Plug-type implant for biological tissue replacement and regeneration, and method for manufacturing said implant

Abstract

A plug-shaped non-biodegradable implant for tissue replacement and regeneration, comprising a base section (2) configured to be fixed to bone tissue, an intermediate section (3) configured to replace cartilage tissue in the intermediate and deep regions of the cartilage layer and to have a thickness of at least 0.2 mm, and an upper section (4) configured to grow cartilage tissue upward and inward to regenerate the superficial zone of the cartilage layer, wherein the intermediate section and the upper section comprise the same thermoplastic elastomer material which is porous in the upper section and non-porous in the intermediate section, the thermoplastic elastomer material comprises a linear block copolymer comprising urethane groups and urea groups and substantially free of added peptide compounds having cartilage regeneration properties, and the base section material comprises a biocompatible metal such as titanium or titanium alloy, a ceramic such as sintered crystalline hydroxylapatite, a mineral such as a phosphate mineral, and a polymer, optionally a hydrogel polymer, and a combination thereof.

Description

Technology Field

[0001] The present invention relates to a plug-shaped implant for replacing and regenerating biological tissue. In particular, the present invention relates to a plug-shaped implant for replacing and regenerating osteochondral structures. Furthermore, the present invention relates to a method for manufacturing said implant and an osteochondral structure comprising said implant. Background Technology

[0002] Osteochondral structures refer to structures containing cartilage and bone. Typical osteochondral structures can be found in the femur, tibia, and patella. These structures fit together snugly and move smoothly because the bone surfaces are covered with a relatively thick layer of articular (hyaline) cartilage. An osteochondral defect is any type of damage to articular cartilage and, optionally, the underlying (subchondral) bone. Typically, osteochondral defects appear at specific weight-bearing points, for example, at the ends of the femur and tibia and the posterior part of the patella. This can range from roughened cartilage, small bone fragments, and cartilage fragments that impede movement, to complete cartilage loss.

[0003] Trauma to the joint surface commonly occurs in active young people participating in sports or as a sequela of accidents. The lesion can involve not only the cartilage layer but often the underlying subchondral bone. Articular cartilage has a very low healing tendency, and the repaired tissue is qualitatively inferior to the original tissue. This invariably leads to the development of osteoarthritis (OA) over time, which is a major cause of reduced quality of life and disability in the elderly. The standard treatment for this condition is ultimately joint replacement with an artificial joint. Although clinically effective, non-biological implants do not last for more than 10 to 20 years, and revision surgery is much less effective and more expensive. For this reason, much research is being conducted to develop biological regenerative therapies that can last a lifetime. However, despite promising in vitro results, no single therapy has to date been proven to be more effective than current standard treatments over a longer period in real-life conditions.

[0004] Because the cartilage layer lacks nerve fibers, patients often fail to perceive the severity of the damage. In the final stages, the affected joint causes bone-on-bone friction, leading to severe pain and limited mobility. By the time patients seek medical treatment, surgical intervention may be necessary to alleviate pain and repair cartilage damage. Joint implants have been developed to avoid or postpone such surgical intervention. Since they can be implanted into the bone structure at the early stages of cartilage damage, they can serve as a preventive treatment to avoid the invisible degeneration of the joint.

[0005] There are numerous treatments available to treat articular cartilage damage in joints such as the knee, ranging from the most conservative and non-invasive options to total joint replacement when damage has spread throughout the entire joint. Currently available treatments include anti-inflammatory drugs in the early stages. While these relieve pain, their effectiveness regarding arthritis symptoms is limited, and they do not repair joint tissue. Cartilage repair methods, such as arthroscopic debridement, attempt to at least delay tissue degeneration. However, these methods are only partially effective for soft tissue repair and cannot restore joint space or improve joint stability. Joint replacement (arthroplasty) is considered a last resort when all other options for pain relief and mobility restoration have failed or are no longer effective. While arthroplasty can be effective, the procedure is highly invasive and technically challenging, which can complicate future treatment options. Cartilage regeneration has also been attempted, particularly through tissue engineering techniques. The use of cells, genes, and growth factors combined with scaffolds plays a fundamental role in the regeneration of functional and viable articular cartilage. All of these approaches are based on stimulating the body's normal healing or repair processes at the cellular level. Many of these compounds are delivered over various carriers or matrices, including woven polylactic acid-based polymers or collagen fibers. Despite various attempts at cartilage regeneration, there is currently no reliable, proven treatment to repair articular cartilage defects.

[0006] Another standard of treatment is for small lesions (≤ 2 cm 2 Microfracture (MFx) for ) and large lesions (> 2 cm 2It consists of Autologous Chondrocyte Implantation (ACI). However, cartilage tissue regenerated using this technique cannot withstand biomechanical problems in the joint and begins to degenerate within 18 months. Therefore, a substantial delay in joint replacement with artificial joints is impossible, let alone preventable. As prior art, U.S. Patent Application Publication No. 2009 / 0164014 discloses a biodegradable osteochondral implant comprising porous top and porous bottom sections separated by a barrier that impermeably impermees agents having a detrimental effect on cartilage regeneration. U.S. Patent Application Publication No. 2005 / 013793 discloses a biodegradable and biocompatible polyurethane composition comprising a hard segment and a soft segment. U.S. Patent Application Publication No. 2012 / 209396 discloses an orthopedic implant having a bone interface member. U.S. Patent Application Publication No. 2008 / 262618 discloses a prosthetic device comprising a body at least partially formed of a biocompatible segment thermoplastic elastomer having a crystallized block and at least one functional component capable of reversibly bonding to the crystallized block, wherein the elastomer is cartilage regeneration It has characteristics.

[0007] The object of the present invention is to provide a plug-shaped implant for the replacement and regeneration of biological tissues, with improved load distribution as well as cartilage regeneration characteristics. Another object is to provide such a plug-type implant for the replacement and regeneration of osteochondral structures. Another object is to provide a method for manufacturing such an implant. Furthermore, the present invention aims to provide an implant capable of repairing articular cartilage lesions in a durable manner, and at least delaying, and preferably preventing, the replacement of the joint with an artificial joint.

[0008] The above and other objectives are provided by a plug-type implant according to claim 1. The plug-type non-biodegradable implant comprises a base section configured to be fixed to bone tissue in particular, a middle section configured to replace cartilage tissue in the middle and deep regions of the cartilage layer and to have a thickness of at least 0.2 mm, and a top section configured to grow cartilage tissue upward and inward to regenerate the superficial zone of the cartilage layer, wherein the middle section and the top section comprise the same thermoplastic elastomer material which is porous in the top section and non-porous in the middle section, the thermoplastic elastomer material comprises a linear block copolymer comprising urethane groups and / or urea groups and substantially free of added peptide compounds having cartilage regeneration properties, and the base section material comprises one of a biocompatible metal, a mineral such as a ceramic or phosphate mineral, and a polymer, optionally a hydrogel polymer, and a combination thereof. Preferably, the thermoplastic elastomer material substantially does not contain any added compounds having cartilage regeneration properties.

[0009] In cartilage, a relatively thin superficial (tangential) region protects the deeper layers from shear stress and accounts for about 10% to 20% of the articular cartilage thickness. Collagen fibers in this region (mainly type II and type IX collagen) are tightly packed and aligned parallel to the joint surface (Fig. 2). The superficial layer contains a relatively large number of flattened chondrocytes, and the integrity of this layer is essential for protecting and maintaining the deeper layers. This region is in contact with synovial fluid and is responsible for most of the tensile properties of the cartilage, which can withstand shear, tensile, and compressive forces applied by the joint.

[0010] The region immediately below or deep within the superficial region is the intermediate (intermediate or transitional) region, which provides an anatomical and functional bridge between the superficial and deep regions. The intermediate region accounts for 40% to 60% of the total cartilage volume and contains proteoglycans and thicker collagen fibrils. In this layer, collagen is obliquely structured, and chondrocytes are spherical and low in density. Functionally, the intermediate region is the first line of resistance to compressive forces.

