WO1997037002A1 - Stimulation de la regeneration de tissus organises - Google Patents

Stimulation de la regeneration de tissus organises Download PDF

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Publication number
WO1997037002A1
WO1997037002A1 PCT/SE1997/000565 SE9700565W WO9737002A1 WO 1997037002 A1 WO1997037002 A1 WO 1997037002A1 SE 9700565 W SE9700565 W SE 9700565W WO 9737002 A1 WO9737002 A1 WO 9737002A1
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WO
WIPO (PCT)
Prior art keywords
wound area
tube
guide
encasement structure
tissue
Prior art date
Application number
PCT/SE1997/000565
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English (en)
Inventor
Hans-Arne Hansson
Original Assignee
Hansson Hans Arne
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 Hansson Hans Arne filed Critical Hansson Hans Arne
Priority to IL12609397A priority Critical patent/IL126093A0/xx
Priority to IL13843697A priority patent/IL138436A0/xx
Priority to BR9708459A priority patent/BR9708459A/pt
Priority to NZ331710A priority patent/NZ331710A/xx
Priority to EP97915831A priority patent/EP0942960A1/fr
Priority to AU23157/97A priority patent/AU717648B2/en
Priority to PL97329483A priority patent/PL329483A1/xx
Priority to JP09535213A priority patent/JP2000510712A/ja
Publication of WO1997037002A1 publication Critical patent/WO1997037002A1/fr
Priority to IS4849A priority patent/IS4849A/is
Priority to NO984534A priority patent/NO984534L/no

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    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
    • 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
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/106—Fibrin; Fibrinogen
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0023—Polysaccharides
    • A—HUMAN NECESSITIES
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    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
    • A61L26/0047—Specific proteins or polypeptides not covered by groups A61L26/0033 - A61L26/0042
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • 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
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/047—Other specific proteins or polypeptides not covered by A61L31/044 - A61L31/046
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
    • A61B17/1128—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis of nerves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
    • A61B17/1146—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis of tendons
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists

Definitions

  • the present invention relates to the promotion of regeneration of organised tissue in a wound area in an organised tissue structure of a living human or animal body, such as for example nerves (spinal and cranial), tendons, ligaments, skeletal muscle, bone, joint capsules, cartilage and aponeuroses.
  • nerves spinal and cranial
  • tendons ligaments
  • skeletal muscle bone
  • joint capsules cartilage
  • cartilage cartilage and aponeuroses.
  • regeneration and derivatives thereof mentioned herein are not to be taken as necessarily meaning the repair of a wound area in an organised tissue structure by the formation of replacement organised tissue in the wound area which is identical to the original organised tissue but simply repair of the wound area by the formation of replacement organised tissue in the wound area per se.
  • guide filaments for the repair of severed nerves has hitherto been suggested (Alexander et al: Proc. Soc. Exp. Biol. Med. 68: 380-383, (1948); Stopford: Lancet, 10 1296-1297, (1920)). This typically consists of threading a suture across the gap between the proximal and distal ends of the severed nerve. It has also been made known to coat the guide filaments with materials such as laminin, collagen and fibronectin. The use of guide filaments, however, has met with limited success.
  • WO88/06872 (Astra Meditec) makes known an implant structure for promoting the regeneration of tendons, ligaments and cruciate ligaments comprising an open-ended tube into the lumen of which the free end of a torn tendon, ligament or cruciate ligament is inserted and through which a plurality of tissue guiding channels extend axially.
  • the guide channels in the tube lumen are defined by the spacing between filaments or members which extend axially through the lumen.
  • fibrin network the network of fibrin and cells including platelets (hereinafter the "fibrin network”) inevitably formed at the surface of an injured tissue structure into account.
  • the Applicant has appreciated the significance that the fibrin network plays in the repair and regeneration process of organised tissues.
  • Outgrowing cells such as regenerating tissue structures demand a physical support for their adhesion and migration.
  • this mechanical supporting structure is provided or determined, in the formative growth stages at any event, by the fibrin network established in the traumatised area as the backbone of a clot.
