the support region 102, the intermediate region 106, and the base region 112. The adhesive or bonding layer may comprise a tacky substance or bonding agent, examples of which are described below, or may represent a chemical bond between the materials used to construct the first layer 802 and the second layer 806. For example, the bonding layer represents a covalent bond between the first layer 802 and the second layer 806. The coupling mechanism 822 may comprise a continuous adhesive or bonding layer that extends over at least 25%, at least 50%, at least 75%, or about 100% of the contact interface between the first layer 802 and the second layer 806. Alternatively, the adhesive or bonding layer comprises a plurality of spaced apart spots of adhesive or bonding agent between the first layer 802 and the second layer 806. Suitable binders and adhesives are described below in the materials section.

[0081] FIG. 8I shows a coupling mechanism 822 comprising a number of pores in the first layer 802. The pores allow interdigitation with the opposing surface, for example, during the manufacture of the implant or by bone / tissue growing into the pores after implantation. The pores may be filled during manufacture (e.g., by injecting the material that at least partially constitutes the second layer 806 into the pores) or by growth or creep of material into the pores over time. For example, the second layer 806 may be bone (e.g., subchondral or cancellous bone), but after the implant is implanted into that bone, the bone grows into the pores of the first layer 802, which may be the base of the implant. At the surface of the first layer 802 that bonds with the second layer 806, the number of pores may form a rough, randomly placed border or edge. The pores may be advantageous for coupling due to the interdigitation of the first and second layers, which increases the robustness of the coupling at the interface.

[0082] Additional interlocking features not shown include ridges, pores, posts, grooves, pyramids, or other features that impart texture to the surface.

[0083] As described above with respect to Figures 1A and 1B, the biomimetic osteochondral grafts provided herein can include one or more surfaces shaped to mate with opposing articular surfaces (e.g., as a conforming or outward facing surface of a support area, such as support area 102), or as an interlayer. The interlayer is configured to impart shape to other layers disposed adjacent to the interlayer (e.g., shaping the underside of the support area, such as the underside 105 of support area 102). Figures 9A-9J show additional surface and graft shapes that can be used for a particular joint or defect. The shapes in Figures 9A-9J can be applied to any of the layers or regions described herein.

[0084] 9A-9D show a circular or elliptical layer 906 having a thickness 907, a shaped first surface 908 having a perimeter 910 and a surface 911, and a second surface 909 disposed opposite the shaped first surface 908. In FIG. 9A, the first surface 908 is flat, while in FIGS. 9B and 9D, the first surface 908 is convex and concave, respectively. It should be understood that the first surface 908 in FIGS. 9B and 9D can be curved in opposite directions of the convex and concave curves to create a saddle shape. FIG. 9C shows an implementation where the surface 908 has concave and convex regions. Other implementations not shown include where both the first surface 908 and the second surface 909 are planar, but where the surface 911 is disposed diagonally (e.g., at an angle) relative to the second surface 909, such that the plane of the first surface 908 intersects the plane of the second surface 909 at a line. Other implementations not shown include a shaped first surface 908 having a saddle shape (i.e., convex along a first axis and concave along a second axis perpendicular to the first axis). Other shapes will be apparent to one of ordinary skill in the art or when designing an implant for a specific joint or defect.

[0085] Figures 9E and 9F show an elongated oval or elliptical layer 906 having a thickness 907, a shaped first side 908 having a perimeter 910 and a surface 911, and a second side 909 disposed opposite the shaped first side 908. In Figure 9E, the first side 908 is flat, while the first side 908 in Figure 9F has a concave region 928 and a convex region 929. The oval or elliptical layer 906 may comprise a first side 908 having a only concave, only convex, angled, or saddle-shaped surface 911.

[0086] 9G-9J show a square or rectangular layer 906 with a thickness 907, a shaped first side 908 having a perimeter 910 and a surface 911, and a second side 909 disposed opposite the shaped first side 908. FIG. 9G shows a flat first side 908. FIGS. 9H and 91 show concave and convex first sides 908, respectively. FIG. 9J includes a first side 908 with a concave region 928 and a convex region 929. The square or rectangular layer 906 may include a first side 908 with a sloping or saddle-shaped surface 911.

[0087] material As discussed above, one or more layers of a biomimetic osteochondral graft, such as the support region 102 of the graft 100 of FIG. 1A, can include a flowable thermoplastic polymer in some implementations. Suitable thermoplastic polymers include, but are not limited to, acrylonitrile butadiene styrene (ABS), polymethyl methacrylate (PMMA), celluloid, cellulose acetate, ethylene vinyl acetate (EVA), ethylene vinyl alcohol (EVAL), Kydex, liquid crystal polymer (LCP), polyacetal (POM), polyacrylate (acrylic), polyacrylonitrile (PAN), polyamide (PA or nylon), polyamideimide (PAI), polyaryletherketone (PAEK), polyhydroxyalkanoates (PHAs), polyketone (PK), polyester, polyetherimide (PB), ... Polyetheretherketone (PEEK), polyetherimide (PEI), polyethersulfone (PES), polyethylene chlorinate (PEC), polyimide (PI), polymethylpentene (PMP), polyphenylene oxide (PPO), polyphenylene sulfide (PPS), polyphthalamide (PPA), polystyrene (PS), polysulfone (PSU), polyvinyl acetate (PVA), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), Spectralon, styrene acrylonitrile (SAN), polydimethylsiloxane (PDMS), and polyurethane (PU). As described herein, a wide variety of polyurethanes can be used, with a variety of hard segment, soft segment, and chain extender compositions.

[0088] In some implementations, the thermoplastic polymer is a thermoplastic polyurethane-based polymer (e.g., polyetherurethane, polycarbonateurethane, polyurethaneurea, silicone polyetherurethane, or silicone polycarbonateurethane) that includes a network of hard and soft segments, which may be swollen with monomer and any solvent, along with an initiator and crosslinker, such that the soft segments are swollen while the hard segment material is largely unaffected. This swelling process does not dissolve the polymer, but rather the hard segments act as physical crosslinks to hold the material together as the soft segments are absorbed by the monomer and any solvent. After polymerization and crosslinking of the monomers, a second polymer network is formed in the presence of the first network, creating an IPN or semi-IPN in which the second polymer network (i.e., the polymerized monomers) are primarily sequestered within the soft, amorphous regions of the first polymer. Despite some degree of intramolecular rearrangement and further phase separation, the hard segments remain largely ordered and crystalline, providing structure and strength to the material. The new properties prepared by such processes depend on the properties of the polymerized monomers that were introduced and, in some implementations, on the modification of subsequently introduced polymerized monomers (e.g., carboxylic acid-containing monomers). Examples of such new properties include lubricity, conductivity, hardness, absorbency, permeability, photoresponsiveness, and thermal responsiveness.

[0089] Any number of chemical structures and stoichiometries can be used to create polyurethane polymers. For example, hard segments can be formed from 1,5-naphthalene diisocyanate (NDI), isophorone isocyanate (IPDI), 3,3-toluene diisocyanate (TODI), methylene bis(p-cyclohexyl isocyanate) (HMDI), cyclohexyl diisocyanate (CHDI), 2,6-toluene diisocyanate or 2,4-toluene diisocyanate (TDI), hexamethyl diisocyanate, or methylene bis(p-phenyl isocyanate). The soft segments may be formed from polyalkylene oxides (e.g., polyethylene oxide (PEO), polypropylene oxide (PPO), and polybutylene oxide (PBO)), polybutadiene, polydimethylsiloxane (PDMS), polyethylene adipate, polycaprolactone, polytetramethylene adipate, polyisobutylene, polyhexamethylene carbonate glycol, poly(1,6-hexyl-1,2-ethyl carbonate). When end groups that react with isocyanates are used, any number of telechelic polymers can be used in the soft segments. For example, hydroxyl or amine terminated poly(vinylpyrrolidone), dimethylacrylamide, carboxylic acid or sulfonated polymers, telechelic hydrocarbon chains (with hydroxyl and / or amine end groups), dimethylolpropionic acid (DMPA), or combinations of these with each other or with the other soft segments mentioned above (e.g., PDMS) can be used.

[0090] Chain extenders include, for example, 1,4-butanediol, ethylenediamine, 4,4′-methylenebis(2-chloroaniline) (MOCA), ethylene glycol, and hexanediol. Any other compatible chain extenders can be used alone or in combination. Crosslinking chain extenders can be used that contain isocyanate-reactive end groups (e.g., hydroxyl or amine), and vinyl-based functional groups (e.g., vinyl, methacrylate, acrylate, allyl ether, or acrylamide) can be used in place of some or all of the chain extender. Examples include 1,4-dihydroxybutane and glycerol methacrylate. Alternatively, crosslinking can be achieved with polyols, such as glycerol, that contain three or more hydroxyl groups for reaction with isocyanates.

[0091] In some implementations, the monomer is a carboxylic acid-containing monomer. Suitable carboxylic acid-containing monomers used to form the second polymer network have the following characteristics: (1) they can swell without dissolving the thermoplastic polymer (e.g., polyurethane), and (2) they can be polymerized. Non-limiting examples include acrylic acid, methacrylic acid, crotonic acid, linoleic acid, maleic acid, fumaric acid, and / or combinations thereof. After optional swelling in a buffered aqueous solution, the second network of the mixed anionic IPN or semi-IPN is ionized, and the mixed anionic IPN or semi-IPN becomes water swollen and lubricated. In this way, hydrophilicity (i.e., water absorption) can be introduced into an otherwise hydrophobic material. A hydrophobic polymeric material such as polyurethane or ABS can be infiltrated with various mixed anionic polymers (e.g., polymers consisting of a combination of underivatized and derivatized carboxylic acid groups) to absorb water. In some implementations, an additional comonomer is used to form the second polymer network. The additional comonomer can be ionic or nonionic. Examples of non-ionic monomers include, but are not limited to, acrylamide, methacrylamide, N-hydroxyethylacrylamide, N-isopropylacrylamide, methyl methacrylate, N,N-dimethylacrylamide, N-vinylpyrrolidone, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, and derivatives thereof.