[0011] Given that collagen fibrils are arranged perpendicularly to the joint surface, the deep region of the cartilage serves to provide the greatest resistance to compressive forces. The deep region contains the largest diameter collagen fibrils arranged radially, the highest proteoglycan content, and the lowest water concentration. Chondrocytes are typically arranged in a columnar orientation parallel to the collagen fibers and perpendicular to the joint line. The deep region accounts for approximately 30% of the volume of articular cartilage.

[0012] The base section material can be formed from any suitable material that provides an appropriate level of mechanical support to the surrounding bone and, preferably, enables bone formation. Suitable materials, including thermoplastic elastomer materials for the middle and upper sections of the implant, are biocompatible, where biocompatibility means being able to coexist with biological tissues or organisms without causing harm. Furthermore, the implant according to the present invention is substantially non-biodegradable and combines cartilage replacement and cartilage regeneration. In the context of the present invention, a non-biodegradable material means a material that does not decompose into compounds having fewer carbon atoms or less complex compounds by the environment of the implanted implant. The weight-average molecular weight of the substantially non-biodegradable material decreases by up to 20%, more preferably up to 10%, even more preferably up to 5%, and even more preferably up to 1% compared to the original weight-average molecular weight one year after implantation.

[0013] Metals suitable as base section materials include, but are not limited to, titanium, zirconium, chromium, aluminum, stainless steel, hafnium, tantalum or molybdenum, and alloys thereof, or combinations thereof. Optionally, a surface layer of the metal may be oxidized, nitrided, carburized, or boronized to form a coated metal base section.

[0014] Ceramics and minerals suitable as base section materials include, but are not limited to, oxides, nitrides, carbides or borides, or combinations thereof. Suitable examples include living glass, calcium phosphate (e.g., tricalcium beta-phosphate (TCP), diphase calcium phosphate), and apatides (e.g., hydroxyapatite, fluoroapatite, chlorapatite and / or calcium-deficient apatite), and combinations thereof.

[0015] Polymers suitable as base section materials (hydrogel) include, but are not limited to, collagen, poly(lact-co-glycolic acid) (PLGA), polylactic acid (PLA), polycaprolactone (PCL), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyacrylamide, polyurethane, polyethylene glycol (PEG), chitin, poly(hydroxyalkyl methacrylate), water-swellable N-vinyl lactam, starch graft copolymers, and derivatives and combinations thereof.

[0016] Other preferred materials for the base section include polyaryletherketone (PAEK) polymers. PAEK polymers comprise semicrystalline thermoplastic polymers containing alternating ketone groups (R-CO-R) and ether groups (ROR). The linker R between the functional groups comprises a 1,4-substituted aryl group. PAEK polymers used for the base section may specifically include PEK (polyetherketone), PEEK (polyetheretherketone), PEKK (polyetherketoneketone), PEEKK (polyetheretherketoneketone), and PEKEKK (polyetherketoneetherketoneketone). Due to their excellent resistance to hydrolysis, polyaryletherketone polymers for the base section are advantageously used in the implants of the present invention. They do not degrade even when sterilized or implanted in the body for a long period. They have also been found to bond particularly well with the elastomer materials of the intermediate and upper sections.

[0017] The material used in the base section of the implant of the present invention may be used as is, or, in one embodiment, may include a reinforcing material selected from the group consisting of fibrous or particulate polymers and / or metals.

[0018] The base section of the implant of the present invention may also include a medical imaging contrast agent that absorbs radiation (e.g., a radiocontrast agent or an MRI contrast agent), or a radiopharmaceutical that emits radiation on its own. The base section may also include a small solid object or body, such as a bead, which may include a refractory metal such as tantalum, for example.

[0019] The base section of a plug-type implant functions as a bone fixator, while the combination of the middle and upper sections functions as a partial replacement for damaged cartilage and a scaffold for cartilage regeneration. In a plug-type implant, the upper section represents the section closest to the cartilage phase at implantation. The base section represents the section furthest from the cartilage phase at implantation. The middle section is located between the upper and base sections.

[0020] The cross-section of the plug-type implant across the horizontal or vertical plane may have any suitable shape. The cross-section may be circular, square, or polygonal, such as hexagonal, octagonal, or decagonal. In some embodiments, the plug-type implant may be tapered to be shaped into a truncated cone structure. Preferably, the implant has a smaller cross-section in the base section than in the upper section. The cross-section (or diameter in the case of a cylindrical implant) may vary continuously between the base section and the upper section, or may exhibit discontinuity, for example, at the interface between the sections.

[0021] If the implant has a tapered profile, the angle of the taper is preferably 1° to 45°. In some embodiments, the taper is about 3° to 30°, more preferably 5° to 30°, and even more preferably 10° to 15°. A tapered profile can facilitate the insertion of the implant into an osteochondral defect and further reduce possible damage to the host tissue. The implant is preferably used without any means of attachment and is retained in the osteochondral structure by its geometry and surrounding tissue structure. The implant may be used in the knee, but may also be used in other joints such as the temporomandibular joint, ankle, hip, shoulder, etc.

[0022] According to the present invention, a plug-type implant located at the top of a base section further comprises an intermediate section configured to replace cartilage tissue and an upper section configured to grow cartilage tissue upward and inward, wherein the intermediate section and the upper section comprise the same thermoplastic elastomer material. This implies that at least their building blocks are chemically identical. As mentioned herein, some physical properties, e.g., weight-average molecular weight, may differ. The thermoplastic elastomer material comprises a linear block copolymer that is porous in the upper section and non-porous in the intermediate section, and contains urethane groups and / or urea groups. Furthermore, the thermoplastic elastomer material substantially lacks any added peptide compounds having cartilage regeneration properties. Surprisingly, it has been found that the implant of the present invention regenerates cartilage tissue, thereby avoiding the use of any functional compound exhibiting cartilage regeneration properties. In particular, the implant according to this embodiment has been found not to require the use of, for example, a peptide containing an RGD sequence. These compounds are known to be able to stimulate cell adhesion by binding to integrins.

[0023] The linear block copolymer of the present invention is a segmented copolymer having elastic properties resulting from hydrogen bonding interactions between molecular chains. Such copolymers may comprise 'hard' crystallized blocks of polyurethane and / or polyurea segments, and may also comprise 'hard' crystallized blocks of polyester and / or polyamide between 'soft' blocks. At room temperature, the low-melting-point 'soft' blocks may be inmiscible with the high-melting-point 'hard' blocks, which induces phase separation by crystallization or liquid-liquid separation. Such copolymers exhibit reversible physical crosslinking resulting from the crystallization of the 'hard' blocks of the segmented copolymer. The thermoplastic elastomer can be formed into any shape at high temperatures, more particularly at temperatures higher than the melting point of the 'hard' blocks. Meanwhile, the thermoplastic elastomer provides mechanical stability and elastic properties at low temperatures, i.e., at typical body temperature. This makes these materials particularly suitable as substitutes for human or animal cartilage.

[0024] The components of a thermoplastic elastomer generally include the following three building blocks: a long-chain diol having a polyether, polyester, or polycarbonate backbone, a difunctional diisocyanate, and finally, a chain extender such as water, another (sometimes short-chain) diol, or a diamine. The chain extender is desirable because it induces bisurea units in the thermoplastic elastomer.

[0025] An embodiment of an implant in which the thermoplastic elastomer material is aliphatic is preferred. This means that all building blocks of the thermoplastic elastomer contain only aliphatic groups and no aromatic groups. The thermoplastic elastomer of the present invention can be prepared by a one-pot procedure in which a long-chain diol is first reacted with an excess amount of diisocyanate to form an isocyanate-functionalized prepolymer. The prepolymer is subsequently reacted with a chain extender (e.g., a preferred diamine) to form a high molecular weight thermoplastic elastomer polymer containing urethane groups. When a diamine is used as a chain extender, the thermoplastic elastomer will also preferably contain bisurea groups.

