EP0968010A2 - Materiau de substitution de l'os, a revetement de surface a base de peptides ayant une sequence d'acides amines rgd - Google Patents

Materiau de substitution de l'os, a revetement de surface a base de peptides ayant une sequence d'acides amines rgd

Info

Publication number
EP0968010A2
EP0968010A2 EP98905418A EP98905418A EP0968010A2 EP 0968010 A2 EP0968010 A2 EP 0968010A2 EP 98905418 A EP98905418 A EP 98905418A EP 98905418 A EP98905418 A EP 98905418A EP 0968010 A2 EP0968010 A2 EP 0968010A2
Authority
EP
European Patent Office
Prior art keywords
bone
bone replacement
peptides
amino acid
acid sequence
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP98905418A
Other languages
German (de)
English (en)
Inventor
Berthold Nies
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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 Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP0968010A2 publication Critical patent/EP0968010A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • 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

  • Bone replacement material with a surface covering with peptides with RGD amino acid sequence
  • the invention relates to bone substitute material based on a porous polymer material which has a surface covering with peptides with RGD-
  • Bone replacement materials are understood to be materials that serve as implants for the replacement or reconstitution of bone structures due to defects after surgical or illness-related surgery.
  • implant shaped bodies such as various types of bone prostheses, bone connecting elements, for example in the form of medullary cavity nails, bone screws and osteosynthesis plates, implant materials for filling cancellous bone defects or tooth extraction cavities, and for plastic surgery treatment of contour defects in the jaw facial area.
  • implant materials are regarded as particularly favorable if they have a high bioactivity, namely in that they are accepted in the organism and integrated into it.
  • Implant materials for bone replacement made of synthetic or non-body related materials can, depending on their nature and nature, show bioinert to bioactive behavior. However, the healing results of the body's own bone grafts have not yet been achieved by any synthetic implant material.
  • integrins proteins in the cell membrane.
  • the integrins recognize and bind to amino acid sequences, for example the RGD sequence, on structural proteins. This controls the adhesion of cells in the body.
  • the loading of implant surfaces with synthetically accessible peptides with RGD sequences with the aim of accelerating the healing of the implants is known.
  • the previously known implants are mostly metallic prostheses, in particular made of titanium or titanium alloys.
  • the invention was therefore based on the problem of providing a bone replacement material which not only can bring about cellular adhesion, but which can also be integrated more quickly into the bone, and thus has a biological activity which comes as close as possible to that of the body's own bone grafts.
  • a bone substitute material which is essentially composed of a porous polymer material with a surface covering with peptides with an RGD amino acid sequence.
  • the loading of implant surfaces with synthetically accessible peptides with RGD sequences is known.
  • the implants known and tested so far are mostly metallic prostheses, in particular made of titanium or titanium alloys.
  • the surfaces mentioned are activated accordingly with reactive groups and reacted with the peptides with a coupling reagent, the peptides being covalently bound.
  • the invention therefore relates to a bone substitute material based on a porous polymer material which has a surface covering with peptides with an RGD amino acid sequence.
  • the invention relates in particular to such a bone replacement material which is in the form of a shaped implant.
  • the invention also relates to an implantation set consisting of two or more separate components, one component of which contains a bone substitute material according to the invention and another component of which comprises a liquid preparation of a peptide with an RGD amino acid sequence.
  • the invention furthermore relates to the use of peptides with an RGD amino acid sequence for loading the surface of a porous and / or surface-structured polymer material for bone replacement, as a result of which biological activation takes place by stimulating the cell adhesion to this surface.
  • the invention furthermore relates to a method for the biological activation of bone replacement materials based on a porous polymer material by stimulating the cell adhesion to their surface, which is characterized in that the surface thereof is coated with a liquid preparation of a peptide with an RGD amino acid sequence.
  • Polymer materials are an otherwise less biocompatible material that, although their mechanical properties can be adapted to the bone, have not been used as a bone substitute so far because they do not bind to the bone.
  • the relevance of the present invention lies in the fact that this little biocompatible polymer material is used for mechanical reasons would be desirable as a bone substitute, optimized by loading with RGD peptides and achieving biocompatibility.
  • porous polymeric materials which are essentially polyacrylic and / or polymethacrylates, polymethyl methacrylates (PMMA),
  • PE Polyethylene
  • PP Polypropylene
  • PTFE Polytetrafluorethylene
  • copolymers of the polymers mentioned with one another and copolymers of these polymers with other polymers can also be used.
