WO2006026981A1 - Implant pour traiter des defauts osteo-chondraux et procede de production associe - Google Patents

Implant pour traiter des defauts osteo-chondraux et procede de production associe Download PDF

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Publication number
WO2006026981A1
WO2006026981A1 PCT/DE2005/001585 DE2005001585W WO2006026981A1 WO 2006026981 A1 WO2006026981 A1 WO 2006026981A1 DE 2005001585 W DE2005001585 W DE 2005001585W WO 2006026981 A1 WO2006026981 A1 WO 2006026981A1
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WO
WIPO (PCT)
Prior art keywords
implant
layers
matrix
bone
layer
Prior art date
Application number
PCT/DE2005/001585
Other languages
German (de)
English (en)
Inventor
Michael Gelinsky
Marlen Eckert
Original Assignee
Technische Universität Dresden
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Technische Universität Dresden filed Critical Technische Universität Dresden
Publication of WO2006026981A1 publication Critical patent/WO2006026981A1/fr

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    • A—HUMAN NECESSITIES
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3886—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells comprising two or more cell types
    • A61L27/3891—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells comprising two or more cell types as distinct cell layers
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    • A61L27/3839—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
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    • A61F2002/30891—Plurality of protrusions
    • A61F2002/30892—Plurality of protrusions parallel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/3094—Designing or manufacturing processes
    • A61F2002/30971—Laminates, i.e. layered products
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0063—Three-dimensional shapes
    • A61F2230/0069—Three-dimensional shapes cylindrical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0014—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0014—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis
    • A61F2250/0023—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis differing in porosity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0014—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis
    • A61F2250/0037—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis differing in height or in length
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00179—Ceramics or ceramic-like structures
    • A61F2310/00293—Ceramics or ceramic-like structures containing a phosphorus-containing compound, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00365—Proteins; Polypeptides; Degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • Implant for the treatment of osteochondral defects and process for its preparation
  • the invention relates to an implant for the treatment of osteochondral defects, and to a method for its production.
  • Osteochondral defects ie defects that involve both the articular cartilage and the bone directly beneath it, can arise in two ways: on the one hand by advanced inflammatory processes such as arthrosis, which have already damaged the bone next to the cartilaginous tissue, and on the other hand by injuries or far advanced wear.
  • Osteochondral defects are also partly consciously produced by the doctor for therapeutic reasons: since a pure cartilage implant can hardly be anchored in the cartilage layer of the joints, which is only 2 mm to 5 mm thick, sometimes not only the damaged cartilage tissue is removed, but the defect as well intentionally enlarged in the direction of the underlying bone, in order then fix an implant then better.
  • both implants derived from natural tissue and implants with tissue replacement materials are used.
  • tissue engineering in the first step an extracellular structure-imitating matrix with many cavities of preferably biodegradable materials is created, the cavities of which are then colonized in the next step with predominantly autologous cells and filled by creating appropriate growth conditions. It is also known to immobilize cells in gelatinous carrier materials. Matrix material and cells are specifically selected according to whether a bony or a cartilaginous tissue is to be implanted.
  • Implants to be used at the interface of two or more different tissue types are optimally biphasic or polyphasic in order to meet the requirements of all the respective surrounding tissues with which the implant comes into contact.
  • Previously known biphasic implant materials for osteochondral defects each consist of two completely different material components, which are then assembled to form a workpiece.
  • ß-TCP porous Calcium phosphate ceramics
  • gels used for cartilage matrix.
  • the problem with these composite implants is the connection of the different components. According to the prior art, this z. As by gluing with fibrin glue, which, however, is not equal to the occurring in the joint Scherbelasronne in the long run.