[0026] The synthesis procedure for manufacturing thermoplastic elastomers can lead to a distribution of 'hard' block lengths. As a result, the phase separation of these block copolymers may be incomplete, and some of the 'hard' blocks, particularly shorter blocks, dissolve into the soft phase, increasing the glass transition temperature. This is less desirable for the low-temperature flexibility and elasticity of the thermoplastic elastomer material in the upper and middle sections. The polydispersity of the 'hard' blocks exhibits a wide melting range and a rubbery plateau in temperature-dependent dynamic mechanical thermal analysis (DMTA). Therefore, a preferred embodiment comprises an elastomer block copolymer containing 'hard' blocks of substantially uniform lengths. This can be prepared by fractionating a mixture of 'hard' block oligomers and subsequently copolymerizing the aforementioned prepolymer with uniform 'hard' block oligomers of specific lengths (or length variations).

[0027] Thermoplastic elastomers can be prepared by the chain extension reaction of an isocyanate-functionalized prepolymer with a diamine, but they may also be prepared by the chain extension reaction of an amine-functionalized prepolymer with a diisocyanate. Examples of suitable and commercially available diamines and isocyanates include alkylene diamines and / or diisocyanates, and arylene diamines and / or diisocyanates. The amine-functionalized prepolymer may also be commercially available, or prepared by cyanoethylation followed by reduction of the cyano group from (easily available) hydroxy-functionalized prepolymers, by Gabriel synthesis (modification to phthalimide following halogenation or tosylation, and finally formation of a primary amine by deprotection of the phthalimide), or by other methods known in the art. Isocyanate-functionalized prepolymers can be prepared by the reaction of a hydroxy-functionalized prepolymer with a diisocyanate, such as, for example, isophorone diisocyanate (IPDI), 1,4-diisocyanatobutane, 1,6-diisocyanatohexane, or 4,4'-methylenebis(phenyl isocyanate). Alternatively, isocyanate-functionalized prepolymers can be prepared by the reaction of an amine-functionalized prepolymer with, for example, di-tert-butyl tricarbonate. Hydroxy-functionalized prepolymers of all kinds of compositions, typically in the range of about 500 g / mol to about 5000 g / mol, are also advantageously used. Examples thereof include prepolymers such as polyethers (e.g., polyethylene glycol, polypropylene glycol, poly(ethylene-co-propylene) glycol and poly(tetrahydrofuran)), polyesters (e.g., poly(caprolactone) or polyadipate, polycarbonate), polyolefins, and hydrogenated polyolefins (e.g., poly(ethylene-butylene)). Polycarbonate is preferred.

[0028] A polycarbonate prepolymer is particularly preferred. Such a prepolymer produces an implant according to an embodiment in which the thermoplastic elastomer material additionally comprises carbonate groups in addition to urethane and / or urea groups. Such an implant has been proven to better satisfy the purpose of the present invention than other implants. In particular, it has been proven beneficial in that its mechanical properties are well matched to the mechanical properties of human or animal cartilage. Surprisingly, cartilage regeneration is improved when such an embodiment is used in an implanted implant.

[0029] A particularly preferred embodiment of the present invention provides an implant comprising a thermoplastic elastomer material comprising poly-urethane-bisurea-alkylene carbonate, more preferably poly-urethane-bisurea-hexylene carbonate.

[0030] In addition to excluding peptide compounds having cartilage regenerative properties from the linear block copolymer, the implant may comprise an agent that promotes the migration, integration, regeneration, proliferation, and growth of cells into and around the injury or defect, promotes the healing of the injury or defect, and is chondrogenic and osteogenic, that is, to build, grow, and generate cartilage and bone, respectively. Such agents include, but are not limited to, cytokine compounds, chemokine compounds, chemical attractants, antimicrobial compounds, antiviral compounds, anti-inflammatory compounds, pro-inflammatory compounds, bone or cartilage regenerative molecules, cells, blood components (e.g., whole blood and platelets), and combinations thereof. Agents that increase strength and promote adhesion may also be included in the implant. In a preferred embodiment, the elastomeric linear block copolymer does not comprise any compound having cartilage regenerative properties.

[0031] In the context of the present invention, a substantially non-porous material means a material having a porosity of less than 20%, preferably 10% or less, more preferably 5% or less, and even more preferably 1% or less based on the total volume of the material. A porous material comprises pores defined as fine openings. The pores may be micropores with a diameter of less than 1 mm or macropores with a diameter greater than 1 mm. The pores may preferably be interconnected, which means that the pores are internally connected or have continuity between parts or elements. In the context of the present invention, a non-porous material does not mean a material impermeable to molecules of any size, and some small molecules may actually pass through the non-porous material. To be precise, in the context of the present invention, a non-porous material refers to a material impermeable to lubricating fluid and / or blood.

[0032] The pore size of the porous portion of the implant can be selected from 100 microns to 1000 microns, more preferably from 100 microns to 500 microns, and most preferably from 300 microns to 500 microns.

[0033] The thermoplastic elastomer used in the upper and middle sections of the implant is particularly advantageous because its mechanical properties can be adjusted to match the mechanical properties of human and animal cartilage. In one embodiment of the present invention, an implant may be provided in which the room temperature elastic modulus of the elastomer material of the middle section is less than 10 MPa, more preferably less than 8 MPa, less than 7 MPa, less than 6 MPa, less than 5 MPa, less than 4 MPa, less than 3 MPa, or less than 2 MPa.

[0034] In the context of the present application, room temperature means a temperature in the range of 20°C to 30°C, more preferably 25°C.

[0035] Likewise, a preferred embodiment of the implant comprises an upper section in which the room temperature elastic modulus of the porous elastomer material of the upper section is less than 80% of the elastic modulus of the elastomer material of the middle section, more preferably less than 50%, even more preferably 10% to 50%, even more preferably 15% to 40%, and most preferably 20% to 30% of the elastic modulus of the elastomer material of the middle section. Such a reduced elastic modulus can be achieved by changing the porosity of the middle section material or by changing the physical properties of the middle section material (e.g., changing the weight-average molecular weight).

[0036] The porosity of the elastomer material of the upper section can be selected within a wide range. The preferred porosity of the elastomer material of the upper section is selected from 20 volume% to 80 volume%, more preferably from 30 volume% to 70 volume%, even more preferably from 40 volume% to 60 volume%, and most preferably from 45 volume% to 55 volume%.

[0037] A useful embodiment of the present invention provides an implant in which the base section comprises a core of a non-porous base section material and, preferably, a circumferential shell of a porous base section material, wherein the thickness of the shell is less than 10% of the maximum diameter of the base section. Another useful embodiment provides an implant in which the thickness of the (circumferential) shell is less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the maximum diameter of the base section. Alternatively, the cross-sectional area of ​​the (circumferential) shell occupies up to 35% of the maximum cross-sectional area of ​​the base section. Another useful embodiment provides an implant in which the cross-sectional area of ​​the (circumferential) shell is less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1% of the maximum cross-sectional area of ​​the base section.

[0038] An embodiment having the above-disclosed preferred combination of mechanical properties of the upper and middle sections tends to promote cartilage regeneration. This is believed to be due to favorable stress (re)distribution of the osteochondral structure containing the implant during (dynamic) loading.

[0039] Another embodiment of the present invention provides an implant in which a base section extends between an upper surface and a lower surface and comprises a layer of porous base section material, wherein the layer is adjacent to the upper surface and its thickness is less than 10% of the maximum height of the base section, and the pores of the base section material of the layer, preferably all pores, comprise a biocompatible elastomer material. In other embodiments, the thickness of the layer adjacent to the upper surface is less than 10%, less than 8%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the maximum height of the base section. All of the above embodiments can improve the adhesion of the intermediate section (and upper section) to the base section to varying degrees. At the same time, the mechanical properties of the base section and the support provided to the implant by the base section are maintained at an appropriate level.

[0040] Another embodiment of the present invention relates to an implant comprising a substantially non-porous polyaryletherketone polymer having a porosity of less than 20% based on the total volume of the polyaryletherketone polymer.

[0041] Another embodiment provides an implant in which the base section comprises a nonporous polyaryletherketone polymer.

[0042] In another embodiment of the present invention, the top surface of the base section of the implant includes irregularity or undulation. The irregularity includes, for example, a ridge having a sawtooth shape. The undulation may be regular or irregular, such as in the shape of a sine curve.