  • the structure of the fibrin network exerts crucial influence on the direction of the cells invading the injured area both with regard to the invading granulation tissue cells and the specific cells characterising the healing structure, that is to say, the fibrin network constitutes a template for the direction and distribution of cells characterising the healing structure in a traumatised area.
  • the track for the regenerating axons and the supporting Schwann cells across a gap or a crushed area of a nerve is largely related to the distribution and organisation of the complex fibrin network.
  • Tendons, ligaments, aponeuroses, skeletal muscle, cartilage, bone and other organised tissue structures all show a similar dependence on the pattern created by the fibrin network in the clot filling substance after injury.
  • the fibrin network formed in a traumatised area of an organised tissue structure has a highly complex, irregular 3-D structure of branched fibrin threads or filaments. Accordingly, in the case of nerve tissue repair the outgrowing Schwann cells and axons advance along the fibrin filaments and branch when the fibrin threads branch or cross each other.
  • the same pattern is true for the connective tissue cells accompanying the nerve regenerate, that is to say, their course largely follows the pattern of the fibrin network filling the gap between the severed nerve ends or the crushed nerve area. This dependence is equally evident in severed structures as after crush injuries or surgical procedures.
  • the presence, distribution and organisation of the fibrin network is thus is a key factor in determining the subsequent organisation of the tissue regenerate formed during the repair process and thus the ability of the injured structure to function properly again.
  • the present invention therefore proposes to enhance wound healing in an organised tissue structure in a living human or animal body by providing means for controlling the direction of tissue regenerate growth.
  • a system for promoting growth of tissue regenerate into a wound area in an organised tissue structure in a living human or animal body from a wound surface of the wound area in a predetermined direction comprising an encasement structure adapted in use to be implanted in the living human or animal body to encase the wound area, mechanical guide means for the tissue regenerate adapted in use to be disposed in the encased wound area so as to extend in the predetermined direction, and a fibrin network formation inhibiting agent administrable to the wound surface of the encased wound area.
  • the fibrin network formation inhibiting agent will be administered to the encased wound area systemically or locally.
  • fibrin network formation inhibiting agent covers both the case of inhibition of the formation of a fibrin network in the wound area and also the degradation of a pre-existing fibrin network in the wound area.
  • a method for promoting growth of tissue regenerate in a wound area of an organised tissue structure in a living human or animal body from a wound surface of the wound area in a predetermined direction comprising the steps of encasing the wound area with an encasement structure, providing mechanical guide means for the tissue regenerate in the encased wound area such that the mechanical guide means extends in the predetermined direction, and administering a fibrin network formation inhibiting agent to the encased wound area.
  • the fibrin network formation inhibiting agent comprises a thrombin inhibitor.
  • the thrombjn inhibitor may be a low molecular weight peptide-based thrombin inhibitor.
  • the term "low molecular weight peptide-based thrombin inhibitor" will be well understood by those skilled in the art to include thrombin inhibitors with one to four peptide linkages, and/or with a molecular weight below 1000, and includes those described in the review paper by Claesson in Blood Coagul. Fibrin. (1994) 5, 411 as well as those disclosed in US patent No. 4346078, Intemational patent application publication Nos.
  • Preferred low molecular weight peptide-based thrombin inhibitors include those collectively known as "gatrans", examples being melagatran (HOOC-CH2-(R)Cgl-Aze-Pab-H: see Intemational patent application publication No. WO94/29336 and the list of abbreviations therein) and inogatran (HOOC-CH2-(R)Cha-Pic-Nag-H: see Intemational patent application publication No. WO93/11152 and the list of abbreviations therein) .
  • the thrombin inhibitor may also be a bisulphated polysaccharide or oligosaccharide such as a chondroitin sulphate, a dermatan sulphate, a dextron sulphate, a keratan sulphate, a heparan sulphate or heparin.
  • the thrombin inhibitor may be a hirudin, a biosynthetic analogue of hirudin, a fragment of hirudin such as a fragment consisting of at least the last 8 C-terminal amino acids of the known sequence in hirudin or the protein NAPc2.