  • a bone-cartilage implant which consists of a plurality of rods regularly arranged in a grid.
  • the connection of the lattice structures happens on the one hand by gluing and on the other hand by fusing or welding of the mesh materials. The latter creates a firmer bond, but requires appropriate materials.
  • a biphasic implant is described.
  • a chamber is closed on one side by a porous bone matrix.
  • the chamber is populated with cartilage cells.
  • the cartilage cells grow into the bone matrix.
  • the colonization with the cartilage cells must be done before the operation.
  • the object of the invention is to specify an implant for the treatment of osteochondral defects in which the bone and cartilage matrix are firmly connected to one another.
  • an implant having at least two superimposed layers, including a porous bone matrix and a porous cartilage matrix, wherein the layer materials are locally mixed at the interfaces of the contacting layers.
  • the local mixing causes the layers to intermesh at their points of contact down to the molecular level.
  • the layer materials penetrate.
  • comparatively similar linkages of the matrix molecules are present as within the layers.
  • the compound is also resilient to shear forces.
  • Such an implant with at least two layers, including a porous bone and a porous cartilage matrix is produced according to the invention with the steps of a) producing the individual layers or the respective layer material, wherein at least one layer or a layer material with a solvent which at least the Can dissolve surfaces of the other layers, is converted into a pasty or liquid state, b) superimposing or layers of the layers or layer materials and c) freeze-drying of the composite.
  • the layers are at least partially in flowable or pasty form and contain a solvent that can also dissolve the surface of the adjacent layer, the layers mix locally at the contacting interfaces.
  • the solvent of the layers is selected so that during freeze-drying, i. H. by applying a vacuum to the frozen material, passes directly from the frozen state to the gaseous state.
  • acetic acid and cyclohexane are further preferred solvents.
  • the pore size of the matrix layers is preferably adjusted by freezing. By freeze-drying, pores remain at the points where solvent crystals were contained in the frozen state.
  • a sponge-like, foam-like material is formed which contains a plurality of randomly distributed pores arranged in an outwardly open pore system. (See M. Gelinsky, U. König, A. Sewing, W. Pompe: Porous scaffolds of mineralized collagen - a biomimetic bone substitute material., Materials Science., 2004, 35, 229-233).
  • the implant can advantageously be shaped as desired and thus adapted in its outer geometry to the size and structure of the bone and cartilage tissue to be replaced.
  • the implant according to the invention is elastic in the wet state and thus adapts to the defect geometry, which guarantees good contact between the tissues and the implant material.
  • the elasticity allows precultivation with cells under cyclic mechanical stimulation. Its compressive strength is higher than that of conventionally produced, uncrosslinked collagen sponges of comparable porosity, the pores of which usually collapse when moistened; It is therefore preferably used for the therapy of minor to moderate defects.
  • an implant with cylinder geometry with a 30% uniaxial compression in the direction of the cylinder axis preferably has an E-mode of 10-40 kPa, more preferably 15 to 25 kPa.
  • the implant is porous, with outwardly open and interconnecting pores, preferably completely resorbable, and may be either cell-free or in vitro pre-populated with one or more cell types.
  • the average pore size is preferably at least 80 .mu.m, more preferably 100 to 200 .mu.m, a diameter which is optimal for colonization with cells.
  • Bone content and cartilage proportion preferably have a comparable porosity (same average pore size, distribution of pores).
  • resorbable material is meant here and in the following text that the material is slowly degraded after implantation in the body by biological or chemical processes or slowly dissolves. Partial absorption of the material may also be used during cell culture in vitro.
  • the implant is fully resorbed in the body within 3 to 24 weeks, preferably between 4 and 8 weeks, and converted into living tissue.
  • the non-mineralized portion of cartilage replacement is preferably populated with autologous cartilage cells (chondrocytes).
  • the bone content is in a particular embodiment pre-colonized with autologous bone cells (osteoblasts) or autologous mesenchymal stem cells of the patient.
  • the bone matrix consists essentially of fibrillar collagen type I, which is preferably mineralized with calcium phosphate, more preferably with hydroxyapatite (HAP) - and thus mimics the composition of the extracellular matrix of the bone tissue.