[0092] Functional groups can be incorporated into an IPN or semi-IPN comprising a second polymer network containing carboxylic acid groups, for example, by replacing pendant carboxylic acid groups present in the poly(carboxylic acid) of the IPN (e.g., poly(acrylic acid) or poly(methacrylic acid)) with the functional group. In some implementations, the functional group is a sulfonic acid group, and the sulfonic acid group can be incorporated into an IPN or semi-IPN containing carboxylic acid groups by reacting the IPN or semi-IPN with a sulfonic acid-containing compound, for example, by reacting a carboxylic acid group of a solid with an aminosulfonic acid compound such that an amide bond is formed between the carboxylic acid group of the poly(carboxylic acid) and the amine group of the aminosulfonic acid compound. In some implementations, the aminosulfonic acid compound is a compound of the formula (H2N)xR(SO3H)y or a salt thereof, where R is an organic moiety, x is a positive integer, and y is a positive integer. In certain implementations, x can range from 1 to 10, typically 1 to 5 (i.e., x can be 1, 2, 3, 4, or 5), and y can range from 1 to 10, typically 1 to 5 (i.e., y can be 1, 2, 3, 4, or 5). In some implementations, the compound of formula (H2N)xR(SO3H)y has a hydrodynamic radius that allows for molecular diffusion within the IPN. For example, R can be a hydrocarbon moiety, including, for example, linear, branched, or cyclic hydrocarbon moieties, or a hydrocarbon moiety having a combination of two or more of linear, branched, and cyclic hydrocarbon substituents. The hydrocarbon moiety can be, for example, a polymer moiety including a C1-C12 hydrocarbon or a heteroatom-containing polymer / oligomer. In certain implementations, the hydrocarbon moiety can be selected from an alkane moiety, an alkene moiety, an alkyne moiety, an aromatic moiety, or a hydrocarbon moiety having a combination of two or more of an alkane moiety, an alkene moiety, an alkyne moiety, or an aromatic moiety. In certain implementations, the aminosulfonic acid can be selected from taurine and taurine derivatives, including 1-substituted, 2-substituted, 1,1-disubstituted, 2,2-disubstituted, and 1,2-disubstituted taurines, such as 1-hydrocarbon substituted, 2-hydrocarbon substituted, 1,1-dihydrocarbon substituted, 2,2-dihydrocarbon substituted, and 1,2-dihydrocarbon substituted taurines.Here, the substituted hydrocarbon can be selected from the hydrocarbon moieties described above, for example. In other implementations, the aminosulfonic acid compound is one that results in the formation of 2-acrylamido-2-methylpropanesulfonic acid or acrylamidoethanesulfonic acid.

[0093] Examples of IPNs and semi-IPNs suitable for use as layers, as well as procedures for their preparation, are disclosed, for example, in U.S. Pat. Nos. 8,883,915, 10,457,803, 10,752,168, 10,792,392, and 10,869,960, the entire contents of which are incorporated by reference for all purposes as if fully set forth herein.

[0094] As mentioned above, the middle layer of the implant, such as the middle region 106 of implant 100 in FIG. 1A, is constructed of a polymer that has greater stiffness than the outer layers that will bond and articulate within the joint.

[0095] In some implementations, the intermediate layer is formed from a first precursor and a second precursor. In some implementations, the intermediate layer can be formed from one or more additional precursors. The first precursor has a first chemical functional group that can form a covalent bond with a second precursor having a second chemical functional group to allow for the formation of a copolymer. The first precursor can have one, two, three, or more than three chemical functional groups, as can the second precursor and any additional precursors. The first, second, and any additional chemical functional groups on one precursor can be the same or different. The functional groups on the different precursors can be the same or different. In some implementations, the precursors have chemical functional groups that can react to a free radical initiator or to other (e.g., ionic / anionic) initiators to form a covalent bond. In some implementations, the chemical functional groups can be unsaturated groups, such as ethylenically unsaturated groups (e.g., vinyl groups).

[0096] In some implementations, the chemical functional group can be an acrylic group, which can have a carbon-carbon double bond and a carbon-oxygen double bond separated by a carbon-carbon single bond. An "acrylic" functional group can be derived, for example, from an α,β-unsaturated carbonyl compound. Molecules containing acrylic groups can be decorated with additional chemical moieties. Examples of acrylic groups that can be used in the precursor include, but are not limited to, acrylic acid, methacrylic acid, hydroxyethyl methacrylate, and methyl methacrylate.