  • the fibrin network formation inhibiting agent comprises a fibrinolytic agent.
  • the fibrinolytic agent may be a plasminogen activator (tPA),
  • hrtPA human plasminogen activator
  • the fibrin network formation inhibiting agent comprises a Factor X inhibitor * a trypsin inhibitor or a protease inhibitor, that is to say, other compounds which affect the activity of the thrombinogen-thrombin system which instigates the fibrin network formation.
  • the fibrin network formation inhibiting agent is immobilised to the inner surface of the encasement structure which in use faces the wound area.
  • the fibrin network formation inhibiting agent is in solution and a pump is provided to administer the fibrin network formation inhibiting agent to the encased wound area.
  • the pump may be an osmotic minipump which may further be adapted to be implanted subcutaneously in the living human or animal body.
  • the fibrin network formation inhibiting agent is incorporated in a matrix material for disposal or delivery to the encased wound area.
  • the matrix material may be formed of a material comprising a polysaccharide such as a chitosan or a hyaluronan such as hyaluronic acid, an agar gel, a hydrogel such as
  • an implantable device for promoting growth of tissue regenerate into a wound area in an organised tissue structure in a living human or animal body from a wound surface of the wound area in a predetermined direction comprising an outer encasement structure which when the device is implanted in the living human or animal body encases the wound area, and an inner gel structure provided with one or more guide channels for the tissue regenerate which when the device is implanted is disposed in the encased wound area such that the guide channels extend in the pre ete ⁇ riined direction.
  • the implantable device may be used in conjunction with a fibrin network formation inhibiting agent in accordance with the invention although this is not strictly necessary.
  • the encasement structure is a patch for a crush wound area or the like of the organised tissue structure.
  • the encasement structure is a tube having an open end adapted to receive the wound surface and the mechanical guide means is adapted in use to extend in the predetermined direction in the lumen of the tube.
  • a uniform distribution of the agent may be promoted by using a tube comprising an outer continuous tube element for inhibiting ingress of granulation tissue to the wound area through which a tube connected to the pump passes and an inner tube element formed of a plurality of longitudinally spaced apart tube sections for axially distributing the agent discharged from the pump into the lumen.
  • the encasement structure is a tube having an open end adapted to receive the wound surface with the or each guide channel extending in the predetermined direction in the lumen of the tube.
  • the wound surface of the wound area is a first wound surface
  • the open end of the tube is a first open end
  • the tube has a second open end adapted to receive a second wound surface of the wound area
  • the mechanical guide means is adapted in use to extend in the lumen of the tube between the first and second open ends in the predetermined direction.
  • the wound surface of the wound area is a first wound surface
  • the open end of the tube is a first open end
  • the tube has a second open end adapted to receive a second wound surface of the wound area and the or each guide channel extends in the lumen of the tube between the first and second open ends in the predetermined direction.
  • the invention can be for promoting growth of tissue regenerate across a gap between the severed or transected free ends of an organised tissue structure such as a nerve, tendon, skeletal muscle or ligament, the open ends of the tube each being adapted to receive one of the severed or transected free ends.
  • the encasement structure is preferably of a biocompatible material and may be biodegradable or non-biodegradable. Biodegradable is preferred however.
  • the encasement structure may be constructed from a material comprising a polysaccharide, for example a chitosan, heparin, a heparanoid or a hyaluronan such as hyaluronic acid.
  • the encasement structure may also be constructed of a material comprising collagen or other protein complexes.
  • the encasement structure may be constructed from a material comprising a polymer or copolymer, for example polylactic acid, polyhydroxybutyric acid, polyglycolic acid, permselective polytetraethylene, polyglucuronic acid, or poly-N-acetylglucosamine or copolymers thereof such as a copolymer of polyhydroxybutyric acid and hydroxyvaleric acid.
  • a polymer or copolymer for example polylactic acid, polyhydroxybutyric acid, polyglycolic acid, permselective polytetraethylene, polyglucuronic acid, or poly-N-acetylglucosamine or copolymers thereof such as a copolymer of polyhydroxybutyric acid and hydroxyvaleric acid.