  • fibrillar collagen type I which is preferably mineralized with calcium phosphate, more preferably with hydroxyapatite (HAP) - and thus mimics the composition of the extracellular matrix of the bone tissue.
  • the mineralized collagen is preferably prepared by the process already known from EP0945146 or EP0945147.
  • the cartilage matrix preferably consists of fibrillar, non-mineralized collagen type I and / or collagen type II or hyaluronic acid or hyaluronic acid derivatives or of a composite of collagen and hyaluronic acid or hyaluronic acid derivatives and optionally other constituents of the extracellular cartilage matrix, such as chondroitin sulfate, dermatan sulfate , Keratan sulfate and / or heparan sulfate.
  • the composite of fibrillar collagen and hyaluronic acid is formed in that the hyaluronic acid is present during fibrillogenesis of the collagen and thus at least partially incorporated into the collagen fibrils forming during fibrillogenesis.
  • the collagen for the bone matrix is preferably Type I which has been recombinantly produced as human collagen or isolated from bovine tendons or other animal sources and is approved for clinical use.
  • an acid-soluble collagen is selected, such as. B acid-soluble bovine collagen I from the manufacturer Syntacoll (Saal / Danube, Germany).
  • the collagen for the cartilage matrix is preferably type I or II or a mixture of both types. It is also preferably recombinantly produced as human collagen or isolated from calf skin or other animal sources and should be approved for clinical use, such as the product Collaplex 1.0 from the manufacturer GfN (Waldmichelbach, Germany).
  • the hyaluronic acid for the cartilage matrix is preferably one produced by microorganisms (eg Streptococcus equi).
  • the term hyaluronic acid also includes its salts, such as.
  • Preferred hyaluronic acid derivatives are hyaluronic acid esters (eg benzyl esters).
  • the implant lies between the layers for the bone substitute and for the cartilage replacement a film-like, resorbable biopolymers existing pore-less or -arme intermediate layer.
  • the intermediate layer preferably consists of a biopolymer which is dissolvable at least on the surface by the solvent of the layers for the bone substitute and the cartilage replacement.
  • the materials of the contacting layers are also locally mixed at the respective interfaces.
  • the intermediate layer consists of a film of hyaluronic acid or hyaluronic acid Drivaten or a film of another glycosaminoglycan, such as.
  • the intermediate layer is preferably dried in air.
  • it is largely pore-free and thus impermeable to chondrocytes and / or osteoblasts or mesenchymal stem cells. It thus fulfills a dual function. In terms of strength of the implant connects them and in terms of ingrowth of the cells acts as a release layer.
  • the implant includes a support structure with openings.
  • the support structure stiffens the implant.
  • the layer materials can touch each other directly and also mix locally
  • a two- or three-dimensional embroidery of resorbable and biocompatible polymer fibers preferably of poly-L-lactide, poly-DL-lactide, polyglycolide, polyhydroxybutyrate or copolymers thereof is used as the support structure.
  • the support structure is ordered from a fiber-flocked support material according to DE 103 12 144.7, wherein the distance between the flock fibers must be dimensioned so that the liquid matrix materials can completely fill the interstices.
  • the preferred spacing of the fibers is approximately 200-1000 ⁇ m.
  • the parallel arrangement of the flock fibers achieves mechanical stabilization in the direction of the fibers.
  • Preferred materials for the fibers are polyhydroxybutyrates or polylactides, and gelatin is preferably used as the adhesive.
  • the carrier material according to DE 103 12 144.7 preferably consists of a layer of a base material which is flocked on one side with fibers.
  • the base material itself consists of a tape of mineralized collagen and forms the lowest layer of the bone replacement portion.
  • the porous bone substitute material portion is preferably on the mineralized collagen tape and surrounds the fibers, but preferably only the lower part or ends (i.e., the ends of the fibers bonded to the base material).
  • the cartilage replacement share layer preferably adjoins the bone substitute material portion layer in such a way that some of the fibers or the tips of the fibers still protrude into the cartilage matrix.
  • the bone replacement component and / or the cartilage replacement component contain active substances, such as, for example, As pharmaceutical substances, amino acids or amino acid derivatives, peptides, proteins, growth factors, cytokines, antibodies, oligonucleotides, cDNA, DNA fragments, nucleic acids or nucleic acid derivatives.
