NL2027199B1

NL2027199B1 - Method of manufacturing a non-biodegradable plug-shaped implant for the replacement and regeneration of biological tissue

Info

Publication number: NL2027199B1
Application number: NL2027199A
Authority: NL
Inventors: G Melsom Mr; Fransen P; G Hermsen Mr; W Van Buul Mr
Original assignee: Jointsphere B V
Priority date: 2020-12-22
Filing date: 2020-12-22
Publication date: 2022-07-20
Also published as: WO2022136416A1

Abstract

A method of manufacturing a non—biodegradable implant for the replacement and regeneration of biological tissue in the shape of a plug is described. The method comprises 5 the subsequent steps of providing a female mold part and a male mold part, wherein the male mold part comprises a plurality of pins that protrude from a surface thereof; providing base section material in a cavity of the female mold part; providing top section material on top of the base section material in the cavity of the female mold part; heating at least one of the female or male mold part to soften at least one of the base and top section 10 materials; bringing the male mold part under pressure into the ﬁlled cavity of the female mold part to compress the base and top section materials present in the female mold part, whereby the surface from Which the plurality of pins protrude contacts the top section material and channels that conform to the pins are produced in the top section material that together define a porous top section; sustaining step e) until the base and top section 15 materials have sufﬁciently adhered to each other; removing the male mold part from the cavity of the female mold part; cooling at least one of the female or male mold part; and taking the consolidated plug out of the female mold part. A plug—shaped implant obtainable by the method is also described.

Description

METHOD OF MANUFACTURING A NON-BIODEGRADABLE PLUG-SHAPED IMPLANT FOR THE REPLACEMENT AND REGENERATION OF BIOLOGICAL TISSUE

TECHNICAL FIELD OF THE INVENTION The invention relates to a method of manufacturing a non-biodegradable implant for the replacement and regeneration of biological tissue in the shape of a plug. The implant comprises a base section configured for anchoring in bone tissue, and a top section configured for replacing cartilage tissue of an intermediate and deep zone of the cartilage layer, and for growing cartilage tissue onto and into, thus regenerating a superficial zone of the cartilage layer. The invention also relates to a plug-shaped implant obtainable with the method.

BACKGROUND OF THE INVENTION An osteochondral structure refers to a structure comprising cartilage and bone. Typical osteochondral structures can be found in the thighbone (femur), shinbone (tibia), and kneecap (patella). Such structures fit tightly together and move smoothly because the bone surface is covered with a relatively thick layer of articular (hyaline) cartilage. An (osteochondral defect is any type of damage to articular cartilage and optionally to underlying (subchondral) bone. Usually, (osteo)chondral defects appear on specific weight-bearing spots at the ends of the thighbone and shinbone and the back of the kneecap for instance. They may range from roughened cartilage, small bone and cartilage fragments that hinder movement, to complete cartilage loss. Trauma of joint surfaces is common in young active people practicing sports, or as a sequel to accidents. Lesions may comprise the cartilage layer only, but often the underlying subchondral bone too. Articular cartilage has a very low tendency for healing and the repair tissue is qualitatively inferior to the original tissue. This invariably leads to the formation of osteoarthritis (OA) over the years, which is a major cause of disability and loss of quality of life in elderly people. The standard treatment for this condition is ultimately joint replacement by artificial joints. Whilst clinically effective, the non-

biological implants do not last longer than 10-20 years and revision surgery is much less effective and very costly. For this reason, much research is dedicated to developing biological regenerative therapies that would be life-long lasting. However, despite promising in vitro results, until now not a single solution has proven to be more effective than the current standard of care over a longer period in real life conditions.

Because the cartilage layer lacks nerve fibers, patients are often not aware of the severity of the damage. During the final stage, an affected joint consists of bone rubbing against bone, which leads to severe pain and limited mobility. By the time patients seek medical treatment, surgical intervention may be required to alleviate pain and repair the cartilage damage. Implants have been developed for the joint in order to avoid or postpone such surgical interventions. These may be implanted in a bone structure at an early stage of cartilage damage, and may thus be provided for preventive treatment, in order to avoid unnoticed degeneration of the joint.

A number of treatments is available to treat articular cartilage damage in joints, such as the knee, starting with the most conservative, non-invasive options and ending with total joint replacement if the damage has spread throughout the joint. Currently available treatments include anti-inflammatory medications in the early stages. Although these may relieve pain, they have limited effect on arthritis symptoms and further do not repair joint tissue. Cartilage repair methods, such as arthroscopic debridement, attempt to at least delay tissue degeneration. These methods however are only partly effective at repairing soft tissue, and do not restore joint spacing or improve joint stability. Joint replacement (arthroplasty) is considered as a final solution, when all other options to relieve pain and restore mobility have failed or are no longer effective. While joint arthroplasty may be effective, the procedure is extremely invasive, technically challenging and may compromise future treatment options. Cartilage regeneration has also been attempted, more in particular by tissue-engineering technology. The use of cells, genes and growth factors combined with scaffolds plays a fundamental role in the regeneration of functional and viable articular cartilage. All of these approaches are based on stimulating the body's normal healing or repair processes at a cellular level. Many of these compounds are delivered on a variety of carriers or matrices including woven polylactic acid based polymers or collagen fibers. Despite various attempts to regenerate cartilage, a reliable and proven treatment does not currently exist for repairing defects to the articular cartilage. Another standard of care consists of Microfracture (MFx) for smaller lesions (<2 cm?) and Autologous Chondrocyte Implantation (ACT) for bigger lesions (> 2 em®). The cartilaginous tissue regenerated with these techniques however is not able to withstand the biomechanical challenges in the joint and starts to degenerate within 18 months already. Substantial delay in joint replacement by artificial joints, let alone preventing it, therefore is not possible.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a method of manufacturing a non- biodegradable plug-shaped implant for the replacement and regeneration of biological tissue having improved load distribution as well as cartilage regenerating properties.

Another aim is to provide a plug-shaped implant that is obtainable by the method and provides for the replacement and regeneration of an osteochondral structure. The invention further aims to provide an implant obtainable by the method and able to repair articular cartilage lesions in a durable fashion, and which at least postpones and, preferably, prevents joint replacement by artificial joints.

The above and other aims are provided by a method in accordance with claim 1. The method of manufacturing a non-biodegradable implant for the replacement and regeneration of biological tissue in the shape of a plug, comprising a base section configured for anchoring in bone tissue, and a top section configured for replacing cartilage tissue of an intermediate and deep zone of the cartilage layer, and for growing cartilage tissue onto and into, thus regenerating a superficial zone of the cartilage layer, comprises the steps of: a) providing a female mold part and a male mold part, wherein the male mold part comprises a plurality of pins that protrude from a surface thereof; b) providing base section material in a cavity of the female mold part; c) providing top section material on top of the base section material in the cavity of the female mold part;

d) heating at least one of the female or male mold part to soften at least one of the base and top section materials; e) bringing the male mold part under pressure into the filled cavity of the female mold part to compress the base and top section materials present in the female mold part, whereby the surface from which the plurality of pins protrude contacts the top section material and channels that conform to the pins are produced in the top section material that together define a porous top section; f) sustaining step e) until the base and top section materials have sufficiently adhered to each other; 10g) removing the male mold part from the cavity of the female mold part; h) cooling at least one of the female or male mold part; and 1) taking the consolidated plug out of the female mold part. The method uses a male mold part comprising a plurality of pins that protrude from a surface thereof. The pins produce a plurality of channels that together define porosity in the top section of the plug-shaped implant. The porosity in the top section may, alternatively, be formed by 3D-printing of the top section material on top of the base section material. However, the use of a male mold part comprising the plurality of pins produces a well-defined porosity in the top section.

The step d) of heating at least one of the female or male mold parts may involve heating by incorporating said mold part in a heated pressurizing means, such as a press, or by other heating means, such as provided by an oven, a heating fluid, and the like.

The step h) of cooling at least one of the female or male mold parts may involve natural cooling, such as occurs by taking said mold part from a pressurizing means, such as a press. It may also involve active cooling of at least one of the female or male mold part, such as provided by a cooling fluid for instance.