[0043] Another useful embodiment relates to an implant in which the base section comprises a central cavity containing a biocompatible elastomer material. Such a cavity can further improve the adhesion of the intermediate section (and upper section) to the base section. The cavity may be cylindrical, or its cross-section may be square or polygonal. The walls of the cavity may also include irregularities or undulations, or may include sections having a cross-sectional area larger than the average cross-sectional area. Some of these cavity sections may be provided at different heights to the base section to form a mechanical locking structure.

[0044] Another embodiment provides an implant comprising a base section having an external surface having irregularities or undulations. Such external surface irregularities may include, for example, ridges having a serrated shape that extend circumferentially across the external surface (part of) of the base section. The undulations may be regular or irregular, such as in a sinusoidal shape. The undulations may likewise extend circumferentially across the external surface (part of) of the base section. The irregularities and undulations may be provided by casting the material into a suitably profiled mold, or alternatively by mechanical processing, for example by rotary milling of the formed implant.

[0045] A useful embodiment of the present invention provides an implant in which an intermediate section comprises a core of a non-porous elastomer material and a cylindrical shell of a porous elastomer material, wherein the thickness of the shell is less than 10% of the maximum diameter of the intermediate section. Another useful embodiment provides an implant in which the thickness of the cylindrical shell is less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the maximum diameter of the intermediate section. The maximum diameter is suitable, for example, in an embodiment in which the plug-type implant is tapered and has a circular cross-section. Alternatively, the cross-sectional area of ​​the cylindrical shell occupies up to 35% of the maximum cross-sectional area of ​​the intermediate section. Another useful embodiment provides an implant in which the cross-sectional area of ​​the cylindrical shell is less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1% of the maximum cross-sectional area of ​​the intermediate section. The maximum cross-sectional area is suitable, for example, in an embodiment where the plug-type implant is tapered.

[0046] The height of the plug-type implant can be selected according to the specific application in the body. The height can vary, for example, from 3 mm to 18 mm. According to a useful embodiment of the present invention, an implant is provided in which the height of the base section, the height of the non-porous intermediate section, and the height of the porous upper section are selected such that, upon implantation, the upper surface of the implant lies below, preferably at a distance of 0.1 mm to 1 mm, the upper surface of the cartilage present on the osteochondral structure. This embodiment promotes the growth of cartilage tissue not only into the upper section but also upward, thereby establishing a strong fixation between the upper section and the newly formed cartilage. It has been found that because the chondrocytes of the host cartilage have a strong affinity for the segmented elastomer of the upper section, they tend to colonize the surface and generate new hyaline cartilage tissue on the upper surface of the implant.

[0047] Another embodiment provides an implant in which the height of the base section, the height of the non-porous middle section, and the height of the porous upper section are selected such that, upon implantation, the lower surface of the middle section is positioned at approximately the same height as the lower surface of the cartilage present on the osteochondral structure.

[0048] Another embodiment of the present invention provides an upper section in which the upper surface of the upper section is slightly curved. In the sagittal plane, the preferred radius of curvature of the upper surface of the upper section is selected to be in the range of 15 mm to 150 mm, more preferably 17 mm to 125 mm, even more preferably 19 mm to 100 mm, even more preferably 21 mm to 75 mm, even more preferably 23 mm to 50 mm, and most preferably 25 mm to 30 mm. Such an embodiment can regenerate a new cartilage layer on the upper surface of the upper section of the implant with a nearly uniform thickness across the upper surface. As a result, the radius of the upper surface of the regenerated cartilage becomes nearly identical to the radius of the surrounding natural cartilage layer next to the implant, thereby exhibiting continuity of radius. The upper surface of the upper section of the implant may be curved in the medial-lateral plane and, preferably, may have a radius of curvature within the range disclosed above with respect to the sagittal plane. In an actual embodiment, the top surface of the upper section of the implant has the same radius of curvature in the sagittal plane and in the medial and lateral planes. Accordingly, this embodiment includes a spherical top surface.

[0049] Another aspect of the present invention provides a method for manufacturing an implant. A method for manufacturing an implant comprising the following steps is provided:

[0050] a) a base section comprising a base section material comprising one of a biocompatible metal, a ceramic, a mineral such as a phosphate mineral, and a polymer, optionally a hydrogel polymer, and a combination thereof, in a mold at room temperature; and a step of providing granules of a thermoplastic elastomer material on top of the base section, wherein the thermoplastic material comprises a linear block copolymer comprising urethane groups and urea groups, and substantially free of an added peptide compound having cartilage regeneration properties;

[0051] b) closing the mold and heating the assembly to a temperature of 100°C to 250°C under a pressure of 1 GPa to 2 GPa so that the thermoplastic elastomer material melts and fuses with the base section; and

[0052] c) a step of cooling the assembly to room temperature to solidify the thermoplastic elastomer material and opening the mold;

[0053] d) A step of providing a void in the upper section of the thermoplastic elastomer material before or after opening the mold.

[0054] A preferred embodiment of the above method comprises: a base section comprising a substantially non-porous polyaryletherketone polymer having a porosity of less than 20% based on the total volume of the polyaryletherketone polymer; and step a) of providing granules of a thermoplastic elastomer material on top of the base section to a mold at room temperature.

[0055] Another embodiment of the present invention provides a method of opening the mold after step b) to add additional granules of a thermoplastic elastomer material to the mold, and repeating step b). In a two-step embodiment of the method, the amount of added material can be selected within a wide range. Increasingly better results are obtained when the ratio between the first addition and the second addition of granules of the thermoplastic elastomer material is selected from 01:99 to 99:01, more preferably from 30:70 to 97:03, and most preferably from 70:30 to 95:05.

[0056] Another embodiment of the present invention provides a method in which the heating temperature of step b) is 110°C to 225°C, more preferably 120°C to 200°C, and most preferably 130°C to 175°C. In all mentioned temperature ranges, the preferred pressure is 1.1 GPa to 1.8 GPa, and more preferably 1.2 GPa to 1.6 GPa.

[0057] Another aspect of the present invention relates to a method for producing a thermoplastic elastomer material comprising a linear block copolymer containing urethane groups and urea groups, and substantially free of added peptide compounds having cartilage regeneration properties. According to the present invention, the method comprises:

[0058] - A step of preparing an isocyanate-terminated prepolymer by reacting a diol with a diisocyanate,

[0059] - Includes the step of polymerizing an isocyanate-terminated prepolymer through chain extension using a diamine;

[0060] The above steps are performed under the exclusion of peptide compounds having cartilage regeneration properties, more preferably under the exclusion of any compound having cartilage regeneration properties.

[0061] In a preferred method according to one embodiment, the diol is selected from polyester diol, polyether diol, and preferably carbonate diol, and combinations thereof.

[0062] Another preferred embodiment provides a method in which the diisocyanate comprises an n-alkylene-diisocyanate.