  • active substances such as, for example, As pharmaceutical substances, amino acids or amino acid derivatives, peptides, proteins, growth factors, cytokines, antibodies, oligonucleotides, cDNA, DNA fragments, nucleic acids or nucleic acid derivatives.
  • the method can easily implants in any shape and size and thus - for the production of implants for osteochondral defects - also produce an individual thickness ratio of bone replacement and cartilage replacement.
  • the stacking is preferably done by pouring over in a three-dimensional container.
  • the matrix materials are preferably present in pasty or liquid form.
  • the geometry and size of the implant are determined by the geometry and size of the container used for stacking the layers, which can advantageously be shaped as desired.
  • both the frozen body (before lyophilization) and the freeze-dried implant can be machined by cutting, milling, drilling, or the like, and thus advantageously further adjusting the size and shape of the implant.
  • the microstructure of the pores, in particular the pore size, of the implant is dependent on the size of the solvent crystals formed during the freezing. This can be advantageously adjusted by the speed and temperature of the freezing. Pores having an average diameter of 100 to 250 ⁇ m, which is optimal for ingrowth of cells, are advantageously formed by slow freezing at -5 ° C to -50 ° C, preferably -15 ° C to -35 ° C. The slow freezing is achieved, for example, by placing the stacked bone substitute portion and the cartilage replacement portion, or the container containing it, in a freezer preheated to the corresponding temperature.
  • the microstructure of the pores is also influenced by the solvent content of the layers for the bone substitute fraction and the cartilage replacement fraction.
  • both layers preferably contain 75 to 98%, particularly preferably 80 to 90%, of solvent before freezing
  • the one layer is poured into a container and frozen.
  • the first (frozen) layer on the surface is then thawed.
  • the second layer then mixes locally with the thawed surface.
  • the second layer is either poured onto the thawed surface, or even slightly heated, so that the surface of the first layer is thawed by the superposition itself.
  • the frozen layer is adapted to the desired shape by cutting, milling, drilling or the like before the superimposing.
  • the implant obtained after lyophilization is chemically cross-linked to stabilize the layers in themselves by the introduction of chemical bonds and to firmly bond them together.
  • the introduction of chemical bonding is preferably done with a chemical crosslinker, such.
  • a chemical crosslinker such as glutaraldehyde or a carbodiimide derivative, particularly preferably with EDC (N-dimethylaminopropyl-N'-ethyl-carbodiimide hydrochloride).
  • EDC N-dimethylaminopropyl-N'-ethyl-carbodiimide hydrochloride
  • EDC N-dimethylaminopropyl-N'-ethyl-carbodiimide hydrochloride
  • a support structure preferably of resorbable and biocompatible polymer fibers (preferably of poly-L-lactide, poly-DL-lactide, polyglycolide, polyhydroxybutyrate or copolymers of these), are introduced into the implant.
  • a two- or three-dimensional fiber structure preferably produced by embroidering, is placed in the mold before filling in the first phase.
  • the pourable solution or suspension of the first phase is then over poured so that the spaces between the fibers are filled.
  • a slight negative pressure can be applied or briefly centrifuged.
  • the second phase is overcoated, the construct is frozen and freeze-dried.
  • the fiber structure can either be in the entire implant or only in one of the two phases.
  • the procedure is analogous: the carrier material, with the base material downwards, is placed in the mold in which the implant is to be produced. Then, as described, the two solutions or suspensions are successively überradagegossen. For a better penetration of the solutions or suspensions in the fiber interstices, a slight negative pressure can be applied or briefly centrifuged.
  • the flock fibers can either penetrate the implant in its entire height, or only a part of the same. In direct contact with the base material, either the bone replacement portion or the cartilage replacement portion may be present.
  • various methods can be used for the preparation of implants which have been functionalized with active ingredients.
  • the active ingredients can be added either one or both phases before stacking, or after the first freeze-drying (and thus before the chemical cross-linking).
  • the active compounds can be suspended in solid form in the solutions or suspensions or else applied as a solution to the freeze-dried implant.
  • Sensitive active substances, in particular growth factors, which could be impaired by the process steps in their biological activity, are preferably applied only after the chemical crosslinking and the second freeze-drying.