The base section material provided in step b) may be in the form of granules for instance. In another embodiment of the method, the base section material may be provided in the form of a pre-formed plug-shaped bases section. Such a base section preform may conveniently be manufactured by compression and/or injection molding and/or computer numerical control {CNC) milling. Another embodiment of the invention provides a method wherein, prior to step a) of the 5 invented method, a middle section material is provided on the base section material with a smooth male mold part that does not comprise a plurality of pins that protrude from a surface thereof, i.e. comprises a smooth surface. In such a method, a female mold part and the smooth male mold part are provided first where after the following subsequent steps are carried out in the indicated order: - providing base section material in a cavity of the female mold part; - providing middle section material on top of the base section material in the cavity of the female mold part; - heating at least one of the female or smooth male mold part to soften at least one of the base and top section materials; - bringing the smooth male mold part under pressure into the filled cavity of the female mold part to compress the base and middle section materials present in the female mold part; - sustaining step e) until the base and middle section materials have sufficiently adhered to each other.

In this embodiment, a consolidated assembly of the base section and a non-porous middle section is produced with the middle section material having a good bonding with the base section material. According to this embodiment, there after, steps a) to 1) are performed to obtain the implant having a top section provided with channels.

The thickness of the middle section may be selected according to the circumstances, and may for instance be from 0.2-0.4 mm, or even from 0.2-0.8 mm. The porosity in the top section may, alternatively, be formed by 3D-printing of the top section material on top of the consolidated assembly of the base section and the non- porous middle section.

The material of the top section is preferably substantially the same as the material of the middle section. Moreover, in producing the consolidated base and middle sections, cooling at least one of the female or smooth male mold part; and/or taking the consolidated base and middle sections out of the female mold part may be effectuated before starting with step a) of the invented method. In an embodiment, step b) may involve providing base section material and middle section material in the cavity of the female mold part, preferably in the form of a consolidated base and middle section. In a preferred method according to an embodiment of the invention, the pins in the plurality of pins are mutually aligned, thereby producing substantially parallel channels in the top section of the implant. This has proven to be beneficial for tissue ingrowth.

A further improved embodiment provides a method wherein the surface of the male mold part extends substantially parallel to a top surface of the implant. This embodiment produces an implant in which the channels in the top section that produce the porosity extend substantially along a vertical direction in an implant that is positioned in an upright position on a bearing surface.

The porosity as created by the channels may be embodied in different geometries. For instance, a first series of channels may be produced that makes an angle (non-zero) with a second series of channels. The angle between the series may be any non-zero angel, for instance 90 degrees. In another embodiment of the invented method, the pins have a variable length.

In another embodiment, a method is provided wherein the pins have the same length, and the length is smaller than a height of the top section. This embodiment of the method produces a top section having channels over a part of its height only. A higher part of the top section comprises channels, whereas a lower part of the top section is not porous. This may be beneficial when implanted in cartilage or bone for instance. The non-porous lower part of the top section resulting from this embodiment is also referred to as a middle section of the plug-shaped implant.

The length of the pins of the male mold part may be chosen within broad ranges, depending on the specific body part that needs to be repaired. An embodiment of the method is provided wherein the length of the pins ranges from 300-1000 pm, more preferably from 400-800 um, and most preferably from 450-550 um.

A cross-dimension such as a diameter of the pins of the male mold part may also be chosen within broad ranges, depending on the specific body part that needs to be repaired. According to an embodiment of the method a diameter of the pins ranges from 200-500 um.

In order to facilitate demolding of the implant after molding, a method according to an embodiment is provided wherein the diameter at a base of a pin is larger than a top of the pin.

The level of porosity of the porous top section can conveniently be set by selecting the areal density of the pins. In an advantageous embodiment, a method is provided wherein the areal density of the pins per surface area ranges from 5-30 pins/mm?, more preferably from 8-20 pins/mm?, and most preferably from 10-15 pins/mm?, Ina further embodiment a method is provided wherein at least the female mold part is heated to a temperature of between 120-200°C, more preferably between 150-170°C.

In another embodiment of the method, the male mold part is pressurized to a pressure of between 0.20-1.00 kN/mm, more preferably of between 0.40-0.80 kN/mm?, According to the method of the invention, step e) is sustained until the base and top section materials have sufficiently adhered to each other. Preferably, a method is provided according to an embodiment wherein step €) in sustained for 5-50 min, more preferably for 10-40 min, and most preferably for 15-30 min.

The method according to a preferred embodiment uses a top section material that comprises a thermoplastic elastomeric material, comprising a linear block copolymer comprising urethane and urea groups, wherein the thermoplastic elastomeric material optionally further comprises carbonate groups. The thermoplastic elastomeric material more preferably comprises a poly-urethane-bisurea-alkylenecarbonate.

The base section material may comprise any material that is suitable for the purpose. In an embodiment of the method, the base section material comprises one of a biocompatible metal, ceramic, mineral, such as phosphate mineral, and polymer, optionally a hydrogel polymer, and combinations thereof.

Particularly preferred is a method wherein the base section material comprises a non- hydrogel polymer, preferably comprising a polyaryletherketone polymer, such as polyether-ketone-ketone (PEKK), polyether-ether-ketone (PEEK), and polyether-ketone- ether-ketone-ketone (PEKEKK).

The base section may be porous or substantially non-porous. A porous base section may be obtained by pre-forming, preferably also using a method in accordance with the invention, i.e. by using a male mold part having protruding pins. Other methods may also be used. A preferred embodiment provides a method wherein the base section material is substantially non-porous with a porosity of less than 20 %, relative to the total volume of the base section material.

A side wall of the female mold part in another embodiment may comprise a surface having irregularities or undulations. This provides a plug-shaped implant an outer surface whereof is also irregular or undulated. This may provide a better anchoring into bone.

Yet another embodiment of the method is characterized in that the surface of the male mold part from which the plurality of pins protrude is slightly curved, having a radius of curvature in a sagittal plane and/or in a medial-lateral plane ranging from 15 mm to 150 mm.

The top and/or base section material may be provided in different physical forms. As already disclosed above, the base section material may be provided as a preformed base section for instance. In such an embodiment, the base section material may be provided in a solid shape that conforms to the cavity of the female mold part.

In another embodiment of the method, the top and/or base section material is provided in the form of granules.

A preferred embodiment provides a method wherein step a) comprises providing a base section material comprising a substantially non-porous polyaryletherketone polymer with a porosity of less than 20 %, relative to the total volume of the polyaryletherketone polymer in a mold at room temperature.

A preferred embodiment provides a method, wherein the thermoplastic elastomeric material is substantially free of an added peptide compound having cartilage regenerative properties, even more preferably of any compound having cartilage regenerative properties.

Another embodiment of the invention provides a method wherein after step b) the mold is opened and additional granules of the thermoplastic elastomeric material are added to the mold, and step b) is repeated.

The amount of material added in the two-step embodiment of the method may be chosen within wide ranges.

Increasingly good results are obtained when the ratio between the first addition and the second addition of granules of the thermoplastic elastomeric material is selected from 01:99 to 99:01, more preferably from 30:70 to 97:03, and most preferably from 70:30 to 95:05. Another aspect of the invention relates to a non-biodegradable implant obtainable by the claimed method for the replacement and regeneration of biological tissue in the shape of a plug, comprising a base section configured for anchoring in bone tissue, and a top section configured for replacing cartilage tissue of an intermediate and deep zone of the cartilage layer, and for growing cartilage tissue onto and into, thus regenerating a superficial zone of the cartilage layer, wherein the top section comprises a plurality of channels.

Another embodiment of the implant that is obtainable by the claimed method comprises a plurality of channels that are mutually aligned.

In another embodiment of the implant, the plurality of channels extends substantially perpendicular to a top surface of the implant.

According to other embodiments, the implant may have channels having a variable length, or, alternatively, may have channels having the same length, whereby the length is smaller than a height of the top section. This embodiment comprises a non-porous middle section positioned between the top section and the base section.

In yet other embodiments, the implant obtainable by the claimed method comprises channels wherein the length of the channels ranges from 300-1000 pm, more preferably from 400-800 um, and most preferably from 450-550 um; and, according to other embodiments, wherein a diameter of the channels ranges from 200-500 um.

The channels in the implant may have a constant diameter over their length. Alternatively, the diameter at a base of a channel is smaller than at a top of the porous channel close to the top surface of the top section.

An important advantage of the implant that is obtainable by the claimed method resides in the fact that its porosity defining channels have well-controlled dimensions, such as their lateral dimensions. In this way, a well-defined geometry of the produced porosity ensues. This has proven to be beneficial for tissue ingrowth. A preferred embodiment relates to an implant obtainable by the claimed method wherein for each combination of two channels 1 and 2, the absolute value of (D2-D1)/D1 < 10%, more preferably < 8%, most preferably < 5%, wherein Di is the diameter of a channel i. Channel dimensions do not differ much from each other in this embodiment.