  • the production of such polymer materials is generally known to the person skilled in the art and need not be explained in more detail here.
  • the porous polymer material itself is present as a shaped implant body in the bone replacement material according to the invention, or in a further preferred embodiment it forms the surface or a surface coating of a shaped implant body.
  • shaped bodies according to the invention are preferred which have a partially or completely interconnecting pore system.
  • Polymers with such pore systems can be produced, for example, analogously to the manner described in patent application EP 0 705 609.
  • the general processes for the production of porous polymer materials are well known to the person skilled in the art and it is therefore not necessary to go into them here. Materials of this type are also commercially available. The skilled worker is familiar with their composition and the way in which they are processed.
  • Polymers or composites of polymers and mineral or metallic additives, in particular in particle or fiber form, are also preferred.
  • the polymer material itself is in the form of a porous implant, it can be produced, for example, by the processes described in EP 0 705 609 already mentioned, by selective fusion of polymethyl methacrylate particles (PMMA). This process is essentially carried out by mixing three different components together.
  • the first component is a solid component, consisting of a finely divided polymer of acrylic and / or methacrylic acid esters (these polymers are commercially available) and optionally other additives such as polymerization catalysts, X-ray contrast agents, fillers and dyes.
  • the second component is a liquid component consisting of acrylic and / or methacrylic acid ester monomers, optionally with additives such as polymerization accelerators and stabilizers.
  • the third component consists of coarse granules, made of a biocompatible material with the largest particle diameter of 0.5 to 10 mm. Preferred materials are based on polyacrylates and / or polymethacrylates, polyolefins, copolymers of acrylates with styrene and / or butadiene and epoxy resins.
  • the three main components are brought together and mixed together. After thorough mixing of the components, the polymerization begins due to the catalyst contained; The mass remains liquid to plastically deformable for a few minutes, after which the cured end product is available.
  • Porous implants can thus be produced from bone cement particles, which preferably have an interconnecting porosity. According to the invention, these materials are then containing RGD
  • This porous bone substitute material can be used in the usual way during the liquid or plastic stage as bone cement for the implantation of bone prostheses.
  • the surgeon can also process the mass into shaped bodies of any shape and size and, after hardening, implant them into the body areas to be treated for the reconstruction of bone defects or as local active substance depots.
  • the porous polymer materials have an average pore size of 0.05 mm to 2.50 mm, particularly preferably 0.10 mm to 1.25 mm.
  • the surface of the shaped implant body must have a porous shape, which can be realized, for example, in the form that a composite material or a bone cement is provided with a porous surface coating or a corresponding roughened surface.
  • porous polymer material forms the surface or the surface coating of a shaped implant body
  • these can consist of all known and customary implant materials, provided that they can be coated with a layer of porous polymer.
  • Implant materials can be divided into the classes mineral, in particular ceramic materials, physiologically acceptable metallic materials, physiologically acceptable polymer materials and composite materials made of two or more materials of the type mentioned.
  • Suitable mineral materials are, for example, materials based on materials containing calcium, such as, in particular, calcium carbonate, calcium phosphates and systems derived from these compounds. From the group of calcium phosphates, preferred are hydroxyapatite, tricalcium phosphate and tetracalcium phosphate.
  • mineral-based implant materials usually only guarantee high mechanical stability if they are used as ceramics, i.e. thus in the form of materials or workpieces sintered at sufficiently high temperatures.
  • Titanium or a titanium alloy is mainly used as the metallic material. Also of particular interest are composite materials that cover a much wider range in their mechanical properties than the pure polymers. In addition to the use of the polymers coated with RGD peptides as bone replacements, the combination of such materials with other implant components is of great importance.
  • a metal prosthesis e.g. titanium
  • a porous polymer treated according to the invention e.g. treated the titanium implant in a manner known per se for bonding with the polymer. This can be done, for example, using the Kevioc process or the Sulicoater process (described in DE 42 25 106).
  • a layer of porous polymer is then applied to the pretreated titanium surface, for example analogously to the manner described in EP 0 705 609.
  • the polymer-coated part of the prosthesis is then subsequently coated with the RGD peptide.
  • Another preferred embodiment of this invention represents the following implant material.
  • a corresponding implant made of a fiber composite material carbon fiber and epoxy resin
  • a porous layer made of, for example, PMMA is coated with a porous layer made of, for example, PMMA, and then the peptide coating takes place.