[0097] Examples of other ethylenically unsaturated groups that may be used in the precursor include acrylamides and methacrylamides (e.g., 2-acrylamido-2-methyl-1-propanesulfonic acid, (3-acrylamidopropyl)trimethylammonium chloride, N-acryloylamido-ethoxyethanol, 3-acryloylamino-1-propanol, N-tert-butylacrylamide, diacetone acrylamide, N,N-dimethylacrylamide, N-[3-(dimethylamino)propyl]methacrylamide, N-diphenylmethylacrylamide, N ,N′-hexamethylenebis(methacrylamide), N-hydroxyethylacrylamide, N-(hydroxymethyl)acrylamide, N-(isobutoxymethyl)acrylamide, N-isopropylacrylamide, N-isopropylmethacrylamide, methacrylamide, N-(3-methoxypropyl)acrylamide, N-phenylacrylamide, N-(triphenylmethyl)methacrylamide, N-[tris(hydroxymethyl)methyl]acrylamide), acid acrylates (e.g., acryloyl chloride, 4-acryloylmorpholine, [ 2-(acryloyloxy)ethyl]trimethylammonium chloride, 2-(4-benzoyl-3-hydroxyphenoxy)ethyl acrylate, benzyl 2-propyl acrylate, butyl acrylate, tert-butyl acrylate, 2-[[(butylamino)carbonyl]oxy]ethyl acrylate, tert-butyl 2-bromoacrylate, 4-tert-butylcyclohexyl acrylate, 2-carboxyethyl acrylate, 2-chloroethyl acrylate, 2-(diethylamino)ethyl acrylate, di(ethylene glycol)ethyl ether Teracrylate, di(ethylene glycol) 2-ethylhexyl ether acrylate, 2-(dimethylamino)ethyl acrylate, 3-(dimethylamino)propyl acrylate, dipentaerythritol penta- / hexa-acrylate, ethyl acrylate, 2-ethyl-acryloyl chloride, ethyl 2-(bromomethyl)acrylate, ethyl cis-(β-cyano)acrylate, ethylene glycol dicyclopentenyl ether acrylate, ethylene glycol methyl ether acrylate, ethylene glycol phenyl ether acrylate,2-Ethyl acrylate, 2-ethylhexyl acrylate, Ethyl 2-propyl acrylate, Ethyl 2-(trimethylsilylmethyl)acrylate, Hexyl acrylate, 4-Hydroxybutyl acrylate, 2-Hydroxyethyl acrylate, 2-Hydroxy-3-phenoxypropyl acrylate, Hydroxypropyl acrylate, Isobornyl acrylate, Isobutyl acrylate, Isodecyl acrylate, Isooctyl acrylate, Lauryl acrylate, 2-Acetamidomethyl acrylate, Methyl acrylate, α-Bromoacrylate Methyl acrylate, Methyl 2-(bromomethyl)acrylate, Methyl 3-hydroxy-2-methylenebutyrate, Methyl 2-(trifluoromethyl)acrylate, Neopentyl glycol methyl ether propoxylate (2PO / OH) acrylate, Octadecyl acrylate, Pentabromobenzyl acrylate, Pentabromophenyl acrylate, Pentafluorophenyl acrylate, Poly(ethylene glycol) methyl ether acrylate, Poly(propylene glycol) acrylate, Soybean oil, Epoxidized acrylates, Acrylic acid 3-sulfopropyl, tetrahydrofurfuryl acrylate, 3-(trimethoxysilyl)propyl acrylate, 5,5-trimethylhexyl acrylate, 10-undecenyl acrylate), acrylic acid and salts of acrylic acid (e.g., acrylic anhydride, 2-bromoacrylic acid, 2-(bromomethyl)acrylic acid, 2-ethylacrylic acid, hafnium carboxyethyl acrylate, methacrylic acid, 2-propylacrylic acid, sodium acrylate, sodium methacrylate, 2-(trifluoromethyl)acrylic acid, zinc acrylate, zirconium acrylate, zirconium bromonorbornane lactone carboxylate triacrylate, and zirconium carboxyethyl acrylate), acrylonitriles (e.g., acrylonitrile, 1-cyanovinyl acetate, and 2-cyanoethyl acrylate), bisphenol acrylates (e.g., bisphenol A ethoxylate diacrylate, bisphenol A glycerolate dimethacrylate, bisphenol A glycerolate (1 glycerol / phenol) diacrylate, bisphenol A dimethacrylate,and bisphenol F ethoxylate (2 EO / phenol) diacrylate), fluorinated acrylics (e.g., 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoroheptyl acrylate, 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,12,12,12-eicosafluoro-11-(trifluoromethyl)dodecyl methacrylate, 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heneicosafluorododecyl acrylate, ,8,8,9,9,10,10,11,11,12,12,12-Heneicosafluorododecyl methacrylate, 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl methacrylate, 2,2,3,3,4,4,4-Heptafluorobutyl acrylate, 2,2,3,3,4,4,4-Heptafluorobutyl methacrylate, 2,2,3,4,4,4-Hexafluorobutyl acrylate, 2,2,3,4,4,4-Hexafluorobutyl methacrylate, 1,1,1,3,3,3- Hexafluoroisopropyl, 1,1,1,3,3,3-hexafluoroisopropyl methacrylate, 2,2,3,3,4,4,5,5-octafluoropentyl acrylate, 2,2,3,3,4,4,5,5-octafluoropentyl methacrylate, 2,2,3,3,3-pentafluoropropyl acrylate, 2,2,3,3,3-pentafluoropropyl methacrylate, 1H,1H,2H,2H-perfluorodecyl acrylate, 2,2,3,3-tetrafluoropropyl methacrylate, 3,3,4,4,5,5,6, 6,7,7,8,8,8-tridecafluorooctyl, 2,2,2-trifluoroethyl methacrylate, 1,1,1-trifluoro-2-(trifluoromethyl)-2-hydroxy-4-methyl-5-pentyl methacrylate, and 2-[(1′,1′,1′-trifluoro-2′-(trifluoromethyl)-2′-hydroxy)propyl]-3-norbornyl methacrylate), maleimides (e.g., 2-[8-(3-hexyl-2,6-dioctylcyclohexyl)octyl]pyromellitic diimide oligomers, maleimide-terminated,2-[8-(3-hexyl-2,6-dioctylcyclohexyl)octyl]pyromellitic diimide oligomer, maleimide terminated, N,N'-(o-phenylene)dimaleimide, N,N'-(1,3-phenylene)dimaleimide, and N,N'-(1,4-phenylene)dimaleimide), methacrylates (e.g., allyl methacrylate, 2-aminoethyl methacrylate, 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate, benzyl methacrylate, bis(2-methacryloyl)oxyethyl disulfide methacrylate, 2-(2-bromoisobutyryloxy)ethyl methacrylate, 2-(tert-butylamino)ethyl methacrylate, butyl methacrylate, tert-butyl methacrylate, 9H-carbazole-9-ethyl methacrylate, 3-chloro-2-hydroxypropyl methacrylate, cyclohexyl methacrylate, 2-(diethylamino)ethyl methacrylate, di(ethylene glycol) methyl ether methacrylate, 2-(diisopropylamino)ethyl methacrylate, 2-(dimethylamino)ethyl methacrylate, 2-ethoxyethyl methacrylate ethyl, ethylene glycol dicyclopentenyl ether methacrylate, ethylene glycol methyl ether methacrylate, ethylene glycol phenyl ether methacrylate, 2-ethylhexyl methacrylate, ethyl methacrylate, ferrocenyl methyl methacrylate, furfuryl methacrylate, glycidyl methacrylate, glycidyl methacrylate, glycosyloxyethyl methacrylate, hexyl methacrylate, hydroxybutyl methacrylate, 2-hydroxyethyl methacrylate, 2-hydroxyethyl methacrylate, hydroxyethyl methacrylate Dipropyl, 2-hydroxypropyl 2-(methacryloyloxy)ethyl phthalate, isobornyl methacrylate, isobutyl methacrylate, 2-isocyanatoethyl methacrylate, isodecyl methacrylate, lauryl methacrylate, methacrylic acid N-hydroxysuccinimide ester, [3-(methacryloylamino)propyl]dimethyl(3-sulfopropyl)ammonium hydroxide, [3-(methacryloylamino)propyl]trimethylammonium chloride, methacryloyl chloride (approximately 95% pure), methacryloyl chloride,[2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide, 2-methacryloyloxyethyl phosphorylcholine, [2-(methacryloyloxy)ethyl]trimethylammonium chloride, [2-(methacryloyloxy)ethyl]trimethylammonium methylsulfate, 2-(methylthio)ethyl methacrylate, mono-2-(methacryloyloxy)ethyl maleate, mono-2-(methacryloyloxy)ethyl succinate, 2-N-morpholinoethyl methacrylate, 1-naphthyl methacrylate , pentabromophenyl methacrylate, pentafluorophenyl methacrylate, phenyl methacrylate, methacrylic acid phosphate 2-hydroxyethyl ester, poly(ethylene glycol) behenyl ether methacrylate, poly(ethylene glycol) 2,4,6-tris(1-phenylethyl)phenyl ether methacrylate, poly(propylene glycol) methacrylate, propyl methacrylate, 1-pyrenemethyl methacrylate, solketal methacrylate, stearyl methacrylate, 3-sulfopropyl methacrylate, methacrylic acid T EMPO, tetrahydrofurfuryl methacrylate, 2,4,6-tribromophenyl methacrylate, 3-(trichlorosilyl)propyl methacrylate, triethylene glycol methyl ether methacrylate, 1,1,1-trifluoro-2-(trifluoromethyl)-2-hydroxy-4-methyl-5-pentyl methacrylate, 2-[(1′,1′,1′-trifluoro-2′-(trifluoromethyl)-2′-hydroxy)propyl]-3-norbornyl methacrylate, 3-(trimethoxysilyl)propyl methacrylate, 3,3 ,5-trimethylcyclohexyl, (trimethylsilyl) methacrylate, 2-(trimethylsilyloxy)ethyl methacrylate, 3-[tris(trimethylsiloxy)silyl]propyl methacrylate, and vinyl methacrylate), as well as multifunctional acrylics (e.g., acrylamides: N,N′-methylenebisacrylamide, 3-(acryloyloxy)-2-hydroxypropyl methacrylate, bis[2-(methacryloyloxy)ethyl] phosphate, bisphenol A propoxylate diacrylate, 1,3-butanediol diacrylate,1,4-butanediol, 1,3-butanediol dimethacrylate, 1,4-butanediol dimethacrylate, N,N'-(1,2-dihydroxyethylene)bisacrylamide, di(trimethylolpropane)tetraacrylate, diurethane dimethacrylate, N,N'-ethylenebis(acrylamide), glycerol 1,3-diglycerolate diacrylate, glycerol dimethacrylate, glycerol propoxylate, 1,6-hexanediol diacrylate, 1,6-hexanediol dimethacrylate, 1,6-hexanediol ethoxylate diacrylate, hydroxypivalyl hydroxypivalate, Bis[6-(acryloyloxy)hexanoate], neopentyl glycol diacrylate, neopentyl glycol propoxylate, pentaerythritol diacrylate monostearate, pentaerythritol tetraacrylate, pentaerythritol triacrylate, poly(propylene glycol) diacrylate, poly(propylene glycol) dimethacrylate, 1,3,5-triacryloylhexahydro-1,3,5-triazine, tricyclo[5.2.1.02,6]decane dimethanol diacrylate, trime trimethylolpropane ethoxylate, trimethylolpropane ethoxylate triacrylate, trimethylolpropane ethoxylate triacrylate, trimethylolpropane ethoxylate triacrylate, trimethylolpropane propoxylate triacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, tri(propylene glycol) diacrylate, and tris[2-(acryloyloxy)ethyl]isocyanurate, and salts and variants thereof.

[0098] In some implementations, the layer is formed from a copolymer of urethane dimethacrylate and methyl methacrylate. Examples are disclosed, for example, in U.S. Patent Nos. 9,750,842 and 10,519,270, and U.S. Patent Application Publication No. 2020 / 0087440, the entire contents of which are incorporated by reference for any purpose as if fully set forth herein. The urethane dimethacrylate can include a soft segment selected from, for example, polybutadiene, polyethylene oxide (PEO), hydroxy-terminated butadiene, hydroxybutyl-terminated polydimethylsiloxane (PDMS), hydroxyl-terminated polyisobutylene, poly(1,6-hexyl-1,2-ethyl carbonate), polycaprolactone, polycarbonate, polyethylene adipate, polyhexamethylene carbonate glycol, polypropylene oxide (PPO), polytetramethylene adipate, poly(dimethylsiloxane), and poly(tetramethylene oxide) (PTMO). The urethane dimethacrylate can include hard segments formed from, for example, 1,5-naphthalene diisocyanate (NDI), 2,6-toluene diisocyanate or 2,4-toluene diisocyanate (TDI), 3,3-toluene diisocyanate (TODI), cyclohexyl diisocyanate (CHDI), hexamethyl diisocyanate (HDI), isophorone diisocyanate (IPDI), methylene bis(p-phenyl)isocyanate, methylene diphenyl isocyanate (MDI), and methylene bis(p-cyclohexyl isocyanate (HMDI). Some In an implementation, the urethane dimethacrylate comprises a soft segment based on PTMO having one or more molecular weights (Mn) between about 100 Da and about 5000 Da (e.g., about 200 Da to about 2000 Da, about 400 Da to about 1500 Da, about 650 Da, or about 1000 Da). In some implementations, the urethane dimethacrylate comprises a soft segment based on a mixture of PTMO having a molecular weight of about 650 Da and PTMO having a molecular weight of about 1000 Da in a defined molar ratio (e.g., 1:1), such as a molar ratio of 1:5, 1:4, 1:3, 1:2, 1:1:2:1, 3:1, 4:1, or 5:1.The molecular weight of the PTMO can be varied to tailor the stiffness of the layer.