Other embodiments that are beneficial to tissue ingrowth relate to implants wherein the areal density of the channels per surface area ranges from 5-30 channels/mm?, more preferably from 8-20 channels/mm?, and most preferably from 10-15 channels/mm*.

The plug-shaped non-biodegradable implant in particular comprises a base section configured for anchoring in bone tissue, and a top section configured for replacing cartilage tissue of an intermediate and deep zone of the cartilage layer, and growing cartilage tissue onto and into, thus regenerating superficial zone of the cartilage layer, wherein the top section comprises a porous thermoplastic elastomeric material. A top section wherein the thermoplastic elastomeric material comprises a linear block copolymer comprising urethane and/or urea groups, and wherein the base section material comprises one of a biocompatible metal, ceramic, mineral, such as phosphate mineral, and polymer, optionally a hydrogel polymer, and combinations thereof has been found to be preferred.

In cartilage, a relatively thin superficial (tangential) zone protects deeper layers from shear stresses and makes up approximately 10% to 20% of articular cartilage thickness. The collagen fibers of this zone (primarily, type II and IX collagen) are packed tightly and aligned parallel to the articular surface (Figure 2). The superficial layer contains a relatively high number of flattened chondrocytes, and the integrity of this layer is imperative in the protection and maintenance of deeper layers. This zone is in contact with synovial fluid and is responsible for most of the tensile properties of cartilage, which enable it to resist the shear, tensile, and compressive forces imposed by articulation.

{5 Immediately deep or below to the superficial zone is the middle (intermediate or transitional) zone, which provides an anatomic and functional bridge between the superficial and deep zones. The middle zone represents 40% to 60% of the total cartilage volume, and it contains proteoglycans and thicker collagen fibrils. In this layer, the collagen is organized obliquely, and the chondrocytes are spherical and at low density.

Functionally, the middle zone is the first line of resistance to compressive forces.

The deep zone of cartilage is responsible for providing the greatest resistance to compressive forces, given that collagen fibrils are arranged perpendicular to the articular surface. The deep zone contains the largest diameter collagen fibrils in a radial disposition, the highest proteoglycan content, and the lowest water concentration. The chondrocytes are typically arranged in columnar orientation, parallel to the collagen fibers and perpendicular to the joint line. The deep zone represents approximately 30% of articular cartilage volume.

The top section of the non-biodegradable implant of the invention replaces at least the middle and deep zones of the cartilage.

The thermoplastic elastomeric material of the top section may be substantially free of an added peptide compound having cartilage regenerative properties, and still produce good ingrowth of cartilage into the porous top section. Even more preferably, the thermoplastic elastomeric material is substantially free of any added compound having cartilage regenerative properties.

The base section material may be formed of any suitable material which provides an appropriate level of mechanical support to the surrounding bone and preferably allows osteogenesis. Suitable materials, including the thermoplastic elastomeric material of the top section of the implant, are biocompatible, by which is meant that these materials are capable of coexistence with living tissues or organisms without causing harm to them. Further, the implant in accordance with the invention is substantially non-biodegradable and combines cartilage replacement with cartilage regeneration. With a non-biodegradable material in the context of the present invention is meant a material that is not broken down {5 into less complex compounds or compounds having fewer carbon atoms by the environment of the implanted implant. The weight-average molecular weight of a substantially non-biodegradable material is reduced by at most 20%, relative to the original weight-average molecular weight after one year of implantation, more preferably at most 10%, still more preferably at most 5%, and more preferably still at most 1%.

Suitable metals as base section material include but are not limited to titanium, zirconium, chromium, aluminum, stainless steel, hafnium, tantalum, cobalt or molybdenum, and their alloys, or any combination thereof. Optionally, a surface layer of the metal may be oxidized, nitrided, carburized or boronized to form a coated metal base section.

Suitable ceramics and minerals as base section material include but are not limited to oxides, nitrides, carbides or borides, or any combination thereof. Suitable examples include bioactive glass, calcium phosphates, such as beta-tricalcium phosphate (TCP), biphasic calcium phosphate and apatite such as hydroxylapatite, fluorapatite, chlorapatite, and/or calcium deficient apatite, and combinations thereof. Suitable (hydrogel) polymers as base section material include but are not limited to collagen, poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polycaprolactone

(PCL), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyacrylamide, polyurethane, polyethylene glycol (PEG), chitin, poly(hydroxyalkyl methacrylate), water- swellable N-vinyl lactams, starch graft copolymers, and derivatives and combinations thereof.

Other preferred materials for the base section comprise a polyaryletherketone (PAEK) polymer. A PAEK polymer comprises a semi-crystalline thermoplastic polymer containing alternately ketone (R-CO-R) and ether groups (R-O-R). The linking group R between the functional groups comprises a 1,4-substituted aryl group. The PAEK polymer used in the base section may inter alia comprise PEK (polyetherketone), PEEK (polyetheretherketone), PEKK (polyetherketoneketone), PEEKK (polyetheretherketoneketone) and PEKEKK (polyetherketoneetherketoneketone). Due to its excellent resistance to hydrolysis, the polyaryletherketone polymer of the base section is advantageously used in the invented implant. It does not break down when sterilized, nor when implanted in the body for an extended time. It also turns out to bond particularly well to the elastomeric material of the top section. The material used in the base section of the invented implant may be used as such, or, in an embodiment, may comprise a reinforcing material selected from the group consisting of fibrous or particulate polymers and/or metals. The base section of the invented implant may also comprise a contrast agent for medical imaging that absorbs radiation, such as a radiocontrast or MRI contrast agent, or a radiopharmaceutical agent that itself emits radiation. The base section may also comprise a small solid object or body, such as a bead, that may for instance comprise a refractory metal such as tantalum. The base section of the plug-shaped implant functions as a bone anchor, whereas the top section functions as partial replacement for the damaged cartilage and as scaffold for cartilage regeneration. In the plug-shaped implant, the top section refers to the section that is closest to the cartilage phase, when implanted. The base section refers to the section that is furthest from the cartilage phase, when implanted. As already disclosed above, the porous part of the top section may not extend over the complete height of the top section.

In such an embodiment, a non-porous middle section is produced located between the porous top section and the base section.

The cross-section of the plug-shaped implant through a horizontal or a vertical plane may have any suitable shape. The cross-section may be circular, square or may be polygonal, such as hexagonal, octagonal, or decagonal. In some embodiments, the plug-shaped implant may be tapered such that it is shaped as a truncated cone structure. Preferably, the implant has a smaller cross-section at the base section than at the top section. The cross- section (or diameter in case of a cylindrical implant) may vary continuously between the base and top section, or may show discontinuities, for instance at the interface between sections.

When the implant has a tapered profile, the angle of the taper is preferably between 1° and 45°. In some embodiments, the taper is between about 3° and 30°, more preferably between 5° and 30°, even more preferably between 10° and 15°. A tapered profile may facilitate insertion of the implant into an osteochondral defect and may further reduce possible damage to host tissue. The implant is preferably used without any means of attachment and remains in the osteochondral structure by its geometry and the surrounding tissue structure. The implant may be used in the knee, but may also be used for other joints, such as a temporal-mandibular joint, an ankle, a hip, a shoulder, and the like. A tapered profile may be readily produced by adopting the shape of the female mold part in accordance with such tapered shape.

As claimed in the invention, the plug-shaped implant comprises a top section on top of the base section, which top section has a dual function: it serves to replace cartilage tissue, and is configured for growing cartilage tissue onto and into. The thermoplastic elastomeric material of the top section is porous, and may comprise a linear block copolymer comprising urethane and/or urea groups.

The linear block copolymers that may be used in the method of the invention are segmented copolymers with elastic properties that originate from hydrogen bonding interaction between molecular chains. Such copolymers comprise ‘hard’ crystallized blocks of polyurethane and/or polyurea segments, and may also comprise ‘hard’

crystallized blocks of polyester and/or polyamide between ‘soft’ blocks.

At room temperature, the low melting ‘soft blocks may be incompatible with the high melting ‘hard’ blocks, which induces phase separation by crystallization or liquid-liquid demixing.

These copolymers exhibit reversible physical crosslinks that originate from crystallization of the ‘hard’ blocks of the segmented copolymer.

The thermoplastic elastomers may be formed into any shape at higher temperatures, more in particular at temperatures above the melting pomt of the ‘hard’ blocks.