  • the encasement structure is constructed from a non-biodegradable material possible materials are silicone and ethylene-vinyl acetate.
  • the mechanical guide means is supported or presented by the inner surface of the encasement structure which in use faces the wound area.
  • the mechanical guide means and the encasement structure could be integrally formed as an implantable body.
  • the mechanical guide means takes the form of guide channels in the encased wound area.
  • an encasement structure which when implanted is a tube-like structure having a transverse spiral cross-section formed for example by rolling up a planar membrane.
  • the guide channels are then defined by the longitudinally extending spaces presented by the spiral cross-section.
  • Another way is to have mechanical guide means which take the form of a gel structure which is provided with one or more guide channels therethrough, the gel stmcture adapted in use to be disposed in the encased wound area such that the guide channels extend in the predetermined direction.
  • the or each guide channel has a cross-sectional dimension in the range of 50 ⁇ m-lmm and preferably a cross-sectional dimension in the range of 150-500 ⁇ m to allow growth of nerve functional units through the channels, that is to say, nerve fascicles.
  • the cross-sectional dimension of the or each guide channel would be chosen to allow growth of the corresponding functional units therethrough.
  • the gel structure is formed from agar, a hydrogel such as methylcellulose gel, albumin or other proteins which can be formed into gel, a polysaccharide such as a chitosan or a hyaluronan such as hyaluronic acid, a lipid which can be formed from agar, a hydrogel such as methylcellulose gel, albumin or other proteins which can be formed into gel, a polysaccharide such as a chitosan or a hyaluronan such as hyaluronic acid, a lipid which can
  • ® ® be formed into a gel, Matrigel or Biomat ⁇ x I .
  • the mechanical guide means comprises one or more guide filaments or fibres adapted in use to extend across the encased wound area in the predetermined direction.
  • the mechanical guide means may for example be monofilaments, multifilaments or woven/non-woven fibres.
  • the or each guide filament or fibre is of a biocompatible material which is also a biodegradable material.
  • the or each guide filament or fibre may though be formed from a non-biodegradable material.
  • each guide filament or fibre is formed from a material comprising a polysaccharide such as a chitosan, heparin, a heparanoid or a hyaluronan such as hyaluronic acid.
  • a polysaccharide such as a chitosan, heparin, a heparanoid or a hyaluronan such as hyaluronic acid.
  • the or each guide filament or fibre is formed from a material comprising a polymer or copolymer.
  • the or each guide filament or fibre may be formed from polylactic acid, polyhydroxybutyric acid, polyglycolic acid, permselective polytetraethylene, poly-N- acetylglucosamine or copolymers thereof such as for example a copolymer of polyhydroxybutyric acid and hydroxyvaleric acid.
  • each guide filament or fibre is formed from collagen or other protein complexes.
  • the mechanical guide means comprises one or more suture filaments formed for example from vicryl, catgut, polyamid, chitin or nylon.
  • silicone is suitable.
  • a growth factor or mixture of growth factors may be administered to the encased wound area.
  • the growth factor may for example be immobilised to the inner surface of the encasement structure.
  • the growth factor may comprise insulin-like growth factors-I, insulin-like growth factors-II, platelet derived growth factors, fibroblast growth factors, transforming growth factors- ⁇ , transforming growth factors- ⁇ , neurotrophines, ciliary neurotrophic factors, EGF or glial growth factors.
  • the growth factor may also comprises Schwann cells, endothelial cells, fibroblasts, macrophages or inflammatory cells or genetically altered cells which can express a growth factor.
  • a system according to the first aspect of the invention for promoting growth of tissue regenerate in a wound area of an organised tissue structure in a living human or animal body from a wound surface of the wound area in a predetermined direction.
  • an implantable device according to the third aspect of the invention for promoting growth of tissue regenerate in a wound area of an organised tissue structure in a living human or animal body from a wound surface of the wound area in a predetermined direction.