[0063] Another preferred embodiment of the present invention relates to a method in which the diamine comprises a primary diamine, preferably an n-alkylene-diamine. Brief explanation of the drawing

[0064] The present invention will now be further explained through the following drawings and examples, but is not limited thereto. In the drawings: FIGS. 1a to 1d show schematic side views of four embodiments of an exemplary implant according to the present invention; FIG. 2a shows a schematic perspective view of a base section according to one embodiment of the present invention; FIG. 2b shows a schematic cross-section of an embodiment of FIG. 2a; FIGS. 2C and 2D show schematic detailed views of parts B and C of the embodiment of FIG. 2B; FIG. 3 shows a schematic diagram of a possible synthesis route to a thermoplastic polycarbonate material according to one embodiment of the present invention; FIG. 4 shows a thermoplastic polycarbonate material according to one embodiment of the present invention. 1 Showing the H-NMR spectrum; FIGS. 5a to 5c show DSC thermograms of a thermoplastic polycarbonate material according to one embodiment of the present invention at different heating rates; FIGS. 6a to 6c illustrate a schematic diagram of an osteochondral structure defect (Fig. 6a), an osteochondral structure including an implant according to one embodiment of the present invention (Fig. 6b), and the same osteochondral structure after upward / inward growth of cartilage (Fig. 6c); FIGS. 7a to 7d illustrate schematic side views of four embodiments of an implant according to another embodiment of the present invention; finally FIGS. 8a to 8c show a schematic diagram of an osteochondral structure defect (Fig. 8a), an osteochondral structure including an implant according to another embodiment of the present invention (Fig. 8b), and the same osteochondral structure after upward / inward growth of cartilage (Fig. 8c). Specific details for implementing the invention

[0065] Referring to FIG. 1a, a side view of an exemplary embodiment of an implant according to the present invention is presented. A plug-shaped implant (1) comprises a base section (2) configured to be fixed to bone tissue, an intermediate section (3) configured to replace cartilage tissue, and an upper section (4) configured to grow cartilage tissue upward and inward. The intermediate section (3) and the upper section (4) comprise the same thermoplastic elastomer material. In this embodiment, the thermoplastic elastomer material comprises poly-urethane-bisurea-hexylene carbonate, the manufacture and properties thereof will be further described below. However, the upper section (4) comprises poly-urethane-bisurea-hexylene carbonate in a porous form, and the intermediate section (3) comprises the same poly-urethane-bisurea-hexylene carbonate without any pores. The base section (2) comprises a nonporous polyaryletherketone polymer, which is a nonporous PEKK polymer in the presented embodiment. The implant (1) is cylindrical, and its diameter (10) is 6 mm. The total height is 6 mm when the height (20) of the base section (2), the height (30) of the middle section (3), and the height (40) of the upper section (4) are added.

[0066] FIG. 1b schematically illustrates a side view of another embodiment of an implant according to the present invention. The implant (1), implemented in a plug shape, comprises a base section (2) configured to be fixed to bone tissue, an intermediate section (3) configured to replace cartilage tissue, and an upper section (4) configured to grow cartilage tissue upward and inward. The intermediate section (3) and the upper section (4) comprise the same polyurethane-bisurea-hexylene carbonate material, which is porous in the upper section (4) and non-porous in the intermediate section (3). The base section (2) comprises a substantially non-porous PEKK polymer having a porosity of less than 20% based on the total volume of the PEKK polymer. The base section (2) of this embodiment specifically comprises a core (21) of the non-porous PEKK polymer and a cylindrical shell (22) of the porous PEKK polymer. The thickness (23) of the shell (22) is about 8% of the diameter (10) of the base section (2) (and implant (1)). The base section (2) extends further between the top surface (24) and the bottom surface (25) and comprises a layer (26) of porous PEKK polymer, said layer (26) adjacent to the top surface (24) and its thickness (27) is about 8% of the height (20) of the base section (2). The pores of the PEKK polymer within said layer (26) comprise biocompatible polyurethane-bisurea-hexylene carbonate derived from the middle section (3) and infiltrated into the pores of the PEKK polymer within said layer (26) during manufacturing. A method for manufacturing the implant will be further described below. As in the embodiment of FIG. 1a, the implant (1) is cylindrical, and its diameter (10) is 6 mm. The total height is 6 mm when the height (20) of the base section (2), the height (30) of the middle section (3), and the height (40) of the upper section (4) are added.

[0067] FIG. 1c schematically illustrates a side view of another embodiment of an implant according to the present invention. The implant (1), implemented in a plug shape, comprises a base section (2) configured to be fixed to bone tissue, an intermediate section (3) configured to replace cartilage tissue, and an upper section (4) configured to grow cartilage tissue upward and inward. The intermediate section (3) and the upper section (4) comprise the same polyurethane-bisurea-hexylene carbonate material, which is porous in the upper section (4) and substantially non-porous in the intermediate section (3). The base section (2) comprises a substantially non-porous PEKK polymer having a porosity of less than 20% based on the total volume of the PEKK polymer. The base section (2) of this embodiment extends particularly between the top surface (24) and the bottom surface (25) and comprises a layer (26) of porous PEKK polymer, said layer (26) adjacent to the top surface (24) and its thickness (27) is about 8% of the height (20) of the base section (2). The pores of the PEKK polymer within said layer (26) comprise biocompatible poly-urethane-bisurea-hexylene carbonate derived from the intermediate section (3) and infiltrated into the pores of the PEKK polymer within said layer (26) during manufacturing. The intermediate section (3) of this embodiment comprises, in particular, a core (31) of non-porous poly-urethane-bisurea-hexylene carbonate polymer and a cylindrical shell (32) of porous poly-urethane-bisurea-hexylene carbonate polymer. The thickness (33) of the shell (32) is about 8% of the diameter (10) of the intermediate section (3) (and implant (1)). The base section (2) extends further between the top surface (24) and the bottom surface (25) and comprises a layer (26) of porous PEKK polymer, said layer (26) adjacent to the top surface (24) and its thickness (27) is about 8% of the height (20) of the base section (2). The dimensions and shape are the same as in the embodiments of FIGS. 1a and 1b.

[0068] FIG. 1d schematically illustrates a side view of another embodiment of an implant according to the present invention. An implant (1) implemented in a plug shape corresponds to that presented in FIG. 1c. Additionally, the intermediate section (3) of this embodiment now has a cylindrical shell (32) of a porous polyurethane-bisurea-hexylene carbonate polymer having a thickness (33) of about 10% of the diameter (10) of the intermediate section (3) (and implant (1)). Furthermore, the base section (2) comprises a layer (26) of a porous PEKK polymer, said layer (26) adjacent to the top surface (24) and its thickness (27) is about 5% of the height (20) of the base section (2). The pores of the PEKK polymer within the layer (26) comprise biocompatible polyurethane-bisurea-hexylene carbonate derived from the intermediate section (3) and infiltrated into the pores of the PEKK polymer within the layer (26) during manufacturing. The base section (2) further comprises a core (21) of non-porous PEKK polymer and a cylindrical shell (22) of porous PEKK polymer. The thickness (23) of the shell (22) is about 5% of the diameter (10) of the base section (2) (and implant (1)). Furthermore, the base section (2) also comprises a layer (28) of porous PEKK polymer, said layer (28) adjacent to the bottom surface (25) and its thickness (29) is about 5% of the height (20) of the base section (2). The dimensions and shape are the same as in the embodiments of FIGS. 1a through 1c.

[0069] It should be noted that in FIG. 1b, FIG. 1c and FIG. 1d, the cylindrical shell (22, 32) is shown in cross-section to indicate the respective thickness (23, 33). In the side view, it will extend over the entire diameter (10) of the implant (1).

[0070] Referring to FIG. 7a, a side view of another embodiment of an implant according to the present invention is presented. A plug-shaped implant (1) comprises the same material and section as shown in FIG. 1a. The dimensions of the implant in FIG. 7a are the same as those of the implant in FIG. 1a, except for one. Instead of having a flat top surface (41) of the upper section (4) (and implant (1)) as in FIG. 1a, the top surface (41a) of the upper section (4) is spherical with a radius of curvature (R) of about 28 mm (not shown in proportion to size).

[0071] Referring to FIG. 7b, a side view of another embodiment of an implant according to the present invention is presented. A plug-shaped implant (1) comprises the same material and section as shown in FIG. 1b. The dimensions of the implant in FIG. 7b are the same as those of the implant in FIG. 1b, except for one. Instead of having a flat top surface (41) of the upper section (4) as in FIG. 1b, the top surface (41a) of the upper section (4) is spherical with a radius of curvature (R) of about 28 mm (not shown in proportion to size).

[0072] Referring to FIG. 7c, a side view of another embodiment of an implant according to the present invention is presented. The plug-shaped implant (1) comprises the same material and section as shown in FIG. 1c. The dimensions of the implant in FIG. 7c are the same as those of the implant in FIG. 1c, except for one. Instead of having a flat top surface (41) of the upper section (4) as in FIG. 1c, the top surface (41a) of the upper section (4) is spherical with a radius of curvature (R) of about 28 mm (not shown in proportion to size).