On the other hand, the thermoplastic elastomers provide mechanical stability and elastic properties at low temperatures, i.e. at typical body temperatures.

This makes these materials particularly suitable as replacement material for human or animal cartilage.

The constituents of the thermoplastic elastomer may generally comprise three building blocks: a long-chain diol, for example with a polyether, polyester or polycarbonate backbone, a bifunctional di-isocyanate, and, finally, a chain extender, such as water,

another (sometimes short-chain) diol, or a diamine.

The latter chain extender is preferred since this leads to bisurea units in the thermoplastic elastomer.

An embodiment of the implant wherein the thermoplastic elastomeric material is aliphatic is preferred.

This means that all building blocks of the thermoplastic elastomer are devoid of aromatic groups and contain aliphatic groups only.

The thermoplastic elastomer of the invention may be prepared in a one pot procedure, in which a long-chain diol is first reacted with an excess of a di-isocyanate to form an isocyanate-functionalized prepolymer.

The latter is subsequently reacted with a chain extender, such as the preferred diamine, which results in the formation of a higher molecular weight thermoplastic elastomeric polymer containing urethane groups.

If a diamine is used as the chain extender, the thermoplastic elastomer will also contain bisurea groups, which is preferred.

The synthetic procedure to prepare the thermoplastic elastomers may lead to a distribution in the ‘hard’ block lengths.

As a result, the phase separation of these block copolymers may be incomplete, in that part of the ‘hard’ blocks, in particular the shorter ones, are dissolved in the soft phase, causing an increase in the glass transition temperature.

This 18 less desired for the low temperature flexibility and elasticity of the thermoplastic elastomeric material of the top section.

The polydispersity in ‘hard’ blocks shows as a broad melting range, and a rubbery plateau in dynamic mechanical thermal analysis (DMTA) that is dependent on temperature. Preferred embodiments therefore comprise elastomeric block copolymers containing ‘hard’ blocks of substantially uniform length. These may be prepared by fractionation of a mixture of ‘hard’ block oligomers, and subsequent copolymerization of the uniform ‘hard’ block oligomers of a specific length (or length variation) with the prepolymer, mentioned above. Although the thermoplastic elastomers may be prepared by a chain extension reaction of an isocyanate-functionalized prepolymer with a diamine, they may also be prepared by a chain extension reaction of an amine-functionalized prepolymer with a di-isocyanate. Examples of suitable, commercially available diamines and di-isocyanates include alkylene diamines and/or di-isocyanates, arylene diamines and/or di-isocyanates. Amine- functionalized prepolymers are also commercially available, or can be prepared from (readily available) hydroxy functionalized prepolymers by cyanoethylation followed by reduction of the cyano-groups, by Gabriel synthesis (halogenation or tosylation followed by modification with phthalimide, and finally formation of the primary amine by deprotection of the phthalimide group) or by other methods that are known in the art. Isocyanate-functionalized prepolymers can be prepared by reaction of hydroxy functionalized prepolymers with di-isocyanates, such as for example isophorone di- isocyanate (IPDI), 1,4-diisocyanato butane, 1,6-diisocyanato hexane or 4,4'-methylene bis(phenyl isocyanate). Alternatively, isocyanate-functionalized prepolymers can be prepared from amine-functionalized prepolymers, for example by reaction with di-tert- butyl tricarbonate. Hydroxy-functionalized prepolymers of molecular weights typically ranging from about 500 g/mol to about 5000 g/mol of all sorts of compositions are also advantageously used. Examples include prepolymers of polyether’s, such as polyethylene glycols, polypropylene glycols, poly(ethylene-co-propylene) glycols and poly(tetrahydrofuran), polyesters, such as poly(caprolactone)s or polyadipates, polycarbonates, polyolefins, hydrogenated polyolefins such as poly(ethylene-butylene)s, and the like. Polycarbonates are preferred.

Particularly preferred are prepolymers of polycarbonates. Such prepolymers yield an implant as claimed in an embodiment, wherein the thermoplastic elastomeric material turther comprises carbonate groups, besides the urethane and/or urea groups. Such an implant has proven to better fulfill the aims of the present invention than other implants. In particular, it has proven to be beneficial in that its mechanical properties are well adapted to the mechanical properties of human or animal cartilage. Surprisingly, regeneration of cartilage is improved when using this embodiment in an implanted implant.

A particularly preferred embodiment of the invention provides an implant, wherein the thermoplastic elastomeric material comprises a poly-urethane-bisurea-alkylenecarbonate, more preferably a poly-urethane-bisurea-hexylenecarbonate.

Apart from preferably disclaiming a peptide compound having cartilage regenerative properties, and in other embodiments disclaiming any compound having cartilage regenerative properties, in the linear block copolymer, the implant may comprise agents that facilitate migration, integration, regeneration, proliferation, and growth of cells into and around the implant or patch composition, and/or the injury or defect, and/or promote healing of the injury or defect, and/or are chondrogenic and osteogenic, i.e., build, grow and produce cartilage and bone, respectively. These agents, include but are not limited to cytokine compounds, chemokine compounds, chemo attractant compounds, anti-microbial compounds, anti-viral compounds, anti-inflammatory compounds, pro-inflammatory compounds, bone or cartilage regenerator molecules, cells, blood components (e.g., whole blood and platelets), and combinations thereof. Agents that increase strength and facilitate attachment can also be included in the implant.

The thermoplastic elastomeric material of the top section is porous. A porous material according to the invention comprises channels, which are defined by the pins provided on the male mold part. The channels may be microchannels, having a diameter of less than 1 mm, and may be macrochannels, having a diameter of greater than 1 mm. The channels may be interconnected, which means that channels are internally connected or there is continuity between parts of interconnecting channels. A non-porous material in the context of the present invention does not mean a material that is impermeable to molecules of any size, and some small molecules may indeed be able to pass through the non-porous material. Rather, a non-porous material in the context of the present invention represents a material that is impermeable to synovial fluid and/or blood. With a substantially non- porous material in the context of the present invention is meant a material having a porosity of less than 20 %, relative to the total volume of the material, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of the total volume of the material The thermoplastic elastomer used in the top section of the implant is particularly advantageous since it allows adapting its mechanical properties to those of human and animal cartilage.

In an embodiment of the invention, an implant may be provided wherein the porous elastomeric material of the top section has an elastic modulus at room temperature of less than 8 MPa, more preferably of less than 6 MPa, of less than 5 MPa, of less than 4 MPa, of less than 3 MPa, of less than 2 MPa, and most preferably of less than 1 MPa.

In the context of the present application, room temperature is meant to be a temperature in the range of 20-30°C, more preferably 25°C.

Embodiments having the above-disclosed preferred mechanical properties of the top section tend to promote regeneration of cartilage.

This is believed to be due to a favorable stress (redistribution of the osteochondral structure including the implant during (dynamic) loading.

The elastic modulus may be influenced by modifying the porosity of the material of the top section, or by modifying physical properties of the material in the top section through changing its weight average molecular weight for instance.

The porosity may be modified by changing the areal density of the pins and/or channels for instance.

The average porosity of the elastomeric material of the top section may be chosen within a broad range.

A preferred average porosity of the elastomeric material of the top section is selected from 20-80% by volume, more preferably from 30-70% by volume, even more preferably from 40-60% by volume, and most preferably from 45-55% by volume.

The porosity of the elastomeric material in the top section may be substantially the same across the top section.

Alternatively, the porosity of the elastomeric material in the top section may vary across the top section.

The porosity of the elastomeric material in the top section may vary in a transverse direction of the plug-shaped implant and/or in a longitudinal direction of the plug-shaped implant.

A preferred embodiment relates to an implant in which the porosity of the elastomeric material in the top section increases in the transverse direction of the plug-shaped implant from a low value at a center of the plug-shaped implant towards a higher value at an outer side of the implant.

In another preferred embodiment, the porosity of the elastomeric material in the top section increases in the longitudinal direction of the plug-shaped implant from a low value at a bottom surface of the top section towards a higher value at a top surface of the top section.

A low value of the porosity may for instance be selected between 20-45 vol.%, more preferably 25-45 vol. %, even more preferably between 30-45 vol.%, and most preferably between 35-45 vol.%. A high value of the porosity may for instance be selected between 45-70 vol.%, more preferably between 45-65 vol.%, even more preferably between 45-60 vol.%, and most preferably between 45-55 vol.%. A spatial variation of the porosity may conveniently be achieved by a spatial variation of the pins of the male mold part.