  • Such an implant has the advantage of bone-adapted elasticity, creating a boundary layer-free bone-implant interface and achieving optimal force transmission from the implant into the bone. Clinically, bone resorption through "stress shielding" is avoided and the prosthesis lasts longer.
  • the porous polymer layer that is applied to a corresponding implant material preferably has a layer thickness of 0.2 mm to 25 mm, particularly preferably from 2.0 mm to 20 mm.
  • the average pore size is preferably in the range from 0.05 mm to
  • 2.50 mm particularly preferred is the range from 0.10 mm to 1.25 mm.
  • Suitable peptides with RGD sequence that can be used according to the invention are all peptides and their compounds with non-peptide substituents that contain the amino acid sequence arginine-glycine-aspartic acid (RGD) and that can adhere to the polymer surfaces via their peptide and non-peptide substituents.
  • RGD arginine-glycine-aspartic acid
  • RGD (Arg-Gly-Asp), GRGD (Gly-Arg-Gly-Asp), GRGDY (Gly-Arg-Gly-Asp-Tyr), RGDS (Arg-Gly-Asp-Ser), GRGDS (Gly-Arg- Gly-Asp-Ser), RGDF (Arg-Gly-Asp-Phe), GRGDF (Gly-Arg-Gly-Asp-Phe), compounds of peptides with fatty acids or acrylate-substituted RGD peptides.
  • the peptides can be both linear and cyclic.
  • the coating of the bone replacement materials according to the invention with a peptide compound or a peptide with an RGD sequence is in itself no problem. It is expedient to start with a suitable liquid solution of the corresponding peptide, into which the material to be loaded is immersed. It could be shown that the final coverage of the implant surface is relatively independent of the concentration of the solution in a wide range. At very low
  • Concentrations can also be achieved by fully extending the exposure by appropriately extending the exposure time.
  • the preferred concentration range for the peptide solution is 10 ng - 100 ⁇ g / ml.
  • the exposure time is preferably 10 minutes to 24 hours.
  • the surface coverage with peptides is preferably 50% to 100% of the free surface.
  • the peptide substance adheres firmly to the polymer surface without further treatment.
  • the implants are sterilized in the usual way, for example by ⁇ -radiation, heat or ethylene oxide, and are then ready for implantation.
  • the bone substitute material according to the invention is in the form of a ready-to-use implantation set consisting of two or more separate components, in which one component comprises a porous polymer material, preferably as a shaped implant, and another component comprises a liquid preparation of a peptide with an RGD sequence.
  • a ready-to-use implantation set consisting of two or more separate components, in which one component comprises a porous polymer material, preferably as a shaped implant, and another component comprises a liquid preparation of a peptide with an RGD sequence.
  • the bone substitute materials according to the invention are used in the form of such an implantation set in such a way that the porous material is inserted shortly before or during the surgical intervention for the implantation polymeric implant material loaded with the RGD peptide-containing solution in the prescribed manner.
  • the bone replacement material according to the invention thus represents an at least equivalent replacement for homologous and autologous bone grafts or is a significant improvement in healing behavior for other forms of bone replacement.
  • the bone substitute materials according to the invention not only bring about cellular adhesion, but tests have shown that these implant materials integrate significantly faster than untreated implants.
  • the positive influence of the RGD coating on the healing behavior of implants for bone replacement can be transferred to practically all types of bone replacement materials and implant materials, provided that they are of such a type or design that they are either entirely or partially made of porous Polymer material exist, or that the implants are coated with such a porous polymer layer.
  • This requirement is also met, for example, by implants that have a porous structure or at least a roughened surface.
  • the bone replacement materials according to the invention can be present not only as shaped implants, but also in powder, granulate, particle or fiber form, depending on the location and the application.
  • a low-viscosity bone cement composition: 31 g
  • Polymethyl methacrylate / polymethylacrylated (94/6) copolymer 6 g of hydroxyapatite powder, 3 g of zirconium dioxide) is mixed with 30 ml of methyl methacrylate monomer in the usual way.
  • the components contain the starter system dibenzoyl peroxide / dimethyl-p-toluidine. 100 g of pure, cylindrical shape are added to this dough
  • the shaped body obtained according to a) is immersed in a solution of the tetrapeptide GRGD concentration 100 ⁇ g / ml,
  • Implants a) porous PMMA molded body b) PMMA molded body according to the invention coated with GRGD
  • Both implants were sterilized by ⁇ -radiation and implanted in rabbit femora.
  • Implantation location In the patellar sliding bearing of the femora, left and right.
  • the implant site shows only a thin circular ring of newly formed bone trabecula, which is interspersed with connective tissue. A direct deposition of the bone trabeculae on the cement pearls cannot be seen.
  • a massive trabecular new bone formation can be found here, which encompasses three quarters of the entire implant; the bone trabeculae are immediately superimposed on the cement pearls.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)