[0099] As mentioned above, a biomimetic osteochondral graft can have a base layer, such as base region 112 of graft 100 of FIG. 1A, that bonds with bone after implantation (e.g., by any of the connection mechanisms described with respect to FIGS. 8A-8I). The base layer can be porous. The base layer can be formed from any biocompatible material that has suitable structural and / or mechanical properties. For example, the biocompatible material can be selected to have the mechanical properties of the bone to which the graft is secured. The porosity of the material can also be designed or selected to favor angiogenesis and bone ingrowth.

[0100] In some implementations, the base layer can be formed from a rigid, non-resorbable thermoplastic material, such as polycarbonate urethane, polyether urethane, and PEEK, that can be made to flow with ultrasonic welding vibrations, ultrasonic energy, laser energy, heat, radio frequency energy, and electrical energy.

[0101] In some implementations, the base layer is porous bone, such as cancellous bone from humans (allografts) or animals (xenografts). If a synthetic bone-like material is used, it can be formed from porous calcium phosphate (or other materials, including but not limited to porous carbonate apatite, beta-tricalcium phosphate, or hydroxyapatite), or a porous resorbable thermoplastic or non-resorbable thermoplastic as described above.

[0102] In some implementations, the base layer includes a metal such as titanium, tantalum, stainless steel, cobalt chrome, nickel titanium alloy (i.e., Nitinol), or zirconium alloy. In some implementations, the base layer is porous titanium. The base layer can be, for example, a metal with a surface coating on one or both of the exterior and interior base surfaces. The base layer can have a plasma sprayed titanium coating or a plasma sprayed ceramic coating on one or both sides.

[0103] In some implementations, the base layer is a ceramic, for example a resorbable ceramic or a non-resorbable ceramic.

[0104] In some implementations, the base layer may include additional materials depending on the intended anatomical application. For example, if the implant is to be used to repair a defect in the glenoid cavity of the scapula, which has very thin cancellous and cortical bone, the base layer may be injected with a material that induces or attracts bone growth. The base layer may also be combined with mechanical fastening means such as screws, pins, anchors, and stems (including any of the coupling mechanisms shown / described in Figures 8A-8I) or may be formed from non-resorbable or resorbable materials designed to be replaced by native tissue over time.

[0105] As described above, a bonding agent (e.g., a polymer adhesive, a bone cement such as PMMA, an epoxy resin, an adhesive, or a grout material) is applied between a first layer 802 (e.g., the inner base surface 115 of the implant 100, the outer base surface 208 or the inner base surface 209 of a two-layer implant 200, or the inner base surface 315 of a three-layer construct 300) and a second layer 806 (e.g., the bone or the underside 205 of the implant 200).

[0106] In some implementations, the binder is a polymer adhesive including the first and second precursors described above. In some implementations, the binder is a polymer adhesive including urethane dimethacrylate and methyl methacrylate. After application, the polymer adhesive may be cured using radiation such as visible light, infrared light, or ultraviolet light using a photoinitiator, or may be cured using a thermal initiator (e.g., benzoyl peroxide), a chemical initiator or catalyst, and / or a redox-activated initiation system, such as one containing camphorquinone. A combination of photoinitiation and non-light-based initiation systems, such as thermal, chemical, and / or redox systems, may be used. Accelerators such as N,N-dimethyl-p-toluidine may be used.

[0107] The urethane dimethacrylate may include a soft segment selected from, for example, polybutadiene, polyethylene oxide (PEO), hydroxy-terminated butadiene, hydroxybutyl-terminated polydimethylsiloxane (PDMS), hydroxyl-terminated polyisobutylene, poly(1,6-hexyl-1,2-ethyl carbonate), polycaprolactone, polycarbonate, polyethylene adipate, polyhexamethylene carbonate glycol, polypropylene oxide (PPO), polytetramethylene adipate, poly(dimethylsiloxane), and poly(tetramethylene oxide) (PTMO). The urethane dimethacrylate may include a hard segment formed from, for example, 1,5-naphthalene diisocyanate (NDI), toluene-2,6-diisocyanate or toluene-2,4-diisocyanate (TDI), 3,3′-bitoluene diisocyanate (TODI), cyclohexyl diisocyanate (CHDI), hexamethyl diisocyanate (HDI), isophorone diisocyanate (IPDI), methylene bis(p-phenyl)isocyanate, methylene diphenyl isocyanate (MDI), and methylene bis(p-cyclohexyl isocyanate (HMDI). In some implementations, the urethane dimethacrylate has a hard segment of between about 100 Da and about 5000 Da (e.g., about 250 Da to about 2500 Da, about 400 Da to about 2000 Da, about 500 Da to about 500 Da). In some implementations, the urethane dimethacrylate comprises a PTMO-based soft segment having one or more molecular weights of about 1250 Da, about 250 Da, about 400 Da, about 500 Da, about 650 Da, about 800 Da, about 1000 Da, about 1250 Da, about 1500 Da, about 2000 Da, about 2500 Da, about 4000 Da, about 5000 Da, or a mixture thereof. and a soft segment based on a mixture of two or more (e.g., two, three, or four) PTMOs (e.g., a mixture of PTMOs having molecular weights of 650 Pa and 1000 Pa in a defined molar ratio (e.g., 1:1), such as a molar ratio of 1:5, 1:4, 1:3, 1:2, 1:1:2:1, 3:1, 4:1, or 5:1) each having a molecular weight of about 500 Da to about 1250 Da.The molecular weight of the PTMO may be varied to tailor the stiffness of the polymer adhesive after it has cured.

[0108] In some implementations, the urethane dimethacrylate comprises about 60% (w / w) to about 80% (w / w), about 60% (w / w) to about 90% (w / w), about 60% (w / w) to about 99% (w / w), or about 70% (w / w) to about 90% (w / w) of the polymer adhesive. In some implementations, the methyl methacrylate comprises about 20% (w / w) to about 40% (w / w), about 1% to about 20% (w / w), about 1% (w / w) to about 40% (w / w), or about 25% (w / w) to about 35% (w / w) of the polymer adhesive. In some implementations, the polymer adhesive is formed from urethane dimethacrylate and methyl methacrylate and defines a tensile modulus between about 30 MPa and about 2000 MPa (e.g., about 100 MPa to about 1000 MPa, about 200 MPa to about 500 MPa, about 200 MPa, about 300 MPa, about 400 MPa, or about 500 MPa). In some implementations, the polymer adhesive is formed from urethane dimethacrylate and methyl methacrylate and defines a failure strain between about 25% and 200%. In some implementations, the polymer adhesive is formed from urethane dimethacrylate and methyl methacrylate and defines a compressibility of between about 30 MPa and about 2000 MPa (e.g., about 30 MPa to about 500 MPa, about 50 MPa to about 250 MPa, about 100 MPa to about 200 MPa, or about 75 MPa, about 100 MPa, about 120 MPa, about 150 MPa, about 180 MPa, or about 200 MPa).

[0109] Examples of polymer adhesives and methods for their preparation are disclosed, for example, in U.S. Pat. Nos. 9,750,842 and 10,519,270, and U.S. Patent Application Publication No. 2020 / 0087440, the entire contents of which are incorporated by reference for all purposes as if fully set forth herein.

[0110] Example 1: Finite Element Analysis (FEA) Contact Pressure Assessment of the Native Knee and Various Circular Implant Designs A study was conducted to create a knee model to evaluate the contact pressure between the femur and tibia and a three-layered implant. The sample consisted essentially of the following materials: 1) a first layer of a semi-interpenetrating polymer network containing polyurethane and sulfonated polyacrylic acid, 2) a second layer of UDMA-MMA copolymer, and 3) a third layer of porous titanium (an example of a three-layered implant). The top layer was a semi-interpenetrating polymer network containing polyurethane and sulfonated polyacrylic acid, the middle layer was formed from UDMA-MMA copolymer, and the bottom layer was porous titanium. The three-layered implant was also compared against a CoCr implant with the same geometry and two polymer layers connected to the same porous material. A range of implant diameters (12 mm to 24 mm) and articular surface curvatures appropriately sized for the femoral condyles were studied.

[0111] A knee model was constructed from imaging data derived from a healthy patient. The model included a femur, tibia, and meniscus. Both the femur and tibia models included articular cartilage tissue. The joint was oriented at a flexion angle of 15° and a load of 3100 N (mean pressure of ~3 MPa) was applied across the joint. This flexion angle and load magnitude are representative of those observed during walking.

[0112] Contact pressures in the native joint were obtained. A cylindrical defect was then created in the medial femoral condyle with the center of pressure observed in the native, uninjured knee. A three-layered implant was then inserted into the defect and the contact pressure measurements were repeated. Finally, a CoCr implant was inserted into the defect and the contact pressure measurements were repeated.

[0113] In all graft cases, the graft was seated within the defect to ensure that the edges of the graft were lower than the adjacent cartilage tissue and that the center of the graft was higher than (as shown in Figure 4A), flush with, or lower than the plane of the native cartilage tissue.