In the implant as claimed in the invention, the base section is in direct contact with the porous top section.

A useful embodiment of the invention provides an implant, wherein the base section comprises a core of non-porous base section material and a, preferably circumferential, shell of porous base section material, wherein the shell has a thickness that is less than 10% of a largest diameter of the base section.

Other useful embodiments provide an implant wherein the (circumferential) shell has a thickness of less than 9%, of less than 8%, of less than 7%, of less than 6%, of less than 5%, of less than 4%, of less than 3%, of less than 2%, or of less than 1% of a largest diameter of the base section.

Alternatively, the cross-sectional area of the (circumferential) shell covers at most 35% of a largest cross-sectional area of the base section.

Other useful embodiments provide an implant wherein the cross-sectional area of the (circumferential) shell is less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1% of a largest cross-sectional area of the base section.

Another embodiment of the invention relates to an implant, comprising a substantially non-porous polyaryletherketone polymer in the base section with a porosity of less than 20 %, relative to the total volume of the polyaryletherketone polymer.

Yet another embodiment provides an implant wherein the base section comprises a non-porous polyaryletherketone polymer.

The implant obtainable by the claimed method may have a base section that comprises a centrally located cavity that comprises the biocompatible elastomeric material.

Such a cavity may further improve the adhesion of the top section to the base section.

The cavity may be cylindrical, or its cross-section may be square, or polygonal.

The walls of the cavity may also be provided with irregularities or undulations, or may comprise sections of a larger cross-sectional area than its average cross-sectional area.

Several of such cavity sections may be provided at different heights of the base section to form mechanical locking structures.

The cavities in the base section may conveniently be produced by providing the female mold part with protrusions that conform to the cavities that need to be formed in the base section.

The height of the plug-shaped implant may be chosen as claimed in the specific application in the body.

Heights may vary from 3 to 18 mm for instance.

As claimed in a useful embodiment of the invention, an implant is provided wherein a height of the base section, and a height of the porous top section are selected such that a top surface of the implant comes to lie below a top surface of cartilage present on an osteochondral structure when implanted, preferably over a distance of between 0.1 - I mm.

This embodiment promotes growing cartilage tissue into, but also onto the top section, whereby a strong fixation is built between the top section and the newly formed cartilage.

It has turned out that cartilage cells from the host cartilage have a strong affinity for the segmented elastomer of the top section, and therefore are prone to colonize the surface thereof to produce new hyaline cartilage tissue on top of the implant.

Another embodiment provides an implant wherein a height of the base section and a height of the porous top section are selected such that a bottom surface of the top section comes to lie about level with a bottom surface of cartilage present on an osteochondral structure when implanted.

Yet another embodiment of the invention provides a top section, a top surface of which is slightly curved.

Preferred radii of curvature of the top surface of the top section in a sagittal plane are selected to range from 15 - 150 mm, more preferably from 17 — 125 mm, even more preferably from 19 — 100 mm, even more preferably from 21 — 75 mm, even more preferably from 23 — 50 mm, and most preferably from 25 — 30 mm.

This embodiment may regenerate a new cartilage layer on the top surface of the top section of the implant of about equal thickness across the top surface. The result may be a radius of a top surface of the regenerated cartilage that is about the same as the radius of the surrounding native cartilage layer next to the implant, thereby showing continuity in radius. The top surface of the top section of the implant may also be curved in a medial- lateral plane, preferably with a radius of curvature with the ranges disclosed above for the sagittal plane. In a practical embodiment, the top surface of the top section of the implant has a radius of curvature that is equal in the sagittal and the medial-lateral plane. This embodiment thus comprises a spherical top surface.

BRIEF DESCRIPTION OF THE FIGURES The invention will now be further elucidated by the following figures and examples, without however being limited thereto. In the figures: Figures 1A to 1D show a schematic side view of four embodiments of an exemplary implant according to the present invention; Figure 2A shows a schematic perspective view of a base section according to an embodiment of the invention; Figure 2B shows a schematic cross-section of the embodiment of figure 2A; Figures 2C and 2D show a schematic detailed view of parts B and C of the embodiment of figure 2B; Figure 3 shows a schematic representation of a possible synthetic route to the thermoplastic polycarbonate material according to an embodiment of the invention; Figure 4 shows a "H-NMR spectrum of the thermoplastic polycarbonate material according to an embodiment of the invention; Figures 5A to 5C show DSC thermograms of the thermoplastic polycarbonate material according to an embodiment of the invention at different heating rates; Figures 6A to 6C show a schematic representation of a defect in an osteochondral structure (6A), the osteochondral structure comprising an implant according to an embodiment of the invention (6B) and the same osteochondral structure after on-/ingrowth of cartilage (6C); Figures 7A to 7D show a schematic side view of four embodiments of an implant according to yet another embodiment of the present invention;

Figures 8A to 8C show a schematic representation of a defect in an osteochondral structure (8A), the osteochondral structure comprising an implant according to another embodiment of the invention (8B) and the same osteochondral structure after on-/ingrowth of cartilage (8C):

Figures 9A and 9B show a schematic perspective view of a male mold part as used in an embodiment of the invented method, and a detail E thereof; Figures 10A and 10B respectively show a top view and a side view of the male mold part of figure 9; Figure 11 schematically shows a detailed view of a pin as used in a male mold part according to an embodiment of the invention;

Figures 12A and 12B respectively show a side view and a top view of a compression molding set-up according to an embodiment of the invention;

Figures 13A and 13B respectively show a sectional view along the line A-A and C-C of the compression molding set-up shown in figures 12A and 12B; and

Figure 14 schematically shows a detail D of the compression set-up shown in figure 13A.

Referring to figure 1A, a side view of an embodiment of an exemplary implant according to the present invention is shown.

The implant 1 in the shape of a plug comprises a base section 2, configured for anchoring in bone tissue, a middle section 3 configured for replacing cartilage tissue, and a top section 4 configured for growing cartilage tissue onto and into.

The middle section 3 and top section 4 comprise the same thermoplastic elastomeric material.

The thermoplastic elastomeric material in this embodiment comprises a poly-urethane-bisurea-hexylenecarbonate, the preparation and properties whereof will be elucidated further below.

The top section 4 however comprises poly-

urethane-bisurea-hexylenecarbonate in porous form, whereas the middle section 3 comprises the same poly-urethane-bisurea-hexylenecarbonate without any pores.

The porous top section 4 comprises channels 42 that extend in a vertical direction over a distance 40. The channels 42 have been provided in the top section 4 according to a method, an embodiment whereof is elucidated in more detail below.

The base section 2 comprises a non-porous polyaryletherketone polymer, which, in the embodiment shown is a non-porous PEKK polymer.

The implant 1 is cylindrical and has a diameter 10 of 6 mm.

The height 20 of the base section 2, the height 30 of the middle section 3, and the height 40 of the top section 4 add up to a total height of 7 mm.

Figure 1B schematically represents a side view of another embodiment of an implant according to the present invention. The embodied implant 1 in the shape of a plug again comprises a base section 2, configured for anchoring in bone tissue, a middle section 3 configured for replacing cartilage tissue, and a top section 4 configured for growing cartilage tissue onto and into. The middle section 3 and top section 4 comprise the same poly-urethane-bisurea-hexylenecarbonate material, which is porous in the top section 4, and non-porous in the middle section 3. Similar to the embodiment shown in figure 1A, the present embodiment has channels 42 in the top section 4. The base section 2 comprises a substantially non-porous PEKK polymer with a porosity of less than 20 %, relative to the total volume of the PEKK polymer. The base section 2 of this embodiment in particular comprises a core 21 of non-porous PEKK polymer and a circumferential shell 22 of porous PEKK polymer. The shell 22 has a thickness 23 of about 8% of the diameter 10 of the base section 2 (and implant 1). The base section 2 further extends between a top surface 24 and a bottom surface 25, and comprises a layer 26 of porous PEKK polymer, which layer 26 is adjacent to the top surface 24 and has a thickness 27 of about 8% of the height 20 of the base section 2. The pores of the PEKK polymer in the layer 26 comprise the biocompatible poly-urethane-bisurea-hexylenecarbonate which originates from the middle section 3 and has infiltrated the pores of the PEKK polymer in the layer 26 during manufacturing. A method for manufacturing the implant will be elucidated further below. As with the embodiment of figure 1A, the implant 1 is cylindrical and has a diameter 10 of 6 mm. The height 20 of the base section 2, the height 30 of the middle section 3, and the height 40 of the top section 4 add up to a total height of 7 mm.

