Medical implant for cartilage replacement and method for manufacturing such an implant

Abstract

The present invention relates to an orthopedic implant having a bone fixation portion comprising a polymer composition comprising a biostable thermoplastic polyurethane (TPU) and inorganic particles comprising 15-70% by weight of zirconia. It has been found that this relatively rigid fixation portion allows the implant to be inserted into a pre-drilled bone hole and form a solid, durable connection to the bone that can be visualized, for example, by X-ray or MRI. Thermoplastic polyurethane compositions exhibit favorable properties, providing flexibility in implant design and sizing, as well as the ability to fabricate the implant using common techniques such as injection molding. In particular, when the implant includes a cartilage replacement portion made from an elastic thermoplastic material that is compatible with polyurethane-zirconia compositions, such as softer TPU compositions, the implant can be fabricated using two-component injection molding techniques. In another aspect, the present invention relates to a method for manufacturing such an orthopedic implant including a bone fixation portion using a multi-component injection molding process. The present invention further relates to a surgical kit of parts comprising the orthopedic implant of the present invention, and the use of the implant or surgical kit of the present invention in orthopedic surgery.

Description

Detailed Description of the Invention

[0001] [Technical Field] The disclosed invention relates to orthopedic implants for use in resurfacing damaged joint surfaces, such as cartilage replacement devices, implants having a bone fixation portion including a composite material, methods of manufacturing orthopedic implants, surgical kits including such implants, and the use of implants and kits in resurfacing damaged joint surfaces.

[0002] [Background] Orthopedic implants are medical implants used in orthopedic surgeries related to conditions involving the human or animal musculoskeletal system. This system makes up the body's bones (skeleton), muscles, cartilage, tendons, ligaments, joints, and other connective tissues (tissues that support and connect tissues and organs together), providing body form, stability, and movement. The main functions of the musculoskeletal system include supporting the body, enabling movement, and protecting vital organs. The joints and musculoskeletal tissues of the human body are susceptible to trauma, disease, and degenerative processes, which can cause joint deterioration or impairment over time, leading to severe pain or immobility. Generally, the ability of a joint to provide a painless joint articulation and carry loads depends on the presence of healthy bone, cartilage, and related musculoskeletal tissues that provide a stable joint. In the context of the present disclosure, orthopedic surgery is also related to maintaining movement in various joints of the human body. Examples of orthopedic implants include devices used in partial or total arthroplasty, artificial knee and hip joints, and osteochondral implants. Examples of orthopedic implants include bone anchors, plugs, and screws applied to fix implants, such as artificial cartilage and tendons, meniscus or labral replacement devices, and cartilage replacement devices.

[0003] Cartilage is a smooth connective tissue on the surface of the ends of bones where they meet to form joints, protecting the bones, cushioning impacts, and absorbing forces transmitted throughout the body. Cartilage is an elastic tissue that enables smooth joint movement, but due to the lack of a direct blood supply, it has limited self-healing ability in cases of fatigue or trauma. Frequent and severe cartilage damage that causes pain and / or immobility is damage to articular cartilage in the knee joint, which is within the joint formed between the femur and tibia. Such initial local defects over time, if left untreated, can cause further degeneration and damage to the cartilage in the joint, necessitating partial or total knee arthroplasty surgery (also called UKR / TKR, hemi / total knee arthroplasty, or HKA / TKA) using artificial joints. However, in such total joint replacement surgeries, the majority of artificial joints have limited durability, and subsequent replacement procedures are associated with longer surgical times and hospital stays, which can induce complications, especially in elderly patients. To delay and even avoid the need for joint replacement such as TKR, orthopedic implants have been developed to locally replace damaged cartilage, thereby creating a new smooth joint surface at the damaged site. Such implants are often called cartilage plugs.

[0004] Such known cartilage plugs, also referred to as osteochondral constructs, cartilage replacement devices, or resurfacing implants, are typically manufactured from a metal such as titanium. However, the use of metal implants causes revision surgery at a high rate, which is related to the large differences in mechanical properties such as stiffness and deformability between the metal and the cartilage (subchondral) bone and cartilage tissue. In numerous publications, alternative devices made from natural and / or synthetic materials have been described or proposed. Cartilage plugs often have a cylindrical or mushroom-like form and may include at least two parts, a cartilage replacement part and a bone fixation part. The cartilage replacement part is typically manufactured from a biocompatible material that mimics some of the properties of natural cartilage, being flexible, elastic, and wear-resistant, while the bone fixation part may be manufactured from a more rigid and hard material that includes metal.

[0005] One approach for manufacturing cartilage plugs from natural materials is to harvest bone and cartilage (autogenous graft or autograft) from the patient and use tissue from a donor who is not genetically similar of the same species (allograft or homograft). For example, U.S. Patent No. 5,782,835 describes an apparatus and method for performing such an allograft approach. However, the use of such grafts presents a risk of transmission of infectious diseases or disorders.

[0006] Alternatively, orthopedic implants such as cartilage plugs can be manufactured from synthetic materials such as biocompatible polymers that can be biodegradable or bioinert. The use of synthetic polymers presents advantages compared to metal implants because the polymers offer a very wide range of properties, cause less damage to the contacting tissue, and are not magnetic, making them more compatible with medical imaging techniques such as MRI.

[0007] U.S. Patent Application Publication No. 2008 / 0249632A1 describes a cartilage plug having a stepped shoulder shape including four or more layers, which aims to distribute a good load by the plug to be implanted and the surrounding tissue and reduce unwanted movement. Different layers of the plug can be selected from a number of natural and synthetic materials and can be made of the same material or different materials, which may be porous or non-porous.

[0008] U.S. Patent Application Publication No. 2011 / 0218647A1 discloses a cartilage plug containing a hydrogel, which contains a hydrophilic polymer, a fibrous filler and 40 - 80% by mass of water. The polymer is preferably cross-linked polyvinyl alcohol. This implant will have a Young's modulus of 0.75 - 50 MPa, preferably 23 - 30 MPa, to allow initial compression to enable placement within an opening and subsequent expansion for proper attachment.

[0009] U.S. Patent No. 6626945B2 describes a cartilage plug formed in a laminated structure to conform to the physiological requirements of the repair site. This plug may be cylindrical and can be formed from three materials fused or joined together. In one embodiment, the first layer closest to the subchondral bone after implantation is made of a thermoplastic polyurethane (TPU) with a Shore hardness of 75 ShD and in vivo stability. The intermediate layer of the implant is made of TPU with a hardness of 55 ShD, while the third layer closest to the surface of the cartilage surrounding the implanted plug is made of a more flexible material such as TPU with a hardness of 80 ShA or a thermoplastic hydrogel. This last layer is stated to exhibit properties similar to those of hyaline cartilage, which is the type of cartilage on the outer surface of a synovial joint, and the material with 75 ShD has an elastic modulus similar to that of subchondral bone.

[0010] WO 2011 / 098473 A1 pamphlet describes orthopedic implants such as meniscus or spinal disc implants that have two or more separate sections, each containing a different but chemically related polymeric material, and the sections are adhered to each other at the contact surface by the interaction between the materials. Preferably, the materials are selected from block copolymers such as thermoplastic polyurethane (TPU). These implants can be made by multi-component molding techniques. A meniscus prosthesis containing different parts made from two non-resorbable polymeric materials having tensile modulus of at most 100 MPa and at least 101 MPa respectively is also described in WO 2015 / 0135907 A1 pamphlet. In experiments, TPU materials with Shore hardness 80 ShA and 75 ShD were used. This material is indicated to be a polymer composition containing TPU and radiopaque filler particles such as up to 25% by mass of barium sulfate.

[0011] Chinese Patent No. 1215890 discloses polyurethane compositions that exhibit anticoagulant properties and are suitable for the manufacture of surgical products such as sutures, catheters and prostheses. These compositions contain 0.1 - 30% by mass of zinc oxide, titanium oxide or zirconium dioxide nanoparticles, and 80 - 99% of the particles have a size of less than 50 nm.

[0012] WO 2007 / 007062 A2 pamphlet describes a cartilage repair implant in which an elastic layer is bonded to a stationary phase, and the stationary part is made from a bone cement composition containing an acrylate polymer containing calcium ions that promote the endochondral growth of bone.

[0013] U.S. Patent Application Publication No. 2008 / 0081061A1 pamphlet discloses an orthopedic device that includes a composite material based on a biocompatible polymer having ceramic particles dispersed therein, and may further include a ceramic-free polymer fully bonded to the composite material. The ceramic material may be in the form of particles or fibers and can be selected from a wide list, like a polymer. In one embodiment, the polymer is ultra-high molecular weight polyethylene (UHMWPE), and examples of the ceramic include hydroxyapatite (HA) particles. Such composite parts are manufactured by mixing UHMWPE powder with (optionally coated) HA particles and compression molding the mixture.

[0014] Geary et al. reported in Mater. Sci. Mater. Med (2008) 19:3355 - 3363 (DOI 10.1007 / s10856 - 008 - 3472 - 8) that thermoplastic polyurethanes such as commercially available Bionate® polycarbonate urethane grades have extremely excellent hydrolysis and aging resistance; and are suitable in vivo stability materials for use in manufacturing devices for replacing diseased or damaged joints, in vivo biomedical devices. Incorporating carbon fibers or hydroxyapatite (HA) particles into such polyurethanes via melt compounding can result in improvement of the mechanical properties of the polymer material. However, it has also been pointed out that such compounding processes enhance the degradation of the polymer and cause a significant reduction in the molar mass of the polymer in the polymer composition. In particular, when blending polyurethane with HA, it has been proven that the above degradation becomes more prominent during melt processing steps such as injection molding. In contrast to carbon fibers, the polyurethane composition based on TPU and HA particles did not show improvement in tensile properties.

[0015] U.S. Patent No. 2009 / 043398 describes a method for manufacturing an articular surface implant such as an exchange plug, where a gradient in density, porosity, and / or concentration is created in the implant by applying centrifugal force to a viscous material, such as by spin casting. The viscous material may be a composite material including a polymer matrix and particles or fibers dispersed therein, and the method results in an article having a concentration gradient of the particles or fibers, and thus a gradient in stiffness.

[0016] U.S. Patent No. 2004 / 0188011 discloses a method for fabricating an artificial device bearing element made from carbon fiber reinforced polymer and including a rigid backing supporting a soft elastomeric polyurethane bearing liner, where joining of the backing to the bearing liner is improved and achieved by laser welding, i.e., passing a laser beam through a transparent bearing liner to cause thermal fusion at the interface between the liner and the laser-opaque backing. [Summary of the Invention]

[0017] Although various approaches have been proposed or described in the literature, there still appears to be a need for orthopedic implants including bone fixation parts and cartilage replacement parts made from synthetic materials, which can provide a durable solution as a replacement device for local cartilage defects within joints and can be monitored during and after implantation using common medical techniques.

[0018] The object of the present disclosure includes providing such an orthopedic implant for use in resurfacing joints in the case of locally damaged cartilage tissue, the implant including a bone fixation part enabling a durable and monitorable connection to bone tissue.

[0019] Aspects and embodiments of the invention described herein and characterized in the claims relate to a surgical implant having a bone fixation portion exhibiting good biocompatibility and mechanical properties compatible with bone tissue, an orthopedic implant that can be monitored during and / or after implantation using medical imaging techniques such as X-ray and MRI, and a method of manufacturing such an implant. Accordingly, one aspect of the invention is an orthopedic implant according to claim 1, more specifically, an orthopedic implant suitable for use as a device for replacing damaged cartilage tissue within a joint, the orthopedic implant having a bone fixation portion comprising a polymer composition comprising a bio-stable thermoplastic polyurethane and inorganic particles comprising 15 to 70% by mass of zirconia.

[0020] The disclosed orthopedic implant can have a substantially cylindrical or mushroom-like shape, such as a cartilage replacement plug, and can include at least two parts. The bone fixation part and the cartilage replacement part are typically made from an elastic and wear-resistant biocompatible material. The relatively rigid fixation part when comprising or being substantially made from the TPU composition containing zirconia particles enables the implant to be inserted into a pre-drilled bone hole to form a firm and durable connection to the surrounding bone tissue, and it has been found that the implant part and its connection to the bone can be visualized or monitored over time, for example, by X-ray or MRI methods. The thermoplastic polyurethane composition exhibits a favorable crystallization behavior, and the (mechanical) properties of the composition are better than those of similar compositions based on, for example, HA filler particles. Further advantages of using the thermoplastic polyurethane composition include the freedom in implant design and dimensioning, and the freedom to fabricate the implant using common techniques such as (multi-component) injection molding, enabling more complex shapes. In particular, when the implant includes a cartilage replacement part made from a thermoplastic material compatible with the polyurethane-zirconia composition, such as a softer or unfilled TPU composition, the implant may be fabricated using multi-component injection molding techniques, which is a relatively simple method that generally provides sufficient adhesion between the bone fixation part and the cartilage replacement part without using, for example, adhesive components.

[0021] In another aspect, the present invention relates to a polymer composition comprising a bio-stable thermoplastic polyurethane and inorganic particles containing 15 to 70% by mass of zirconia, and a method for manufacturing the composition.

[0022] In a further aspect, the present invention relates to a method for manufacturing the orthopedic implant comprising a bone fixation part, which includes forming the implant by a multi-component injection molding process including the step of molding the bone fixation part from a polymer composition comprising a bio-stable thermoplastic polyurethane and inorganic particles containing 15 to 70% by mass of zirconia.

[0023] In a further aspect, the present invention relates to an orthopedic implant comprising a bone fixation portion and a cartilage replacement portion, wherein the bone fixation portion comprises a rigid polymer composition, and the surface of the bone fixation portion in contact with the cartilage replacement portion is structured to have protrusions and / or depressions of 0.05 to 3.0 mm, and to a method for manufacturing such an orthopedic implant.

[0024] In another aspect, the present invention relates to a surgical kit for a component comprising at least one orthopedic implant of the present invention, in particular a kit comprising a set of at least two implants having different sizes.

[0025] A further aspect includes the use of the orthopedic implant of the present invention and the use of the surgical kit of the present invention in resurfacing joints where cartilage tissue is locally degenerated or damaged, such as the knee joint of a mammal. Such use for locally replacing damaged cartilage within the joint can delay the need for total joint replacement surgery such as TKR and in some cases even avoid it.

[0026] The present invention is further illustrated by the following exemplary drawings without being limited thereto. In the drawings, like numbers represent like elements.

Brief Description of the Drawings

[0027]

Figure 1

Figure 2A

Figure 2B

Figure 3

Figure 4

Figure 5A

Figure 5B

Figure 5C

Figure 6A

Figure 6B

Figure 6C

Figure 7

Figure 8

Figure 9

Figure 10A

Figure 10B

Figure 10C

Figure 11

[0028] [Detailed Description] Within the context of the present disclosure, a biocompatible material is biologically compatible by not causing a toxic, harmful, or immunological response when in contact with living tissue. Biodegradability means that the material undergoes chemical decomposition or alteration into simpler components under physiological conditions by biological means, for example, by enzymatic action. In vivo stability or bioinertness means that the material is not substantially biodegradable under the conditions and for the time of its intended use when in contact with living tissue.

[0029] According to one aspect, the present invention provides a biostable implant for orthopedic use, for example, a biostable implant suitable for use in the repair of damaged cartilage tissue, the implant having a bone fixation portion comprising a polymer composition comprising a biostable thermoplastic polyurethane and inorganic particles containing 15 to 70% by mass of zirconia.

[0030] The polymer composition within the bone fixation part contains a thermoplastic polyurethane (TPU) that is stable in vivo. The thermoplastic polyurethane has essentially linear polymer chains, is soluble in good solvents, can be melted by raising the temperature, and can then be re-solidified by cooling; for example, it is a non-crosslinked polyurethane that enables melt processing via extrusion molding or injection molding. The thermoplastic polyurethane is typically a block copolymer (also called a segmented copolymer).

[0031] A block copolymer is a polymer that comprises a plurality of blocks (also referred to as segments) of polymers (including oligomers) that are chemically distinct and exhibit different thermal and mechanical properties as well as different solubilities. Often, the blocks in a block copolymer containing two (or more) types of blocks are described as "hard" and "soft" polymer blocks, and such (chemically) different blocks result in microphase separation into domains where either the hard or soft blocks are in excess. The hard blocks within a block copolymer typically comprise a rigid or highly elastic polymer having a melting temperature (T m ) or glass transition temperature (T g ) higher than the use temperature, typically around 35 - 40 °C. The soft blocks within a block copolymer generally comprise a flexible, low-elasticity amorphous polymer having a T g below 25 °C, preferably below 0 °C. For most mechanical properties, thermal parameters such as T m and T g are generally determined on dry samples using well-known techniques such as DSC or DMA. In such phase-separated block copolymers, the hard segments function as physical (and non-magnetic) crosslinks for the flexible soft segments, and materials with properties ranging from very rigid to flexible and elastic result, depending, for example, on the ratio of hard blocks to soft blocks. Depending on the type and content of the hard blocks, polyurethane block copolymers can exhibit good stability and elasticity in the desired temperature range without the need for chemical crosslinking and can generally be processed as thermoplastics. The term thermoplastic polyurethane basically means a group of polymers having a main chain that comprises the reaction product of at least three main components, namely diisocyanates, diol chain extenders, and polymeric diols or macroglycols. Optionally, monofunctional compounds may be used as chain terminators and as additional components to form (non-reactive) end groups. In embodiments, the main chain of the polyurethane or TPU applied in the present invention is substantially linear.

[0032] In an embodiment, the TPU includes, within a repeating unit, a hard block containing urethane groups and optionally urea groups obtained from the reaction of a diol as a reactive chain extender for the diisocyanate and optionally a diamine.

[0033] Suitable diisocyanates include aromatic, aliphatic, and cycloaliphatic compounds having an average of 1.9 to 2.1 isocyanate groups per molecule. In one embodiment, the diisocyanate includes 4,4'-diphenylmethane diisocyanate (MDI), 2,4-toluene diisocyanate, 2,6-toluene diisocyanate (TDI), 1,4-phenylene diisocyanate, hexamethylene diisocyanate (HDI), tetramethylene-1,4-diisocyanate, cyclohexane-1,4-diisocyanate, dicyclohexylmethane-4,4'-diisocyanate (CHMDI), isophorone diisocyanate (IPDI), or a mixture thereof. In one embodiment, the diisocyanate includes hexamethylene diisocyanate, dicyclohexylmethane 4,4'-diisocyanate, isophorone diisocyanate, or a mixture thereof. In one embodiment, the diisocyanate consists of hexamethylene diisocyanate, dicyclohexylmethane 4,4'-diisocyanate, isophorone diisocyanate, or a mixture thereof. In another embodiment, the diisocyanate includes 4,4'-diphenylmethane diisocyanate, 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, or 1,4-phenylene diisocyanate. In one embodiment, the diisocyanate consists of 4,4'-diphenylmethane diisocyanate, 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, 1,4-phenylene diisocyanate, or a mixture thereof. In one embodiment, the molar mass of the diisocyanate is 100 to 500 g / mol. In one embodiment, the molar mass of the diisocyanate is 150 to 260 g / mol.