Abstract

L'invention concerne un matériau de substitution de l'os, à base d'un matériau polymérique poreux dont la surface est revêtue de peptides ayant une séquence d'acides aminés RGD.
EP98905418A 1997-02-20 1998-02-11 Materiau de substitution de l'os, a revetement de surface a base de peptides ayant une sequence d'acides amines rgd Withdrawn EP0968010A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19706667A DE19706667A1 (de) 1997-02-20 1997-02-20 Knochenersatzmaterial mit einer Oberflächenbelegung mit Peptiden mit RGD-Aminosäuresequenz
DE19706667 1997-02-20
PCT/EP1998/000742 WO1998036782A2 (fr) 1997-02-20 1998-02-11 Materiau de substitution de l'os, a revetement de surface a base de peptides ayant une sequence d'acides amines rgd

Publications (1)

Publication Number Publication Date
EP0968010A2 true EP0968010A2 (fr) 2000-01-05

Family

ID=7820899

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98905418A Withdrawn EP0968010A2 (fr) 1997-02-20 1998-02-11 Materiau de substitution de l'os, a revetement de surface a base de peptides ayant une sequence d'acides amines rgd

Country Status (11)

Country Link
EP (1) EP0968010A2 (fr)
JP (1) JP2001512344A (fr)
KR (1) KR20000075463A (fr)
CN (1) CN1247474A (fr)
AU (1) AU6100498A (fr)
CA (1) CA2281608A1 (fr)
DE (1) DE19706667A1 (fr)
HU (1) HUP0000900A3 (fr)
PL (1) PL335103A1 (fr)
WO (1) WO1998036782A2 (fr)
ZA (1) ZA981393B (fr)