Figure IC schematically represents a side view of yet another embodiment of an implant according to the present invention. The embodied implant 1 in the shape of a plug again comprises a base section 2, configured for anchoring in bone tissue, a middle section 3 configured for replacing cartilage tissue, and a top section 4 configured for growing cartilage tissue onto and into. The middle section 3 and top section 4 comprise the same poly-urethane-bisurea-hexylenecarbonate material, which is porous in the top section 4, and substantially non-porous in the middle section 3. Similar to the embodiments shown in figures 1A and 2A, the present embodiment has channels 42 in the top section 4. The base section 2 comprises a substantially non-porous PEKK polymer with a porosity of less than

20 %, relative to the total volume of the PEKK polymer. The base section 2 of this embodiment in particular extends between a top surface 24 and a bottom surface 25, and comprises a layer 26 of porous PEKK polymer, which layer 26 is adjacent to the top surface 24 and has a thickness 27 of about 8% of the height 20 of the base section 2. The pores of the PEKK polymer in the layer 26 comprise the biocompatible poly-urethane- bisurea-hexylenecarbonate which originates from the middle section 3 and has infiltrated the pores of the PEKK polymer in the layer 26 during manufacturing. The middle section 3 of this embodiment in particular comprises a core 31 of non-porous poly-urethane-bisurea- hexylenecarbonate polymer and a circumferential shell 32 of porous poly-urethane- bisurea-hexylenecarbonate polymer. The shell 32 has a thickness 33 of about 8% of the diameter 10 of the middle section 3 (and implant 1). The base section 2 further extends between a top surface 24 and a bottom surface 25, and comprises a layer 26 of porous PEKK polymer, which layer 26 is adjacent to the top surface 24 and has a thickness 27 of about 8% of the height 20 of the base section 2. The dimensions and shape are the same as in the embodiments of figures 1A and 1B.

Figure 1D schematically represents a side view of yet another embodiment of an implant according to the present invention. The embodied implant 1 in the shape of a plug corresponds to the one shown in figure 1C. In addition, the middle section 3 of this embodiment now has a circumferential shell 32 of porous poly-urethane-bisurea- hexylenecarbonate polymer having a thickness 33 of about 10% of the diameter 10 of the middle section 3 (and implant 1). Similar to the embodiments shown in figures 1 A-3A, the present embodiment has channels 42 in the top section 4, and the circumferential shell 32 may also provide channels 41. Further, the base section 2 comprises a layer 26 of porous PEKK polymer, which layer 26 is adjacent to the top surface 24 and has a thickness 27 of about 5% of the height 20 of the base section 2. The pores of the PEKK polymer in the layer 26 comprise the biocompatible poly-urethane-bisurea-hexylenecarbonate which originates from the middle section 3 and has infiltrated the pores of the PEKK polymer in the layer 26 during manufacturing. The base section 2 further comprises a core 21 of non- porous PEKK polymer and a circumferential shell 22 of porous PEKK polymer. The shell 22 has a thickness 23 of about 5% of the diameter 10 of the base section 2 (and implant 1). Finally, the base section 2 also comprises a layer 28 of porous PEKK polymer, which layer 28 is adjacent to the bottom surface 25 and has a thickness 29 of about 5% of the height 20 of the base section 2. The dimensions and shape are the same as in the embodiments of figures 1A to IC. Please note that in figures 1B, 1C, and 1D the circumferential shells (22, 32) are shown in cross-section to show their respective thicknesses (23, 33). In a side view, they would extend over the complete diameter 10 of the implant 1. Referring to figure 7A, a side view of another embodiment of the implant according to the present invention is shown. The implant 1 in the shape of a plug comprises the same materials and sections as shown in figure 1A. The dimensions of the implant of figure 7A are the same as those of the implant of figure 1A with one exception. Instead of having a flat top surface 41 of the top section 4 (and the implant 1), as in figure 1A, the top surface 41a of the top section 4 is spherical with a radius of curvature R of about 28 mm (not drawn to scale).

Referring to figure 7B, a side view of another embodiment of the implant according to the present invention is shown. The implant 1 in the shape of a plug comprises the same materials and sections as shown in figure 1B. The dimensions of the implant of figure 7B are the same as those of the implant of figure 1B with one exception. Instead of having a flat top surface 41 of the top section 4, as in figure 1B, the top surface 41a of the top section 4 is spherical with a radius of curvature R of about 28 mm (not drawn to scale). Referring to figure 7C, a side view of another embodiment of the implant according to the present invention is shown. The implant 1 in the shape of a plug comprises the same materials and sections as shown in figure 1C. The dimensions of the implant of figure 7C are the same as those of the implant of figure 1C with one exception. Instead of having a flat top surface 41 of the top section 4, as in figure IC, the top surface 41a of the top section 4 is spherical with a radius of curvature R of about 28 mm (not drawn to scale). Referring to figure 7D, a side view of another embodiment of the implant according to the present invention is shown. The implant 1 in the shape of a plug comprises the same materials and sections as shown in figure 1D. The dimensions of the implant of figure 7D are the same as those of the implant of figure 1D with one exception. Instead of having a flat top surface 41 of the top section 4, as in figure 1D, the top surface 41a of the top section 4 is spherical with a radius of curvature R of about 28 mm {not drawn to scale). Again note that in figures 7B, 7C, and 7D the circumferential shells (22, 32) are shown in cross-section to show their respective thicknesses (23, 33). In a side view, they would extend over the complete diameter 10 of the implant 1 (not drawn to scale). Referring to figures 2A to 2D, an embodiment of a base section 2 of the invented implant 1 is schematically shown. The base section 2 shown is essentially cylindrical-shaped with a diameter 10, and a height 20. The top surface 24 of the base section has a circumferential tlat rim part 240 that gradually extends into a centrally located cavity 241. The cavity 241 is provided with locking parts 242 that have a larger diameter than the diameter of the cavity 241. A shown in detail in figure 2C, the locking parts 242 of the cavity 241 are disk- shaped whereby the outer rim of the disk makes an angle 246 with the longitudinal direction 247 of the base section 2 of between 1° and 20°, more preferably between 5° and 15°. The cavity 241 (and parts 242) during manufacturing of the implant fills with part of the biocompatible elastomeric material to provide an adequate locking of the middle section 3 to the base section 2. As discussed above, the base section 2 comprises a PEKK polymer which may be non-porous or substantially non-porous, the latter embodiment including the examples disclosed above. The base section 2 is further seen to comprise an outer surface having irregularities or undulations. In the present embodiment, these comprise circumferential ridges 243 which, in cross-section, are saw-tooth-shaped, as shown in detail in figure 2D. The angle 244 under which the saw-tooth flanks extend with respect to the transverse direction 245 of the base section 2, is preferably between 70° and 85°, more preferably between 75° and 80°.

PREPARATION OF THE ELASTOMERIC MATERIAL OF THE TOP AND MIDDLE

SECTION The aliphatic poly-urethane-urea-hexylene carbonate biomaterial of the middle section 3 and the top section 4 was manufactured as follows (with reference to figure 3). Poly(hexylene carbonate) diol (23.9 g, 11.9 mmol) was weighed in a 500 mL 3-necked flask and dried by heating to 75 °C overnight under vacuum, after which it was allowed to cool to room temperature.

Under an argon atmosphere, 1,6-diisocyanatohexane (4.1 g, 23.9 mmol), DMAc (20 mL) and a drop of Sn(Il)bis(2-ethylhexanoate) were added, after which the mixture was heated and stirred for 3 hours upon which the viscosity increased.

The mixture was allowed to cool to room temperature, was diluted with DMAc (100 mL) and a solution of 1,6-diaminohexane (1.4 g, 11.9 mmol) in DMAc (50 mL) was added at once under thorough mixing.

A gel was immediately formed upon addition and mixing.

The mixture was further diluted with DMAc (150 mL) and was heated in an oil bath of 130 °C to acquire a homogeneous viscous slurry.

After cooling to room temperature, the mixture was precipitated in a water/brine mixture (2.75 L water + 0.25 L saturated brine) to yield a soft white material.

This material was cut into smaller pieces and was stirred in a 1:5 mixture of methanol and water (3 L) for 64 hours.

After decanting the supernatant, the resulting solid was stirred in a 2:1 mixture of methanol and water (0.75 L) for 6 hours.