[0034] The chain extender is typically a low molar mass aliphatic compound having two or more, preferably two, hydroxyl or amine groups. A difunctional chain extender results in a linear, generally thermoplastic polymer, while a polyfunctional chain extender and / or isocyanate leads to a branched or crosslinked product. In one embodiment, the difunctional chain extender has a molar mass of at least 60 g / mol, at least 70 g / mol, at least 80 g / mol, at least 90 g / mol, or at least 100 g / mol. In one embodiment, the chain extender has a molar mass of up to 500 g / mol, up to 400 g / mol, up to 300 g / mol, up to 200 g / mol, or up to 150 g / mol. In one embodiment, the chain extender includes ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, or 1,8-octanediol, and / or such corresponding diamines. In embodiments, the thermoplastic polyurethane includes only a diol chain extender.

[0035] In other embodiments, the TPU includes a hard block having both urethane and urea bonds. The advantage is the enhanced interaction between the hard blocks, allowing for a higher softening temperature and / or a higher soft block content; a block copolymer is obtained that exhibits enhanced flexibility and elasticity, as well as excellent flexural strength or fatigue resistance. Depending on the diol / diamine ratio, the polyurethane chains can exhibit such strong interactions, so there can be thermal decomposition at the melt processing temperature, and solution processing is preferred for optimal performance. Commercially available examples of such polyurethanes, which are also sometimes called polyurethane ureas and include both urethane and urea bonds, include Biospan® products (available, for example, from DSM Biomedical BV, Sittard-Geleen NL).

[0036] In a further embodiment, the thermoplastic polyurethane comprises a soft block derived from at least one aliphatic polymer diol or polyol selected from the group consisting of polyethers, polyesters, polyacrylates, polyolefins, and polysiloxanes (also called silicones), wherein the polymer has a difunctional hydroxy (or amine) end group. Such polymer diols for the soft block are understood herein to include oligomers, homopolymers, and copolymers, and polyesters are considered to include polycarbonates. Polyurethane block copolymers and methods generally known for preparing these copolymers are described, inter alia, in U.S. Patent Nos. 4,739,013; 4,810,749; 5,133,742; and 5,229,431.

[0037] In an embodiment of the present disclosure, the thermoplastic polyurethane comprises, in the soft block, at least one polymer diol selected from aliphatic polyester diols, aliphatic polyether diols, poly(isobutylene) diols, and polysiloxane diols. With regard to the chain extender, some amine-functional soft blocks that provide additional urea linkages can be used. The biocompatibility and in vivo stability of such polyurethane block copolymers in the human body have been demonstrated.

[0038] The mechanical and other properties of the thermoplastic polyurethane can be adjusted by changing the chemical composition and / or molar mass of the blocks. The hard blocks of the thermoplastic polyurethane contained in the composition of the present invention can have a molar mass of about 160 to 10,000 Da, more preferably about 200 to 2000 Da. The molar mass of the soft segments can typically be 200 to 100,000 Da, and preferably at least about 400, 600, 800 or 1000 Da, and up to about 10,000, 7500, 5000, 4000, 3000 or 2500 Da. Within the scope of the present disclosure, the molar masses of the polymers and oligomers forming the blocks in the polymer refer to the number average molar mass (M n ) derived, for example, from GPC measurements. The ratio of soft block to hard block can be selected to provide a given stiffness or hardness of the polyurethane. Typically, the hardness of the polyurethane measured by a Shore durometer hardness test using scale A or D can be 40ShA to 90ShD, generally representing a flexural modulus range of about 10 to 2000 MPa. In embodiments, the thermoplastic polyurethane has a hardness of 45ShA to 90ShA, preferably at least 50, 55 or 60ShA. The advantage of using a considerably low hardness TPU may be a higher toughness of the resulting composition, which further contains zirconia. In other embodiments, the TPU in the polymer composition will result in a higher stiffness of the composition and thus has a hardness of 90ShA to 90ShD. In further embodiments, the TPU has a stiffness of at least 40, 50 or 60ShD and a hardness of up to 85 or 80ShD for a good balance between stiffness and processing behavior.

[0039] In a further embodiment of the present invention, the thermoplastic polyurethane contains, in the soft block, an aliphatic polyether, an aliphatic polyester or an aliphatic polycarbonate, more particularly an aliphatic polycarbonate. The composition of the soft block preferably has a T gIt is selected so as to produce an essentially amorphous oligomer or polymer having. Suitable aliphatic polyethers include poly(propylene oxide) diol, poly(tetramethylene oxide) diol, and copolymers thereof. Suitable aliphatic polyesters are generally produced from at least one aliphatic dicarboxylic acid and at least one aliphatic diol. Aliphatic polycarbonate diols are based on aliphatic diols similar to those used for polyester diols and can be synthesized via various routes known in the art. Suitable examples include poly(hexamethylene carbonate) diol and poly(tetrahydrofuran carbonate) diol. Such polycarbonate-based TPUs exhibit favorable biocompatibility such as blood compatibility and enhanced in vivo stability. In one embodiment, the soft block of the TPU is based on poly(hexamethylene carbonate) diol, poly(polytetrahydrofuran carbonate) diol, or a mixture thereof. In a preferred embodiment, the TPU contains or is substantially based on poly(hexamethylene carbonate) diol in the soft block.

[0040] In a further embodiment, the soft block of the TPU comprises a polysiloxane diol such as poly(dimethylsiloxane) diol, polycarbonate diol, or poly(tetramethylene oxide) diol. In one embodiment, the soft block is based on a polysiloxane diol, polycarbonate diol, poly(tetramethylene oxide) diol, or a mixture thereof. In one embodiment, the soft block comprises a mixture of two or more of a polysiloxane diol, polycarbonate diol, or poly(tetramethylene oxide) diol. Such mixtures enable the production of biocompatible polyurethanes exhibiting enhanced hydrolytic stability combined with high toughness. In one embodiment, the soft block is based on a mixture of two or more of a polysiloxane diol, polycarbonate diol, or poly(tetramethylene oxide) diol. In one embodiment, the soft block comprises a polysiloxane diol and one or more of a polycarbonate diol and poly(tetramethylene oxide) diol. In one embodiment, the soft block is based on a polysiloxane diol and one or more of a polycarbonate diol and poly(tetramethylene oxide) diol.

[0041] In one embodiment, the soft block is C2 - C 16 fluoroalkyl diol or C2 - C 16It may further contain fluoroalkyl ether diol. In one embodiment, the soft block in the polyurethane main chain is 1H,1H,4H,4H-perfluoro-1,4-butanediol, 1H,1H,5H,5H-perfluoro-1,5-pentanediol, 1H,1H,6H,6H-perfluoro-1,6-hexanediol, 1H,1H,8H,8H-perfluoro-1,8-octanediol, 1H,1H,9H,9H-perfluoro-1,9-nonanediol, 1H,1H,10H,10H-perfluoro-1,10-decanediol, 1H,1H,12H,12H-perfluoro-1,12-dodecanediol, 1H,1H,8H,8H-perfluoro-3,6-dioxaoctane-1,8-diol, 1H,1H,11H,11H-perfluoro-3,6,9-trioxaundecane-1,11-diol, fluorinated triethylene glycol, or a residue of fluorinated tetraethylene glycol.

[0042] In one embodiment, C2 - C 16 fluoroalkyldiol or C2 - C 16 The fluoroalkyl ether diol has an M of at least 150 g / mol, at least 250 g / mol, or at least 500 g / mol. n In one embodiment, the fluoroalkyl diol or fluoroalkyl ether diol has a molar mass of at most 1500 g / mol, at most 1000 g / mol, or at most 850 g / mol. In one embodiment, C2 - C 16 fluoroalkyldiol or C2 - C 16 The fluoroalkyl ether diol is present in an amount of at least 1 wt%, at least 2 wt%, or at least 5 wt% based on the total mass of the polyurethane. In one embodiment, C2 - C 16 fluoroalkyldiol or C2 - C 16 The fluoroalkyl ether diol is present in an amount of at most 15 wt%, at most 10 wt%, or at most 8 wt% based on the total mass of the polyurethane.

[0043] In an embodiment, the polyurethane may include one or more hydrophobic or hydrophilic end groups. Generally, an end group is a non-reactive moiety present at the end of a molecule. In one embodiment, the polyurethane includes end groups at each terminus of the main chain; that is, the polyurethane has an average of about two end groups. In one embodiment, the end groups are linear compounds. In another embodiment, the end groups are branched. The end groups may be formed by reacting terminal isocyanate groups present during or after the formation of the polymer backbone with co-reactive groups on a monofunctional compound, also called a chain terminator. For example, a formulation for forming a polyurethane may include a diisocyanate, a polymeric aliphatic diol, a chain extender, and a monofunctional alcohol or amine such as 1-octanol or octylamine to form C8 alkyl end groups.

[0044] In one embodiment, the end groups include, for example, C2-C 20 alkyl, C2-C 16 fluoroalkyl, C2-C 16 fluoroalkyl ether, hydrophobic poly(alkylene oxide), or hydrophobic end groups including polysiloxane. In one embodiment, the hydrophobic poly(alkylene oxide) is poly(propylene oxide), poly(tetramethylene oxide), or a copolymer thereof. In one embodiment, the hydrophobic end group is a polysiloxane such as poly(dimethylsiloxane). In one embodiment, the end groups include C2-C 20 alkyl, C2-C 16 fluoroalkyl, C2-C 16 fluoroalkyl ether, or hydrophobic poly(alkylene oxide). Such end groups can be formed using a monofunctional alcohol containing a carbinol or the above amines. Such polyurethane elastomers having hydrophobic end groups have been found to positively affect the properties of the polyurethane, as well as its interaction with other materials including other polymers such as polyolefins and body fluids such as body tissues and blood.

[0045] In one embodiment, the hydrophobic end group is C2-C16 Fluoroalkyl or C2-C 16 It contains fluoroalkyl ether. Such end groups are C2-C 16 Fluoroalkyl or C2-C 16 It can be formed by a monofunctional alcohol or amine containing fluoroalkyl ether. In one embodiment, the end group is 1H,1H-perfluoro-3,6-dioxaheptan-1-ol, 1H,1H-nonafluoro-1-pentanol, 1H,1H-perfluoro-1-hexyl alcohol, 1H,1H-perfluoro-3,6,9-trioxadecane-1-ol, 1H,1H-perfluoro-1-heptyl alcohol, 1H,1H-perfluoro-3,6-dioxadecane-1-ol, 1H,1H-perfluoro-1-octyl alcohol, 1H,1H-perfluoro-1-nonyl alcohol, 1H,1H-perfluoro-3,6,9-trioxatridecane-1-ol, 1H,1H-perfluoro-1-decyl alcohol, 1H,1H-perfluoro-1-undecyl alcohol, 1H,1H-perfluoro-1-lauryl alcohol, 1H,1H-perfluoro-1-myristyl alcohol, or 1H,1H-perfluoro-1-palmityl alcohol.

[0046] In yet another embodiment, the end group is a hydrophilic end group formed from a hydrophilic monofunctional alcohol or amine compound. Such compounds are typically water-soluble and can exhibit surface activity, such as polyethylene oxide or sulfonate-functional compounds. Such hydrophilic end groups can interact with or affect other materials and, for example, enhance the dispersion of certain inorganic filler particles.

[0047] In yet another embodiment, the polyurethane contains a mixture of hydrophobic end groups and hydrophilic end groups. Such modification allows for the adjustment of the hydrophobic-hydrophilic balance of the polymer. A general advantage of using TPU with end groups is to modify and control the properties of the polymer without incorporating additives that can introduce potential problems of migration from the polymer and implant.

[0048] In one embodiment, the end groups are monomeric and have a molar mass of 200 g / mol or more, 300 g / mol or more, or 500 g / mol or more, and 1,000 g / mol or less or 800 g / mol or less. In other embodiments, the end groups are polymeric and have a molar mass of 10,000 g / mol or less, 8,000 g / mol or less, 6,000 g / mol or less or 4,000 g / mol or less. In one embodiment, the end groups are polymeric and have a molar mass of 500 g / mol or more, 1,000 g / mol or more or 2,000 g / mol or more.

[0049] In one embodiment, the end groups are present in an amount of at least 0.1% by mass, at least 0.2% by mass, at least 0.3% by mass, or at least 0.5% by mass, based on the total mass of the polyurethane. In one embodiment, the end groups are present in an amount of at most 3% by mass, at most 2% by mass or at most 1% by mass, based on the total mass of the polyurethane. In one embodiment, the end groups are present in an amount of at least 0.1% by mass, at least 0.2% by mass, at least 0.3% by mass, or at least 0.5% by mass, and in an amount of at most 3% by mass, at most 2% by mass or at most 1% by mass, based on the total mass of the polyurethane.

[0050] In one embodiment, the polyurethane contains less than 0.1% by mass of end groups, based on the total weight of the polyurethane. In one embodiment, the polyurethane is substantially free of end groups. In one embodiment, the polyurethane is free of end groups.

[0051] The hard blocks in TPU are typically based on aromatic diisocyanates such as toluene diisocyanate (TDI) or methylene diphenyl diisocyanate (MDI) and low molecular weight aliphatic diols such as 1,4 - butanediol. Polyether and polycarbonate polyurethanes can be suitably used for biomedical applications considering their flexibility, strength, in vivo stability, biocompatibility and wear resistance. TPU containing a combination of polyether and polysiloxane or polycarbonate and polysiloxane in the soft block exhibits a unique combination of properties and can be advantageously used as a polyurethane in polymer compositions. Commercially available examples of such polymers include Pursil® and Carbosil® products (available from DSM Biomedical BV, Sittard - Geleen NL).

[0052] In a further embodiment, the TPU may be a blend of two or more polymers, for example, a blend of at least two biocompatible TPU grades having at least different hardnesses, such as a combination of 80ShA and 75ShD grades.

[0053] In other embodiments, the TPU may contain one or more conventional additives that are acceptable for the targeted use of the TPU and polymer compositions in implants, for example, in addition to catalyst residues. Examples of additives include stabilizers, antioxidants, processing aids, lubricants, surfactants, antistatic agents, colorants, etc. The additives may be present in typically effective amounts known in the art, such as 0.01 - 5 wt%, preferably 0.1 - 2 wt%, based on the amount of the polyurethane. In another embodiment, the TPU is substantially free of additives.

[0054] In some embodiments, the polymer composition consists essentially of or consists of a) 30 - 85 wt% of a biostable thermoplastic polyurethane and b) 15 - 70 wt% of zirconia particles, and the sum of a) and b) is 100 wt%.

[0055] In other embodiments, the polymer composition consists of a) 20 to 85% by mass of a biostable thermoplastic polyurethane, b) 15 to 70% by mass of zirconia particles, and c) 0 to 10% by mass of other compounds, and the sum of a) and b) is 100% by mass. Examples of other compounds include bioactive compounds such as antibacterial or anti-inflammatory agents, active agents or drugs that reduce pain or improve healing or bone formation; or, for example, residual amounts of solvents that can be used in the production of the composition, including the cleaning devices used, or dispersants or other compounds added intentionally. The (bio)active compound may be present as such in the composition or as a formulation that controls the release of the active compound into the surrounding tissue. Such other compounds generally are present in relatively small amounts, for example about 0.1 to 5% by mass based on the total polymer composition. In some embodiments, the composition and parts thereof contain at most 5, 4, 3 or 2% by mass of other compounds and at most 1000 ppm of solvent, preferably at most 800, 600, 500 or 400 ppm of solvent.

[0056] The polymer composition included in the bone fixation part contains inorganic particles containing 15 to 70% by mass of zirconia. Zirconia is also called ZrO2, which is white crystalline oxide of zirconium dioxide or zirconium. Zirconia is known to be radiopaque, and radiopacity can be added to an organic polymer by mixing a certain amount of particulate material into such a matrix.

[0057] In some embodiments, the inorganic particles in the polymer composition consist essentially of or consist of zirconia.

[0058] In some embodiments, the zirconia particles form at least 60, 70 or 75 wt% and at most 98, 95, 90, 85 or 80 wt% of the total amount of inorganic particles in the polymer composition. The main use of zirconia is, for example, in the manufacture of hard ceramics, such as by sintering at high temperatures. The use of such ceramics within the biomedical field is typically as dental crowns and bridges. Other uses include protective, optical and heat insulating coatings, ceramic knives and diamond analogs in jewelry. Unlike many other mineral particles, zirconia is rarely used as a filler or reinforcing agent in thermoplastic polymer compositions (also called polymer compounds).

[0059] Zirconia itself is chemically stable, but at high temperatures; that is, during the injection molding of the composition or during the use of an implant manufactured therefrom, at much higher temperatures than during compounding with thermoplastic polyurethane, it can be exposed to a phase change. Commercially available zirconia grades may contain other elements such as MgO, Y2O3, CaO or Ce2O3 added in amounts up to 1 - 10 mol% or more as dopants to thermally stabilize a given layer. Further, zirconia grades may contain small amounts of elements such as Al, Si, Fe, Na. Thus, within the context of the present disclosure, zirconia is understood to include substantially pure ZrO2 as well as mixed oxides containing ZrO2 and up to about 20 wt%, preferably up to a maximum of 15, 10 or 5 wt% of other inorganic oxides.

[0060] In other embodiments, the inorganic particles in the polymer composition are radiopaque biocompatible transition metal compound particles, such as transition metal salt particles or preferably transition metal oxide particles, as inorganic particles.

[0061] In embodiments, the biocompatible transition metal compound particles include at least one salt, preferably an oxide, of titanium (Ti), zinc (Zn), yttrium (Y), zirconium (Zr), lanthanum (La), ytterbium (Yb), hafnium (Hf), and tantalum (Ta). In other embodiments, the inorganic particles include at least one salt, preferably an oxide, of Ti, Zn, Y, Zr, and Ta. Alternatively, the polymer composition includes inorganic particles consisting essentially of one or more of the salts or oxides.

[0062] In some embodiments, the polymer composition includes inorganic particles containing titanium oxide, preferably the particles consist of or are derived from titania, which is also known as titanium dioxide or TiO2. Titania exists in different mineral forms such as rutile and anatase and is mainly used as a white pigment in paints, plastics, foods, toothpaste pastes, and pills.

[0063] In some embodiments, the polymer composition includes particles containing zinc oxide, preferably the polymer composition includes particles consisting essentially of or consisting of zinc oxide (ZnO). Naturally occurring zinc oxide typically contains a number of impurities and is generally synthesized from metallic zinc. Pure zinc oxide is a white powder and is applied to many different uses including paints, as a filler in plastics, rubbers, and cements, ceramics, and dental and skincare products (from the perspective of its antibacterial properties).