[0073] Referring to FIG. 7d, a side view of another embodiment of an implant according to the present invention is presented. The plug-shaped implant (1) comprises the same material and section as shown in FIG. 1d. The dimensions of the implant in FIG. 7d are the same as those of the implant in FIG. 1d, except for one. Instead of having a flat top surface (41) of the upper section (4) as in FIG. 1d, the top surface (41a) of the upper section (4) is spherical with a radius of curvature (R) of about 28 mm (not shown in proportion to size).

[0074] Again, it should be noted that in FIGS. 7b, 7c, and 7d, the cylindrical shells (22, 32) are shown in cross-section to indicate their respective thicknesses (23, 33). In the side view, this will extend over the entire diameter (10) of the implant (1) (not shown in proportion to size).

[0075] Referring to FIGS. 2a through 2d, an embodiment of the base section (2) of the implant (1) of the present invention is schematically presented. The presented base section (2) is essentially cylindrical in shape having a diameter (10) and a height (20). The top surface (24) of the base section has a cylindrical flat rim portion (240) that gradually extends into a central cavity (241). The cavity (241) is provided with a locking portion (242) having a diameter larger than the diameter of the cavity (241). As shown in detail in FIG. 2c, since the locking portion (242) of the cavity (241) is disc-shaped, the outer rim of the disc forms an angle (246) between 1° and 20°, more preferably between 5° and 15°, with respect to the longitudinal direction (247) of the base section (2). During the manufacture of the implant, the cavity (241) (and portion (242)) is filled with a portion of a biocompatible elastomer material to provide proper locking of the intermediate section (3) to the base section (2). As discussed above, the base section (2) comprises a PEKK polymer that may be non-porous or substantially non-porous, the latter embodiment including the example disclosed above. The base section (2) further appears to comprise an outer surface having irregularities or undulations. In an embodiment of the present invention, it comprises a cylindrical ridge (243) that is serrated in cross-section, as shown in detail in FIG. 2d. The angle (244) at which the serration extends with respect to the transverse direction (245) of the base section (2) is preferably 70° to 85°, more preferably 75° to 80°.

[0076] Preparation of elastomer materials for the upper and middle sections

[0077] Example 1: Polycarbonate - Aliphatic: Poly(hexylene carbonate urethane)-bis-urea biomaterial MVH313, see Table 1 below.

[0078] A biomaterial MVH313 produced in a one-pot, two-step process was prepared by functionalizing 1.0 molar equivalent of poly(hexylene carbonate) diol (MW = 2000) with 2.0 molar equivalents of 1,6-diisocyanatohexane (step 1) and subsequently extending the chain using 1.0 molar equivalents of 1,6-diaminohexane (step 2).

[0079] In particular, an aliphatic polyurethane-urea-hexylene carbonate biomaterial of the middle section (3) and upper section (4) was prepared as follows (see FIG. 3). Poly(hexylene carbonate) diol (MW=2000; 23.9 g, 11.9 mmol) was weighed into a 500 mL three-necked flask, heated overnight to 75°C under vacuum to dry, and then cooled to room temperature. Under an argon atmosphere, 1,6-diisocyanatohexane (4.1 g, 23.9 mmol), DMAc (20 mL), and one drop of Sn(II)bis(2-ethylhexanoate) were added, and the mixture was heated and stirred for 3 hours, at which point the viscosity increased. The mixture was cooled to room temperature, diluted with DMAc (100 mL), and a solution of 1,6-diaminohexane (1.4 g, 11.9 mmol) in DMAc (50 mL) was added all at once while mixing. A gel formed immediately upon addition and mixing. The mixture was further diluted with DMAc (150 mL) and heated in a 130°C oil bath to obtain a homogeneous viscous slurry. After cooling to room temperature, the mixture was precipitated in a water / salt mixture (2.75 L water + 0.25 L saturated salt) to obtain a soft white material. This material was cut into smaller pieces and stirred for 64 hours in a 1:5 mixture of methanol and water (3 L). After decanting the supernatant, the resulting solid was stirred for 6 hours in a 2:1 mixture of methanol and water (0.75 L). The supernatant was decanted and stirred for 16 hours in a 2:1 mixture of methanol and water (0.75 L), the supernatant was decanted, and the solid was dried under vacuum at 70°C to obtain a flexible and tough elastomer polymer.

[0080] For polymers produced at 298K using a Varian 200, Varian 400 MHz, or 400 MHz Bruker spectrometer 1¹H NMR spectroscopy was performed. DSC was performed using a Q2000 instrument (TA Instruments). For the evaluation of melting temperature (Tm) and glass transition temperature (Tg), heating scan rates of 10°C / min and 40°C / min were used, respectively. Tm was determined as the peak melting temperature, and Tg was determined at the inflection point.

[0081] All reagents, chemicals, materials, and solvents were obtained from commercial sources and used without further purification. The average molecular weight of the poly(hexylene carbonate) diol used was approximately 2 kg / mol. Figures 4 and 5 show, respectively, the obtained polymer 1 The H NMR spectrum and DSC thermal analysis curve are shown. 1 The H NMR spectrum results can be summarized as follows: 1 H NMR (400 MHz, HFIP-d2): δ = 4.23 (m, n*4H, n ~ 14.3), 4.10 (m, 4H), 3.17 (m, 12H), 1.87–1.32 (multiple signals for aliphatic CH2 methylene) ppm. The average molecular weight of the repeating hard / soft block sections is approximately 2.5 kDa. The DSC results can be summarized as follows: DSC (10°C / min, Fig. 5a): Tm (highest temperature) = 20.9°C (soft block melted); DSC (40°C / min, Fig. 5b): Tg = -38.0°C. For the hard block, no second melting point was observed up to 200°C. However, in the final heating run to 250°C at 10°C / min (Fig. 5c), a small, broad melting transition was observed at approximately 227°C. In the DSC diagram, the endothermic melting peak is plotted downwards, while the exothermic crystallization is plotted upwards.

[0082] The elastic modulus of the non-porous aliphatic polyurethane-urea-hexylene carbonate biomaterial according to ASTM D638 was 3.6 ± 0.03 MPa.

[0083] Example 2: Polyether - Aromatic: Poly(tetrahydrofuranurethane)-bis-urea biomaterial MVH309B, see Table 1 below.

[0084] Biomaterial MVH309B was also produced by a one-pot, two-step experimental procedure similar to that described in detail for biomaterial MVH313. Specifically, biomaterial MVH309B was prepared by functionalizing 1.0 molar equivalent of poly-tetrahydrofuran diol (MW = 2000) with 1.33 molar equivalents of bis(4-isocyanatophenyl)methane (MDI) (Step 1), and subsequently extending the chain using 0.33 molar equivalents of 1,6-diaminohexane (Step 2). Biomaterial MVH309B was isolated as a white, flexible, and tough elastomer polymer.

[0085] Example 3: Polyether - Aliphatic: Poly(tetrahydrofuranurethane)-bis-urea biomaterial MVH312, see Table 1 below.

[0086] Biomaterial MVH312 was also produced by a one-pot, two-step experimental procedure similar to that described in detail for biomaterial MVH313. Specifically, biomaterial MVH312 was prepared by functionalizing 1.0 molar equivalent of poly-tetrahydrofuran diol (MW = 2000) with 2.0 molar equivalent of 1,6-diisocyanatohexane (Step 1), and subsequently extending the chain using 1.0 molar equivalent of 1,6-diaminohexane (Step 2). Biomaterial MVH312 was isolated as a flexible and tough elastomer polymer.

[0087] Example 4: Polycarbonate - Aromatic: Poly(hexylene carbonate urethane)-bis-urea biomaterial MVH311, see Table 1 below.

[0088] Biomaterial MVH311 was also produced by a one-pot, two-step experimental procedure similar to that described in detail for biomaterial MVH313. Specifically, biomaterial MVH311 was prepared by functionalizing 1.0 molar equivalent of poly(hexylene carbonate) diol (MW = 2000) with 1.33 molar equivalents of bis(4-isocyanatophenyl)methane (MDI) (Step 1), and subsequently extending the chain using 0.33 molar equivalents of 1,6-diaminohexane (Step 2). Biomaterial MVH311 was isolated into a flexible and tough elastomer polymer.