Decanting of supernatant, stirring in a 2:1 mixture of methanol and water (0.75 L) for 16 hours, decanting of the supernatant, and drying of the solid at 70 °C in vacuo yielded a flexible, tough elastomeric polymer. '"H NMR spectroscopy was performed on the resulting polymer, using a Varian 200, a Varian 400 MHz, or a 400 MHz Bruker spectrometer at 298K.

DSC was performed using a Q2000 machine (TA Instruments). Heating scan rates of 10 °C/min and 40 °C/min were used for the assessment of the melting temperature (Tm) and the glass transition temperature (Tg), respectively.

The Tm was determined by the peak melting temperature and the Tg was determined from the inflection point.

All reagents, chemicals, materials, and solvents were obtained from commercial sources and were used without further purification.

The used poly{hexylene carbonate) diol had an average molecular weight of approximately 2 kg/mol.

Figures 4 and 5 show the "H NMR spectrum and DSC thermograms of the obtained polymer, respectively.

The 'H NMR spectrum results may be summarized as follows: 'H NMR (400 MHz, HFIP-d2): 6 =4.23 (m, n*4H, n ~ 14.3), 4.10 (m, 4H), 3.17 (mm, 12H), 1.87-1.32 (multiple signals for aliphatic CH2 methylenes) ppm.

The average molecular weight of the repeating hard/soft block sections 1s about 2.5 kDa.

The DSC results may be summarized as follows: DSC (10 °C/min, figure SA): Tm (top) = 20.9 °C (soft block melt); DSC (40 °C/min, figure 5B): Tg =-38.0 °C.

No second melting point for the hard block was observed up to 200 °C.

However, in a final heating run up to 250 °C at 10 °C/min (figure 5C), a small and broad melting transition was observed at ca. 227 °C. In the DSC-diagrams, the endothermic melting peaks are plotted downwards, whereas the exothermic crystallizations are plotted upwards.

The non-porous aliphatic poly-urethane-urea-hexylene carbonate biomaterial had an elastic modulus according to ASTM D638 of 3.6 = 0.03 MPa. PREPARATION OF BIOMATERIAL-CAPPED PEKK BONE ANCHORS The implant 1 was manufactured by attaching the top and middle sections (4, 3) to a PEKK base section 2 which serves as bone anchor. In a method according to an embodiment of the invention, PEKK bone anchors were capped with the poly-urethane-urea-hexylene carbonate biomaterial by pressing small granules of the aliphatic polycarbonate polymer on top of and into the PEKK anchors. For this purpose, a custom press setup was used. According to an embodiment of the invented method, a male mold part in the form of a plunger 9 is provided. The male mold plunger 9 has a base part 90, a flattened cylindrical part 91, and a pressure part 92, a surface 93 whereof is provided with a plurality of pins 94 that protrude from the surface 93. As shown in the top view of figure 10A, the embodiment shown has 128 pins 94 regularly distributed over the circular surface 93, having a diameter of about 9.7 mm. The pins 94 have a diameter of about 0.4 mm, and contact each other with their base. As shown in figure 11, each pin 94 has a broader base part 94a and a cylindrical smaller top part 94b with a diameter of about 0.37 mm. The height of the smaller top part 94b is about 0.50 mm. In a suitable method, and referring to figures 12A, 12B, 13A, 13B and 14, a compression molding set-up 6 according to an embodiment of the invention is used. The set-up 6 comprises a pair of bottom plates (60a, 60b) and a pair of top plates (61a, 61b), movable in a vertical direction 62 along 4 guiding pins 63. A central cylindrical part 64, provided between the plates (60b, 61b) has a central cavity 64a and serves a female mold part. The male mold part 9 fits inside the cavity 64a and may be pressurized by the top plates (61a, 61b), or by other means. The cylindrical part 64 may be attached to the plates 60b and 61b by screw connections 65. In figure 12A, a base section 2 is shown to be provided in the cavity 64a. The base section 2 is supported by a support pin 66 that extends between the bottom plate 60a and an underside of the base section 2. As shown in figure 14, a thermocouple 67 may be used to monitor the temperature inside the female mold part 64. The female mold part 64 may conveniently be heated by providing a heating jacket around the cylindrical part {or female mold part) 64. Other methods of heating are also possible. Figures 13A and 13B respectively show a sectional view along the line A-A and C-C of the compression molding set-up 6 shown in figures 12A and 12B. Figure 14 schematically shows a detail D of the compression molding set-up 6 shown in figure 13A. The female mold or cylindrical part 64 has a central cavity 64a that is about the shape of the base section 2 that is shown in figure 2 and that was molded and/or CNC milled before (pre-formed). This PEKK base section 2 is first provided in the cavity 64a of the female mold part 64. Top section 4 material in the form of granulate of the non-porous aliphatic poly-urethane-urea-hexylene carbonate biomaterial is then provided in the cavity of the female mold part on top of the base section 2. At least the female mold part is then heated by conventional means to heat, and possibly soften, the PEKK base section 2 and top section 4 materials. The male mold plunger 9 is then brought under pressure into the filled cavity 64a of the female mold part 64 to compress the PEKK base 2 and top section 4 materials present in the female mold part. In this process, the surface 93 from which the plurality of pins 94 protrude contacts the top section 4 material and channels 42 that conform to the pins 94 are produced in the top section 4 material that together define a porous top section 4. The height over which the channels 42 extend into the top section 4 material depend on the height of the pins 94, which in the example shown is 0,50 mm. The height of the channels 42 corresponds and defines the height 40 of the porous top section

4. In case the height of the pins 94 does not extend completely into the top section material, a middle section 3 ensues that is essentially channel-free. In another embodiment, a middle section 3 is first compression molded onto the base section 2 before, in a separate step, adding top section material 4 to produce the porous top section 4. The former step of compression molding is sustained until the base 2 and top section 4 (or middle section 3) materials have sufficiently adhered to each other. Thereafter, the male mold plunger 9 is removed from the cavity of the female mold part, and at least one of the female or male mold part is cooled actively or passively, for instance by taking it out from a heated pressurizing means. Finally, the consolidated plug 1 is taken out of the female mold part.

Various temperatures (100 °C to about 150 °C), compressive forces (20 kN to about 40 kN) and methods may be used in the invented method. Good results may be obtained using a two-step procedure, employing a temperature of 150 °C and using a compressive force of 40 kN (4 tons, or 4000 kg; corresponding to a pressure of 1.4 GPa). Lower temperatures than 150 °C seemed to give less homogenously pressed poly-urethane-urea-hexylene carbonate biomaterial layers (sections 3 and 4), while higher temperatures are less desired as the urea groups in the poly-urethane-urea-hexylene carbonate biomaterial may then degrade to some extent. In a first step, ca. 50 mg of the polymer 12 was pressed onto and into the PEKK bone anchor for 15 minutes, while in a second step, ca. 2 mg of polymer 12 was added to the setup and the sample was pressed for another 15 minutes under the same conditions (150 °C and 40 kN). The samples were subsequently removed from the compression setup and were then allowed to cool. After the second pressing step, the surface of the poly-urethane-urea-hexylene carbonate biomaterial layer (sections 3 and 4) on top of the base section 2 seemed to be substantially flat. The biomaterial was almost transparent and colorless.. A central hole (241, 242) of the base section 2 was about 4.5 mm deep and about 2 mm in diameter. The hole was substantially filled with the poly-urethane-urea-hexylene carbonate biomaterial, and the attachment of the biomaterial to the PEKK base section 2 seemed quite strong and robust. Removing the biomaterial from the PEKK base section by force, or loosening the connection at the PEKK -biomaterial interfaces, proved practically impossible. All used equipment and accessories that were intended to come into contact with the PEKK base section 2 and/or with the elastomeric biomaterial were rinsed with ethanol or isopropanol and were thereafter dried. After pressing, and cutting the frays, the PEKK-biomaterial plug implant was rinsed with isopropanol and dried. The plugs may also be produced in a sterilized environment, if needed.

As assessed by measuring, the PEKK base section was 6 mm in diameter and 6 mm tall (a height of 6 mm). The central cavity in the base section was about 2 mm in diameter and about 4.5 mm deep. The elastomeric biomaterial (the aliphatic polycarbonate) positioned onto the PEKK base section was about 6 mm in diameter and about 1 mm high.