[0064] Parts made from a polymer composition containing polyurethane, zirconia, and optionally other inorganic particles and other compounds are radiopaque, MRI - compatible, and thus such implant parts can be distinguished from other materials and tissues using medical X - ray techniques. Radiopacity (radiodensity or radiodense, and radiopaque or radiodense) means that the part containing such inorganic particles inhibits (or absorbs) the passage of radio waves and X - ray parts of the electromagnetic spectrum, so that sufficient contrast with natural tissue is enhanced to be visible in medical X - ray imaging techniques (also called radiography). The factors contributing to radiopacity are electron density and atomic number. MRI compatibility or suitability means that the material does not pose known risks in all MRI environments, that is, it is non - conductive, non - metallic, and non - magnetic. Zirconia is not magnetic and does not pose known risks in MRI environments. Thus, by adding zirconia to polyurethane, it is also possible to image parts made from this composition using MRI techniques. Thus, implants made from this polymer composition can be visualized using common medical imaging techniques such as X - rays and MRI, enabling proper monitoring of the position of the implant at the target implantation site during surgery and postoperative examination of its position in relation to the surrounding tissues.

[0065] The inorganic particles containing zirconia in the polymer composition typically have an average particle size in the range of 0.03 - 10 μm, preferably 0.1 - 5 μm. Within the scope of the present disclosure, the particle size of the inorganic particles is the D 50 value, that is, the median diameter or the median value of the particle size distribution, measured by light diffraction according to ISO 13320:2009, for example, using a Malvern Mastersizer 2000. The measured particle size refers to the size of the particles dispersed in water, which may be different from the particle size distribution in the polymer composition because the primary particles may not be de - aggregated or dispersed in the same way during mixing with the (more viscous) polymer.

[0066] The inorganic particles in the polymer composition can have different types of particle shapes, and can be in a regular or irregular form. The shape of the particles can be substantially spherical to more elongated or flat shapes, including circular, elliptical, triangular, quadrilateral cross-sections, and with an average aspect ratio of at least 1, 2, 4, 6, 8, or up to more than 10, and can range from cigar-like, platelet-shaped, needle-shaped or fibrous shapes. The advantage of substantially circular particles is the isotropic properties of the composition, while on the other hand, an elongated shape can result in a composition with better mechanical properties, which is often dependent on the orientation of the particles. In an embodiment, the polymer composition includes a mixture of particles of various shapes, such as a mixture of substantially spherical particles and elongated particles.

[0067] In an embodiment, the particles generally have an operability such as flow behavior and administration behavior that improves with particle size, with a D size of at least 0.05, 0.10, 0.15, 0.20, 0.25, or 0.30 μm. 50 Considering the dispersibility in polyurethane and the mechanical properties of the polymer composition, the particle size of the inorganic particles is at most 8, 7, 6, 5, 4, 3, or 2 μm. The inorganic particles in the composition can further be a mixture of various sizes, such as a mixture of particles having a size at the lower end and a size at the upper end of the said range, in order to optimize mechanical properties such as the density and rigidity or toughness of the composition.

[0068] In an embodiment, the polymer composition contained in the bone fixation part contains a thermoplastic polyurethane with in vivo stability and inorganic particles containing 15 to 70% by mass of zirconia particles. A relatively large amount of such particles will enhance the rigidity, such as the tensile modulus, of the parts manufactured from this composition, but may deteriorate the stretchability and toughness of this composition. Further, polymer degradation due to shear during compounding to manufacture the composition may be enhanced by a large amount of particles. Therefore, in an embodiment, this composition contains at least 20, 25, 30, or 35% by mass and at most 68, 66, 64, 62, 60, 58, 56, 54, 52, 50, 48, or 46% by mass of inorganic particles.

[0069] In an embodiment, the polymer composition within the bone fixation portion comprises from 15 to 70% by weight of a combination of zirconia particles and one or more other biocompatible inorganic particles including other transition metal compound particles as defined above and / or natural mineral particles such as (nano)clay, mica, talc, etc., which may be dispersed in the polyurethane. The other inorganic particles typically have a similar particle size range as zirconia, but may be of different sizes and have different particle shapes, for example to provide a combination of spherical particles and acicular or fibrous particles. The presence of fibrous or other elongated particles can enhance the mechanical properties of the polymer composition. The other particles may be inert, such as bio - glass or other silicated bioceramics, or may exhibit bioactivity such as osteoconductivity. In an embodiment, up to 40% by weight of the total amount of zirconia and other filler particles present in the polymer composition is preferably formed by other inorganic particles of up to 30, 25, 20, 15, 10 or 5% by weight.

[0070] In a further embodiment, the polymer composition substantially does not contain calcium phosphate - based particles such as hydroxyapatite from the perspective that the degradation as reported in the literature and observed after the production of such polyurethane compositions (see experiments) is enhanced. More generally, in an embodiment, the composition substantially does not contain inorganic particles or other compounds that may initiate or enhance the (hydrolytic) degradation of the polyurethane, because such particles or compounds contain reactive groups that promote such degradation, or have such hygroscopic properties that they cannot be properly dried to a sufficiently low water content, such as less than 250, 150 or 100 ppm.

[0071] The polymer composition contained in the bone fixation portion can be manufactured using different mixing devices and processes, as known to those skilled in the art, for example by using a solvent - assisted mixing process or a melt - mixing process.

[0072] In one aspect, the present invention provides a method for producing the above polymer composition, including all variations and preferred embodiments and combinations thereof, · providing a biostable thermoplastic polyurethane having a water content of up to 300 ppm; · providing inorganic particles containing zirconia with a water content of 250 ppm or less; · optionally, mechanically or chemically treating the inorganic particles; · optionally, providing other compounds having a water content of at most 250 ppm; · mixing the polyurethane, the inorganic particles and any other compounds; and the method includes the above steps.

[0073] Generally, the polyurethane polymer and any zirconia or other inorganic particles added are dried sufficiently before mixing. Typically, the polyurethane is dried for several hours, e.g., 4 to 30 hours, at a temperature below its softening point or melting point to obtain a water level of up to 300 ppm, preferably up to 250, 200 or 150 ppm. The zirconia and other particles may be dried at a relatively high temperature for a long time, e.g., at 100 to 200 °C for 20 to 40 hours, to obtain a water level of up to 250 ppm, preferably up to 150 or 100 ppm.

[0074] In an embodiment, the method includes a step of mechanically or chemically (pre-)treating (dried) inorganic particles in order to further enhance the properties of the resulting polymer composition. In an embodiment, the step of mechanically treating includes milling or grinding the particles, optionally in the presence of an auxiliary component. Such auxiliary components may be low-viscosity or low-viscosity liquids, dispersing aids and / or polymers, each of which is biocompatible and compatible with polyurethane. Such treatment can be facilitated using sonication to break up aggregates of the particles and / or enhance dispersion. Such a mechanical treatment step can result in a powder, dispersant, paste or solid composition containing the inorganic particles, the use of which can result in an improved level of dispersion of the particles in the polyurethane in a subsequent mixing step. The treated inorganic particles can be dried to reach a moisture level of up to 250 ppm.

[0075] In a further embodiment, the method comprises chemically treating (dried) zirconia and optional inorganic particles to vary the type and / or amount of functional groups on the surface of the particles; and, therewith, the dispersibility in polyurethane and / or the interfacial adhesion to polyurethane. This treatment may include corona treatment, plasma treatment, and / or wet chemical treatment. Corona or plasma treatment alone can condition the surface of the particles, as is known to those skilled in the art, and can be further combined with wet chemical modification. In wet chemical treatment, the particles are typically first dispersed in a suitable liquid, and then the reagent is generally added in an amount of 5 to 300% by weight based on the particles. The dispersion can be facilitated using sonication to break up aggregates of the particles. Suitable reagents are, for example, alkyl, amine, carboxylic acid or peroxide functional groups, or silane compounds. Examples include carbon dioxide, oxygen, unsaturated hydrocarbons, alkylamines, carboxylic acids, and various amine-functional and / or alkoxy-functional silanes such as 3-aminopropyltriethoxysilane. Such compounds are also referred to in the art as coupling agents. Considering the intended medical use of the polymer composition, the addition of other components such as catalysts is preferably excluded, and the liquid is practically completely removed after pretreatment, with the moisture level being maximized at 250 ppm. Those skilled in the art will be able to select the reagent and suitable treatment conditions based on general knowledge and optionally some routine experimentation.

[0076] In an embodiment, the other compounds described above for the polymer composition may be provided, provided that those compounds have a water content of at most 250 ppm. Examples of other compounds include bioactive compounds, stabilizers, and compounds that assist in the dispersion of inorganic particles within the TPU during mixing.

[0077] In an embodiment, a method for manufacturing a polymer composition comprising a biostable polyurethane and 15 to 70% by mass of inorganic particles includes the step of adding dry (zirconia) particles or a dry masterbatch containing such particles during the synthesis of the polyurethane. For example, such addition can be carried out in a first step - before the polymerization reaction, for example, by mixing with liquid, starting chemicals, or in a second step - during the polymerization, for example, by mixing the particles with the prepolymer before or during a second polymerization step.

[0078] In other embodiments, a method for manufacturing a polymer composition comprising a biostable thermoplastic polyurethane and inorganic particles includes the steps of providing a polymerized polyurethane and using a solvent-assisted mixing step. For example, first, a solution of dry polyurethane in an excellent solvent for the polymer, such as THF, is prepared, and then a step of mixing with dry particles or pre-dispersed particles in a liquid, preferably in the same excellent solvent, is carried out. In an embodiment, a biocompatible dispersant can optionally be added to help disperse the particles homogeneously. Depending on the concentration of the polyurethane and the amount of particles in the mixture, a liquid dispersant or a paste-like mixture can be obtained. In a subsequent step, the solvent can preferably be removed by known methods such as evaporation under high temperature and / or reduced pressure. The resulting solidified polymer composition can then be made into a suitable form, for example, by cutting or polishing, for use in a molding step such as compression molding or injection molding. Advantages of such a solvent-assisted mixing method include considerably low shear forces and low temperature, i.e., a low risk of polymer degradation, and a relatively small scale at which it can be operated.

[0079] In a further embodiment, the method of manufacturing the polymer composition comprises a step of melt mixing, also called compounding, the components using a known apparatus such as a batch mixer or a continuous mixer such as a single-screw or twin-screw extruder at a temperature above the softening point or melting point of the polyurethane. Optionally, a biocompatible wetting agent or dispersant can be added before or during the melt mixing to enhance the dispersion of the particles. Before the melt mixing, the inorganic particles comprising the polyurethane and zirconia are completely dried to minimize hydrolytic decomposition during melting, as pointed out above. For the same reason, the melt mixing apparatus and mixing conditions are selected such that the temperature of the composition is maintained as low as possible. In an embodiment, the polymer composition is produced by a step of mixing the dried components on a twin-screw extruder while applying conditions such as screw speed, extrusion rate, and temperature settings that produce sufficient shear or torque for proper dispersion of the inorganic particles in the polyurethane while minimizing overheating and polymer chain scission and / or reduction of molar mass. In an embodiment, the temperature setting of the barrel of the twin-screw extruder is at most 210 °C, preferably about 205 or 200 °C. It has been observed that the step of melt mixing the polyurethane with the dried inorganic particles containing zirconia under such conditions results in significantly lower polymer decomposition than found for the same thermoplastic polyurethane such as hydroxyapatite and bismuth oxide.

[0080] In an embodiment, the bone fixation portion of the implant can be fabricated, or the TPU in the polymer composition from which the implant component is fabricated has a weight average molar mass Mw of at least 70 kDa. The molar mass and molar mass distribution are typically measured using the GPC method as described in the experimental section. It should be noted that in the present disclosure, the ISO term "molar mass" is generally used instead of the still commonly used term "molecular weight". Parts produced from a polymer composition produced by the step of (melt) mixing TPU and zirconia particles exhibit certain minimum desired properties, such as a predetermined elongation at break point, when the TPU in the composition has such a minimum molar mass. In a preferred embodiment, the TPU in the composition has a molar mass Mw of at least 75, 80, 85, 90, 95 or 100 kDa. The molar mass Mw of the TPU used to produce the present composition also meets such a minimum value, but is typically higher; still preferably not so high as to impede the processing and mixing with particles containing zirconia; this further limits the molar mass of the TPU in the resulting polymer composition. In an embodiment, the TPU in the produced polymer composition has a molar mass of up to 400, 300, 250, or 200 kDa in order to produce a well-balanced combination of processability and mechanical properties.

[0081] In an embodiment, the polymer composition has a modulus of elasticity of at least 800 to 3000 Mpa, preferably at least 850 or 900 Mpa, and at most 2500, 2000, 1800 or 1600 Mpa when measured at 20° C. on a sample dried during molding. Alternatively, the polymer composition is characterized by having an E modulus of elasticity of 200 to 700 when measured on a sample conditioned to a wet state at 37° C. to mimic the biological conditions of its targeted use in an implant. In some embodiments, such an E-modulus of the wet state is at least 225 MPa and at most 600, 550, 500 or 450 MPa. Without wishing to be bound by any theory, the inventors believe that in order for the bone fixation parts of the implant to obtain more durable results, they should mimic the mechanical properties, particularly the stiffness or modulus of elasticity, of the surrounding bone tissue. In this regard, the inventors have noted that the bone fixation parts of the implant will mainly contact cancellous bone (also called trabecular bone or spongy bone) rather than subchondral bone or cortical bone, which form the subchondral hard layer and the hard outer layer of the bone, respectively; and will contact the hard outer layer and the hard outer layer of the bone. For example, if the fixation part has a modulus of elasticity below the above level, micromotion between the implant and the surrounding bone may induce the formation of a fibrous tissue interface instead of the desired direct bonding. If the implant has too low a stiffness, the implant may also be deformed or damaged during loading. If the modulus of elasticity of the implant part is too high, stress shielding may occur, in which case the load on the implant, for example a cartilage replacement cap, can be mainly propagated inside the implant itself without loading the surrounding bone tissue. When the bone is not loaded, the bone can be remodeled and / or resorbed in the unloaded area, ultimately resulting in loosening of the implant. Further, the present polymer composition exhibits reduced creep deformation and plastic deformation compared to materials such as unfilled polyurethane; this contributes to better stability of the implant.

[0082] In an embodiment, and similar to the above paragraphs, the polymer composition exhibits at least 5%, preferably at least 10, 20, 30, 40 or 50% elongation at break (Eab; dry / 20 °C) during a tensile test, or at least 10, 20, 30, 40 or 50% Eab (wet / 37 °C). In an embodiment, the polymer composition has an elongation at break tensile strength (TS; dry / 20 °C) of at least 30, 35 or 40 Mpa, or a TS of at least 15, 20 or 25 MPa (wet / 37 °C) after conditioning. Such stiffness and strength characteristics of the present composition in a state conditioned with the same indicators as those of cancellous bone have been found to enhance the compatibility and adhesion over time between an implant made from the present composition and such biological tissue. It further makes it easier or improves the insertion of the implant into the bone cavity, with a lower risk of damaging the tissue, compared to implants made from metal. Furthermore, implants made from the polymer composition are strong enough to withstand typical implantation techniques applied by an orthopedic surgeon, i.e., using a hammer and a directional guide that may further limit the depth of penetration and typically his perceptual responsiveness (such as noticing changes in the acoustics during hammering) at the damaged cartilage site and inserting the implant into the holes drilled in the bone, etc.

[0083] In an embodiment, the polymer composition has a Shore hardness of 76 - 85 ShD, typically 78 - 82 ShD (dry / 20 °C). In some embodiments, the orthopedic implant has a bone fixation portion substantially consisting of a polymer composition comprising a biostable thermoplastic polyurethane and 15 - 70% by mass of inorganic particles. Such parts can be made from the polymer composition, for example, by an injection molding process. The bone fixation portion may have, for example, a smooth outer surface or a textured outer surface to affect the interaction with body tissue, and optionally may be provided with a surface coating.

[0084] In an embodiment, the outer surface of the bone fixation portion of the implant has a textured surface such as a surface having a surface roughness Ra of at least 1 μm to enhance interaction with the surrounding bone tissue after implantation. Such a surface roughness may be introduced during or after the manufacture of the component, for example, by applying a mold having a specific surface texture, as defined, for example, by the VDI3400 scale commonly used in the industry. An example of a polymeric implant having such a textured surface and a method of making the same are referred to herein as WO 2019 / 068903. In a further embodiment, the bone fixation portion of the implant has a surface roughness Ra of at least 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18 or 20 μm and a maximum of 25 μm.

[0085] In some embodiments, the orthopedic implant has a bone fixation portion comprising a biostable thermoplastic polyurethane and an inorganic particle-containing polymer composition of 15 to 70% by mass, for example, to induce osteoconductivity, and optionally other components such as functional particles or functional coatings on its (smooth or textured) surface. In some embodiments, the bone fixation portion has a bioactive coating, preferably an osteoconductive coating, to further promote interaction with the tissue. Based on both organic and inorganic bioactive materials, various bioactive or osteoconductive coatings as described in the art may be present on the bone fixation portion of the present implant.

[0086] In a further embodiment, the bioactive ceramic particles are present on an optionally textured surface of the bone fixation portion, and these particles provide osteoconductive properties to the relevant part of the implant, for example. Suitable bioactive ceramic particles include, for example, all inorganic materials that exhibit the ability to directly adhere to living bone through the formation of bioactive bone-like apatite through the interaction or chemical reaction between the particle surface and the surrounding body fluid. Examples of suitable osteoconductive materials include various calcium phosphates, so-called bioglass, and other silica-based ceramics (so-called silica-coated ceramics). For such applications, various types of calcium phosphates such as dicalcium phosphate anhydride (CaHPO4; DCPA), dicalcium phosphate dihydrate (CaHPO4.2H2O; DCPD), octacalcium phosphate (Ca8(HPO4)2.5H2O; OCP), tricalcium phosphate (Ca3(PO4)2; TCP), and hydroxyapatite (Ca 10 (PO4)6(OH)2; HA) have been described. Furthermore, different types of blends such as mixtures of HA and TCP or HA and bioglass can also be applied or may even show advantages. The ceramic particles may contain, in addition to their main components, small or trace amounts of other (inorganic) elements or ions such as Si, Na, Mg, Fe, Zn, Ti, Ag, Cu or -SO4, or -CO3, which can improve specific properties of the particles.

[0087] The term "bioglass", including commercial Bioglass® products, refers to mixed inorganic oxides or silicate ceramics that have a surface-reactive glass film compatible with tissues; and can be used as surface coatings in medical and dental implants. For example, Bioglass® 45S5 grade is stated to be a glass composed of 45 wt% SiO2, 24.5 wt% CaO, 24.5 wt% Na2O, and 6.0 wt% P2O5. The high ratio of calcium to phosphorus in this material will promote the formation of apatite crystals; calcium ions and silica ions can function as crystallization nuclei. Glasses are amorphous non-crystalline solids generally composed of silica-based materials containing small amounts of other inorganic elements. An overview of suitable bioactive ceramics and methods for applying these to substrates as coating materials is provided, for example, by G. Brunello et al.; DOI: 10.3390 / ma12182929.

[0088] In one embodiment, the bioactive ceramic particles have a particle size in the range of 0.1 to 10 μm. The particle size and particle size distribution can be measured using SEM or an optical microscope, or using (laser) light refraction techniques. Within the scope of the present disclosure, for example, the D 50 value measured by a light refraction method in accordance with ISO 13320:2009 using a Malvern Mastersizer 2000 is defined as the particle size of the bioceramic particles. Although this particle size does not seem to be particularly important, larger particles may be more effective when interacting with body fluids and cells. Considering operability, ceramic particles having a particle size of at least 0.2 μm, or at least 0.3, 0.4, or 0.5 μm are preferred. In a further embodiment, the implant has ceramic particles having a particle size of up to 10, 8, 6, 5, 4, 3, 2 μm, or up to 1 μm on the surface of the bone fixation part.