[0114] In a series of simulations of peak contact pressures for various conditions and implants, the tri-layered implant consistently exhibited lower peak contact pressures than the native knee, while the CoCr implant consistently exhibited higher peak contact pressures than the native knee. To demonstrate the difference in peak contact pressures between the various implants and situations examined, the pressures are plotted in Figure 10. The plot shows the range of values ​​observed for the tri-layered implant and the CoCr implant. The results showed that the tri-layered implant was successful in reducing peak contact pressures at the knee without a perfect match of the articular surfaces. In direct comparison with CoCr, the contact pressures of the tri-layered implant were observed to range from 3.4 to 5.8 MPa, less than those observed for the CoCr implant in comparable settings (geometry and seating conditions) (5.0 MPa to 10.5 MPa). Example 2: Creep and Relaxation Evaluation of First Polymer, Second Polymer, and Tri-Layer Implants

[0115] A study was conducted to evaluate the restraint creep and relaxation under physiological loading of sample implants, examples of the biomimetic osteochondral implants described herein. Three samples were tested: 1) an 8 mm diameter piece of a semi-interpenetrating polymer network comprising polyurethane and sulfonated polyacrylic acid, 2) an 8 mm diameter piece of UDMA-MMA copolymer, and 3) an 8 mm diameter construct having a semi-IPN layer, a UDMA-MMA copolymer layer, and a porous titanium layer (an example of a three-layer implant).

[0116] A load of 3 MPa was applied to each material for 1 hour to allow for restrained creep and then relaxation for 30 minutes. The semi-IPN experienced 10% to 20% creep and 50% to 100% recovery. The UDMA-MMA copolymer experienced 2% to 10% creep and 60% to 90% recovery. The composite experienced 5% to 7% creep and 90% to 100% recovery. Representative curves from this test can be seen in Figures 11A, 11B, and 11C.

[0117] How to transplant Further provided herein are methods of implanting the biomimetic osteochondral grafts described herein. Any of the grafts shown in and described with respect to Figures 1A-9J may be implanted according to these methods.

[0118] In some implementations, biomimetic osteochondral grafts are used to repair osteochondral defects in joints. After gaining access to the osteochondral defect in an appropriate manner for a given joint, a sizing device is used to aid in the selection of a graft that will cover the defect and provide a stable margin of cartilage. A wire (e.g., k-wire) or pin (e.g., Steinmann pin) is then centered over the defect using a guide that approximates the size of the graft. The guide ensures that the wire is placed perpendicular to the plane of the joint. The guide can have a shape that matches the articular surface of the joint being treated. After insertion of the wire or pin, the guide is removed from the surgical site.

[0119] A dissection or cutting tool can be used to cut the cartilage tissue to create clean margins. The cutting teeth are placed over the previously placed guide wire to ensure proper alignment. A drill, burr, or reamer is then used to create a cavity in the bone designed to receive the graft (i.e., the implantation site). The drill, burr, or reamer is placed over the wire or pin to ensure proper alignment. The cavity may create a press fit with the graft to provide initial fixation. The cavity may also be designed to receive posts, threads, or other means of securing the graft within the created cavity. The cavity may also be created to gain access to the cancellous bone for adhesive entry and connection when the second polymer layer is attached to the bone in vivo via the bonding agent. The drill may be used with another guide or may have a shoulder to ensure the cavity is drilled to the proper depth with markings. After the cavity is created, the wire or pin is removed.

[0120] The cavity is then checked for accuracy and fit using a test specimen. The test specimen mimics the shape of the graft and allows for evaluation of the desired graft seating depth and placement. After that evaluation is complete, the test specimen is removed from the cavity. If necessary, if the graft is not seated deeply enough, a wire or pin can be reinserted and the drill can be used again to adjust the cavity depth. The graft is then placed into the cavity. The exact insertion technique depends on the graft shape selected (e.g., press fit, stake, thread, etc.).

[0121] In some implementations, the implant is seated with the center of the implant elevated above the natural joint line and the edges of the implant recessed below the surrounding cartilage (Figure 4A). As the implant is loaded, a combination of elastic deformation of the support zone and time-dependent creep allows the implant to improve in vivo and conform to the surrounding cartilage (Figure 4B).

[0122] FIG. 12 is a flow chart illustrating a method 1200 of repairing cartilage damage at an articulating surface in a joint (e.g., a diarthrodial joint). The joint includes bone, and the damage is at least partially surrounded by external cartilage at the articulating surface, a portion of the external cartilage providing an area with a natural tissue line for articulation. The method 1200 includes steps 1202, 1204, 1206, and 1208. Step 1202 includes preparing a surgical site at the external cartilage area by removing at least a portion of the cartilage surrounding the damage and leaving a hole extending through the external cartilage area and into the bone. The external cartilage hole has an internal diameter. Step 1204 includes providing a biomimetic osteochondral graft including a support area and a base construct. The graft can be any of the grafts described herein, such as the grafts shown in and described with reference to FIGS. 1A-9J. The support zone has a lower surface and a conforming surface having an outer surface and a first periphery having an outer diameter. The conforming surface is configured to change shape upon articulation in the diarthrodial joint such that the outer surface conforms to the shape of an opposing surface of the orthopedic joint. Step 1206 includes threading the implant through the hole and into the bone such that the base construct bonds directly with the bone. Step 1208 includes securing the implant to the bone such that the outer surface of the conforming surface is offset in height relative to the natural tissue line of the external cartilage tissue.

[0123] The support area can have a first stiffness and the base construct can have a second stiffness greater than the first stiffness. The support area can have a stiffness gradient extending from the conforming surface to the lower surface. For example, the stiffness of the conforming surface can be less than the stiffness of the lower surface. As above, the support area can include a two-phase polymer with a water composition gradient as described above. The support area can include urethane. The support area can be smooth or non-smooth on its surface. The base construct can include metal, ceramic, bone, synthetic bone, or polymer.

[0124] In some implementations, the support zone is a first polymer layer disposed between the conforming surface and the lower surface, and the base construct includes a porous layer configured to couple directly to bone, and a second polymer layer. The second polymer layer is coupled to the first polymer layer at an intermediate interface between the lower surface and the shaped surface of the second polymer layer such that the second layer is disposed between the intermediate interface and the porous layer. The first polymer layer has a first stiffness, and the second polymer layer has a second stiffness, the second stiffness being greater than the first stiffness. The first polymer layer can have a first stiffness, and the second polymer layer can have a second stiffness, the second stiffness being greater than the first stiffness. Additionally, the porous layer can have a third stiffness greater than the second stiffness.

[0125] In some implementations, the first polymer layer is a water-swellable interpenetrating polymer network (IPN) or semi-IPN including a first polymer network and a second polymer network of a thermoplastic polymer, hi some implementations, the second polymer layer includes a copolymer of urethane dimethacrylate and methyl methacrylate monomers with hard and soft segments. The urethane dimethacrylate hard segment of the first polymer adhesive can be formed from one or more of 1,5-naphthalene diisocyanate (NDI), 2,6-toluene diisocyanate or 2,4-toluene diisocyanate (TDI), 3,3-bitoluene diisocyanate (TODI), cyclohexyl diisocyanate (CHDI), hexamethyl diisocyanate (HDI), isophorone diisocyanate (IPDI), methylene bis(p-phenyl)isocyanate, methylene diphenyl isocyanate (MDI), and methylene bis(p-cyclohexyl)isocyanate (HMDI). The soft segment of the urethane dimethacrylate monomer can be formed from one or more of polybutadiene, polyethylene oxide (PEO), hydroxy-terminated butadiene, hydroxybutyl-terminated polydimethylsiloxane (PDMS), hydroxyl-terminated polyisobutylene, poly(1,6-hexyl-1,2-ethyl carbonate), polycaprolactone, polycarbonate, polyethylene adipate, polyhexamethylene carbonate glycol, polypropylene oxide (PPO), polytetramethylene adipate, poly(dimethylsiloxane), and poly(tetramethylene oxide) (PTMO).

[0126] The implants described herein can be planar, plano-convex, or plano-concave, or any combination thereof. The support zone can be aligned laterally with the surrounding external cartilage along the first circumference, such that the supporting cartilage abuts the external cartilage along the first circumference. The sides of the implant can be fully abutted with the surrounding cartilage defining the hole, such that the implant is press-fit into the hole when implanted and secured. The conforming surface can be offset from the natural tissue lines in a distal direction to the bone or in a proximal direction to the bone. The support zone can vary in thickness, such that the edges of the conforming surface are offset from the natural tissue lines in one direction and the center of the conforming surface is offset from the natural tissue lines in the opposite direction.

[0127] Method 1200 can be used for osteochondral defect repair at various physiological sites, including, but not limited to, articulating surfaces of diarthrodial joints. Suitable sites include the knee joint (e.g., condyles, patellofemoral joint, total knee joint, meniscus, patella, or tibial plateau), ankle joint (e.g., talar surface or tibial surface), elbow joint (e.g., proximal ulna, distal humerus, or radial head), shoulder joint (e.g., labrum, glenoid cavity, humeral head, or any part thereof), wrist joint (e.g., metacarpal joint, knuckle, thumb joint, or base of thumb), hip joint (e.g., acetabular surface, femoral head, or part of either surface), foot joint (e.g., metatarsal joint or toe joint), temporomandibular joint (e.g., temporomandibular joint), wrist joint, spinal joint (e.g., facet joint), and any part thereof. The method 1200 is not limited to use in humans, but may be used for osteochondral repair in other organisms, particularly orthopedic joints or those with articulating cartilage tissue.

[0128] In some implementations, step 1202 includes using at least one of an awl, a surgical drill, a bur, a reamer, an alignment guide, a pin, a cutting blade, a cutter, or a wire. Any of these tools can be used to prepare the surgical site or to remove cartilage tissue. Step 1202 can include inserting a wire or pin through the guide into the injury, placing a drill, bur, or reamer over the wire or pin, and forming a hole with the drill, bur, or reamer. In some implementations, step 1202 includes reshaping bone in the hole.

[0129] In some implementations, prior to step 1206, the method 1200 further comprises verifying the depth of the hole. Verifying the depth can include inserting a test implant into the hole if the test implant mimics the size and shape of the implant.