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DE69920198T2 (de) 1998-04-13 2005-09-22 Massachusetts Institute Of Technology, Cambridge Kamm-polymere zur regelung der zelloberflächenwechselwirkung
DE19908318A1 (de) * 1999-02-26 2000-08-31 Michael Hoffmann Hämokompatible Oberflächen und Verfahren zu deren Herstellung
JP2002539172A (ja) 1999-03-17 2002-11-19 ノバルティス アクチエンゲゼルシャフト Ｔｇｆ−ベータを含む医薬組成物
DE19950386A1 (de) * 1999-10-19 2001-05-10 Miladin Lazarov Biokompatibler Gegenstand
GB0108767D0 (en) * 2001-04-07 2001-05-30 Univ Leeds Coatings
DE10119096A1 (de) * 2001-04-19 2002-10-24 Keramed Medizintechnik Gmbh Biologisch funktionalisierte, metabolisch induktive Implantatoberflächen
KR20040032297A (ko) * 2002-10-09 2004-04-17 (주)아미티에 생분해성 골접합용 코팅 임플란트
NL1023602C2 (nl) * 2003-06-05 2004-12-07 Univ Eindhoven Tech Werkwijze voor het bereiden van een aminozuren bevattende oplossing en de toepassing van een dergelijke oplossing.
KR101013999B1 (ko) * 2004-03-19 2011-02-14 재단법인서울대학교산학협력재단 표면에 골조직 형성 증진 펩타이드가 고정된 차폐막 및임플란트
US8696564B2 (en) 2004-07-09 2014-04-15 Cardiac Pacemakers, Inc. Implantable sensor with biocompatible coating for controlling or inhibiting tissue growth
DE102004043908A1 (de) * 2004-09-10 2006-03-30 GRÄTER, Stefan Oberflächenstrukturierte polymere Substrate und ihre Herstellung
FR2876916B1 (fr) * 2004-10-25 2007-01-05 Midi Pyrenees Incubateur Produit implantable de surface fonctionnalisee au moyen de dendrimeres a terminaisons anioniques
KR100676945B1 (ko) * 2005-03-18 2007-02-01 재단법인서울대학교산학협력재단 표면에 골조직 형성 증진 펩타이드가 고정된 골이식재 및 조직공학용 지지체
DE102006047248B4 (de) * 2006-10-06 2012-05-31 Celgen Ag Dreidimensionale künstliche Kallusdistraktion
CN101006944B (zh) * 2007-01-31 2010-06-09 浙江大学 一种在多孔纯钛牙种植体表面组装rgd的方法
DE102009042493B4 (de) 2009-09-14 2016-07-21 Celgen3D Ag Granulatmischung, umfassend zwei verschiedene Granulate, zur künstlichen Kallusdistraktion
CN102716513B (zh) * 2012-05-02 2014-12-24 清华大学 一种在钙磷陶瓷材料表面修饰rgd的方法
US20150224224A1 (en) * 2012-07-14 2015-08-13 Nobel Biocare Services Ag Bioactivated material
GB2503950A (en) * 2012-07-14 2014-01-15 Nobel Biocare Services Ag An agent for promoting osseointegration of bone substitute materials
CN103845759A (zh) * 2014-03-14 2014-06-11 国家纳米科学中心 一种组织工程界面修饰材料、其修饰方法及应用
CN104474590A (zh) * 2014-12-12 2015-04-01 北京博恩康生物科技有限公司 一种可注射活性骨修复材料及其制备方法

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Also Published As

Publication number Publication date
CA2281608A1 (fr) 1998-08-27
AU6100498A (en) 1998-09-09
DE19706667A1 (de) 1998-08-27
HUP0000900A3 (en) 2000-12-28
WO1998036782A2 (fr) 1998-08-27
HUP0000900A2 (hu) 2000-10-28
KR20000075463A (ko) 2000-12-15
ZA981393B (en) 1998-08-24
JP2001512344A (ja) 2001-08-21
WO1998036782A3 (fr) 1998-11-19
CN1247474A (zh) 2000-03-15
PL335103A1 (en) 2000-04-10

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