[0089] An orthopedic implant including a bone fixation portion may be a bone anchor such as a plug or a screw, and can be used to fix additional parts such as sutures, artificial ligaments or tendons, menisci, acetabular labral replacement devices, and cartilage replacement portions to bone. In an embodiment, such additional parts form an integral part of the implant. In an embodiment, the implant includes at least two parts, that is, further includes a cartilage replacement portion. The cartilage replacement portion is typically permanently connected to the bone fixation portion and is made of at least partially elastic and wear-resistant biocompatible material. In an embodiment, the cartilage replacement portion is made of a biostable, biocompatible polymer having mechanical properties such as an elastic modulus and hardness equivalent to those of the natural cartilage layer it replaces. For example, various so-called hydrogels for cartilage replacement have been proposed, such as hydrogels based on water-swellable or water-soluble hydrophilic polymers that can be bio-stable or biodegradable, as described in U.S. Patent Application Publication No. 2011 / 0218647. Typically, a hydrogel is a cross-linked non-thermoplastic material.

[0090] In an embodiment of the present invention, the implant has a cartilage replacement portion made of a biostable and elastic thermoplastic polymer such as a segmented block copolymer having hard segments based on polyester, polyamide or polyurethane. In an embodiment, the cartilage replacement portion is made of biostable, elastic thermoplastic polyurethane (TPU). The advantage of applying the TPU material to both the bone fixation portion and the cartilage replacement portion of the implant is that, for example, by applying an insert molding method or by a multi-component or two-component molding method, the two parts can be injection molded to form an article having two adhesive parts or an integrated part. Alternatively, the parts may be welded to each other using, for example, a laser source, or may be joined to each other using a biostable and biocompatible adhesion promoting composition containing a polyurethane-based composition.

[0091] In an embodiment, a part of the implant, the cartilage replacement part, is made of an elastic biostable thermoplastic polyurethane having a Shore hardness of 55 to 100 ShA. Polyurethanes are typically block copolymers containing multiple blocks (also called segments) of polymers (including oligomers) that are chemically different, exhibit different thermal and mechanical properties, and different solubilities. In many cases, the blocks in a block copolymer containing two (or more) types of blocks are called "hard" and "soft" polymer blocks, and such (chemically) different blocks result in microphase separation of the hard and soft blocks. The hard blocks in the block copolymer typically include a rigid or high modulus polymer having a melting temperature (T m ) or glass transition temperature (T g ) higher than the use temperature, typically about 35 to 40 °C. The soft blocks in the block copolymer generally include a flexible and low modulus amorphous polymer having a T g below 25 °C, preferably below 0 °C. For most mechanical properties, thermal parameters such as T m and T g are generally determined on dry samples using well-known techniques such as DSC or DMA. In such phase-separated block copolymers, the hard segments function as physical crosslinks for the flexible soft segments, and as a result, materials with properties ranging from fairly rigid to flexible and elastic depending on the ratio of the hard and soft blocks are obtained. Depending on the type and content of the hard blocks, the polyurethane block copolymer can exhibit good stability and elasticity over a desired temperature range without the need for chemical crosslinking and can generally be processed as a thermoplastic. Thermoplastic polyurethanes are basically a family of polymers having a backbone containing the reaction products of at least three main components, which are diisocyanates, diol chain extenders, and polymeric diols or macroglycols. Optionally, monofunctional compounds may function as chain terminators and be used as additional components to form (non-reactive) end groups. In an embodiment, the backbone of the TPU applied to the cartilage replacement part is substantially linear.

[0092] In some embodiments, the TPU of the cartilage replacement portion includes hard blocks, soft blocks, and optionally end groups, which are (chemically) similar to the blocks and end groups included in the TPU present in the polymer composition of the bone fixation portion as defined hereinabove, but typically have at least different ratios of hard blocks to soft blocks and / or different block lengths. Such similar TPUs can enhance the interfacial strength between portions of the implant.

[0093] In some embodiments, the TPU includes hard blocks that contain urethane groups and optionally urea groups in the repeating units, and these groups are obtained from the reaction of a diisocyanate with a diol and optionally a diamine as respective chain extenders.

[0094] Suitable diisocyanates include aromatic, aliphatic, and alicyclic compounds having an average of 1.9 to 2.1 isocyanate groups per molecule. In one embodiment, the diisocyanate includes 4,4'-diphenylmethane diisocyanate (MDI), 2,4-toluene diisocyanate, 2,6-toluene diisocyanate (TDI), 1,4-phenylene diisocyanate, hexamethylene diisocyanate (HDI), tetramethylene-1,4-diisocyanate, cyclohexane-1,4-diisocyanate, dicyclohexylmethane-4,4'-diisocyanate (CHMDI), isophorone diisocyanate (IPDI), or a mixture thereof. In one embodiment, the diisocyanate includes hexamethylene diisocyanate, dicyclohexylmethane 4,4'-diisocyanate, isophorone diisocyanate, or a mixture thereof. In one embodiment, the diisocyanate consists of hexamethylene diisocyanate, dicyclohexylmethane 4,4'-diisocyanate, isophorone diisocyanate, or a mixture thereof. In another embodiment, the diisocyanate includes 4,4'-diphenylmethane diisocyanate, 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, or 1,4-phenylene diisocyanate. In one embodiment, the diisocyanate consists of 4,4'-diphenylmethane diisocyanate, 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, 1,4-phenylene diisocyanate, or a mixture thereof. In one embodiment, the molar mass of the diisocyanate is 100 to 500 g / mol. In one embodiment, the molar mass of the diisocyanate is 150 to 260 g / mol.

[0095] Chain extenders are typically low molar mass aliphatic compounds having two or more, preferably two, hydroxyl or amine groups. Bifunctional chain extenders generally result in linear thermoplastic polymers, while polyfunctional chain extenders and / or isocyanates result in branched or crosslinked products. In one embodiment, the bifunctional chain extender has a molar mass of at least 60 g / mol, at least 70 g / mol, at least 80 g / mol, at least 90 g / mol, or at least 100 g / mol. In one embodiment, the chain extender has a molar mass of up to 500 g / mol, up to 400 g / mol, up to 300 g / mol, up to 200 g / mol, or up to 150 g / mol. In one embodiment, the chain extender includes ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, or 1,8-octanediol, and / or the corresponding diamines thereof. In some embodiments, the thermoplastic polyurethane includes only a diol chain extender.

[0096] In other embodiments, the TPU includes hard blocks having both urethane and urea bonds. The advantage is that the interaction between the hard blocks is enhanced, resulting in a higher softening temperature and / or enabling a higher soft block content, and a block copolymer exhibiting improved flexibility and elasticity, as well as excellent flex life or fatigue resistance, is obtained. Depending on the diol / diamine ratio, the polyurethane chains may exhibit strong interactions such that thermal decomposition can occur at the melt processing temperature, and solution processing is preferred for optimal performance. Commercially available examples of such relatively low hardness polyurethanes, also called polyurethane ureas, include Biospan® products (available, for example, from DSM Biomedical BV, Sittard-Geleen NL).

[0097] In a further embodiment, the thermoplastic polyurethane comprises a soft block derived from at least one aliphatic polymer diol or polyol selected from the group consisting of polyethers, polyesters, polyacrylates, polyolefins and polysiloxanes (also referred to as silicones), and the polymer is bifunctional with hydroxyl (or amine) end groups. Such polymer diols for the soft block are understood herein to include oligomers, homopolymers and copolymers, and polyesters are considered to include polycarbonates. Commonly known polyurethane block copolymers and methods for preparing these copolymers are described, inter alia, in U.S. Patent Nos. 4,739,013, 4,810,749, 5,133,742 and 5,229,431.

[0098] In embodiments of the present disclosure, the thermoplastic polyurethane comprises as a soft block at least one polymer diol selected from aliphatic polyester diols, aliphatic polycarbonate diols, aliphatic polyether diols, poly(isobutylene) diols and polysiloxane diols. Similarly or as chain extenders, some amine-functional soft blocks can also be used, resulting in additional urea linkages. The biocompatibility and biostability of such polyurethane block copolymers in the human body have been demonstrated.

[0099] The mechanical and other properties of the thermoplastic polyurethane can be adjusted by varying the chemical composition and / or molar mass of the blocks. The hard blocks of the thermoplastic polyurethane contained in the compositions of the present invention can have a molar mass of from about 160 to 10,000 Da, more preferably from about 200 to 2000 Da. The molar mass of the soft segments can typically be from about 200 to 100,000 Da, preferably at least about 400, 600, 800 or 1000 Da, and at most about 10,000, 7500, 5000, 4000, 3000 or 2500 Da. Within the context of the present disclosure, the molar mass of the polymers and oligomers forming the blocks in the polymer is, for example, the number average molar mass (M obtained from GPC measurements nrefers to ([0]). The ratio of the soft block to the hard block can be selected to provide a specific stiffness or hardness of the polyurethane. The hardness of the polyurethane measured by the Shore durometer hardness test can be from 55ShA to 100ShA, and generally represents a tensile elastic modulus range of about 10 to 100 MPa (dry forming). In embodiments, the thermoplastic polyurethane has a hardness of at least 60, 65, or 70ShA. The advantage of using a relatively low hardness TPU can be a better cushioning effect at the joint. A higher hardness can result in more durable wear resistance. In other embodiments, for a good balance between elasticity and wear resistance, the TPU of the cartilage replacement part has a hardness of up to 95, 90 or 85ShA. In other embodiments, the TPU in the cartilage replacement part has a tensile elastic modulus (wet state at 37 ° C) of about 2 to 50 MPa, preferably 5 to 40 or 8 to 30 MPa.

[0100] In a further embodiment of the present invention, the thermoplastic polyurethane comprises an aliphatic polyether, an aliphatic polyester, an aliphatic polycarbonate or a combination thereof as a soft block, more specifically an aliphatic polycarbonate. The composition of the soft block preferably has a T of less than 10 ° C, less than 0 ° C, preferably less than -10 ° C gwhich results in an essentially amorphous oligomer or polymer having the same. Suitable aliphatic polyethers include poly(propylene oxide) diol, poly(tetramethylene oxide) diol, and copolymers thereof. Suitable aliphatic polyesters are generally made from at least one aliphatic dicarboxylic acid and at least one aliphatic diol. Aliphatic polycarbonate diols are based on the same aliphatic diols used for polyester diols and can be synthesized via different routes known in the art. Suitable examples include poly(hexamethylene carbonate) diol and poly(tetrahydrofuran carbonate) diol. Such polycarbonate-based TPUs exhibit favorable biocompatibility such as blood compatibility and improved biostability. In one embodiment, the soft block of the TPU is based on poly(hexamethylene carbonate) diol, poly(polytetrahydrofuran carbonate) diol, or a mixture thereof. In a preferred embodiment, the TPU contains poly(hexamethylene carbonate) diol as the soft block.

[0101] In a further embodiment, the soft block of the TPU comprises a polysiloxane diol such as poly(dimethylsiloxane) diol, polycarbonate diol, or poly(tetramethylene oxide) diol. In one embodiment, the soft block is based on a polysiloxane diol, polycarbonate diol, poly(tetramethylene oxide) diol, or a mixture thereof. In one embodiment, the soft block comprises a mixture of two or more of a polysiloxane diol, polycarbonate diol, or poly(tetramethylene oxide) diol. Such mixtures enable the production of biocompatible polyurethanes that exhibit improved hydrolytic stability in combination with high toughness. In one embodiment, the soft block is based on a mixture of two or more of a polysiloxane diol, polycarbonate diol, or poly(tetramethylene oxide) diol. In one embodiment, the soft block comprises a polysiloxane diol and one or more of a polycarbonate diol and poly(tetramethylene oxide) diol. In one embodiment, the soft block is based on a polysiloxane diol and one or more of a polycarbonate diol and poly(tetramethylene oxide) diol.

[0102] In one embodiment, the soft block is C2-C 16 fluoroalkyl diol or C2-C 16It may further contain a fluoroalkyl ether diol. In one embodiment, the soft block in the polyurethane main chain is 1H,1H,4H,4H-perfluoro-1,4-butanediol, 1H,1H,5H,5H-perfluoro-1,5-pentanediol, 1H,1H,6H,6H-perfluoro-1,6-hexanediol, 1H,1H,8H,8H-perfluoro-1,8-octanediol, 1H,1H,9H,9H-perfluoro-1,9-nonanediol, 1H,1H,10H,10H-perfluoro-1,10-decanediol, 1H,1H,12H,12H-perfluoro-1,12-dodecanediol, 1H,1H,8H,8H-perfluoro-3,6-dioxaoctane-1,8-diol, 1H,1H,11H,11H-perfluoro-3,6,9-trioxaundecane-1,11-diol, fluorinated triethylene glycol, or fluorinated tetraethylene glycol.

[0103] In one embodiment, C2-C 16 fluoroalkyl diol or C2-C 16 The fluoroalkyl ether diol has an M of at least 150 g / mol, at least 250 g / mol, or at least 500 g / mol. n In one embodiment, the fluoroalkyl diol or fluoroalkyl ether diol has a molar mass of at most 1500 g / mol, at most 1000 g / mol, or at most 850 g / mol. In one embodiment, C2-C 16 fluoroalkyl diol or C2-C 16 The fluoroalkyl ether diol is present in an amount of at least 1 wt%, at least 2 wt%, or at least 5 wt% based on the total mass of the polyurethane. In one embodiment, C2-C 16 fluoroalkyl diol or C2-C 16 The fluoroalkyl ether diol is present in an amount of at most 15 wt%, at most 10 wt%, or at most 8 wt% based on the total mass of the polyurethane.

[0104] In some embodiments, the polyurethane may include one or more hydrophobic or hydrophilic end groups. End groups are generally non-reactive moieties present at the ends of the molecule. In one embodiment, the polyurethane includes end groups at each end of the main chain, i.e., it has on average about two end groups. In one embodiment, the end groups are linear compounds. In another embodiment, the end groups are branched. The end groups may be formed by reacting terminal isocyanate groups present during or after formation of the polymer backbone with co-reactive groups on a monofunctional compound, also referred to as a chain terminator. For example, a formulation for forming a polyurethane includes a diisocyanate, a polymeric aliphatic diol, a chain extender, and a monofunctional alcohol or amine such as 1-octanol or octylamine to form C8 alkyl end groups.

[0105] In an embodiment, the end group is a hydrophobic end group, for example, C2-C 20 alkyl, C2-C 16 fluoroalkyl, C2-C 16 fluoroalkyl ether, a hydrophobic poly(alkylene oxide) or a polysiloxane (including copolymers thereof). In one embodiment, the hydrophobic poly(alkylene oxide) is poly(propylene oxide), poly(tetramethylene oxide) or a copolymer thereof. In one embodiment, the hydrophobic end group is a polysiloxane such as poly(dimethylsiloxane). In one embodiment, the end group is C2-C 20 alkyl, C2-C 16 fluoroalkyl, C2-C 16 fluoroalkyl ether, or a hydrophobic poly(alkylene oxide). Such end groups can be formed with a monofunctional alcohol containing a carbinol or the aforementioned amine. Such polyurethane elastomers having hydrophobic end groups have been found to have a positive effect on the properties of the polyurethane and its interaction with other polymers such as polyolefins and other materials including fluids such as body tissues and blood.

[0106] In one embodiment, the hydrophobic end group is C2-C 16Fluoroalkyl or C2-C 16 contains fluoroalkyl ether. Such end groups are C2-C 16 fluoroalkyl or C2-C 16 It can be formed using a monofunctional alcohol or amine containing fluoroalkyl ether. In one embodiment, the end group is 1H,1H-perfluoro-3,6-dioxaheptan-1-ol, 1H,1H-nonafluoro-1-pentanol, 1H,1H-perfluoro-1-hexyl alcohol, 1H,1H-perfluoro-3,6,9-trioxadecane-1-ol, 1H,1H-perfluoro-1-heptyl alcohol, 1H,1H-perfluoro-3,6-dioxadecane-1-ol, 1H,1H-perfluoro-1-octyl alcohol, 1H,1H-perfluoro-1-nonyl alcohol, 1H,1H-perfluoro-3,6,9-trioxatridecane-1-ol, 1H,1H-perfluoro-1-decyl alcohol, 1H,1H-perfluoro-1-undecyl alcohol, 1H,1H-perfluoro-lauryl alcohol, 1H,1H-perfluoro-1-myristyl alcohol, or 1H,1H-perfluoro-1-palmityl alcohol.

[0107] In another embodiment, the end group is a hydrophilic end group formed from a hydrophilic monofunctional alcohol or amine compound. Such compounds are typically water-soluble and may exhibit surface activity, such as polyethylene oxide or sulfonate-functional compounds. Such hydrophilic end groups can have a positive effect on the interaction with other materials, including biological tissues or body fluids.

[0108] In another embodiment, the polyurethane contains a mixture of hydrophobic end groups and hydrophilic end groups. Such modification makes it possible to control the hydrophobic-hydrophilic balance of the polymer. A common advantage of using TPU with end groups is to modify and control the properties of the polymer without incorporating additives that may pose potential problems for the movement from the polymer and the implant.

[0109] In one embodiment, the end group is a monomer and has a molar mass of 200 g / mol or more, 300 g / mol or more, or 500 g / mol or more, and 1,000 g / mol or less or 800 g / mol or less. In one embodiment, the end group is polymeric and has a molar mass of 10,000 g / mol or less, 8,000 g / mol or less, 6,000 g / mol or less, or 4,000 g / mol or less. In one embodiment, the end group is polymeric and has a molar mass of 500 g / mol or more, 1,000 g / mol or more, or 2,000 g / mol or more.

[0110] In one embodiment, the end group is present in an amount of at least 0.1% by mass, at least 0.2% by mass, at least 0.3% by mass, or at least 0.5% by mass based on the total mass of the polyurethane. In one embodiment, the end group is present in an amount of up to 3% by mass, up to 2% by mass, or up to 1% by mass based on the total mass of the polyurethane. In one embodiment, the end group is present in an amount of at least 0.1% by mass, at least 0.2% by mass, at least 0.3% by mass, or at least 0.5% by mass, and up to 3% by mass, up to 2% by mass, or up to 1% by mass based on the total mass of the polyurethane.

[0111] In one embodiment, the polyurethane contains less than 0.1% by mass of end groups based on the total weight of the polyurethane. In one embodiment, the polyurethane is substantially free of end groups. In one embodiment, the polyurethane is free of end groups.