[0130] Step 1206 may include using an implant insertion device, such as a clamp or threaded rod, to releasably hold the implant. Step 1208 may include using a mallet and tamp to fully seat the implant into the hole. Step 1208 may include using any of the coupling mechanisms 822 of FIGS. 8A-8I. Step 1208 may include bone growing new bone material into the base construct. For example, step 1208 may span a period of time, at the beginning of which the base construct and the bone are physically bonded, and at the end of which new bone material has grown from the bone into the base construct. Method 1200 further includes closing the surgical site. In some implementations, one or more of steps 1202-1208 are performed through an arthroscope.

[0131] Figures 13A-13D show an example of the implantation method 1200 of Figure 12 using a three-layered implant 1300. Figure 13A shows a lesion 1324 in native tissue 1318 and on bone 1316. The native tissue 1318 has a native tissue plane line 1319, represented by a dashed line, where the native tissue articulates with the opposing joint surface prior to the lesion formation.

[0132] 13B shows a hole 1326 formed during step 1202 of method 1200. The hole 1326 extends from the native tissue plane line 1319 to the bone 1316 and is surrounded by native tissue 1318. The hole 1326 is sized and shaped to fit the implant 1300, which can be any of the three-layer implants generally disclosed or specifically provided herein (e.g., implant 100, implant 300, implant 400, or implant 500).

[0133] 13C illustrates the insertion of an implant 1300 in step 1206 of method 1200. The implant 1300 includes a conforming surface 1304 and a support region, intermediate region, and base region, e.g., as described above with respect to Figure 3 or Figure 4. The implant 1300 is inserted into the bone 1316 through the hole 1326 such that the base region directly bonds with the bone 1316.

[0134] 13D shows the implant 1300 fully secured to the bone 1316. The conforming surface 1304 is offset in height relative to a natural tissue plane line 1319 of the surrounding natural cartilage tissue 1318. As explained above, the center of the conforming surface 1304 can overhang the natural tissue plane line 1319 such that under physiological loads, the conforming surface 1304 will conform in compression to the opposing joint surface to mimic the natural tissue plane line 1319.

[0135] Example 3: Implant curvature matching An 8 mm diameter version of the implant described in Example 1 was implanted into the medial femoral condyle of a skeletally developed Boer cross goat. Using a parapatellar approach, an osteochondral defect was created with a surgical drill and depth guide. The implant was press-fit into the defect and the incision was closed. Unrestricted weight bearing and activity was allowed. The joint was explanted at 8 weeks. Figures 14A-B show the appearance of the implant at the time of implantation, with the edges of the implant recessed against the surrounding cartilage. This is better visualized in Figure 14B, where a thin foil was used to create an imprint to confirm the initial seating of the implant. Figure 14C shows the appearance of the implant after 8 weeks, where it was found to be perfectly aligned with the surrounding cartilage.

[0136] Size and Shape of the Exemplary Embodiment As indicated above, the methods and implants described herein are adaptable for use in partial or complete repair of a variety of anatomical joints. The construction of a suitable implant will take into account a variety of design parameters to provide the appropriate shape and size (as well as the appropriate gradient as disclosed herein) for the desired anatomical location in accordance with this disclosure. Table 1 shows examples of configurations that may be used.

[0137] Table 1: Examples of graft configurations TIFF2024524156000002.tif98167

[0138] The foregoing is merely illustrative of the principles of the present disclosure, and the device may be practiced in other than the described embodiments, which are presented for purposes of illustration and not limitation. It should be understood that the subject matter and methods disclosed herein, while indicated for repair of cartilage tissue damage, may be applied to other forms of osteochondral, subchondral bone, or other bone repair.

[0139] Variations and modifications will occur to those skilled in the art after reviewing this disclosure. The disclosed features may be implemented in any combination and subcombination (including multiple dependent combinations and subcombinations) with one or more other features described herein. Various features described or shown above may be incorporated or integrated into other systems, including any components of those features. Additionally, certain features may be omitted or not implemented.

[0140] Examples of changes, substitutions, and alterations are ascertainable by one skilled in the art and can be made without departing from the scope of the information disclosed herein. All references cited herein are incorporated by reference in their entirety and made a part of this application. Example implementation

[0141] Item 1. A biomimetic osteochondral graft, a support region, a base region configured to be coupled to bone upon implantation of the implant, and a hydrophobic intermediate region disposed between the support region and the base region; the support zone comprises a conforming surface configured for articulation in an orthopaedic joint, a lower surface, a first thickness extending between the conforming surface and the lower surface, and a first compressibility having a first stiffness; the intermediate region has a shaped first surface, a second surface, and a second thickness extending between the shaped first surface and the second surface, the shaped first surface including a periphery and an exterior surface spaced apart within the periphery and connected to the lower surface of the support region, the lower surface of the support region conforming in shape to the surface, the intermediate region further having a second compressibility having a second stiffness greater than the first stiffness; The base region has an outer base surface connected to the second surface of the intermediate region, an inner base surface configured to connect to the bone, a third thickness extending between the inner base surface and the outer base surface, and a third compressibility having a third stiffness greater than the second stiffness.

[0142] Item 2. The implant of item 1, wherein the support region comprises a two-phase polymer.

[0143] Item 3. The implant according to item 2, wherein the two-phase polymer has a water composition of at least 10%.

[0144] Item 4. The implant according to item 3, wherein the water composition is at least 20% or at least 30%.

[0145] Item 5. The implant of any one of items 2 to 4, wherein the two-phase polymer has a water composition gradient between the conforming surface and the lower surface, the gradient comprising a water composition at the conforming surface, a water composition at the lower surface, and a bulk water composition extending between the conforming surface and the lower surface.

[0146] Item 6. The implant of item 5, wherein the water composition at the conforming surface is greater than the bulk water composition, and the bulk water composition is greater than the water composition at the lower surface.

[0147] Item 7. The implant according to item 6, wherein the water composition at the lower surface is less than 1%.

[0148] Item 8. The implant according to any one of items 5 to 7, wherein the bulk water composition has a gradient of 20% to 45%.

[0149] Item 9. The implant of item 8, wherein the water composition at the fitting surface is 40%-45% and the gradient of the bulk water composition is 27%-41%.

[0150] Item 10. The implant of any one of items 1 to 9, wherein the fitting surface is smooth.

[0151] Item 11. The implant of any one of items 1 to 10, wherein the underside is not smooth.

[0152] Item 12. The implant of any one of items 1, 10, or 11, wherein the support area comprises urethane.

[0153] Item 13. The implant of any one of items 1 to 12, comprising a contact interface formed between the front surface and the underside, the contact interface extending over at least 50% of the surface.

[0154] Item 14. The implant of item 13, wherein the contact interface extends over at least 75% of the surface.

[0155] Item 15. The implant of item 14, wherein the contact interface extends over at least 95% of the surface.

[0156] Item 16. The implant of any one of items 2 to 15, wherein the intermediate region, the support region, or both, comprise a separate polymer network.

[0157] Item 17. The implant of item 16, wherein the support region and the intermediate region are joined together via a chemical bond or a mechanical bond.

[0158] Item 18. The implant of item 17, wherein the support region and the intermediate region are joined together via a covalent bond.

[0159] Item 19. The implant of item 17, wherein the support region and the intermediate region are joined together via non-covalent bonds.

[0160] Item 20. The implant of item 17, wherein the support region and the intermediate region are joined together via polymer entanglement.

[0161] Item 21. The implant of any one of items 16 to 20, wherein the intermediate region and the base region are not entangled at a molecular level.

[0162] Item 22. The implant of any one of items 16 to 20, wherein the boundary between the intermediate zone and the base zone comprises an interdigitation of material of the intermediate zone and material of the base zone.

[0163] Item 23. The implant of item 22, wherein the material of the intermediate region is a polymer and the material of the base region is a porous metal.

[0164] Item 24. The implant of any one of items 1 to 23, wherein the intermediate region is or comprises an adhesive.

[0165] Item 25. The implant of item 24, wherein the adhesive is an injectable adhesive.

[0166] Item 26. The implant of any one of items 24 or 25, wherein the adhesive is light curable.

[0167] Item 27. The implant according to any one of items 1 to 26, comprising at least one pile structure in the intermediate region.

[0168] Item 28. The implant according to item 27, wherein the at least one pile structure comprises a plurality of piles in the intermediate region.

[0169] Item 29. The implant according to any one of items 27 or 28, wherein the at least one pile structure is disposed on the shaped first surface.

[0170] Item 30. The implant according to any one of items 27 or 28, wherein the at least one pile structure is disposed on the second surface.

[0171] Item 31. The implant of any one of items 1 to 30, comprising a central axis extending through the support region, the intermediate region, and the base region, wherein the support region, the intermediate region, and the base region each have an axis and are coaxially aligned along the central axis.

[0172] Item 32. The implant of item 31, wherein the second thickness is variable by a first height extending between the second surface and the first surface at a first location along the first surface and a second height extending between the second surface and the first surface at a second location along the first surface.

[0173] Item 33. The implant of item 32, wherein the first height is greatest at a location along the perimeter and the second height is greatest at a location within the surface.

[0174] Item 34. The implant of item 33, wherein the second height is coaxially aligned with the axis of the base region.

[0175] Item 35. The implant of any one of items 32 to 34, wherein one or more of the support zone or the intermediate zone is convex, concave, plano-convex, or plano-concave.

[0176] Item 36. The implant of item 35 comprising a tapered region extending along said surface from a maximum second height toward said outer periphery.