  • Examples of the organised tissue structures on which the invention can be used for promoting the growth of tissue regenerate in a wound area are nerves, tendons, ligaments, joint capsules, cartilage, bone, aponeuroses and skeletal muscles.
  • the invention thus provides for inhibiting or controlling the formation of the fibrin network in injured tissue coupled with the provision of mechanical guide means to enable the cells emerging in the wound area from the wound surface to. follow the track offered by the mechanical guide means.
  • the advantage of this is that the cells do not show any branching or irregular path as a coherent path for growth is provided. It is therefore possible to achieve regeneration of organised specific cells, such as Schwann cells from peripheral nerves or tenocytes from tendons, to bridge the defect induced by an injury with minimal diversions and irregularities in the organisation of the newly formed tissue.
  • Fig. 1 is a cross-sectional side view of a guide tube having a lumen into the opposing ends of which the proximal and distal ends of a transected sciatic nerve of an adult rat are sutured and through which a guide filament extends schematically illustrating the fibrin network formed in the lumen between the proximal and distal ends in the absence of administration of a fibrin network formation inhibiting agent.
  • Fig. 2 is a cross-sectional side view of a guide tube and guide filament assembly corresponding to that of Fig. 1 into the opposing ends of the tube of which the proximal and distal ends of a transected sciatic nerve of an adult rat are sutured schematically illustrating the fibrin network formed with administration of a fibrin network formation inhibiting agent.
  • Fig. 3 is a cross-sectional side view of a guide tube corresponding to that of Fig. 1 into the lumen of which only the proximal end of a transected sciatic nerve of an adult rat is sutured schematically illustrating the fibrin network formed in the absence of administration of a fibrin network formation inhibiting agent.
  • Fig. 4 is a cross-sectional side view of a guide tube corresponding to that of Fig. 1 into the lumen of which only the proximal end of a transected sciatic nerve of an adult rat is sutured schematically illustrating the fibrin network formed with administration of a fibrin network formation inhibiting agent
  • Fig. 5 is a cross-sectional side view of a guide tube and guide filament assembly corresponding to that of Fig. 1 into the lumen of the tube of which only the proximal end of a transected sciatic nerve of an adult rat is sutured schematically illustrating the fibrin network formed in the absence of administration of a fibrin network formation inhibiting agent.
  • Fig. 6 is a cross-sectional side view of a guide tube and guide filament assembly corresponding to that of Fig. 1 into the lumen of which only the proximal end of a transected sciatic nerve of an adult rat is sutured schematically illustrating the fibrin network formed with administration of a fibrin network formation inhibiting agent.
  • Fig. 7 is a cross-sectional side view of a guide tube comprising an outer continuous tube element and an inner tube element formed from longitudinally spaced apart sections having a lumen into one end of which the proximal end of a transected sciatic nerve of an adult rat is sutured and through which a guide filament extends schematically illustrating the fibrin network formed with local administration of a fibrin network formation inhibiting agent by infusion from an implanted osmotic minipump.
  • Fig. 8 is a schematic cross-sectional side view of a guide tube having a lumen into which the proximal and distal ends of a transected sciatic nerve of an adult rat are sutured at opposing open ends and which is filled with a gel provided with longitudinally extending guide channels.
  • a silicone guide tube 5 into the opposite open ends of which the proximal end 1 and the distal end 3 of a transected sciatic nerve of an adult rat have been inserted and fixed in place by sutures 7.
  • the guide tube 5 prevents or inhibits access of granulation tissue to the wound area and surfaces by isolating the injured nerve structure from the surrounding tissue, usually connective tissue with blood vessels. This makes it easier to control the repair and modelling of the tissue regenerate formed between the severed ends of the injured sciatic nerve .
  • the guide tube 5 further acts as a delivery system for compounds interfering with the formation of a fibrin network in the wound area as will become apparent and may also act as a slow delivery system for growth stimulating agents.