  • Another variant represents the functionalization of the implant with active ingredients directly before the operation: in this case, the active ingredient or the active ingredients are applied in sterile form to the likewise sterile implant, preferably as a solution dripped.
  • the bone replacement portion and the cartilage replacement portion can be functionalized in all cases either with the same active ingredients, or with different - or else only the bone or cartilage replacement portion is functionalized with one or more active ingredients.
  • Fig. 1 shows a schematic representation of an osteochondral defect A, in which both the articular cartilage B and the underlying (subchondral) bone C is affected.
  • FIG. 2 shows schematically on the left the construction of a biphasic implant for osteochondral defects with cylinder geometry, which is constructed from a cartilage matrix 1 and a bone matrix 2.
  • the cartilage matrix 1 consists of a collagen-hyaluronic acid composite, the bone matrix 2 of mineralized collagen.
  • the mineralized collagen is separated by centrifugation.
  • the gelatinous precipitate is stirred vigorously and then filled into suitable centrifuge tubes (eg metal cup for 200 ml or glass tube for 50 ml). It is centrifuged for 15 min at 2500 rpm in a refrigerated centrifuge (to prevent heating of the product) and then poured off the supernatant; 120 ml of the supernatant are stored for later use. Now refill the collagen suspension and repeat the centrifugation until all 2 liters have been treated appropriately. After the last time the supernatant is poured off, the pellets are removed from the tubes with a spatula and collected in a 125 ml beaker. While stirring with a heavy stirring fish just enough mother liquor is added dropwise until a pourable suspension is formed.
  • a suspension of collagen and hyaluronic acid with 20% by weight hyaluronic acid is first prepared.
  • hyaluronic acid hyaluronic acid sodium salt from Streptococcus equi, Fa. Fluka (Sigma / Aldrich, Taufkirchen) dissolved in 40 ml of deionized water and stirred for 1 h until a colorless, transparent suspension of high viscosity is formed.
  • acid-soluble collagen eg Collaplex 1.0, calfskin type I collagen isolated from GfN, Waldmichelbach
  • 1 g of acid-soluble collagen is added to 1 l of 10 mM HCl in an Erlenmeyer flask and dissolved with stirring (magnetic stirrer).
  • the flask is then placed in a heated to 37 0 C heat bath for about 14 h.
  • the resulting composite of fibrillar collagen and hyaluronic acid precipitates as an insoluble precipitate.
  • the suspension is stirred up, filled into suitable centrifuge glasses and centrifuged for 15 min at 2500 rpm. From the resulting supernatant about 100 ml are stored.
  • the pellets of the collagen-hyaluronic acid composite produced by the centrifugation are thoroughly stirred in a beaker with just enough supernatant (magnetic stirrer) until a homogeneous suspension which can be pipetted is formed.
  • the resulting porous, sponge-like scaffold is removed from the corrugated sheet and chemically cross-linked for one hour in a 1% solution of N-dimethylaminopropyl-N'-ethyl-carbodiimide hydrochloride (EDC) in 80% by volume of ethanol. Following the cross-linking, the scaffold is first thoroughly distilled. Water, then with a 1% aqueous glycine solution and finally again with dist. Washed water. Finally, the implant is frozen again and freeze-dried.
  • EDC N-dimethylaminopropyl-N'-ethyl-carbodiimide hydrochloride
  • Fig. 3 shows a light micrograph of a thin section in the longitudinal direction by - as described for Fig. 2 produced - implant (magnification 10 *).
  • the mineralized bone matrix 2 (top) is dark colored - the non-mineralized cartilage matrix 1 (bottom) is much brighter. It can be clearly seen that the matrix materials are directly connected to each other and penetrate each other at the interface 3. Both phases have a pore diameter of about 50-200 microns to a comparable porosity.
  • FIG. 4 shows a scanning electron micrograph (SEM) of a longitudinal section through an implant produced as described for FIG. 2 (magnification 15x).
  • the mineralized (appearing brighter) Knochematrix 2 part is on the left in the picture, the cartilage matrix 1 on the right. It is again clearly recognizable that the matrix materials are directly connected to one another and penetrate one another at the interface 3, wherein both layers have a comparable porosity.
  • FIG. 5 shows SEM element mapping of the interface between the mineralized bone matrix 2 (left) and the non-mineralized cartilage matrix 1 (right) of the implant fabricated as described with reference to FIG. 2.
  • the figures are each a detail of FIG (Magnification: 5Ox each).
  • the mineralized (appearing brighter) bone matrix 2 is located on the left side of the image, cartilage matrix 1 on the right.
  • a normal SEM image is shown (Fig. 5A).