[0177] Item 37. The implant according to item 36, wherein the maximum first height is higher than the maximum second height.

[0178] Item 38. The implant of item 37, wherein the tapered region forms a concave curved surface.

[0179] Item 39. The implant according to item 38, wherein the maximum first height is less than the maximum second height.

[0180] Item 40. The implant of item 39, wherein the tapered region forms a convex curved surface.

[0181] Item 41. The implant of any one of items 32 to 40, wherein the outer periphery includes a curvilinear edge extending circumferentially about the central axis.

[0182] Item 42. The implant of any one of items 32 to 41, comprising raised regions extending radially across the surface.

[0183] Item 43. The implant of any one of items 32 to 42, comprising a plurality of ridges protruding into the underside.

[0184] Item 44. The implant of any one of items 32 to 43, wherein the surface comprises a plurality of regions each having a different radius of curvature.

[0185] Item 45. The implant according to any one of items 32 to 44, wherein the second thickness at locations along the periphery has a border height of 0.01 mm to 10 mm.

[0186] Item 46. The implant according to item 45, wherein the border height of the thickness of the intermediate region is 0.2 mm to 5 mm.

[0187] Item 47. The implant of any one of items 45 or 46, wherein the first height is about 1 mm.

[0188] Item 48. The implant of item 47, wherein the second thickness of the intermediate region tapers toward the periphery such that the border height is less than 0.1 mm.

[0189] Item 49. The implant of any one of items 47 or 48, wherein the support zone and the intermediate zone extend axially from the outer base surface to the conforming surface over an axial length of between 2 mm and 10 mm.

[0190] Item 50. The implant according to item 49, wherein the axial length is between 4 mm and 4.5 mm.

[0191] Item 51. The implant according to any one of items 1 to 50, wherein the perimeter encompasses an area having a width of 5 mm to 15 mm.

[0192] Item 52. The implant according to any one of items 1 to 51, wherein the second stiffness is 50 MPa to 500 MPa.

[0193] Item 53. The implant according to item 52, wherein the first stiffness is 40 MPa to 150 MPa and the third stiffness is 1.5 GPa to 11 GPa.

[0194] Item 54. The implant of any one of items 1 to 53, wherein the support zone has a stiffness gradient extending from the lower surface to the conforming surface of 1 kPa / mm or greater.

[0195] Item 55. The implant of any one of items 1 to 54, wherein the base region comprises at least one of a metal, a polymer, a ceramic, a bone, or a synthetic bone.

[0196] Item 56. The implant of item 55, wherein the metal comprises one or more of titanium, tantalum, stainless steel, cobalt chromium, nickel titanium alloy, zirconium alloy, plasma sprayed titanium coated metal, plasma sprayed ceramic coated metal, and the polymer comprises one or more of polyetheretherketone, polyethylene, polysulfone, or polypropylene.

[0197] Item 57. The implant of any one of items 1 to 56, wherein the medial base surface is configured to be coupled to a distal femur.

[0198] Item 58. The implant of any one of items 1 to 56, wherein the medial base surface is configured to be coupled to a proximal tibia.

[0199] Item 59. The implant according to any one of items 1 to 58, wherein the first thickness is 1 mm to 5 mm.

[0200] Item 60. The implant of any one of items 1 to 59, wherein the support region comprises a water-swellable interpenetrating polymer network (IPN) or semi-IPN, the base region comprises porous metal, and the intermediate region comprises a copolymer of urethane dimethacrylate monomers and monomers selected from methyl methacrylate, acrylamide, and dimethylacrylamide.

[0201] Item 61. The implant of any one of items 1 to 60, wherein the support zone has the ability to repeatedly deform between 2% and 25% under physiological load and recover more than 70% of the deformation upon removal of the load.

[0202] Item 62. The implant of item 61, wherein the intermediate zone is configured to deform between 2% and 10% under physiological load and repeatably recover 70% or more of the deformation upon removal of the physiological load.

[0203] Item 63. The implant according to any one of items 1 to 62, wherein when the support layer and the intermediate layer are connected, the implant has the ability to repeatedly deform between 5% and 20% under physiological load and recover by 80% or more.

[0204] Item 64. The graft according to item 63, wherein the repeatable recovery is 95% or more.

[0205] Item 65. A method of repairing a cartilage defect at an articulating surface in a diarthrodial joint comprising bone, said defect being at least partially surrounded by external cartilage at said articulating surface, a portion of said external cartilage providing an area with a natural tissue line for articulation, (i) preparing a surgical site in the outer cartilage region by removing at least a portion of the cartilage surrounding the defect to leave an outer cartilage cavity having an internal diameter extending through the outer cartilage region and into the bone; (ii) providing a biomimetic osteochondral graft comprising a support zone and a base construct, said support zone having an underside and a conforming surface having an outer surface and a first periphery having an outer diameter, said conforming surface configured to change shape upon articulation within said diarthrodial joint such that said outer surface conforms to a shape of an opposing surface of said orthopaedic joint; (iii) threading the implant into the hole and toward the bone such that the base construct bonds directly with the bone; (iv) fixing the implant to the bone such that the outer surface of the conforming surface is offset in height relative to the native tissue line of the external cartilage tissue.

[0206] Item 66. The method of item 65, wherein the support area comprises a two-phase polymer.

[0207] Item 67. The method of item 66, wherein the two-phase polymer has a water composition of at least 10%.

[0208] Item 68. The method according to Item 67, wherein the water composition is at least 20%.

[0209] Item 69. The method according to Item 68, wherein the water composition is at least 30%.

[0210] Item 70. The method of any one of items 68 or 69, wherein the two-phase polymer has a water composition gradient between the conformable surface and the lower surface.

[0211] Item 71. The method of item 70, wherein the water composition gradient has a water composition of less than 5% at the lower surface.

[0212] Item 72. The method of item 71, wherein the water composition at the lower surface is less than 1%.

[0213] Item 73. The method according to any one of items 70 to 72, wherein the water composition gradient has a water composition of at least 40% at the matching surface.

[0214] Item 74. The method of any one of items 65 to 73, wherein the fitting surface is smooth.

[0215] Item 75. The method of any one of items 65 to 74, wherein the lower surface is not smooth.

[0216] Item 76. The method of any one of items 65, 74, or 75, wherein the support area comprises urethane.

[0217] Item 77. The method of any one of items 65 to 76, wherein the implant is plano-convex or plano-concave.

[0218] Item 78. The method of any one of items 65 to 76, wherein the base composition comprises a porous metal.

[0219] Item 79. The method of any one of items 65 to 78, wherein the surgical site is at the distal femur, the proximal tibia, or the patella.

[0220] Item 80. The method of any one of items 65 to 78, wherein the surgical site is at the distal tibia, distal fibula, calcaneus, or talus.

[0221] Item 81. The method of any one of items 65 to 78, wherein the surgical site is at the tibiofibular joint.

[0222] Item 82. The method of any one of items 65 to 78, wherein the surgical site is in the proximal humerus or glenoid fossa.

[0223] Item 83. The method of any one of items 65 to 78, wherein the surgical site is in the proximal thigh or pelvis.

[0224] Item 84. The method of any one of items 65 to 78, wherein the surgical site is at the distal humerus, the proximal ulna, or the proximal radius.

[0225] Item 85. The method of any one of items 65 to 78, wherein the surgical site is at the distal radius, the distal ulna, or the carpal bones.

[0226] Item 86. The method of any one of items 65 to 78, wherein the surgical site is at the metatarsophalangeal joint, the tarsometatarsal joint, the intermetatarsal joint, the distal metacarpal, or the proximal phalange.

[0227] Item 87. The method of any one of items 65 to 78, wherein step (i) includes using at least one of an awl, a surgical drill, a bur, a reamer, an alignment guide, a pin, an incisor, a cutter, or a wire.

[0228] Item 88. The method of any one of items 65 to 78, wherein the injury is at least partially surrounded by tissue.

[0229] Item 89. The method of any one of items 65 to 78, further comprising verifying the depth of the hole prior to step (iii).

[0230] Item 90. The method of item 89, wherein verifying the depth includes inserting a test implant that mimics the implant into the hole.

[0231] Item 91. The method of any one of items 65 to 90, wherein step (iii) comprises using an implant insertion device to releasably hold the implant.

[0232] Item 92. The method of any one of items 65 to 91, wherein step (iv) includes using a mallet and tamp to fully seat the graft within the hole.

[0233] Item 93. The method of any one of items 65 to 92, wherein step (i) comprises remodeling the bone in the hole.

[0234] Item 94. The method of any one of items 65 to 93, wherein one or more of steps (i) to (iv) are performed through an arthroscope.

[0235] Item 95. The method of any one of items 65 to 94, wherein the support area is laterally aligned with the external cartilage tissue along the first circumference such that the support area contacts the external cartilage tissue.

[0236] Item 96. The method of any one of items 65 to 95, further comprising closing the surgical site.

[0237] Item 97. The method of any one of items 65 to 96, wherein step (i) comprises inserting one or both of a guide wire or a pin through the guide into the injury, placing at least one of a drill, a burr, or a reamer over the wire or pin, and forming the hole with the drill, burr, or reamer.

[0238] Item 98. The method of any one of items 65 to 97, wherein the hole is shaped such that the implant will be a press fit into the hole when secured.

[0239] Item 99. The method of any one of items 65 to 98, wherein the conforming surface is offset from the native tissue line in a distal direction relative to the bone.

[0240] Item 100. The method of any one of items 65 to 98, wherein the conforming surface is offset from the native tissue line in a proximal direction relative to the bone.