Accordingly, the total PEKK-biomaterial plug implant was about 7 mm tall. The porous (provided with the channels 41) aliphatic poly-urethane-urea-hexylene carbonate biomaterial of the top section 4 had an elastic modulus according to ASTM D638 of 2.60 + 1.4 MPa.

The implant 1 may be implanted into an osteochondral defect 8 as shown in figures 6A to 6C. In a typical method, a cartilage defect extending into the subchondral bone (figure 6 A) is drilled out and a plug-shaped implant 1 is implanted into the drilled hole under some pressure (‘press fit’), as shown in figure 6B. Bone then grows onto, and in some embodiments into, the PEKK base section 2, anchoring the implant 1. Surrounding native cartilage 5 grows onto a top side 41 of the top section 4 and new cartilage 5a is generated on top of the implant 1, as shown in figure 6C. As is also shown in figure 6C, the height 20 of the base section 2, the height 30 of the non-porous middle section 3, and the height 40 of the porous top section 4 are selected such that a top surface 41 of the implant 1 comes to lie below a top surface 50 of cartilage 5 present on an osteochondral structure (5, 6) when implanted, preferably over a distance 51 of between 0.1 - 1 mm. In the present case, this distance was about 0.5 mm. The osteochondral structure (5, 6) comprises subchondral bone 6 and a cartilage layer 5 on top of it. A synovial cavity 7 is generally also present.

As also shown in figures 6B and 6C, the height 20 of the base section 2, the height 30 of the non-porous middle section 3, and the height 40 of the porous top section 4 are selected such that a bottom surface 24 of the middle section 3 (or top surface 24 of the base section 2) comes to lie about level with a bottom surface 51 of the cartilage layer 5 of the osteochondral structure (5, 6) when implanted.

Finally, the implant according to the embodiment shown in figures 7A to 7D may also be implanted into an osteochondral defect 8 as shown in figures 8A to 8C. Due to a spherical top surface 41a of the top layer 4, this embodiment may regenerate a new cartilage layer 5a on the top surface 41a of the top section 4 of the implant 1 of about equal thickness across the top surface 41a. The result may be a radius of a top surface 50 of the regenerated cartilage Sa that is about the same as the radius of the surrounding native cartilage layer 5 next to the implant, thereby showing continuity in radius.

It will be apparent that many variations and applications are possible for a skilled person in the field within the scope of the appended claims of the invention.

Claims

CONCLUSIONS

A method of manufacturing a non-biodegradable implant in the form of a plug for replacing and regenerating biological tissue, comprising a base section adapted for anchoring in bone tissue and an upper section adapted for replacing cartilage tissue of an intermediate and deep zone of the cartilage layer, and for ingrowth and growth of cartilage tissue, thus regenerating a superficial zone of the cartilage layer, the method comprising the successive steps of: a) providing a female mold part and a male mold part, wherein the male mold part has an amount includes pins projecting from a surface thereof; b) providing base section material in a cavity of the female mold part; c) providing top section material on top of the base section material in the cavity of the female mold part; d) heating at least one of the female or male mold part to soften at least one of the base and top section materials; e) pressurizing the male mold part into the filled cavity of the female mold part to compress the base and top section materials contained in the female mold part, wherein the surface from which the plurality of pins protrude comes into contact with the top section material and channels in the top section material in the form of the pins, the channels together forming a porous top section; f) continuing step e) until the base and top section materials are sufficiently bonded together; g) removing the male mold part from the cavity of the female mold part; h) cooling at least one of the female or male mold part; and 1) taking out the consolidated plug from the female mold part.

The method of claim 1, wherein, prior to step a), a waist section material is provided on the base section material with a smooth male mold portion not including a plurality of pins protruding from a surface thereof, the method comprising

- providing a female mold part and the smooth male mold part: - providing base section material in a cavity of the female mold part; - providing waist section material on top of the base section material in the cavity of the female mold part; - heating at least one of the female or smooth male mold part to soften at least one of the base and middle section materials; - pressurizing the smooth male mold part into the filled cavity of the female mold part to compress the base and middle section materials contained in the female mold part; - continuing step e) until the base and middle section materials are sufficiently bonded together; wherein, optionally, the top section material and the middle section material are substantially the same.

The method of claim 1 or 2, wherein the pins in the plurality of pins are mutually aligned, producing substantially parallel channels in the top section of the implant.

A method according to claim 1, 2 or 3, wherein the surface of the male mold part extends substantially parallel to the top surface of the implant.

A method according to any one of the preceding claims, wherein the pins have a variable length.

A method according to any one of the preceding claims, wherein the pins have the same length, and the length is less than a height of the top section.

A method according to claim 5 or 6, wherein the length of the pins extends from 300-1000 µm, more preferably from 400-800 µm, and most preferably from 450-550 µm.

A method according to any one of the preceding claims, wherein a diameter of the pins extends from 200-500 µm.

The method of claim 8, wherein the diameter at a base of a pin is greater than a top of the pin.

A method according to any one of the preceding claims, wherein the areal density of the pins per area ranges from 5-30 pins/mm 2 , more preferably from 8-20 pins/mm), and most preferably from 10-15 pins /mm”.

Il. Method according to any one of the preceding claims, wherein at least the female mold part is heated to a temperature between 120-200°C, more preferably between 150-170°C.

A method according to any one of the preceding claims, wherein the male mold part is pressurized to a pressure between 0.20-1.00 kN/mm', more preferably between

0.40-0.60 kN/mm'.

A method according to any one of the preceding claims, wherein step e) is maintained for 5-50 min, more preferably for 10-40 min, and most preferably for 15-30 min.

A method according to any preceding claim, wherein the top section material comprises a thermoplastic elastomeric material comprising a linear block copolymer comprising urethane and urea groups, wherein the thermoplastic elastomeric material optionally further comprises carbonate groups.

The method of claim 14, wherein the thermoplastic elastomeric material comprises a polyurethane-bisurea-alkylene carbonate.

A method according to any preceding claim, wherein the base section material comprises one of a biocompatible metal, a ceramic material, a mineral material, such as a phosphate mineral, and a polymer, optionally a hydrogel polymer, and combinations thereof.

A method according to any one of the preceding claims, wherein the base section material comprises a non-hydrogel polymer, preferably comprising a polyaryletherketone polymer, such as polyetherketoneketone (PEKK), polyetheretherketone (PEEK), and polyetherketoneetherether. ketone-ketone (PEKEKK).

A method according to any one of the preceding claims, wherein the base section material is substantially non-porous with a porosity of less than 20% relative to the total volume of the base section material.

A method according to any one of the preceding claims, wherein a side wall of the female mold part comprises a surface with irregularities or undulations.

A method according to any one of the preceding claims, wherein the surface of the male mold part from which the plurality of pins protrudes is slightly curved, and has a radius of curvature in a sagittal plane and/or a medial-lateral plane of 15 mm to 150 mm.

A method according to any one of the preceding claims, wherein the top and/or base section material is provided in the form of granulate.

A method according to any preceding claim, wherein the base section material is provided in a solid shape conforming to the cavity of the female mold part.

A non-biodegradable implant for replacing and regenerating biological tissue in the form of a plug, comprising a base section adapted for anchoring in bone tissue, and an upper section adapted for replacement of cartilage tissue of an intermediate and deep zone of the cartilage layer, and for ingrowth and growth of cartilage tissue, regenerating a superficial zone of the cartilage layer, wherein the upper section comprises a plurality of channels.

The implant of claim 23, wherein the plurality of channels are mutually aligned.

The implant of claim 23 or 24, wherein the plurality of channels extend substantially perpendicular to an upper surface of the implant.

An implant according to any one of claims 23-25, wherein the channels are of variable length.

An implant according to any one of claims 23-26, wherein the channels have the same length, and the length is less than a height of the top section.

An implant according to claim 26 or 27, wherein the length of the channels extends from 300-1000 µm, more preferably from 400-800 µm, and most preferably from 450-550 µm.

An implant according to any one of claims 23-28, wherein a diameter of the channels extends from 200-500 µm.

The implant of claim 29, wherein a base diameter at a base of a channel is less than the diameter of the porous channel near the top surface of the top section.

The implant of claim 29 or 30, wherein for any combination of two channels 1 and 2, the absolute value of (D 1 -D 1 )/D; <10%, more preferably <8%, most preferably <5%, wherein D; is the diameter of a channel i.

An implant according to any one of claims 23-31, wherein the areal density of the channels per surface ranges from 5-30 channels/mm 2 , more preferably from 8-20 channels/mm 2 , and most preferably from 10 - 15 channels/mm?.