  • Figs 1 and 2 show the injured nerve extending only a short distance into the guide tube 5
  • both the proximal and distal ends 1, 3 may be covered by longer lengths of the guide tube 5. This distance may extend up to the point where division of a nerve fascicle at the distal end prevents further encasement.
  • a guide filament 1 1 formed from an ophthalmic suture material extends between the proximal and distal ends 1, 3 of the injured sciatic nerve through the lumen of the guide tube 5.
  • a plurality of guide filaments can be used instead.
  • the guide filament 11 When the guide filament 11 is surgically inserted a segment of the filament projects outside the guide tube 5. This segment is then cut away when the surgical repair procedure is completed.
  • Fig. 1 the injured sciatic nerve was left to regenerate in the presence of saline introduced into the guide tube 5 at surgery. The result after a few days is a large complex fibrin network 13 of branching filaments formed along the guide filament 11 in the gap between the proximal and distal ends 1, 3 of the sciatic nerve for subsequent regenerating nerve tissue to follow.
  • the guide tube 5 in the Fig. 2 set up was also filled with saline at surgery.
  • melagatran was systemically administered to the wound area by subcutaneous infusion with an implanted minipump (not shown).
  • a narrower fibrin network 14 outlined the central guide filament 11 in the gap between the transected nerve ends. More importantly, the fibrin network 14 exhibited a coherent structure of fibrin platelets and fragments aligned in the direction of the filament 11 for subsequent regenerating nerve tissue to follow.
  • Figs 3 and 4 there is shown a silicone guide tube 105 corresponding to the guide tube 5 of Figs 1 and 2.
  • a silicone guide tube 105 corresponding to the guide tube 5 of Figs 1 and 2.
  • a suture 107 and no guide filament extends through the lumen.
  • one of the open ends 102 of the tube is left open.
  • saline was introduced into the lumen of the tube 105 at surgery.
  • FIG. 3 In the Fig. 3 set up no further treatment was provided. A tiny clot 115 consisting of fibrin, platelets and other blood cells was formed just covering the proximal end but no fibrin network formed in the rest of the tube. No substantial fibrin network was thus formed to support subsequent nerve tissue regenerate growth.
  • Fig. 4 melagatran was additionally systemically a ⁇ lministered to the wound area by infusion subcutaneously with an implanted minipump.
  • a small clot 116 of fibrin and cells was formed just covering the proximal nerve end. There was no fibrin network in the rest of the tube. No substantial fibrin network was thus formed to support subsequent nerve tissue regenerate growth.
  • Figs 5 and 6 there is shown a silicone guide tube 205 corresponding to the guide tube 5 of Figs 1 and 2.
  • the proximal end 201 of a transected sciatic nerve of an adult rat is held in the tube 205 with a suture 207 and the lumen of the tube filled with saline at surgery.
  • a guide filament 211 in the form of an ophthalmic suture extends from the proximal end 201 into the lumen.
  • a narrow complex clot 217 consisting of irregularly organised fibrin filaments, platelets and other blood cells was formed along the guiding filament 211 throughout the tube 205 for subsequent regenerating nerve tissue to follow.
  • melagatran was systemically administered to the wound area by infusion subcutaneously with an implanted minipump.
  • a small clot 218 of coherent fibrin platelets, fibrin fragments and cells was formed along and aligned with the guiding filament 211 in the centre of the tube for subsequent regenerating nerve tissue to follow.
  • FIG. 7 there is shown an open-ended guide tube 305 comprising an outer continuous tube element 306 and an inner tube element 308 formed from a plurality of longitudinally spaced sections 310.
  • the proximal end 301 of a transected sciatic nerve of an adult rat is inserted into the tube and maintained in place with a suture 307.
  • a guide filament 311 in the form of an ophthalmic suture extends through the lumen of the tube from the proximal end.
  • the tube was filled with saline ,at surgery and then melagatran infused locally to the encased wound area with an implanted osmotic minipump 312.
  • the longitudinally spaced sections 310 assist in distributing the melagatran throughout the gap in the lumen.
  • a narrow .coherent clot 319 of coherent fibrin platelets, fibrin fragments and cells was formed along, and aligned with, the length of the guiding filament 311 in the centre of the tube for subsequent regenerating nerve tissue to follow.