[0112] The hard blocks in TPU are typically based on aromatic diisocyanates such as toluene diisocyanate (TDI) or methylene diphenyl diisocyanate (MDI), and low molar mass aliphatic diols such as 1,4 - butanediol. Polyether and polycarbonate polyurethanes can be suitably used for biomedical applications from the viewpoints of their flexibility, strength, biostability, biocompatibility, and abrasion resistance. TPU containing a combination of polyether and polysiloxane or polycarbonate and polysiloxane in the soft block exhibits a combination of unique properties and can be advantageously used as a polyurethane in a polymer composition. Commercially available examples of such polymers include Pursil® and Carbosil® products (available from DSM Biomedical BV, Sittard - Geleen NL).

[0113] In a further embodiment, the TPU may be a blend of two or more polymers, for example, a blend of two biocompatible TPU grades having different hardnesses, such as a combination of 50ShA and 50ShD grades, or a blend of two TPU grades having different soft blocks and / or end groups. The TPU can also be a blend of TPU with another biocompatible polymer, preferably another low modulus elastomeric material. Typically, such other biocompatible polymers are dispersed within the TPU and form a blend of up to 40 volume %, preferably up to 30, 20, or 10 volume %.

[0114] In other embodiments, the TPU can include one or more conventional additives that are acceptable for the targeted use of the TPU in an implant, in addition to, for example, catalyst residues. Examples of additives include stabilizers, antioxidants, processing aids, lubricants, surfactants, antistatic agents, biologically active compounds such as anti-inflammatory agents, filler particles including inorganic particles such as those included in the polymer composition of the bone fixation part, and the like. The additives may be present in a typically effective amount known in the art, such as 0.01 to 10% by mass, preferably up to 8, 6, 4, 3, or 2% by mass, based on the amount of the polyurethane. In another embodiment, the TPU is substantially free of additives.

[0115] The cartilage replacement part of the implant generally has a thickness that is the same as or substantially matches the thickness of the cartilage layer of the joint to be locally replaced. Such a thickness is intended such that, after implantation, the side surface of the cartilage replacement part contacts only the original cartilage to which it is substantially adjacent, while the upper surface of the part is available to be adjacent to the opposite cartilage surface within the joint. Such a design has been found to result in good integration with natural cartilage and reduce the risk of damage by contacting harder bone tissue. Similarly, the implant is designed such that the contact between the more rigid bone fixation part and natural cartilage is limited or further prevented, reducing the corresponding risk of damage. This is further shown in FIGS. 1 to 3 with reference to the following.

[0116] In an embodiment, the cartilage replacement part of the implant has a thickness of about 0.2 to 5 mm, preferably at least 0.4, 0.6, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 or 1.5 mm, and at most 4.5, 4.0, 3.8, 3.6, 3.4, 3.2, 3.0, 2.9 or 2.8 mm. In an embodiment, the cartilage replacement part of the orthopedic implant for cartilage replacement is a layer of substantially constant or uniform thickness such that its properties and performance in the joint are similar across its surface area.

[0117] In an embodiment, for example, an implant having a mushroom-like design on a cap and stem portion, a cap, and thus a cartilage replacement portion or layer has a curved or undulating upper surface, such as the surface of the joint in which it is placed. Such a curvature may be characterized by one radius or by two or more different radii in different directions, such as biaxial curvature. The curvature is typically convex, but may be a combination of convex and concave, as in the case of the saddle-shaped surface of a joint. A cartilage replacement portion or layer having multiple radii of curvature can have a thickness that varies somewhat within the thickness range, and preferably the layer thickness is substantially uniform. When the cartilage replacement portion of an orthopedic implant is of substantially uniform thickness, the upper surface for bone fixation has a curvature similar to that described above for the cartilage replacement portion.

[0118] The curvature of the bone of a joint varies widely from person to person, depending inter alia on the joint, its location, gender and age. In the knee joint, for example, the curvature can be characterized by a radius of 15 to 70 mm. Considering that defects most frequently occur in the central part of the joint, embodiments of the present invention include implants having at least one surface curvature in the range of 20 to 60 mm radius, and such implants may be suitable for use in most patients.

[0119] An orthopedic implant including a bone fixation portion and optionally a cartilage replacement portion can have various forms or shapes, and preferably at least a part of the implant, such as the implant or the bone fixation portion, has axial symmetry.

[0120] In an embodiment, the implant 1 has a cylindrical shape with a substantially constant diameter, where a large cylindrical section 3 represents the bone fixation part and the cartilage replacement part is a section (or layer) 2 at one end of the cylinder. The diameter of the cylinder may be 5 - 20 mm, 10 - 18 mm, 12 - 17 mm, or typically about 15 mm. Alternatively, the substantial cylindrical form may show some tapering from top to bottom, but the cartilage replacement part or layer has a diameter that is at most 10% larger than the minimum diameter of the bone fixation part. The slightly tapered bone fixation part has been found to be beneficial not only when releasing the part from the mold in which it is manufactured, but also when placing it in the bone hole to ensure contact with the bone after implantation. The outer side may show a taper of 1 - 5°, preferably at least 1.5, or 2.0° and at most 4.5, 4.0, 3.5 or 3.0° compared to the longitudinal direction of the fixation part.

[0121] Although not shown in FIG. 1, the edge of the cylinder may be somewhat rounded to reduce stress concentration during loading, and part 2 may be curved. The cartilage replacement part, or at least its upper surface, may be substantially flat, but preferably has a curvature or undulation so as to mimic the curvature of the joint joint to be implanted. In an embodiment, the upper curvature is defined by at least two different radii, such as two radii in mutually rectangular directions, i.e., the surface has a biplanar curvature. In this way, the typical curvature of the articular surface of the bone within the joint can be simulated in a relatively simple way. This not only simplifies the manufacture of the mold and the implant, but also reduces the number of implant plugs having different sizes and / or geometries, i.e., plugs having different curvatures and optionally different diameters, which need to be held in stock or present in a kit in order to be able to select the implant most suitable for a given patient.

[0122] In other embodiments, the implant 1 has a mushroom-like shape with a cap and at least one stem, the cap being wider, for example having a larger diameter than the stem. Such an implant can have a basic axisymmetry with a circular cap, but the cap can also be elliptical or oval, and / or the implant can have two or more stems. In an embodiment, the implant has substantial axisymmetry in at least one stem of the bone fixation part. The schematic diagrams shown in FIGS. 2A and 2B schematically represent a perspective top view and a side view of such a mushroom-like implant. In these figures, the stem 3b is cylindrical with a substantially constant diameter, but alternatively can be tapered or conical, and together with the lower part 3a of the cap forms the bone fixation part 3. With respect to its longitudinal orientation, the outside of the stem can exhibit a taper of 1 to 5° as described above, and the diameter of the stem decreases slightly from the cap to the bottom end. Both parts 3a and 3b forming the bone fixation part 3 are preferably made from the same polymer composition, such as the composition described in this disclosure. The upper part (or layer) 2 of the cap is made from, for example, elastic TPU and represents a cartilage replacement part supported and adhered by the part 3a of the bone fixation part. The diameter of the stem can be about 5 to 15 mm, typically about 6 to 10 mm, and the cap can have a diameter of about 5 to 25, 10 to 20, 12 to 18, or about 15 mm. In practice, typically, a series of implants of different sizes, especially having different cap sizes, can be made available, for example as part of a kit, to enable selection of the appropriate implant before or during surgery depending on the patient being treated. The edges of the plug, as well as the transition from the cap to the stem and from the side wall of the stem to the bottom, etc., are preferably rounded to reduce stress concentration during implantation and / or loading during use (not shown in FIG. 2).

[0123] In an embodiment, the implant has a rounded edge and / or transition portion, which may have a rounding radius of 0.1 to 4.0 mm, depending also on other dimensions of the implant. For example, a load distribution simulation on an implanted plug by applying finite element analysis (FEA; also referred to as finite element modeling, FEM) has shown that the forces applied to the surface of the cartilage replacement portion can be better distributed over the entire implant, and high local stress concentrations can be prevented by optimizing the sizing of the edge and transition portions. In an embodiment, the edge and transition portions of the implant are rounded with a radius of at least 0.2, 0.5, 1.0, 1.5, or 2.0 mm and up to 3.5 or 3.0 mm at most.

[0124] In an embodiment, as described above, the upper surface of the cartilage replacement portion 2 of the implant may be curved or contoured in at least one, preferably at least two directions so as to mimic the curvature of the joint articulation in which it can be implanted. In an embodiment, the cap has a two-plane surface curvature, i.e., the upper curvature is characterized by two different radii in a rectangular direction with respect to each other. Such an embodiment is further illustrated by FIG. 3, which shows only a part of the cartilage replacement portion 2 of the implant having a two-plane curvature and a substantially uniform thickness. Such an implant with a two-plane curvature cannot fully reproduce the natural curvature, but such an approximation allows the typical curvature of the bone joint surface in the joint to be simulated in a relatively simple way. Further, the two-plane curvature simplifies the casting mold and thus the manufacture of the implant and limits the number of plugs of different geometries and sizes having different curvatures and optionally different diameters of the stem and / or cap that need to be held in stock or present in a parts kit to select the implant most suitable for a given patient.

[0125] In other embodiments, the implant has a surface curvature that can be described by one radius. In further embodiments, the implant has a surface curvature that can be described by three or more radii, defining a surface that more closely follows the complex surface curvature at a particular location of the joint. Further, the upper surface typically has a convex curvature in one or more directions, but may have a combination of convex and concave curvatures, such as the saddle-shaped portion of the articular surface. Generally, the radius (or radii) of curvature of a cartilage replacement portion of the implant of the present disclosure may depend on the type of joint and the patient, and one of ordinary skill in the art can select an appropriate range. In an embodiment, the radius of curvature is in the range of 15 to 70 mm, preferably the radius is at least 20 or 25 mm and at most 65, 60, 55 or 50 mm.

[0126] In an embodiment, referring again to FIG. 2, at least a portion of the lower surface of the cap 3a forming part of the bone fixation portion is substantially flat. This portion 3a supports the cartilage replacement portion 2, including dispersing the forces acting on the layer, connects the portion 2 and the stem portion 3b, and plays a role in fixation to the bone. When implanting, the bone hole is made to have the same (or slightly smaller than) the dimensions of the stem 3b of the plug, but the damaged cartilage is removed with a diameter and depth such that the cancellous bone tissue is exposed and the side and lower surfaces of the portion 3a contact the patient's bone tissue. The same applies to the stem 3b. Then, the cartilage replacement portion 2 contacts the natural cartilage mainly on its side or only on its side alone.

[0127] The dimensions of the bone fixation part 3, such as the thickness 3a and the diameter and length 3b, depend on various factors such as the joint functioning as an implant, typical loads, and the size of the cartilage replacement part. A person skilled in the art can select appropriate dimensions based on the above considerations, for example, with the help of some model calculations. In an embodiment, the part 3a can have a thickness of about 1 to 5 mm, preferably at least 1.5 or 2 mm, and up to 4.5, 4, 3.5 or 3 mm. In the case of a curved cartilage replacement part with a substantially constant thickness, the upper surface of 3a of the bone fixation part 3 has a similar curvature, and its thickness may not be constant and may be reverse from the edge towards the center. The thickness may be about 1 to 7 mm, preferably at least 1.5 or 2 mm, and up to 6.5, 6.0, 5.5, 5.0, 4.5, 4, 3.5 or 3 mm, and especially depends on the dimensions (especially the diameter) of the cap part. Optionally, in the case of a relatively large plug with a large cap, the connection or transfer zone between 3a and 3b may be rounded with a relatively large radius or may be gradual like stepped or conical to better disperse the load to the edge zone of the part 2 of the cap. Alternatively, a reinforcing rib connecting 3a and 3b can be used to further support the part 3a and further strengthen the implant and its durability.

[0128] In other embodiments, the orthopedic implant does not have overall axial symmetry, but can be considered to include two similar implant portions that have partial axial symmetry, together with a cap, for example, like a mushroom twin. An example of such an implant has a mushroom-like shape and has a substantially elliptical or oval cap with a contoured upper surface and two substantially identical cylindrical or tapered stems, as schematically shown in the cross-sectional view of FIG. 4. Here, the top layer 2 of the cap has a substantially uniform thickness and forms a cartilage replacement portion, and the lower side of the cap 3a forms a bone fixation portion 3 together with the two stems 3b' and 3b''. Note the rounded edge and the transition from 3a to 3b. In FIG. 5, such an implant is further illustrated by different schematic views. FIGS. 5A and 5B provide side views of the long and short sides of the non-cylindrical implant, respectively, showing both or only one of the single cap and stem. FIG. 5C represents a perspective top view of the implant showing the two-plane contour surface of the elliptical cap.

[0129] In an embodiment, as shown in FIGS. 1 and 2 respectively, for example, the size of the bone fixation portion 3 of the implant, or portions 3a and 3b thereof, is selected from a limited set of standard lengths and / or diameters to simplify surgical procedures such as preparing appropriate bone holes, limit the number of implants held in inventory, or included in a kit of parts. Typically, such a bone fixation portion has a length of about 5 to 10 mm, for example about 7 mm, and the diameter can be 5 to 20 mm for a cylindrical implant and 5 to 15 mm for a mushroom-like design.

[0130] In an embodiment, an orthopedic implant includes a bone fixation portion and a cartilage replacement portion. The bone fixation portion has a surface that contacts the cartilage replacement portion, and the surface is structured with protrusions and / or depressions having a height and / or depth, and a width of 0.05 to 3.0 mm. In an embodiment, the dimensions are at least 0.1, 0.2, 0.3, 0.4 or 0.5 mm and at most 2.5, 2.0, 1.5 or 1.0 mm. The width relates to the cross-sectional dimension of a (semi)circular protrusion or depression structure, and in the case of an elongated structure, it relates to a smaller dimension (the length may be longer, for example, in the case of a bent or spiral structure, and may be infinite in the case of a circular structure). These structures generally do not have sharp edges and have rounded edges, for example, a rounding radius of 0.1 to 0.5 mm. A bone fixation portion having such a surface structure means that the connected cartilage replacement portion has a surface having a similar structure in a positive-negative relationship. In other words, such an implant has a structured interface between the bone fixation portion and the cartilage replacement portion.

[0131] In another aspect, the present invention provides an orthopedic implant, such as a biostable implant suitable for use in repairing damaged cartilage tissue. The implant includes a bone fixation portion and a cartilage replacement portion. The surface of the bone fixation portion that contacts the cartilage replacement portion is structured with protrusions and / or depressions having a height and / or depth and a width of 0.05 to 3.0 mm. The width relates to the cross-sectional dimension of a (semi)circular protrusion or depression structure, and in the case of an elongated structure, it relates to a smaller cross-sectional dimension (the length may be longer, for example, in the case of a bent or spiral structure, and may be infinite in the case of a circular structure). These structures generally have rounded edges, for example, a rounding radius of about 0.2 mm. A bone fixation portion having such a surface structure means that the connected cartilage replacement portion has a surface having a similar structure in a positive-negative relationship. In other words, such an implant has a structured interface between the bone contact portion and the cartilage replacement portion.

[0132] In an embodiment of an orthopedic implant having a bone fixation portion with a structured surface, the bone fixation portion includes a rigid polymer composition such as a polymer composition comprising a biostable thermoplastic polyurethane (TPU) and inorganic particles containing 15 to 70% by mass of zirconia particles, and includes any and any possible combination of the features described in the various embodiments hereinabove.

[0133] In a further embodiment, the orthopedic implant having a bone fixation portion with a structured surface includes a cartilage replacement portion made of an elastic wear-resistant biocompatible material such as from a biostable TPU as described in the various embodiments hereinabove, in any possible combination.

[0134] While not wishing to be bound by any theory, the inventors believe that the structured interface between the bone contact portion and the cartilage replacement portion provides a larger contact surface, suppresses or reduces the deformation of the elastic cartilage replacement layer under varying loads, and improves the adhesion between components. Further, the type, size, and number of the structures (protrusions and / or depressions) affect the distribution of the load applied to the cartilage replacement portion surface to the bone fixation portion, and can be selected, for example, to prevent the generation of stress concentrations that can induce local defects, such as the initiation of delamination at the interface between components. The structured interface can have the structure of one design, but there may be combinations of different protrusion structures and / or depression structures. The identification and selection of appropriate protrusion structures and / or depression structures and their effects can be supported, for example, by model calculations using FEA tools.

[0135] In an embodiment, an orthopedic implant has a bone fixation portion with a structured surface having protrusions and / or depressions, the protrusions including extended mounds or ridges and / or valleys sunken into the surface, the mounds or valleys may be continuous or discontinuous, and may more or less follow the outer contour of the implant, such as being within a circle with a decreasing diameter as schematically shown in FIG. 6. FIG. 6A shows a mushroom-shaped implant 1 having a cartilage replacement portion 2 (optionally transparent or translucent) that contacts the smooth (unstructured) surface of portion 3a of the bone fixation portion 3. In FIG. 6B, a number of concentric ridges 4 (4', 4'', etc.) are shown protruding from the surface of 3a into portion 2 (having corresponding valleys). Another exemplary embodiment is shown in FIG. 6C, where a number of individual conical protrusions (4', 4'', etc.) are present on the surface of 3a (having corresponding depressions in portion 2).

[0136] In an embodiment, an orthopedic implant has a bone fixation portion with a structured surface having protrusions and / or depressions 4, the protruding structures having a height of up to 50% of the thickness of the cartilage replacement portion 2 from which they protrude, preferably the height being up to 45, 40, 35, 30, or 25% of the thickness of the cartilage replacement layer. Similarly, the depressed structure 4 can have a depth of up to 50, 45, 40, 35, 30, or 25% of the thickness of the cross-section 3a of the bone fixation portion.

[0137] In an embodiment, an orthopedic implant has a bone fixation portion with a structured surface having protrusions and / or depressions 4 having a height and / or depth and width of 0.05 to 3.0 mm. In an embodiment, the dimensions are at least 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, or 0.45 mm and at most 2.5, 2.0, 1.8, 1.6, 1.4, 1.2, or 1.0 mm. In other embodiments, these structures do not have sharp edges and have rounded edges, for example, a rounding radius of 0.1 to 0.5 mm.

[0138] In another aspect, the present invention provides an orthopedic implant, such as a biostable implant suitable for use in the repair of damaged cartilage tissue, the implant having a bone fixation portion and a cartilage replacement portion, the cartilage replacement portion including a layer of an elastic and wear-resistant biocompatible material, such as a biostable thermoplastic polyurethane, the layer having a substantially constant or uniform thickness of about 0.2 to 5 mm, preferably at least 0.4, 0.6, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 or 1.5 mm, and up to 4.5, 4.0, 3.8, 3.6, 3.4, 3.2, 3.0, 2.9 or 2.8 mm, and the cartilage replacement portion and its upper surface being contoured in two or more directions. In embodiments, such an orthopedic implant can have one or more additional features corresponding to those described in various embodiments of the present disclosure, in any possible combination.

[0139] In a further embodiment of the implant, the upper surface of the cartilage replacement portion of the implant is contoured in two or more directions, such that the implant, such as a plug, does not have axial symmetry. In such a case, it is important that the implant can be placed in an appropriate orientation of such contouring with respect to the bone curvature at the target implant site. To facilitate or enable the implant to be in such a desired orientation during surgery, the orthopedic implant can further include an orientation marker that can be seen by eye and / or by imaging techniques.