[0241] Item 101. The method of any one of items 65 to 100, wherein the support area comprises a stiffness gradient between the conforming surface and the lower surface.

[0242] Item 102. The method of item 101, wherein the stiffness gradient comprises a stiffness of the conforming surface that is less than a stiffness of the lower surface.

[0243] Item 103. The method of any one of items 65 to 102, wherein the support area is a first polymer layer disposed between the conforming surface and the lower surface, and the base construct includes a porous layer configured to directly couple to the bone and a second polymer layer, the second polymer layer being coupled to the first polymer layer at an intermediate interface between the lower surface and a molded surface of the second polymer layer such that the second layer is disposed between the intermediate interface and the porous layer.

[0244] Item 104. The method of item 103, wherein the first polymer layer has a first stiffness and the second polymer layer has a second stiffness, the second stiffness being greater than the first stiffness.

[0245] Item 105. The method of item 104, wherein the porous layer has a third stiffness greater than the second stiffness.

[0246] Item 106. The method of any one of items 103 to 105, wherein the second polymer layer comprises a copolymer of a urethane dimethacrylate monomer having a hard segment and a soft segment and a methyl methacrylate monomer.

[0247] Item 107. The method of item 106, wherein the hard segment of the urethane dimethacrylate of the first polymer adhesive is formed from one or more of 1,5-naphthalene diisocyanate (NDI), 2,6-toluene diisocyanate or 2,4-toluene diisocyanate (TDI), 3,3-bitoluene diisocyanate (TODI), cyclohexyl diisocyanate (CHDI), hexamethyl diisocyanate (HDI), isophorone diisocyanate (IPDI), methylene bis(p-phenyl)isocyanate, methylene diphenyl isocyanate (MDI), and methylene bis(p-cyclohexyl)isocyanate (HMDI).

[0248] Item 108. The method of any one of items 106 or 107, wherein the soft segment of the urethane dimethacrylate monomer is formed from one or more of polybutadiene, polyethylene oxide (PEO), hydroxy-terminated butadiene, hydroxybutyl-terminated polydimethylsiloxane (PDMS), hydroxyl-terminated polyisobutylene, poly(1,6-hexyl-1,2-ethyl carbonate), polycaprolactone, polycarbonate, polyethylene adipate, polyhexamethylene carbonate glycol, polypropylene oxide (PPO), polytetramethylene adipate, poly(dimethylsiloxane), and poly(tetramethylene oxide) (PTMO).

[0249] Item 109. The method of any one of items 103 to 108, wherein the first polymer layer is a water-swellable interpenetrating polymer network (IPN) or semi-IPN comprising a first polymer network and a second polymer network of a thermoplastic polymer.

[0250] Item 110. The method according to any one of items 65 to 109, wherein the graft is a graft according to any one of items 1 to 64.

Claims

**Claim 1** A biomimetic osteochondral graft, comprising a support region, a base region configured to be connected to bone upon implantation of the graft, and a hydrophobic intermediate region disposed between the support region and the base region, wherein the support region comprises a biphasic polymer, a smooth conforming surface configured for joint articulation within an orthopedic joint, a non-smooth lower surface, a first thickness extending between the smooth conforming surface and the non-smooth lower surface, and a first compression modulus having a first stiffness, wherein the hydrophobic intermediate region has a formed first surface, a second surface, and a second thickness extending between the formed first surface and the second surface, the formed first surface including an outer perimeter and an outer surface spaced within the outer perimeter and connected to the non-smooth lower surface of the support region, the non-smooth lower surface of the support region having a shape conforming to the outer surface, and the hydrophobic intermediate region further having a second compression modulus having a second stiffness greater than the first stiffness, wherein the base region has an outer base surface connected to the second surface of the hydrophobic intermediate region, an inner base surface configured to be connected to the bone, and a third thickness extending between the inner base surface and the outer base surface, and a third compression modulus having a third stiffness greater than the second stiffness, the biomimetic osteochondral graft. **Claim 2** The graft according to claim 1, wherein the biphasic polymer has a water composition of at least 10%. **Claim 3** The graft according to claim 1, wherein the biphasic polymer has a water composition gradient between the smooth conforming surface and the non-smooth lower surface, the gradient comprising a water composition at the smooth conforming surface, a water composition at the non-smooth lower surface, and a bulk water composition extending between the smooth conforming surface and the non-smooth lower surface. **Claim 4** The graft according to claim 3, wherein the water composition at the smooth conforming surface is greater than the bulk water composition, and the bulk water composition is greater than the water composition at the non-smooth lower surface. **Claim 5** The graft according to claim 3, wherein the bulk water composition has a gradient of 20% to 45%, the water composition at the smooth conforming surface is 40% to 45%, and the water composition at the non-smooth lower surface is less than 1%. **Claim 6** The graft according to claim 1, wherein the support region comprises urethane. **Claim 7** The graft according to claim 1, comprising a contact interface formed between the outer surface and the non-smooth lower surface and extending over at least 50%, at least 75%, or at least 95% of the outer surface.

8. The graft according to claim 1, further comprising at least one pile structure in the hydrophobic intermediate region, the at least one pile structure comprising a plurality of piles in the hydrophobic intermediate region.

9. The graft according to claim 8, wherein the at least one pile structure is disposed on the formed first surface or the second surface.

10. Further comprising a central axis extending through the support region, the hydrophobic intermediate region, and the base region, the support region, the hydrophobic intermediate region, and the base region each having an axis and being coaxially aligned along the central axis. The graft according to claim 1, wherein the second thickness is variable by a first height extending between the second surface and the first surface at a first position along the first surface and a second height extending between the second surface and the first surface at a second position along the first surface.

11. The graft according to claim 10, wherein the first height is maximum at a position along the outer periphery and the second height is maximum at a position within the outer surface.

12. The graft according to claim 11, wherein the second height is aligned coaxially with the axis of the base region.

13. The graft according to claim 11, wherein one or more of the support region or the hydrophobic intermediate region is convex, concave, plano-convex, or plano-concave.

14. Further comprising a tapered region extending along the outer surface from the maximum second height towards the outer periphery. The maximum first height is higher than the maximum second height and the tapered region forms a concave curved surface, or The maximum first height is lower than the maximum second height and the tapered region forms a convex curved surface. The graft according to claim 13.

15. The graft according to claim 10, wherein the outer periphery includes a curved edge extending circumferentially around the central axis.

16. The graft according to claim 10, further comprising a raised region having at least one raised portion extending radially across the outer surface and protruding into the non-smooth lower surface.

17. The graft according to claim 10, wherein the outer surface includes a plurality of regions having different radii of curvature.

18. The second thickness at a position along the outer periphery has a boundary height of 0.01 mm to 10 mm or 0.2 mm to 5 mm, and the implant according to claim 10.

19. The support region and the hydrophobic intermediate region extend axially over an axial length of 2 mm to 10 mm or 4 mm to 4.5 mm from the outer base surface to the smooth conforming surface, and the implant according to claim 18.

20. The outer periphery surrounds a region having a width of 5 mm to 15 mm, and the implant according to claim 1.

21. The second rigidity is 50 MPa to 500 MPa, the first rigidity is 40 MPa to 150 MPa, and the third rigidity is 1.5 GPa to 11 GPa, and the implant according to claim 1.

22. The support region has a rigidity gradient of 1 kPa / mm or more extending from the non-smooth lower surface to the smooth conforming surface, and the implant according to claim 1.

23. The base region includes at least one of metal, polymer, ceramic, bone, or synthetic bone, The metal includes one or more of titanium, tantalum, stainless steel, cobalt chromium, nickel titanium alloy, zirconium alloy, metal coated with plasma-sprayed titanium, metal coated with plasma-sprayed ceramic, and the polymer includes one or more of polyetheretherketone, polyethylene, polysulfone, or polypropylene, and the implant according to claim 1.

24. The inner base surface is configured to be connected to the distal part of the thigh, the proximal part of the tibia, the patella, the condyle, the distal part of the tibia, the distal part of the fibula, the calcaneus, the talus, the tibiofibular joint, the proximal part of the humerus, the articular labrum, the head of the humerus, the glenoid fossa, the proximal part of the thigh, the pelvis, the distal part of the humerus, the proximal part of the ulna, the proximal part of the radius, the distal part of the radius, the distal part of the ulna, the carpal bones, the distal part of the metacarpal bones, the phalanges, the midfoot bones, the temporomandibular joint, or the spine, and the implant according to claim 1.

25. The first thickness is 1 mm to 5 mm, and the implant according to claim 1.

26. The support region includes a water-swellable interpenetrating polymer network structure (IPN) or semi-IPN, the base region includes a porous metal, and the hydrophobic intermediate region includes a copolymer composed of a urethane dimethacrylate monomer and a monomer selected from methyl methacrylate, acrylamide, and dimethylacrylamide, and the implant according to claim 1.

27. The support region is capable of deforming between 2% and 25% under physiological load and repeating a recovery of 70% or more of the deformation when the load is removed. The graft according to claim 1, wherein the hydrophobic intermediate region is configured to deform between 2% and 10% under physiological load and repeat a recovery of 70% or more of the deformation when the physiological load is removed.

28. When the support layer and the hydrophobic intermediate layer are connected, the graft according to claim 1 has the ability to deform between 5% and 20% under physiological load and repeat a recovery of 80% or more or 95% or more.

29. The graft according to claim 1, further comprising a bonding layer extending over at least 25% of the substantially hydrophobic contact interface.

30. The graft according to claim 29, wherein the bonding layer comprises a covalent bond.

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