  • the construction of the guide tube shown in Fig. 7 may be varied such that each isolated longitudinal section is provided with one or more guide filaments.
  • the guide tube and filament assembly is thus essentially comprised of smaller individual assemblies of similar construction. This facilitates the separation of regenerating nerve fascicles since the longitudinal sections act as a separate guide for each fascicle
  • FIG. 8 there is shown an open-ended guide tube 405 into the opposing ends of which the proximal and distal ends 401, 403 of a transected or severed sciatic nerve of an adult rat have been inserted and fixed with sutures 407.
  • the lumen of the tube 405 in this case is filled with agar gel 402 through which a plurality of axial guide channels 404 extend.
  • the gel structure 402 is shown spaced from the end surfaces of the transected nerve structure for the sake of clarity although needless to say it is not a strict requirement for the gel structure to abut the nerve end surfaces.
  • the result of the set up is the formation of a coherent fibrin network in the guide channels having long fibrin filaments or cables axially aligned with the guide channels for subsequent regenerating nerve tissue to follow.
  • the guide tube may be formed from biocompatible bioresorbable or non-bioresorbable materials which may be permeable or impermeable to materials soluble in aqueous solutions. Use of a bioresorbable or biodegradable material, though, is preferred.
  • Materials of which the guide tube may be constructed include, but are not limited to, collagen complexes, heparin and heparonoids, chitosan and related polysaccharides, polylactic acid, polyglycolic acid, polyhydroxybutyric acid, permselective polytetraethylene, poly-N-acetylglucosamine, or polymers into which growth factors may be inco ⁇ orated directly (e.g. ethylene-vinyl acetate).
  • these may be formed from biocompatible materials similar or identical to the materials used for the guide tube.
  • Other materials that may be used include presently available suture materials, such as vicryl, catgut, nylon, chitin as well as other materials which can act as a compatible substrate for the formation of a cable of regenerating tissue such as nerve axons.
  • the sciatic nerve of adult rats was exposed unilaterally on the mid thigh and transected.
  • the proximal and distal ends were then inserted into a silicone guide tube of the type shown in Figs 1 to 6 of the accompanying drawings to leave a 10mm gap therebetween filled with phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the silicone tube was sutured to the perineurium of the inserted nerve ends with 9-0 " ⁇ traumatic" ophthalmic sutures (Ethicon).
  • the regenerate formed in the gap was after 2 and 4 weeks examined with regard to the distribution and direction of the axons and of the Schwann cells, as visualised by immunohistochemistry.
  • the axons were fairly few and showed extensive aberration, often arranged as loops.
  • the Schwann cells were identified in the central parts of the regenerate arranged in a seemingly random pattern. Fibroblasts formed an enclosing perineurium-like structure. Numerous macrophages were distributed throughout the gap region as were scattered erythrocytes.
  • Nerve regeneration was thus blocked in absence of a mechanical guiding structure bridging the gap between the nerve ends, such as a fibrin network covered guide filament.
  • the sciatic nerve of adult rats was exposed unilaterally on the mid thigh and transected.
  • the proximal and distal ends were then inserted into a silicone guide tube to leave a 10mm gap therebetween.
  • the silicone tube was sutured to the perineurium of the inserted nerve ends with 9-0 "atraumatic" ophthalmic sutures (Ethicon).
  • the gap was filled with PBS and a single central guiding filament (10-0 monofilament nylon) positioned in the lumen of the tube to connect the proximal and distal nerve ends.
  • the regenerate formed in the gap was after 2 and 4 weeks examined with regard to the distribution and direction of the axons and of the Schwann cells, as visualised by immunohistochemistry.
  • the axons appeared to be slightly more numerous than in Example 1 but still showed extensive aberration, again often arranged as loops.
  • the Schwann cells were identified in the central parts of the regenerate arranged in a seemingly random pattern. Fibroblasts formed an enclosing perineurium-like structure. Numerous macrophages were distributed throughout the gap region as were scattered erythrocytes.