  • the light coloration to be seen in the left-hand area of FIG. 5B detects the presence of atoms of higher order number. This light coloration is due to the calcium and phosphorus atoms of the calcium phosphate contained in the bone matrix.
  • Fig. 5 show the detection of calcium (lower left, Fig. 5C) and the lower right detection of phosphorus (Fig. 5D) individually.
  • the light color indicates calcium (FIG. 5C) or phosphorus (FIG. 5D).
  • Fig. 5 illustrates the only partial mineralization of the implant: the components of calcium phosphate (calcium and phosphorus) can be detected only in the mineralized bone matrix 2 (in the pictures on the left). The interface 3 is clearly visible only in FIGS. 5B-D.
  • Fig. 6 shows a detail of the interface between the non-mineralized cartilage matrix 1 (top) and the mineralized bone matrix 2 (bottom).
  • the figure shows a detail of Fig. 4 (magnification: 500x).
  • Fig. 4 (magnification: 500x).
  • Clearly visible are the bright appearing calcium phosphate crystallites in the lower part of the image, which characterize the mineralized phase and make their surface look rougher.
  • the above-mentioned cartilage matrix 1 consisting of a composite of collagen I and hyaluronic acid, on the other hand, has a smooth surface.
  • Fig. 7 shows an enlarged section of the direct contact area between the cartilage matrix 1 (top) and the mineralized bone matrix 2 (bottom) (magnification: 100Ox). The intimate connection of both phases in the area of the composite surface 3 can be clearly seen.
  • a sterile cylindrical biphasic implant having a diameter of 10 mm and a height of 6 mm (3 mm cartilage replacement and 3 mm bone replacement phase) for 24 hours in 5 ml of modified DMEM cell culture medium ( Gibco Life Technologies GmbH, Düsseldorf) and swelled, the medium is changed 4 times.
  • the implant is removed from the medium and placed on a sterile filter paper, so that the medium is largely sucked out of the porous structure.
  • 5 ⁇ 10 5 primary human chondrocytes, suspended in 200 ⁇ l of cell culture medium are pipetted onto the cartilage replacement phase located above. After 2 hours storage in the incubator, the colonized implants are transferred to a 24 well plate with fresh cell culture medium and cultured according to standard conditions until implantation.
  • suspensions of mineralized collagen or a collagen-hyaluronic acid composite are prepared as described under a.) And b.).
  • a hyaluronic acid film is produced by drying a saturated aqueous solution of hyaluronic acid sodium salt from Streptococcus equi (Fluka, Sigma / Aldrich, Taufkirchen) in air.
  • a hyaluronic acid solution is conveniently poured into a Petri dish.
  • 1 ml of the mineralized collagen suspension is pipetted into the well of a 24 well plate.
  • a suitably cut piece of the hyaluronic acid film is now placed on the suspension, whereupon in turn the suspension of the collagen-hyaluronic acid composite is pipetted. As described under c.), The resulting biphasic construct is frozen, freeze-dried, chemically cross-linked, washed and finally freeze-dried again.
  • Fig. 8 shows schematically the cross-section through such an implant, with 1 the cartilage matrix (top), with 2 the mineralized bone matrix (bottom) and 4 the Hyaluronklafolie referred to as a release layer.
  • a biphasic implant is produced by stacking two suspensions, with the difference that a bead of polyhydroxybutyrate threads is inserted into the latter before the first phase is filled into the mold provided for this purpose. For better penetration of the suspension in the interstices of the embroidery is centrifuged after pipetting up the two suspensions each for 5 min. For 1000 rev / min.
  • Fig. 9 demonstrates the schematic structure of such an implant in the form of a cross section through a cylindrical sample.
  • 1 is the cartilage matrix (top)
  • 2 is the mineralized bone matrix (below)
  • 5 is the polyhydroxybutyrate threads that penetrate both phases.
  • the procedure is analogous to that described under f.), If one intends to integrate a carrier material produced in accordance with DE 103 12 144.7 by means of flocking technology into the implant as a support structure.
  • the support material - consisting of a base material of a mineralized collagen membrane, an adhesive layer of gelatin and flock fibers of polyhydroxybutyrate - is placed, with the base material down, in the recess of a 24-well plate in which the implant is to be produced.
  • 1 ml of the two suspensions poured successively überrgicgegossen. For better penetration of the suspensions in the fiber interstices, as described in f.) Briefly centrifuged. Continue as described under c.) And f.).
  • FIG. 10 shows the result as a schematic longitudinal section, with 1 the cartilage matrix (top), with 2 the mineralized bone matrix (bottom), with 6 the base material (membrane of mineralized collagen), with 7 the adhesive layer (gelatin) and with the 8 Flock fibers (polyhydroxybutyrate) of the carrier material are designated.