[0140] In embodiments, the implant has a transparent or translucent cartilage replacement layer and an orientation marker is present at the interface between the bone fixation portion and the cartilage replacement portion. For example, if the implant includes a bone fixation portion having a structured surface with protrusions and / or depressions as described above, the protrusions and / or depressions may be arranged such that they also function as visual orientation markers. Alternatively and in other embodiments, a small elongated portion having optical properties, such as a color distinguishable from other parts of the implant, is present at the interface, and this elongated portion may be inserted during a subsequent step of fabricating the portion, as described below.

[0141] In a further embodiment, a relatively small radiopaque elongate portion, such as a short length of thin metal wire or a number of small metal pieces arranged in a row, is present as an orientation marker. An orientation marker such as a metal wire can have a length of, for example, about 2 - 6 mm and can be a tantalum wire. In an embodiment, such an elongate radiopaque marker is present between the bone fixation portion and the cartilage replacement portion, and for example, its length is directed in the direction of the larger radius of curvature of the upper surface of the cartilage replacement portion. Such an orientation marker is represented as line 5 in FIG. 2b. In such a case, the surgeon can thus not only place the plug in the desired orientation during the operation, but also confirm its position and any potential changes therein postoperatively using appropriate medical imaging techniques.

[0142] In a further aspect, the present invention relates to a method of manufacturing such an orthopedic implant including a bone fixation portion, the method including forming the implant in an injection molding process including molding the bone fixation portion from the polymer composition as defined above, preferably including a biostable thermoplastic polyurethane and 15 - 70% by mass of zirconia particles. Such methods are well known to those skilled in the art.

[0143] In another aspect, the present invention relates to a method of manufacturing such an orthopedic implant including a bone fixation portion and a cartilage replacement portion, the method comprising injecting a polymer composition including a preferably bio-stable thermoplastic polyurethane and inorganic particles including 15 to 70% by mass of zirconia into a mold including an insert in the form of a cartilage replacement portion to form a bone fixation portion, and then removing the insert from the mold, and injecting an elastic and wear-resistant biocompatible material such as TPU into the mold partially filled with the polymer composition to form a cartilage replacement portion, including forming the implant in a multi-component injection molding process. Manufacturing an implant by a multi-component molding technique from different polymer grades is known in the art. For example, WO 2011 / 098473 describes the manufacture of orthopedic implants such as meniscus implants or intervertebral disc implants having two or more separate parts each including a different but chemically related polymer material such as different TPU grades.

[0144] In a further aspect, the present invention relates to a method of manufacturing an orthopedic implant including a bone fixation portion and a cartilage replacement portion, the method comprising injecting a rigid polymer composition into a mold including an insert in the form of a cartilage replacement portion and having protrusions and / or depressions with a height and / or depth and a width of 0.05 to 3.0 mm on a surface contacting an upper portion of the bone fixation portion to be formed, and then removing the insert from the mold, and injecting an elastic and wear-resistant biocompatible material into the mold partially filled with the polymer composition to form a cartilage replacement portion of the implant, including forming the implant in a multi-component injection molding process.

[0145] In some embodiments, the method includes injecting a robust polymer composition including a bio-stable thermoplastic polyurethane and inorganic particles including 15 to 70% by mass of zirconia, and injecting an elastic and wear-resistant biocompatible material, the composition and the material being as defined above herein and including any features and combinations thereof.

[0146] In other embodiments, the various methods of making an orthopedic implant preferably include, between the step of injecting a polymeric composition to form a bone fixation portion and the step of injecting a biocompatible material into a mold, a further step of inserting an orientation marker, such as a radiopaque marker, into the implant. The radiopaque marker, such as a strip of thin tantalum wire, is preferably arranged in line with one of the directions of two or more different radii of curvature of the contoured upper surface to enable, for example, monitoring of the orientation and proper positioning of the implant during and after implantation.

[0147] In an embodiment, the mold used in the method is provided to a bone fixation forming portion having a defined surface roughness, for example according to VDI 3400 36, resulting in a shaped part having a bone fixation portion with a surface roughness Ra of at least 5 μm. See, for example, the method described in WO 2019 / 068903.

[0148] In a further embodiment, the method of making the orthopedic implant further includes the step of providing, on the surface of the bone fixation portion of the shaped implant, a bioactive, preferably osteoconductive, particle or a bioactive, preferably osteoconductive, coating, for example, in a solvent for polyurethane contained in the polymeric composition, with a dispersion of bioactive ceramic particles such as calcium phosphate, by treating a surface that may be textured. Details of such solvent-based surface treatment are described in WO 2019 / 068903.

[0149] In another aspect, the present invention relates to a surgical kit for parts including at least one orthopedic implant as described above in this specification, and more specifically, to a surgical kit including a set of at least two implants having different sizes. Implants having different sizes may differ, for example, in the size and / or curvature of the cartilage replacement part and / or the dimensions of the bone fixation part. Such a surgical kit may further include auxiliary tools for preparing an implant position for receiving one or more orthopedic implants, such as induction and perforation tools for forming bone holes and tools for inserting the orthopedic implant into the bone holes.

[0150] A further aspect includes the use of the orthopedic implant as described above in this specification and the use of the surgical kit as described above in this specification when repairing degenerated or damaged cartilage tissue such as the knee joint of a mammal. Such use for local treatment of damaged cartilage within the joint can delay the need for total joint replacement surgery such as TKR and in some cases even avoid it.

[0151] The various aspects, embodiments and methods of implementing the present invention as described above are further summarized below by a series of exemplary embodiments. [1] An orthopedic implant having a bone fixation part including a polymer composition containing a biostable thermoplastic polyurethane (TPU) and inorganic particles containing 15 to 70% by mass of zirconia. [2] An orthopedic implant having a bone fixation part and a cartilage replacement part, wherein the surface of the bone fixation part in contact with the cartilage replacement part is composed of protrusions and / or depressions having a height and / or depth and a width of 0.05 to 3.0 mm. [3] An orthopedic implant having a bone fixation part and a cartilage replacement part, wherein the cartilage replacement part includes a layer made of an elastic and wear-resistant biocompatible material, the layer having a substantially constant or uniform thickness of 0.2 to 5 mm and being contoured in two or more directions. [4] The implant of Embodiment 2 or 3, wherein the bone fixation part comprises a polymer composition containing a rigid polymer composition, preferably a biostable TPU, and inorganic particles containing 15 to 70% by mass of zirconia. [5] A method for manufacturing an orthopedic implant comprising a bone fixation part, the method comprising forming the implant by an injection molding process including a step of molding the bone fixation part from a polymer composition containing a biostable TPU and inorganic particles containing 15 to 70% by mass of zirconia. [6] A method for producing an orthopedic implant comprising a bone fixation part and a cartilage replacement part, the method comprising injecting a polymer composition containing a biostable TPU and inorganic particles containing 15 to 70% by mass of zirconia into a mold including an insert in the form of the cartilage replacement part to form the bone fixation part, then removing the insert from the mold, and injecting an elastic and wear-resistant biocompatible material into the mold partially filled with the polymer composition to form the cartilage replacement part of the implant, the method comprising forming the implant by a multi-component injection molding process. [7] The implant or method of any one of Embodiments 1 to 6, wherein the biostable implant is suitable for use in the repair of damaged cartilage tissue. [8] The implant or method of any one of Embodiments 1 to 7, wherein the TPU is a phase-separated block copolymer containing a plurality of "hard" and "soft" polymer blocks. [9] The implant or method of any one of Embodiments 1 to 8, wherein the TPU contains a hard block containing urethane groups and optionally urea groups in repeating units resulting from the reaction of a diisocyanate with a diol and optionally a diamine as respective chain extenders.

[10] The diisocyanate-containing implant or method of Embodiment 9, wherein the diisocyanate comprises 4,4'-diphenylmethane diisocyanate, 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, or 1,4-phenylene diisocyanate. In one embodiment, the diisocyanate consists of 4,4'-diphenylmethane diisocyanate, 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, 1,4-phenylene diisocyanate, or a mixture thereof.

[11] The chain extender-containing implant or method of Embodiment 9, wherein the chain extender comprises ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, or 1,8-octanediol, and / or the corresponding diamine as described above.

[12] The implant or method according to any one of Embodiments 9 to 11, wherein the TPU contains only a diol chain extender.

[13] The implant or method according to any one of Embodiments 9 to 11, wherein the TPU contains a hard block having both urethane bonds and urea bonds.

[14] The implant or method according to any one of Embodiments 8 to 13, wherein the TPU contains a soft block derived from at least one aliphatic polymer diol or polyol selected from the group consisting of polyethers, polyesters, polyacrylates, polyolefins, and polysiloxanes (also called silicones), and the polymer is bifunctional with hydroxyl (or amine) end groups.

[15] The implant or method according to any one of Embodiments 8 to 14, wherein the TPU contains a soft block derived from at least one polymer diol selected from aliphatic polyester diols, aliphatic polycarbonate diols, aliphatic polyether diols, poly(isobutylene) diols, and polysiloxane diols.

[16] The implant or method according to any one of Embodiments 8 to 15, wherein the hard block of the TPU has a molar mass of about 160 to 10,000 Da, or about 200 to 2000 Da.

[17] An implant or method according to any one of embodiments 8 to 16, wherein the molar mass of the soft block is from about 200 to 100,000 Da, or at least about 400, 600, 800 or 1000 Da, and at most about 10,000, 7500, 5000, 4000, 3000 or 2500 Da.

[18] An implant or method according to any one of embodiments 1 to 17, wherein the TPU has a hardness of 40 ShA to 90 ShD when measured by a Shore durometer test using scale A or D.

[19] An implant or method according to any one of embodiments 1 to 17, wherein the TPU has a hardness of at least 45, 50, 55 or 60 ShA and at most 90 ShA.

[20] An implant or method according to any one of embodiments 1 to 17, wherein the TPU has a hardness of at least 90 ShA, 40 ShD, 50 ShD or 60 ShD, and at most 85 or 80 ShD.

[21] An implant or method according to any one of embodiments 8 to 20, wherein the TPU comprises an aliphatic polyether, aliphatic polyester or aliphatic polycarbonate, preferably an aliphatic polycarbonate, such as poly(hexamethylene carbonate), poly(polytetrahydrofuran carbonate) or a mixture thereof, in the soft block.

[22] An implant or method according to any one of embodiments 8 to 21, wherein the TPU comprises a soft block that is essentially amorphous, and the TPU has a T of less than 10, 0, or -10 °C g as shown.

[23] An implant or method according to any one of embodiments 8 to 22, wherein the TPU comprises a soft block derived from a polysiloxane diol, polycarbonate diol, poly(tetramethylene oxide) diol, or a mixture thereof.

[24] An implant or method according to any one of embodiments 8 to 22, wherein the soft block is derived from one or more of a polysiloxane diol and a polycarbonate diol and a poly(tetramethylene oxide) diol.

[25] The soft block is C2-C 16 fluoroalkyl diol or C2-C 16An implant or method according to any one of embodiments 8 to 24, further comprising a fluoroalkyl ether diol.

[26] C2-C 16 Fluoroalkyl diol or C2-C 16 A fluoroalkyl ether diol having an M of at least 150, 250 or 500 g / mol and at most 1500, 1000 or 850 g / mol, of any one of embodiments 25. n An implant or method according to any one of embodiments 25.

[27] C2-C 16 Fluoroalkyl diol or C2-C 16 A fluoroalkyl ether diol is present in an amount of at least 1, 2 or 5% by mass and at most 15, 10 or 8% by mass, based on the total mass of the polyurethane, of any one of embodiments 25 to 26.

[28] An implant or method according to any one of embodiments 8 to 27, wherein the TPU comprises one or more hydrophobic or hydrophilic end groups.

[29] An implant or method according to any one of embodiments 8 to 28, wherein the TPU comprises end groups at each end of the backbone.

[30] An implant or method according to any one of embodiments 28 to 29, wherein the end group is a hydrophobic end group.

[31] The end group is C2-C 20 alkyl, C2-C 16 fluoroalkyl, C2-C 16 An implant or method according to any one of embodiments 30, comprising a fluoroalkyl ether, a hydrophobic poly(alkylene oxide) or a polysiloxane (including their copolymers).

[32] An implant or method according to any one of embodiments 28 to 29, wherein the end group is a hydrophilic end group such as polyethylene oxide or a sulfonate-functional compound.

[33] An implant or method according to any one of embodiments 28 to 29, wherein the TPU comprises a mixture of hydrophobic and hydrophilic end groups.

[34] An implant or method according to any one of embodiments 28 to 33, wherein the end group is a monomer and has a molar mass of at least 200, 300, 500 g / mol and at most 1,000 or 800 g / mol.

[35] An implant or method according to any one of embodiments 28 to 33, wherein the end group is polymeric and has a molar mass of at least 5,00, 1,000 or 2,000 g / mol and at most 10,000, 8,000, 6,000 or 4,000 g / mol.

[36] An implant or method according to any one of embodiments 28 to 35, wherein the end group is present in an amount of at least 0.1, 0.2, 0.3 or 0.5% by mass and at most 3, 2 or 1% by mass based on the total mass of the TPU.

[37] An implant or method according to any one of embodiments 28 to 35, wherein the TPU contains less than 0.1% by weight of end groups based on the total weight of the TPU or is substantially free of end groups.

[38] An implant or method according to any one of embodiments 1 to 37, wherein the TPU contains one or more conventional additives such as stabilizers, antioxidants, processing aids, lubricants, surfactants, antistatic agents or colorants.

[39] An implant or method according to any one of embodiments 38, wherein the additive is present in an amount of 0.01 to 5% by mass, preferably 0.1 to 2% by mass, based on the amount of the TPU.

[40] An implant or method according to any one of embodiments 1 to 39, wherein the TPU is a blend of two or more polymers, for example a blend of at least two biocompatible TPU grades having different hardnesses, such as a combination of 80ShA and 75ShD grades.

[41] An implant or method according to any one of embodiments 1 to 40, wherein the polymer composition consists essentially of or consists of a) 30 to 85% by mass of a biostable TPU and b) 15 to 70% by mass of inorganic particles, and the sum of a) and b) is 100% by mass.

[42] An implant or method according to any one of Embodiments 1 to 40, wherein the polymer composition consists of a) 20 to 85% by mass of a biostable TPU, b) 15 to 70% by mass of inorganic particles, and c) 0 to 10% by mass of other compounds, and the sum of a) and b) is 100% by mass.

[43] An implant or method according to any one of Embodiment 42, wherein the other compounds include bioactive compounds such as antibacterial agents, anti-inflammatory agents or activators, dispersants or residual solvents.

[44] An implant or method according to any one of Embodiments 42 to 43, wherein the composition includes up to 5, 4, 3 or 2% by mass of other compounds and up to 1000 ppm of a solvent, preferably up to 800, 600, 500 or 400 ppm of a solvent.

[45] An implant or method according to any one of Embodiments 1 to 44, wherein the inorganic particles in the polymer composition consist essentially of zirconia or consist of zirconia.

[46] An implant or method according to any one of Embodiments 1 to 44, wherein the zirconia particles form at least 60, 70 or 75% by mass and at most 98, 95, 90, 85 or 80% by mass of the total amount of inorganic particles in the polymer composition.

[47] An implant or method according to any one of Embodiments 1 to 46, wherein the zirconia is substantially pure ZrO2 or a mixed oxide containing ZrO2 and up to about 20% by mass, preferably up to 15, 10 or 5% by mass of other inorganic oxides.

[48] An implant or method according to any one of Embodiments 1 to 44 and 46 to 47, wherein the inorganic particles further include radiopaque biocompatible transition metal compound particles such as transition metal oxide particles or transition metal salt particles.

[49] An implant or method according to any one of Embodiments 1 to 44 and 46 to 47, wherein the inorganic particles further include at least one salt, preferably an oxide, of titanium (Ti), zinc (Zn), yttrium (Y), lanthanum (La), ytterbium (Yb), hafnium (Hf), and tantalum (Ta).

[50] An implant or method according to any one of embodiments 48, wherein the inorganic particles comprise or consist of zirconia and at least one of Ti, Zn, Y, and Ta, in the form of a salt, preferably an oxide.

[51] An implant or method according to any one of embodiments 1 to 50, wherein the inorganic particles containing zirconia have an average particle size in the range of 0.03 to 10 μm, preferably 0.1 to 5 μm (determined as the D 50 value using light diffraction according to ISO 13320:2009).

[52] An implant or method according to any one of embodiments 1 to 51, wherein the inorganic particles in the polymer composition have a regular or irregular shape ranging from substantially spherical to more elongated or flat shapes, such as cigar-shaped, platelet-shaped, needle-shaped, or fiber-like shapes.

[53] An implant or method according to any one of embodiments 52, wherein the polymer composition contains a mixture of inorganic particles of different shapes, such as a mixture of substantially spherical particles and elongated particles having an average aspect ratio of at least 1, 2, 4, 6, 8, or 10.

[54] An implant or method according to any one of embodiments 1 to 53, wherein the inorganic particles containing zirconia have an average particle size D of at least 0.05, 0.10, 0.15, 0.20, 0.25, or 0.30 μm and at most 8, 7, 6, 5, 4, 3, or 2 μm. 50

[55] An implant or method according to any one of embodiments 1 to 54, wherein the inorganic particles are one or more other biocompatible inorganic particles selected from zirconia particles, transition metal compound particles, and natural mineral particles such as (nano)clay, mica, and talcum.

[56] An implant or method according to any one of embodiments 1 to 55, wherein at least 60, 70, 75, 80, 85, 90, or 95 mass% of the total amount of the inorganic particles are zirconia particles.

[57] An implant or method according to any one of embodiments 1 to 56, wherein the polymer composition contains at least 20, 25, 30, or 35 mass% of inorganic particles and at most 68, 66, 64, 62, 60, 58, 56, 54, 52, 50, 48, or 46 mass%.

[58] An implant or method according to any one of Embodiments 1 to 57, wherein the TPU in the polymer composition has a molar mass Mw of at least 70, 75, 80, 85, 90, 95 or 100 kDa and at most 400, 300, 250 or 200 kDa as measured by the GPC method described in the experimental section.

[59] An implant or method according to any one of Embodiments 1 to 58, wherein the polymer composition has an E modulus of 800 to 3000 MPa when measured on a dry-molded sample (dried / 20 °C), or the E modulus is at least 850 or 900 MPa and at most 2500, 2000, 1800 or 1600 MPa.

[60] An implant or method according to any one of Embodiments 1 to 59, wherein the polymer composition has an E modulus of 200 to 700 when measured on a conditioned sample (wet / 37 °C), or the E modulus is at least 225 MPa and at most 600, 550, 500 or 450 MPa.

[61] An implant or method according to any one of Embodiments 1 to 60, wherein the polymer composition has an elongation at break Eab of at least 5%, or at least 10, 20, 30, 40 or 50% during a tensile test (dried / 20 °C).

[62] An implant or method according to any one of Embodiments 1 to 61, wherein the polymer composition has an Eab of at least 10%, or at least 20, 30, 40 or 50% when conditioned (wet / 37 °C).