[0089] Mechanical properties of the elastomer material in the intermediate section

[0090] Stress relaxation testing was performed on the two aromatic and two aliphatic polymers of Examples 1 through 4, as well as on three horse cartilage specimens obtained from the Utrecht Medical Centre. Descriptions of the specimens (e.g., polymer classes) and their dimensions are listed in Table 1. Using an Instron Electropulse E10000, each specimen was compressed at a strain rate of 0.005 s⁻¹ to a strain of 0.05 mm / mm maintained constant for 1800 seconds. All tests were performed in triplicate. During the test, load, displacement, and time were recorded, and stress relaxation curves were subsequently obtained from the data. Stress relaxation was indicated by determining the stress relaxation coefficient G(t) at the onset of stress relaxation (G(0)) and 1800 seconds after the onset of stress relaxation (G(1800)) using the following equations: G ( t ) = σ ( t ) / ε 0(where σ(t) is compressive stress and ε0 is a set (constant) strain).

[0091]

[0092] The results are presented in Table 2 below.

[0093]

[0094] Preparation of biomaterial-capped PEKK bone anchors

[0095] The implant (1) was manufactured by attaching the upper and middle sections (4, 3) to a PEKK base section (2) that serves as a bone anchor. In a method according to one embodiment of the present invention, the PEKK bone anchor was capped with a polyurethane-urea-hexylene carbonate biomaterial by pushing small granules of an aliphatic polycarbonate polymer over and into the PEKK anchor. For this purpose, a customized compression setting was used. Tests were conducted at various temperatures (100°C to about 150°C), compression forces (2 kN to about 4 kN), and methods. The best results were obtained using a two-step procedure, a temperature of 150°C, and a compression force of 40 kN (4 tons or 4000 kg; equivalent to a pressure of 1.4 GPa). Temperatures lower than 150°C provide a less homogeneously compressed poly-urethane-urea-hexylene carbonate biomaterial layer (sections (3) and (4)), and higher temperatures are less desirable because the urea groups within the poly-urethane-urea-hexylene carbonate biomaterial may decompose to some extent. In the first step, about 50 mg of polymer (12) was pushed over and into the PEKK bone anchor for 15 minutes, and in the second step, about 2 mg of polymer (12) was added to the setup, and the sample was compressed for an additional 15 minutes under the same conditions (150°C and 40 kN). Subsequently, the sample was removed from the compression setup and cooled. After the second compression step, the surface of the poly-urethane-urea-hexylene carbonate biomaterial layer (sections (3) and (4)) on top of the base section (2) appeared substantially flat. The biomaterial was nearly transparent and colorless. Some fringes or frays were visible on the edges of the biomaterial, and these were removed using a scalpel.

[0096] The central hole (241, 242) of the base section (2) was about 4.5 mm deep and about 2 mm in diameter. The hole was substantially filled with polyurethane-urea-hexylene carbonate biomaterial, and the attachment of the biomaterial to the PEKK base section (2) appeared to be considerably strong and robust. It was found to be practically impossible to remove the biomaterial from the PEKK base section by force or by loosening the connection at the PEKK-biomaterial interface. All used equipment and accessories that come into contact with the PEKK base section (2) and / or the elastomer biomaterial were rinsed with ethanol or isopropanol and dried. After compression and frame cutting, the PEKK-biomaterial plug implant was rinsed with isopropanol and dried. If necessary, the plug may also be produced in a sterile environment.

[0097] As evaluated by measurement, the diameter of the PEKK base section was 6 mm and the height was 6 mm (height 6 mm). The diameter of the central cavity of the base section was approximately 2 mm, and the depth was approximately 4.5 mm. The diameter of the elastomer biomaterial (aliphatic polycarbonate) located on the PEKK base section was approximately 6 mm, and the height was approximately 1 mm. Therefore, the height of the entire PEKK-biomaterial plug implant was approximately 7 mm.

[0098] A void was provided in the upper section (4) by drilling holes with an average diameter of 300 microns until the final porosity was 50 volume%. The elastic modulus of the porous aliphatic polyurethane-urea-hexylene carbonate biomaterial of the upper section (4) according to ASTM D638 was 0.9 ± 0.2 MPa.

[0099] As shown in FIGS. 6a through 6c, an implant (1) can be implanted into an osteochondral defect (8). In a typical method, a hole is drilled in the cartilage defect (Fig. 6a) extending to the subchondral bone, and a plug-type implant (1) is implanted ('pressure') into the drilled hole under slight pressure as shown in FIG. 6b. Subsequently, bone grows over the PEKK base section (2) and, in some embodiments, inward to secure the implant (1). Surrounding natural cartilage (5) grows over the upper surface (41) of the upper section (4), and new cartilage (5a) is formed on the implant (1) as shown in FIG. 6c. Additionally, as shown in FIG. 6c, the height (20) of the base section (2), the height (30) of the non-porous intermediate section (3), and the height (40) of the porous upper section (4) are selected such that, upon implantation, the upper surface (41) of the implant (1) is positioned below the upper surface (50) of the cartilage (5) present on the osteochondral structure (5, 6), preferably at a distance (51) of 0.1 mm to 1 mm. In the case of the present invention, this distance was approximately 0.5 mm. The osteochondral structure (5, 6) comprises subchondral bone (6) and a cartilage layer (5) thereon. A lubricating cavity (7) is also generally present.

[0100] Also, as shown in FIGS. 6b and 6c, the height (20) of the base section (2), the height (30) of the non-porous middle section (3) and the height (40) of the porous upper section (4) are selected so that when implanted, the bottom surface (24) of the middle section (3) (or the top surface (24) of the base section (2)) is placed at approximately the same height as the bottom surface (51) of the cartilage layer (5) of the osteochondral structure (5, 6).

[0101] Preparation of biomaterial-capped metallic bone anchors

[0102] Another embodiment of the implant (1) was fabricated by attaching the upper and middle sections (4, 3) to a titanium base section (2) that serves as a bone anchor. The titanium used was the readily commercially available alloy Ti6A14V. The titanium base section was provided with pores having an average pore size of about 300 microns. In a method according to one embodiment of the present invention, the titanium bone anchor was capped with a poly-urethane-urea-hexylene carbonate biomaterial by pushing small granules of an aliphatic polycarbonate polymer over and into the pores of the titanium anchor. For this purpose, the same customized compression settings used in the previous embodiment were used. Optimal results were again obtained by using a two-step procedure, a temperature of 150°C, and a compression force of 40 kN (4 tons or 4000 kg; equivalent to a pressure of 1.4 GPa). In the first step, about 50 mg of elastomer polymer was pushed over and into the titanium bone anchor for 15 minutes, and in the second step, about 2 mg of elastomer polymer was added to the setup, and the sample was compressed for an additional 15 minutes under the same conditions (150°C and 40 kN). Subsequently, the sample was removed from the compression setup and cooled. After the second compression step, the surface of the polyurethane-urea-hexylene carbonate biomaterial layer (sections (3) and (4)) on top of the base section (2) appeared substantially flat. The biomaterial was nearly transparent and colorless. Fringe or fring was visible on some edges of the biomaterial, which was removed using a scalpel.

[0103] As with the PEKK base anchor, the titanium base anchor was also provided with a central hole (241, 242) of the same dimensions. The hole was substantially filled with a polyurethane-urea-hexylene carbonate biomaterial, and the attachment of the biomaterial to the titanium base section (2) was satisfactory.

[0104] The dimensions of the titanium base section (2) were the same as those of the PEKK base section. Since the same mold was used, the diameter of the elastomer biomaterial (aliphatic polycarbonate) located on the titanium base section was about 6 mm, and the height was about 1 mm. Therefore, the height of the entire titanium-biomaterial plug implant was about 7 mm.

[0105] A void was provided in the upper section (4) by drilling holes with an average diameter of 300 microns until the final porosity was 50 volume%. The elastic modulus of the porous aliphatic polyurethane-urea-hexylene carbonate biomaterial of the upper section (4) according to ASTM D638 was 0.9 ± 0.2 MPa.