Abstract

L'invention concerne un implant destiné à traiter des défauts ostéo-chondraux, ainsi qu'un procédé de production associé. Selon l'invention, l'implant comprend au moins deux couches superposées, une matrice osseuse (2) poreuse, située en dessous des deux couches et une matrice cartilagineuse (1) poreuse, les matériaux produisant les couches étant mélangés localement sur les surfaces limites des couches qui se touchent. La production de l'implant comprend les étapes suivantes : a) production de chaque couche ou de la matières de couches, au moins une couche ou un matériau de couche étant transportés dans un état liquide ou pâteux, par un milieu de solution, qui peut corroder les surfaces des autres couches, b) superposition des couches ou des matériaux pour les couches les uns sur les autres ; et c) lyophilisation de l'ensemble.
PCT/DE2005/001585 2004-09-07 2005-09-07 Implant pour traiter des defauts osteo-chondraux et procede de production associe WO2006026981A1 (fr)

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DE102004044102.2A DE102004044102B4 (de) 2004-09-07 2004-09-07 Implantat zur Behandlung von osteochondralen Defekten, sowie Verfahren zu dessen Herstellung
DE102004044102.2 2004-09-07

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Cited By (6)

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WO2009129285A1 (fr) * 2008-04-15 2009-10-22 Zimmer, Inc. Implants fibreux pour réparation ou remplacement d'un cartilage
USRE43714E1 (en) 1999-12-15 2012-10-02 Zimmer Orthobiologics, Inc. Preparation for repairing cartilage defects or cartilage/bone defects in human or animal joints
US8753406B2 (en) 2010-08-31 2014-06-17 Zimmer Inc. Osteochondral graft delivery device and uses thereof
EP3266418A3 (fr) * 2016-07-08 2018-05-23 Mako Surgical Corporation Échafaudage pour implant composite allo-prosthétique
GB2567173A (en) * 2017-10-04 2019-04-10 Univ Oxford Innovation Ltd Cartilage plug
WO2021146442A1 (fr) * 2020-01-14 2021-07-22 Musculoskeletal Transplant Foundation Greffes à éléments multiples permettant le traitement de défauts de tissu et leurs procédés de fabrication et d'utilisation

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DE102011002530A1 (de) * 2011-01-11 2012-07-12 Aesculap Ag Medizinisches Produkt und Verfahren zu seiner Herstellung, insbesondere zur regenerativen Behandlung von Knorpelschäden
DE102022209599A1 (de) 2022-09-14 2024-03-14 Resorba Medical Gmbh Knochenimplantat-Körper und Verfahren zu dessen Herstellung

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EP1277450A2 (fr) * 2001-06-28 2003-01-22 Ethicon, Inc. Matrice d'échafaudage composite avec tige d'ancrage pour la réparation et la régénération de tissu

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EP0505634A1 (fr) * 1991-03-29 1992-09-30 Kyocera Corporation Prothèse
DE19926083A1 (de) * 1999-06-08 2000-12-14 Universitaetsklinikum Freiburg Biologisches Gelenkkonstrukt
EP1277450A2 (fr) * 2001-06-28 2003-01-22 Ethicon, Inc. Matrice d'échafaudage composite avec tige d'ancrage pour la réparation et la régénération de tissu

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE43714E1 (en) 1999-12-15 2012-10-02 Zimmer Orthobiologics, Inc. Preparation for repairing cartilage defects or cartilage/bone defects in human or animal joints
WO2009129285A1 (fr) * 2008-04-15 2009-10-22 Zimmer, Inc. Implants fibreux pour réparation ou remplacement d'un cartilage
US8753406B2 (en) 2010-08-31 2014-06-17 Zimmer Inc. Osteochondral graft delivery device and uses thereof
EP3266418A3 (fr) * 2016-07-08 2018-05-23 Mako Surgical Corporation Échafaudage pour implant composite allo-prosthétique
EP3616653A1 (fr) * 2016-07-08 2020-03-04 MAKO Surgical Corp. Matrice pour implant composite allo-prosthétique
US11013602B2 (en) 2016-07-08 2021-05-25 Mako Surgical Corp. Scaffold for alloprosthetic composite implant
GB2567173A (en) * 2017-10-04 2019-04-10 Univ Oxford Innovation Ltd Cartilage plug
WO2021146442A1 (fr) * 2020-01-14 2021-07-22 Musculoskeletal Transplant Foundation Greffes à éléments multiples permettant le traitement de défauts de tissu et leurs procédés de fabrication et d'utilisation

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