[63] An implant or method according to any one of Embodiments 1 to 62, wherein the polymer composition has a tensile strength at break TS of at least 30 MPa, or at least 35 or 40 MPa (dried / 20 °C).

[64] An implant or method according to any one of Embodiments 1 to 63, wherein the polymer composition has a TS of at least 15 MPa, or at least 20 or 25 MPa when conditioned (wet / 37 °C).

[65] An implant or method according to any one of Embodiments 1 to 64, wherein the polymer composition has a Shore hardness of 76 to 85 ShD, or 78 to 82 ShD (dried / 20 °C).

[66] The implant or method of any one of embodiments 1 to 65, wherein the bone fixation part of the implant has a textured outer surface having a surface roughness Ra of at least 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18 or 20 μm and a maximum of 25 μm.

[67] The implant or method of any one of embodiments 1 to 66, wherein the bone fixation part of the implant has a bioactive coating, preferably an osteoconductive coating.

[68] The implant or method of any one of embodiments 66 or 67, wherein bioactive ceramic particles such as calcium phosphate, bioglass or silicated ceramic are present on the surface of the bone fixation part.

[69] The implant or method of any one of embodiments 68, wherein the bioactive ceramic particles are selected from dicalcium phosphate anhydride (CaHPO4; DCPA), dicalcium phosphate dihydrate (CaHPO4·2H2O; DCPD), octacalcium phosphate (Ca8(HPO4)2·5H2O; OCP), tricalcium phosphate (Ca3(PO4)2; TCP), hydroxyapatite (Ca 10 (PO4)6(OH)2; HA), and bioglass, or a mixture of two or more thereof.

[70] The implant or method of any one of embodiments 68, wherein the bioactive ceramic particles have a particle size D in the range of 0.1 to 10 μm 50 and preferably D 50 is at least 0.2, 0.3, 0.4 or 0.5 μm and at most 10, 8, 6, 5, 4, 3, 2 or 1 μm.

[71] The implant or method of any one of embodiments 1 to 70, wherein the bone fixation part is a bone anchor such as a plug or a screw and can be used to fix a further part to the bone.

[72] The implant or method of any one of embodiments 1 to 71, wherein the implant comprises at least a bone fixation part and a cartilage replacement part.

[73] The implant or method of any one of embodiments 72, wherein the cartilage replacement part is permanently connected to the bone fixation part and is made of an elastic and wear-resistant biocompatible material.

[74] An implant or method according to any one of embodiments 72-73, wherein the cartilage replacement part is made of a biostable, elastic, thermoplastic block copolymer having hard segments based on polyester, polyamide or polyurethane.

[75] An implant or method according to any one of embodiments 72-74, wherein the cartilage replacement part is made of a biostable, elastic, thermoplastic polyurethane (TPU) having a Shore hardness of 55-100 ShA.

[76] An implant or method according to any one of embodiments 75, wherein the TPU of the cartilage replacement part is a block copolymer comprising hard blocks and soft blocks, and optionally end groups, as defined for the TPU of the polymer composition in any one of embodiments 8-17 and 21-39.

[77] An implant or method according to any one of embodiments 72-76, wherein the TPU of the cartilage replacement part is a blend of two or more polymers, such as a blend of two biocompatible TPU grades having different hardnesses in the range of 50 ShA to 50 ShD, or a blend of two TPU grades having different soft blocks and / or end groups.

[78] An implant or method according to any one of embodiments 72-76, wherein the TPU of the cartilage replacement part is a blend of polyurethane and another biocompatible low elastic modulus polymer, preferably the other biocompatible polymer forms up to 40% by volume, preferably up to 30, 20 or 10% by volume of the blend.

[79] An implant or method according to any one of embodiments 72-78, wherein the TPU of the cartilage replacement part has hard blocks and soft blocks, and optionally end groups, (chemically) similar to those contained in the TPU in the polymer composition of the bone fixation part.

[80] An implant or method according to any one of embodiments 79, wherein the TPU of the cartilage replacement part is different from the TPU in the polymer composition, at least in terms of the ratio of hard blocks to soft blocks and / or the block length.

[81] An implant or method according to any one of embodiments 72 to 80, wherein the TPU of the cartilage replacement part has a hardness of at least 60, 65, or 70 ShA and at most 95, 90, or 85 ShA.

[82] An implant or method according to any one of embodiments 72 to 81, wherein the TPU of the cartilage replacement part has a tensile elastic modulus of 10 to 100 MPa (dry / 20 °C) and 2 to 50 MPa (wet / 37 °C).

[83] An implant or method according to any one of embodiments 72 to 82, wherein the cartilage replacement part of the implant has a thickness similar to or identical to the thickness of the cartilage layer of the joint to be locally replaced.

[84] An implant or method according to any one of embodiments 72 to 83, wherein the cartilage replacement part of the implant is a layer of substantially constant or uniform thickness, the layer is connected to the bone fixation part and supported by the bone fixation part.

[85] An implant or method according to any one of embodiments 84, wherein the cartilage replacement part of the implant has a thickness of 0.2 to 5 mm, preferably at least 0.4, 0.6, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 or 1.5 mm, and at most 4.5, 4.0, 3.8, 3.6, 3.4, 3.2, 3.0, 2.9 or 2.8 mm.

[86] An implant or method according to any one of embodiments 72 to 85, wherein the cartilage replacement part has a curvature characterized by at least one radius of 15 to 70 mm, preferably at least 20 or 25 mm, and at most 65, 60, 55 or 50 mm, has a curved upper surface that is curved in at least one direction or inclined.

[87] An implant or method according to any one of embodiments 86, wherein the cartilage replacement part has a surface curvature characterized by at least two different radii in at least two directions, preferably the part has a two-plane curvature.

[88] An implant or method according to any one of embodiments 1 to 85, wherein the implant including the bone fixation part and optionally the cartilage replacement part has axial symmetry.

[89] An implant or method according to any one of embodiments 1 to 88, wherein the implant has a cylindrical shape with a diameter of 5 to 20 mm and a length of 5 to 15 mm, the upper part forms the cartilage replacement part, and the remaining part forms the bone fixation part.

[90] The bone fixation portion has a tapering of 1 to 5° from the cartilage replacement portion to the bottom end, and preferably, the tapering is at least 1.5 or 2.0° and at most 4.5, 4.0, 3.5 or 3.0°, any one implant or method of Embodiment 89.

[91] The implant has a mushroom-like shape having a cap and at least one stem, the upper part of the cap forms a cartilage replacement portion, and the remaining part of the cap and at least one stem together form a bone fixation portion, any one implant or method of Embodiments 1 to 88.

[92] The implant has a circular cap having a diameter of 5 to 25 mm, preferably 10 to 20, 12 to 18, or about 15 mm, and one stem having a diameter of 5 to 15 mm, preferably 6 to 10 mm, any one implant or method of Embodiment 91.

[93] The implant has an oval cap having a width of 5 to 25 mm and a length of 10 to 40 mm, and two stems each having a diameter of 5 to 15 mm, any one implant or method of Embodiment 91.

[94] The stem shows a taper of 1° to 5° from the cap to the bottom end, and preferably, the taper is at least 1.5° or 2.0° and at most 4.5, 4.0, 3.5 or 3.0°, any one implant or method of Embodiments 91 to 93.

[95] The implant has a rounded edge and a transition portion from one part to another rounded with a rounding radius of 0.1 to 4.0 mm, preferably at least 0.2, 0.5, 1.0, 1.5, or 2.0 mm, and a corner radius of at most 3.5 or 3.0 mm, any one implant or method of Embodiments 1 to 94.

[96] The implant includes a bone fixation portion and a cartilage replacement portion having a structured interface, and the surface of the bone fixation portion in contact with the cartilage replacement portion has a protruding structure and / or a recessed structure having a height and / or depth, and a width of 0.05 to 3.0 mm, preferably at least 0.1, 0.2, 0.3, 0.4 or 0.5 mm, and at most 2.5, 2.0, 1.5 or 1.0 mm, any one implant or method of Embodiments 2 to 95.

[97] An implant or method according to any one of embodiments 96, wherein the structure has a rounded edge with a radius of roundness of 0.1 to 0.5 mm.

[98] An implant or method according to any one of embodiments 96-97, wherein the structure includes mounds or ridges protruding from the surface and / or valleys recessed in the surface, and the structure is continuous and / or discontinuous.

[99] An implant or method according to any one of embodiments 96-98, wherein the structure follows the outer contour of the implant, such as a circular pattern with a decreasing diameter.

[0100] An implant or method according to any one of embodiments 96-99, wherein the structure has a height and / or depth of up to 50% of the thickness of the cartilage replacement part, preferably the height is up to 45, 40, 35, 30 or 25% of the thickness of the cartilage replacement part.

[0101] An implant or method according to any one of embodiments 1-100, wherein the surface of the cartilage replacement part is contoured in two or more directions, and the implant further includes an orientation marker visible in the eye and / or imaging technology.

[0102] An implant or method according to any one of embodiments 101, wherein the cartilage replacement layer is transparent or translucent, and the visual orientation marker is at the interface between the bone fixation part and the cartilage replacement part.

[0103] An implant or method according to any one of embodiments 101, wherein the orientation marker is a radiopaque elongated part.

[0104] A method for manufacturing an implant according to any one of embodiments 2 and 96-100, including an insert in the form of a cartilage replacement part, injecting a rigid polymer composition into a mold having protrusions and / or depressions with a height and / or depth and width of 0.05 to 3.0 mm on the surface contacting the formed bone fixation part, then removing the insert from the mold, and injecting an elastic and wear-resistant biocompatible material into the mold partially filled with the polymer composition to form the cartilage replacement part of the implant.

[0105] A method according to any one of embodiments 104, wherein the rigid polymer composition includes a biostable thermoplastic polyurethane and inorganic particles containing 15 to 70% by mass of zirconia. A method according to any one of Embodiments 1 to 105, including a further step of inserting an orientation marker between the step of injecting a polymer composition to form a bone fixation portion and the step of injecting a biocompatible material into a mold. A method according to any one of Embodiments 106, wherein the orientation marker is arranged in a straight line with one of at least two different radii of curvature of the upper surface on which the contour of the cartilage replacement portion is formed. A method according to any one of Embodiments 1 to 107, wherein the mold has a surface roughness having a roughness according to, for example, VDI3400 36 in its bone fixation forming portion, resulting in a molding portion having a bone fixation portion having a surface roughness Ra of at least 5 μm. A method according to any one of Embodiments 1 to 107, further including the step of providing a bioactive, preferably osteoconductive, particle or a bioactive, preferably osteoconductive, coating on the surface of the bone fixation portion of the implant. A method according to any one of Embodiments 109, wherein the further step includes treating the surface with a dispersion of bioactive ceramic particles in a solvent for the polyurethane contained in the polymer composition. A surgical kit including at least one orthopedic implant according to any one of Embodiments 1 to 110. A kit according to any one of Embodiments 111, wherein the surgical kit includes a set of at least two implants having different sizes, and the implants have different sizes and / or curvatures of the cartilage replacement portion and / or dimensions of the bone fixation portion. A kit according to any one of Embodiments 111 to 112, wherein the surgical kit further includes an auxiliary tool for preparing an implant position for receiving one or more orthopedic implants, such as a guiding and perforating tool for forming a bone hole and a tool for placing an orthopedic implant into the bone hole. Use of an orthopedic implant according to any one of Embodiments 1 to 109 and use of a surgical kit according to any one of Embodiments 110 to 113 in repairing a degenerated or damaged cartilage tissue such as a mammalian knee joint.

[0152] The terms "a", "an", "the", and similar uses related to the description of the present invention (especially related to the following claims) are to be construed as including both the singular and the plural, unless otherwise indicated herein or clearly contrary to the context. The terms "comprising", "having", "including", and "containing" are to be construed as non-limiting terms (i.e., meaning "including but not limited to") unless specifically stated otherwise. The recitation of ranges of values herein is merely intended to serve as a convenient method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein. Unless otherwise claimed, the use of any and all examples, or exemplary language (e.g., "such as" or "like") provided herein is merely intended to better illustrate the invention and does not impose a limitation on the scope of the invention. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0153] Preferred embodiments of the present invention, including the best mode known to the inventors for carrying out the invention, are described herein. Variations of those preferred embodiments will be apparent to those skilled in the art upon reading the above description. The inventors expect those skilled in the art to appropriately use such variations, and the inventors intend the invention to be practiced in ways other than those specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Although specific features may be described as embodiments of the invention, this description is intended to include, unless otherwise separately indicated or physically impossible, all combinations of these embodiments, and is particularly meant to be disclosed.

[0154] The following experiments and samples further illustrate embodiments of the invention, but of course should not be construed as limiting the claims in any way.

[0155] [Experimental Section] [Method] [Molar Mass] The molar mass and molar mass distribution of the samples were measured by GPC (gel permeation chromatography, also known as size exclusion chromatography or SEC) on a Viscotek GPCMax VE2001 system equipped with a TDA302 triple detector array and three Phenogel™ columns (10E6A of 10 μm, 10E4A of 10 μm, and 100A of 10 μm) as described in ASTM D5296-11. The detector and columns were operated at 80 °C. The polymer sample was dissolved at a concentration of 1.0 mg / ml in DMF containing 0.05 wt% LiBr and 300 mg / l DHT at 70 °C for up to 4 hours and filtered through a 0.2 μm PTFE membrane. This solvent composition was also used as the eluent. The molar mass calculation was based on a calibration curve obtained using EasyCal polystyrene standards, and the results were adjusted using polyurethane samples with known molar masses.

[0156] [Hardness] The hardness of the molded samples was measured using a Zwick Shore hardness tester 3131 according to ISO868 (measurement time 15 seconds, average of 5 inspections at 20.9 °C / relative humidity 51.1%).

[0157] [Tensile Properties] The tensile modulus, (absolute) tensile strength, and elongation at break were measured on a Zwick Z010 universal tensile testing machine equipped with a 2.5 kN pneumatic gripper and a temperature chamber using a method based on ISO 527. Injection-molded test bars (Type 1BA of ISO 527) were conditioned at 20 °C in the as-molded and dried state and in water at 37 °C and then tested at 37 °C. Samples for measurement in the as-molded and dried state were dried overnight using an 80 °C vacuum oven with a small N2 flow rate and stored in a sealed box filled with silica gel. The samples were conditioned by immersing the samples in water maintained at 37 °C until the change was less than 0.1 mass% (typically at least 360 hours), and the mass increase was measured every 24 hours. Each sample was stored under the above conditions for a short time before being placed in the temperature chamber of the tensile testing machine. Immediately before the test, the width and thickness of the sample were measured at the center of the test piece. The samples were placed in grippers with a gripper spacing of 54 mm at the starting position. A preload of 0.5 N was applied before starting the tensile experiment. The elastic modulus of the sample was determined between the first 0.05 - 0.25% strain at a rate of 1 mm / min. Thereafter, the stress and strain were measured at 50 mm / min until the sample broke, and the elongation was measured with an extensometer until 60% strain was measured.

[0158] [Particle size] Particle size distribution and particle size (D 10 , D 50 and D 90 ) were measured on samples dispersed in water using a Malvern Mastersizer 2000 in accordance with ISO 13320:2009.

[0159] [Crystallization behavior] Differential scanning calorimetry (DSC) was carried out using a standard heat flux DSC from Mettler Toledo. A sample with a mass of approximately 5 mg was cut from the pellet, weighed using a precision balance, and encapsulated in an aluminum pan of known mass (crimped). An identical empty pan was used as the reference material. Nitrogen was purged at a rate of 50 ml / min. A heating-cooling-heating cycle was applied to determine the parameters that numerically characterize the thermal behavior of the material under investigation. The applied temperature program was: [1] 0.0 to 70.0 °C, 10.00 K / min; [2] 70.0 °C, 60.00 min; [3] 70.0 to 90.0 °C, -10.00 K / min; [4] -90.0 °C, 10.00 min; [5] -90.0 to 240.0 °C, 10.00 K / min; [6] 240.0 °C, 2.00 min; [7] 240.0 to 90.0 °C, -10.00 K / min; [8] -90.0 °C, 10.00 min; [9] -90.0 to 240.0 °C, 10.00 K / min.

[0160] [Polymer composition] [Experiments 1 - 3] In the experiments, a polycarbonate urethane with a hardness of 75 ShD and a mass average molar mass Mw of 388 kDa, based on MDI, butanediol, and poly(hexamethylene carbonate) diol, was used after drying at 80 °C for 24 hours to a water content of 113 ppm. Hydroxyapatite with a particle size of 5 μm (Merck, hydroxyapatite for bioceramics) was dried at 120 °C for 24 hours until it reached a water level of approximately 2650 ppm.

[0161] The polyurethane and filler components were melt - mixed on a Coperion ZSK Mc18 twin - screw extruder equipped with two Colortronic LabLine feeders and having a die - plate with one 3 - mm opening. Polyurethane granules were taken in and fed into the barrel, and HA powder was fed onto the side - feeder for intake into barrel 2 at a mass ratio of 80 / 20 of TPU / HA. The temperature setting for all zones was 190 °C. The screw rotated at 150 - 200 rpm, the extrusion rate was about 2.5 kg / h, and the torque level fluctuated to some extent within the range of 50 - 70%. The extrusion conditions were selected so that a melting temperature of up to about 200 °C occurred to enable a stable formulation that produced smooth and regular strands. The extruded strands were cooled in a water bath with a total cooling length of 2 m and then cut into pellets using an electric strand pick - up and a Scheer 50E pelletizer (operated at low speed).

[0162] The extruder was rinsed before and after a mixing experiment using polyurethane for 5 - 10 minutes at an extrusion rate of 2 kg / h.

[0163] The obtained pellets were dried at 120 °C under vacuum / N2 for 24 hours and then injection - molded into test bars on an Xplore IM12 micro - injection molding machine. The barrel temperature was set at 200 °C and the molding temperature was set at 100 °C. After a melting time of at least 5 minutes, the material was injected into a vented mold at an injection pressure of 10 bar for 2.2 seconds and a packing pressure of 10 bar for 10 seconds.

[0164] Tensile properties were determined at room temperature (20 °C) on specimens dried during molding and in the wet state at 37 °C to mimic the conditions when used as an implant material.

[0165] Table 1 summarizes the results as (comparative) experiment 2. This table also presents the molar mass data (Mw) determined on the pellets and the molded test specimens.

[0166] Experiment 1 was injection molded and tested as in Experiment 2 above, and relates to the results of a reference test carried out on unfilled polyurethane pellets with a molding temperature of 235 °C and a pressure of 15 bar applied.

[0167] Experiment 3 was carried out in the same manner as Experiment 2, but the amount of HA fed into the extruder was 40% by mass.

[0168] The tensile test measurement results summarized in Table 1 suggest that hydroxyapatite particles act as a non-reinforcing filler in polyurethane; the modulus of elasticity in the dry state did not change significantly, the tensile strength and elongation decreased significantly, but the water uptake decreased and had little effect on the properties (20 °C / dry vs. 37 °C / wet). The Shore hardness of the molded bars increased from 75.7 ShD (Experiment 1) to 80.2 ShD (Experiment 2). The GPC results show a significant decrease in molar mass compared to the unfilled material, probably induced by the residual water content contained in the crystalline HA particles that induce polymer degradation mainly during the compounding process, perhaps during the melt processing steps. The observation that the melt temperature during compounding must be maintained below 200 °C in order for stable strand extrusion to be possible would support such an explanation.