[0106] As previously described above, as shown in FIGS. 6a through 6c, the implant (1) can be implanted into the osteochondral defect (8). In a typical method, a hole is drilled in the cartilage defect (Fig. 6a) extending to the subchondral bone, and a plug-type implant (1) is implanted into the drilled hole as shown in FIG. 6b. Due to the relatively high rigidity of the titanium base section (2), indentation was not appropriate. Instead, the dimensions of the drilled subchondral bone were slightly larger than the dimensions of the titanium base section (2). Bone appears to grow over the titanium base section (2) to secure the implant (1). The surrounding natural cartilage (5) grows over the upper surface (41) of the upper section (4), and new cartilage (5a) is formed over the implant (1) as shown in FIG. 6c. Additionally, as shown in FIG. 6c, the height (20) of the base section (2), the height (30) of the non-porous intermediate section (3), and the height (40) of the porous upper section (4) are selected such that, upon implantation, the upper surface (41) of the implant (1) is positioned below the upper surface (50) of the cartilage (5) present on the osteochondral structure (5, 6), preferably at a distance (51) of 0.1 mm to 1 mm. In the case of the present invention, this distance was approximately 0.5 mm. The osteochondral structure (5, 6) comprises subchondral bone (6) and a cartilage layer (5) thereon. A lubricating cavity (7) is also generally present.

[0107] Also, as shown in FIGS. 6b and 6c, the height (20) of the base section (2), the height (30) of the non-porous middle section (3) and the height (40) of the porous upper section (4) are selected so that when implanted, the bottom surface (24) of the middle section (3) (or the top surface (24) of the base section (2)) is placed at approximately the same height as the bottom surface (51) of the cartilage layer (5) of the osteochondral structure (5, 6).

[0108] Finally, the implant according to the embodiment shown in FIGS. 7a to 7d can also be implanted into the osteochondral defect (8) as shown in FIGS. 8a to 8c. Due to the spherical top surface (41a) of the upper layer (4), this embodiment can regenerate a new cartilage layer (5a) on the top surface (41a) of the upper section (4) of the implant (1) with nearly equal thickness across the top surface (41a). As a result, the radius of the top surface (50) of the regenerated cartilage (5a) becomes nearly equal to the radius of the surrounding natural cartilage layer (5) next to the implant, thereby demonstrating continuity of radius.

[0109] It will be apparent to those skilled in the art that numerous modifications and applications are possible within the scope of the appended claims of the present invention.

Claims

Claim 1 A plug comprising a base section configured to be fixed to bone tissue, a middle section configured to replace the cartilage tissue in the middle and deep regions of the cartilage layer and to have a thickness of at least 0.2 mm, and a top section configured to grow the cartilage tissue upward and inward to regenerate the superficial zone of the cartilage layer, wherein the middle section and the top section comprise the same non-biodegradable thermoplastic elastomer material which is porous in the top section and non-porous in the middle section, the thermoplastic elastomer material comprises a linear block copolymer containing urethane and urea groups and is free of added peptide compounds having cartilage regeneration properties, the base section material comprises one of a biocompatible metal, ceramic, and non-biodegradable polymer, and a combination thereof, and the base section comprises a core of a non-porous base section material and a circumferential shell of a porous base section material, wherein the cross-sectional area of ​​the circumferential shell occupies up to 35% of the maximum cross-sectional area of ​​the base section. Non-biodegradable implants for the replacement and regeneration of biological tissues. Claim 2 A plug-shaped non-biodegradable implant for biological tissue replacement and regeneration according to claim 1, wherein the thermoplastic elastomer material further comprises carbonate groups. Claim 3 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1 or 2, wherein the thermoplastic elastomer material comprises poly-urethane-bisurea-alkylene carbonate. Claim 4 A plug-shaped non-biodegradable implant for tissue replacement and regeneration, wherein the thermoplastic elastomer material is aliphatic in claim 1. Claim 5 A plug-shaped non-biodegradable implant for biological tissue replacement and regeneration according to claim 1, wherein the room temperature elastic modulus of the elastomer material of the intermediate section is less than 10 MPa. Claim 6 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the room temperature elastic modulus of the porous elastomer material of the upper section is less than 80% of the elastic modulus of the elastomer material of the middle section. Claim 7 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the base section comprising a core of the non-porous base section material and a cylindrical shell of the porous base section material is characterized in that the thickness of the shell is less than 10% of the maximum diameter of the base section. Claim 8 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the base section extends between an upper surface and a lower surface and comprises a layer of porous base section material, wherein the layer is adjacent to the upper surface and its thickness is less than 10% of the maximum height of the base section, and the pores of the base section material of the layer comprise a biocompatible elastomer material. Claim 9 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the base section material comprises a metal selected from titanium, zirconium, chromium, aluminum, stainless steel, hafnium, tantalum, molybdenum, and alloys thereof. Claim 10 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the base section material comprises a ceramic or mineral selected from oxides, nitrides, carbides, or borides, or a combination thereof. Claim 11 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the base section material comprises a polymer or hydrogel polymer selected from collagen, poly(lact-co-glycolic acid) (PLGA), polylactic acid (PLA), polycaprolactone (PCL), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyacrylamide, polyurethane, polyethylene glycol (PEG), chitin, poly(hydroxyalkyl methacrylate), water-swellable N-vinyl lactam, starch graft copolymer, and derivatives and combinations thereof. Claim 12 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the base section material comprises a non-hydrogel polymer. Claim 13 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 12, comprising a non-porous polyaryletherketone polymer, wherein the porosity of the non-porous polyaryletherketone polymer is less than 20% based on the total volume of the non-porous polyaryletherketone polymer. Claim 14 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 12 or 13, wherein the base section comprises a non-porous polyaryletherketone polymer. Claim 15 A plug-shaped non-biodegradable implant for tissue replacement and regeneration, further comprising a medical imaging contrast agent, a contrast corpuscle, a radiopharmaceutical, or a radiopharmaceutical in claim 1. Claim 16 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the upper surface of the base section comprises irregularity or undulation. Claim 17 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the base section comprises a central cavity containing an elastomer material. Claim 18 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the base section comprises an outer surface having irregularities or undulations. Claim 19 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the height of the base section, the height of the non-porous middle section, and the height of the porous upper section are selected so that, upon implantation, the upper surface of the implant is placed below the upper surface of the cartilage present on the osteochondral structure. Claim 20 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the height of the base section, the height of the non-porous intermediate section, and the height of the porous upper section are selected so that, upon implantation, the lower surface of the intermediate section is positioned at the same height as the lower surface of the cartilage existing on the osteochondral structure. Claim 21 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, comprising an upper section having a curved upper surface having a radius of curvature in the sagittal plane and / or medial-lateral plane ranging from 15 mm to 150 mm. Claim 22 A plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 1, wherein the base section material comprises a reinforcing material selected from the group consisting of fibrous polymers, microparticle polymers, metals, or combinations thereof. Claim 23 A method for manufacturing a plug-shaped non-biodegradable implant for biological tissue replacement and regeneration according to claim 1, comprising the following steps: a) providing an assembly comprising a base section and granules of a thermoplastic elastomer material on top of the base section in a mold at room temperature, wherein the base section comprises a base section material, the base section material comprises one of a biocompatible metal, ceramic, mineral, and polymer, and combinations thereof, the thermoplastic elastomer material comprises a linear block copolymer and does not comprise an added peptide compound having cartilage regeneration properties, and the linear block copolymer comprises urethane groups and urea groups; b) closing the mold and heating the assembly to a temperature of 100°C to 250°C under a pressure of 1 GPa to 2 GPa so that the thermoplastic elastomer material melts and fuses with the base section; c) cooling the assembly to room temperature to solidify the thermoplastic elastomer material and opening the mold; and d) a step of providing an upper section of a thermoplastic elastomer material having voids before or after opening the mold. Claim 24 A method for manufacturing a plug-shaped non-biodegradable implant for tissue replacement and regeneration according to claim 23, wherein, after step b), the mold is opened to add granules of additional thermoplastic elastomer material to the mold, and step b) is repeated. Claim 25 delete

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