[0169] [Experiment 4] Similar to the compounding methods of Experiments 2 and 3, instead of HA, bismuth oxide particles (Bi2O3) with a particle size of 4 μm dried to a water content of 153 ppm at 120 °C for 24 hours (D 50 ; 5N Plus Product datasheet (Helos / Rodos) was used. Various changes in the processing conditions were tried, and the experiment was stopped when stable processing became impossible and / or when foaming and discoloration of the extrudate were observed. This was probably induced by excessive degradation of the polyurethane. No further experiments were carried out using this material.

[0170] [Experiments 5 - 6] In these experiments, zirconium oxide TZ-0 (Tosoh Europe BV), a free-flowing powder with a (primary) particle size of 0.04 μm (according to Tosoh's brochure), was added as a filler to the polyurethane during compounding. The samples were dried at 120 °C for 24 hours and compounded with the same 75ShD polyurethane applying the procedures of Experiments 2 and 3. By setting the barrel temperature to 200 °C and increasing the screw speed to 300 rpm, strand breakage during compounding was prevented and the particle size distribution seemed to be improved. The torque level was limited to 60 - 70% and the melt temperature was up to 212 °C. The powder dosing behavior was very good, but thickness-thin fluctuations were observed in the extruded strands, suggesting that the particles were not well dispersed.

[0171] The addition of these zirconia particles at 20 and 40 mass% loadings results in a decrease in strength; at 40 mass% loading, the composition is even brittle. This is most likely induced by the insufficient dispersion of the aggregated primary particles within the polyurethane matrix. To enhance the dispersibility and to improve the mechanical properties, pretreatment of the particles and / or addition of a dispersing agent can be applied.

[0172] [Experiments 7 - 8] Under the same conditions and using the same methods as in Experiments 5 - 6, a polyurethane composition of 75ShD containing zirconium oxide TZ - Y3 - E (Tosoh) was produced. This zirconia grade TZ - Y3 contains 3 mol% yttrium and is also commercially available as a free - flowing powder with a (primary) particle size of 0.04 μm. The processing was similar to that observed for the TZ - 0 powder. As in the case of the pure zirconia grade, the polyurethane composition tended to exhibit brittle fracture during the tensile test, especially at a load of 60 mass%. The determined particle size distributions of the TZ - 0 and TZ - Y3 grades shown in FIG. 6 confirm that the particles are much larger than their primary particles, with maximum values of approximately 60 and 50 μm respectively, and a smaller maximum value of approximately 1 μm. This again suggests that the observed processing and brittleness problems can be overcome if these particles are pretreated and / or (partially) de - aggregated before mixing with the polymer and / or if a dispersing aid is added during mixing. Furthermore, applying a mixing device that enables higher throughput rather than the small laboratory - scale device used may also enhance the dispersion.

[0173] [Experiments 9 - 11] In these examples, medical - grade zirconium oxide obtained from Sigma Aldrich (referred to herein as ZrO / SA) was used after drying at 120 °C for 24 hours. These particles had a particle size D of approximately 1.8 μm 50It has been found to have; this is much smaller than the particle sizes found for the particles used in Experiments 5 - 8 above, as also shown in Figure 6. The formulation was carried out similarly, but dried and some additional mixing elements were used in the feeder to ensure proper feeding of somewhat viscous powder. Polymer strands and granules were produced in the stability process. The produced compositions showed an increase in the tensile modulus with increasing zirconia loading (20, 40 and 60 wt%), but the tensile strength and elongation decreased. All samples showed a tensile property profile that would be suitable (even in the conditioned state) for using the composition in the manufacture of bone anchors. The addition of zirconia increased the hardness from 75.7 ShD (Experiment 1) to 81.1 and 80.2 ShD (Examples 10 and 11).

[0174] The GPC measurements show a decrease in the molar mass after the melt processing treatment, especially during compounding; however, these decreases seem to be significantly smaller than those observed for the compositions containing HA particles. The unfilled polyurethane shows a higher molar mass after injection molding; however, this material did not undergo the previous compounding steps.

[0175] The crystallization behavior of the selected samples was investigated using a conventional DSC; the relevant results (temperature and enthalpy, J / g sample) are summarized in Table 2 and the DSC curves for Experiments 1 and 9 - 10 - 11 are shown in Figure 7. For the composition TPU / HA 80 / 20 (Experiment 2), crystallization seems to start during cooling at a higher temperature than for the reference polyurethane (Experiment 1), which may be related to the low molar mass of the degraded polyurethane and / or some nucleating action of the hydroxyapatite particles. On the other hand, the broadening of the crystallization and melting peaks, especially seen for larger amounts of filler particles, would indicate an interference (slowing down) of the polymer crystallization. The compositions containing zirconia particles show a nucleating action during cooling and a higher melting temperature in the reheating scan.

[0176] [Cartilage plug] The prototype cartilage plugs with mushroom-like shapes shown in FIGS. 2A - B were fabricated on a bench-top Xplore IM12 micro-injection molding machine using a mold holder part containing a two-part mold and applying a set of inserts to enable two-component molding.

[0177] The materials used were a TPU composition containing 60 wt% zirconia (Experiment 11) and unfilled end-group modified polycarbonate urethane with a hardness of 80 ShA (Bionate® II 80A; DSM Biomedical BV, Sittard-Geleen, NL). The materials were dried under vacuum / nitrogen gas flush at 120 °C for 24 h or at 80 °C for 72 h respectively before use.

[0178] The parts of the different molds together define an implant part with the following basic dimensions: a stem section with a length of 6.5 mm, a diameter of 6.1 mm, and a rounded lower end at an angle of 45 °C; an upper surface with a mutually rectangular contour with a diameter of 10.1 mm and two radii of 11 and 18 mm, and a cap section with a total cap height of 3.5 mm, 1.0 mm of which below is joined to the stem made of a rigid polymer composition. All other edges were rounded with a radius of 0.5 mm. The mold part defining the stem section was etched to produce a texture with a roughness of VDI3400 36.

[0179] [Table 1]

[0180] [Table 2]

[0181] In the first step, the polyurethane / zirconia composition was injected into a mold containing an insert within the cap section by applying a barrel temperature of 210 °C, a mold temperature of 80 °C, an injection pressure of 10 bar for 2.2 seconds, and a filling pressure of 10 bar for 10 seconds. Next, the insert was removed from the mold, and a 4 mm long tantalum wire preheated on a hot plate set at 250 °C and oriented using the 18 mm radius of the cap was placed within the mold on the injection surface. Subsequently, an elastic polyurethane material was injected to form the top section of the cap by applying a barrel temperature of 235 °C for 2.2 seconds, a mold temperature of 80 °C, an injection pressure of 12 bar, and a filling pressure of 12 bar for 10 seconds.

[0182] The formed plugs were coated with a dispersion of BCP particles (biphasic calcium phosphate; Cam BioCeramics) in THF on the stem and the underside of the cap; the samples were air-dried and functionalized with bioceramic particles by rinsing and drying multiple times (under reduced pressure at 50 °C) using ethanol. These plugs according to the invention were designated as Plug I).

[0183] Similar to the above method, the plugs were molded from the corresponding unfilled materials, i.e., the stem section from polycarbonate urethane with a hardness of 75 ShD (Bionate® 75D; DSM Biomedical BV, Sittard-Geleen NL) and the cap section from Bionate® II 80A material. These unfilled plugs are referred to as Plug U below.

[0184] Furthermore, metal plugs with a shape and dimensions corresponding to the polymeric plugs were manufactured. In this case, the stem part was made of titanium, the cap part was made of cobalt-chromium, and the stem was post-treated by alumina jet machining (designated as Plug M).

[0185] [In vivo test] The three types of plugs described above were evaluated in an animal study by implanting the device into the knee joints of 326 female Dutch dairy goats. This study was approved by the local and national animal ethics committees under project license number PV2015-018-003.

[0186] The knee joints of the animals (32×2) were divided into four groups, and 16 plugs I, U, and M were implanted into each of three of the groups; and the remaining group had a sham operation (a placebo operation without inserting a plug) as a reference for natural cartilage degeneration.

[0187] The surgical procedure included making a skin incision around the medial patella, opening the joint capsule to expose the medial femoral condyle, and positioning the center of the weight-bearing part. To implant the plug, an osteochondral defect was created using a cannulated drill under the guidance of a K-wire. The depth of the drill hole was adjusted so that the implant was flush with or slightly recessed from the adjacent cartilage. The plug was then inserted using press-fit fixation while adjusting the double curvature of the cap using an orientation marker to match the shape of the knee joint. No intraoperative or postoperative complications occurred.

[0188] After 26 weeks (6 months) in the experimental animal testing facility at Maastricht University, four animals from each group were euthanized by an overdose of pentobarbital (200 mg / kg (body weight)). The knee joints were excised and then dissected. The medial femoral condyles and tibial plateaus were isolated and fixed in neutral buffered formalin solution. The fixed specimens were dehydrated by incubating them in an aqueous ethanol solution while increasing the concentration up to 100% ethanol. The medial femoral condyles were embedded in a hydroxyethyl methacrylate-based resin (Technovit 8100, Hereaus Kulzer, Hanua, DE) under vacuum. Next, to prevent swelling, a mantle made of polymethyl methacrylate (PMMA, Technovit 3040, Hereaus Kulzer, Hanua, DE) was made for each block. Next, the plastic blocks were cut using a tape to orient the implant horizontally, and the blocks were attached to a diamond saw (SP1600, Leica Biosystems, Nussloch, DE) using an ultra-low viscosity cyanoacrylate paste. A cut was made through the center of the implant. Safranin-O / fast green (Carl Roth, Karlsruhe, DE) staining was applied. The tissue was gently blotted to dry and air-dried for 5 - 10 minutes. A glass coverslip was adhered to the tissue using cyanoacrylate paste. Sections of 50 - 70 μm were cut and adhered to glass slides using cyanoacrylate paste. These sections were scanned using a high-illumination optical microscope (M8 Microscope, Precipoint, Freising, DE) at a magnification of 200x. A custom MATLAB script (MathWorks, Natick MA, US) was used to determine the bone-implant-contact rate (BIC), which was defined as the percentage of the implant surface in direct contact with bone.

[0189] The remaining 16 animals were euthanized 12 months after surgery, and the knee joints and implants were evaluated using the above-described method.

[0190] The results of the BIC scoring of the implants at 6 and 12 months, presented as average numerical scores (%), are shown in Figure 9. Plug I, which had a stem manufactured from a zirconia-TPU composite material and had BCP particles provided on its surface, showed the highest average BIC score; this type of plug demonstrated better bone-implant contact or in vivo osteointegration of the plug than was observed for plugs M and U. One plug M and one I were found to show little bone contact after 6 months. This was thought to be induced by misalignment or tilting of the metal plug and cracks initiated at air-entrapped locations within the plug, for example, based on a filled polymer composition. Four out of eight implants manufactured entirely from unfilled polyurethane had extremely low BIC scores, presumably induced by deformation due to the load of the relatively soft plugs.

[0191] Twelve months after implantation, one out of eight plugs M, four out of eight plugs I, and eight out of eight plugs U had (almost) 0% BIC scores. Again, unfilled plugs appeared to lack sufficient rigidity, and in the case of metal and composite plugs, the low osteointegration scores seemed to stem from defects caused by the applied small-scale compounding and / or molding processes or the method of plug insertion during operation. The other plugs M and I both functioned well, and the photographs showed an increase in osseointegration compared to the 6-month results. In the case of metal plugs, this was not unexpected as metal plugs are initially known to show relatively slow bonding to bone, but after several years, the so-called stress shielding effect generally causes detachment. Ignoring the above-mentioned incorrect results, the BIC scores of plugs M and I at the 12-month time point (as shown in Figure 9) were on the order of 35 - 60%, and the average score of plug I was higher (46 ± 13 vs 40 ± 5%). It is expected that the observed defects and negative results can be reduced or even prevented if the manufacturing of the polymer composition and the molding of the composite plug I are upscaled and improved, and the injection of the plug is better controlled with optimized tools.

[0192] The above is further shown by representative photographs of histological slices as shown in FIG. 10 for each plug type (using transmitted light after 6 months). It should be noted that these photographs are grayscale versions of the original color photographs. Nevertheless, it can be clearly concluded that Plug I shows a close fit with the surrounding tissue without voids or other irregularities at the interface or in the tissue. Also note the distinct visible distinction between the upper cartilage replacement part and the bone fixation part of the TPU-based plug, and the presence of tantalum orientation markers (shown as dark dots, with the elongated markers oriented perpendicular to the slice) at the interface of both parts.

[0193] Furthermore, MRI images taken of the knee joint containing the implant 6 months after implantation showed no substantial difference between Plug I and U, although it was also recognized that the image of Plug I showed a clearer contrast between the plug and the tissue. Neither plug seemed to interfere with the MRI evaluation of the cartilage within the joint, while on the other hand, MRI imaging of the metal plug M and the adjacent cartilage was not feasible due to artifacts induced by the metal parts. Similar to Plug M, the stem part of Plug I was clearly visible on radiographs, while Plug U was only partially and faintly visible.

[0194] After fixation and dehydration of the tibial plateau, at 6 and 12 months, coronal osteochondral slabs with a thickness of 3 - 4 mm were cut from the tibial plateau using a band saw. Next, the individual slabs were decalcified in formic acid at room temperature for at least 6 weeks. The specimens were then embedded in paraffin and 5-μm-thick sections were prepared using a standard microtome (Leica RM2245, Leica Biosystems, Nussloch, DE). The sections were stained using safranin-O / fast green (Carl Roth, Karlsruhe, DE) and subsequently digitized using a high-illumination optical microscope slide scanner at a magnification of 200× (M8 Microscope, Precipoint, Freising, DE). Finally, scoring of the tibial cartilage quality was performed using the modified Mankin scoring (MMS) system as described by Little et al. (DOI: 10.1016 / j.joca.2010.04.016). Figure 11 summarizes the results of the numerical scoring of cartilage damage or degeneration on the opposing bone surfaces. In these cases, it was found that the metal implants induced substantially more severe cartilage damage than the TPU-based plugs and the sham-operated group. Plug I, which has a zirconia-filled polyurethane stem and an unfilled polyurethane cartilage contact part, was found to function similarly to the sham-operated goats, i.e., those having only natural cartilage in their knee joints. Plug U showed a similar scoring to Plug I, which is a soft polyurethane that did not induce damage, but is not shown in Figure 11 for simplicity.

[0195] In summary, a cartilage plug having a stem made of a zirconia / TPU composition and a cartilage replacement cap made of un-reinforced TPU (Plug I) exhibits the best overall performance, has appropriate handleability and implantability, shows good osseointegration, causes little damage to the opposite cartilage surface, and is imageable as an implant with micro-CT, X-ray, and MRI techniques. Further, the present disclosure also describes the properties of the filled TPU composition, the design of the cartilage plug made using it, and several options for further improving the performance of such implants.

Claims

1. An orthopedic implant having a bone fixation part comprising a polymer composition containing a biostable thermoplastic polyurethane (TPU) and inorganic particles containing 15 to 70% by mass of zirconia, wherein the inorganic particles containing zirconia have an average particle size in the range of 0.03 to 10 μm, and the orthopedic implant further comprises a cartilage replacement part made of an elastic and wear-resistant biocompatible material.

2. The orthopedic implant according to claim 1, wherein the TPU of the bone fixation part has a hardness of 50 to 90 ShD.

3. The orthopedic implant according to claim 1, wherein the TPU of the bone fixation part has a hardness of 60 to 85 ShD.

4. The orthopedic implant according to any one of claims 1 to 3, wherein the TPU of the bone fixation part contains an aliphatic polyether, an aliphatic polyester, an aliphatic polycarbonate, or a combination thereof as a soft block.

5. The orthopedic implant according to claim 4, wherein the TPU of the bone fixation part contains an aliphatic polycarbonate.

6. The orthopedic implant according to any one of claims 1 to 5, wherein the inorganic particles containing zirconia have an average particle size in the range of 0.1 to 5 μm.

7. The orthopedic implant according to any one of claims 1 to 6, wherein the bone fixation part has an outer surface having a surface texture with a roughness Ra of at least 1 μm.

8. The orthopedic implant according to any one of claims 1 to 7, wherein the bone fixation part has bioactive particles or a bioactive coating on its surface.

9. The orthopedic implant according to any one of claims 1 to 8, wherein the cartilage replacement part is made of a biostable thermoplastic polyurethane (TPU) containing an aliphatic polyether, an aliphatic polyester, an aliphatic polycarbonate, or a combination thereof as a soft block.

10. The orthopedic implant according to claim 9, wherein the cartilage replacement part is made of a biostable thermoplastic polyurethane (TPU) containing an aliphatic polycarbonate.

11. The orthopedic implant according to claim 9 or 10, wherein the TPU of the cartilage replacement part has a hardness of 55 to 100 ShA.

12. The orthopedic implant according to claim 9 or 10, wherein the TPU of the cartilage replacement part has a hardness of 70 to 90 ShA.

13. The orthopedic implant according to any one of claims 9 to 12, wherein the TPU of the cartilage replacement part contains an average of two terminal groups.

14. The orthopedic implant according to claim 13, wherein the terminal group is hydrophobic.

15. The orthopedic implant according to any one of claims 9 to 14, wherein the cartilage replacement part of the orthopedic implant has a thickness of 0.2 to 5 mm.

16. The orthopedic implant according to any one of claims 9 to 14, wherein the cartilage replacement part of the orthopedic implant has a thickness of 0.8 to 3.4 mm.

17. The orthopedic implant according to any one of claims 9 to 16, wherein the cartilage replacement part has a contoured upper surface with a curvature characterized by two different radii in directions perpendicular to each other.

18. The orthopedic implant according to any one of claims 1 to 17, wherein the orthopedic implant includes a bone fixation part and a cartilage replacement part, the bone fixation part has a surface that contacts the cartilage replacement part, and the surface is structured with protrusions and / or depressions having a height and / or depth and width of 0.05 to 3.0 mm.

19. The orthopedic implant according to any one of claims 1 to 18, wherein the orthopedic implant further includes an orientation marker, preferably an elongated radiopaque marker.

20. A method for manufacturing the orthopedic implant according to any one of claims 1 to 19 using a multi-component injection molding process, the method comprising injecting a polymer composition comprising a biostable thermoplastic polyurethane and inorganic particles containing 15 to 70% by mass of zirconia into a mold containing an insert in the form of the cartilage replacement part to form the bone fixation part, and then removing the insert from the mold, and injecting an elastic wear-resistant biocompatible material into the mold partially filled with the polymer composition to form the cartilage replacement part.

21. A surgical kit comprising a component including the orthopedic implant according to any one of claims 1 to 19, an implant position for receiving the orthopedic implant, and an auxiliary tool for inserting the orthopedic implant into a bone hole.

Images