  • the sciatic nerve of adult rats was exposed unilaterally on the mid thigh and transected.
  • the proximal and distal ends were then inserted 2mm into a silicone guide tube having an inner diameter of 1.5mm to leave a 10mm gap therebetween.
  • the silicone tube was sutured to the perineurium of the inserted nerve ends with 9-0 "atraumatic" ophthalmic sutures (Ethicon).
  • the regenerate formed in the gap was after 2 and 4 weeks examined with regard to the distribution and direction of the axons and of the Schwann cells, as visualised by immunohistochemistry.
  • the axons were at least as numerous as in Example 1 and 2, showed rare aberration and were arranged parallel to the central guiding filament, i.e. exhibited a very high degree of coherence.
  • the Schwann cells showed a high degree of coherence being mainly arranged parallel to the central guiding filament and few cells diverged from that direction. There was hardly any random pattern in the organisation of the Schwann cells. Fibroblasts formed an enclosing perineurium-like structure. A striking feature was the absence of macrophages and blood cells outside the regenerate.
  • the sciatic nerve of adult rats was exposed unilaterally on the mid thigh and transected.
  • the proximal and distal ends were then inserted 2mm into a silicone guide tube to leave a 10mm gap therebetween.
  • the silicone tube was sutured to the perineurium of the inserted nerve ends with 9-0 "atraumatic" ophthalmic sutures (Ethicon).
  • Example 3 a single central guiding filament (10-0 monofilament nylon) was positioned in the lumen of the tube to connect the proximal and distal nerve ends, the gap was filled with PBS and melagatran administered.
  • the regenerate formed in the gap was after 2 and 4 weeks examined with regard to the distribution and direction of the axons and of the Schwann cells, as visualised by immunohistochemistry.
  • the axons were at least as numerous as in Examples 1 to 3, showed rare aberration and were arranged parallel to the central guiding filament, i.e. exhibited a very high degree of coherence.
  • the Schwann cells were mainly arranged parallel to the central guiding filament and few cells diverged from that direction. There was no random pattern in the organisation of the Schwann cells. Fibroblasts formed an enclosing perineurium-like structure. There were no macrophages and blood cells outside the regenerate.
  • the sciatic nerve of adult rats was transected and the proximal end inserted into a silicone guide tube filled with PBS.
  • Nerve regeneration was thus blocked in the absence of a mechanical guiding structure extending from the proximal nerve end, such as a fibrin network covered guide filament
  • the sciatic nerve of adult rats was transected and the proximal end inserted into a silicone guide tube filled with PBS and to which melagatran was infused systemically with the aid of an implanted osmotic minipump.
  • Example 5 Although no regenerate formed from the proximal nerve end after 2 or 4 weeks. Macrophages and blood cells could be recognised close to the proximal nerve end.
  • Nerve regeneration was thus blocked in the absence of a mechanical guiding structure extending from the proximal nerve end, such as a fibrin network covered guide filament.
  • the sciatic nerve was exposed unilaterally on the mid thigh of adult rats and transected. Immediately thereafter the proximal and distal nerve ends were inserted 2 mm into a silicone tube of the type shown in Figs 1 to 6 prefilled with buffered saline. The gap between the nerve ends was 10 mm. The silicone tube was sutured to the perineurium of the inserted nerve ends with 9-0 "atraumatic" ophthalmic sutures (Ethicon).
  • the nerves and the tube with its gap were examined after 2 and 4 weeks with regard to the distribution, direction and coherence of the axons and of the Schwann cells, as visualised by immunohistochemistry with the aid of antibodies to neurofilaments (N 0142 & N 5389,
  • Nerve regeneration was thus blocked in the absence of a mechanical guiding structure bridging the gap between the nerve ends, such as a fibrin network covered guide filament
  • the sciatic nerve was exposed unilaterally on the mid thigh of adult rats and transected.
  • proximal and distal nerve ends were inserted 2 mm into a silicone tube of the type shown in Figs 1 to 6 prefilled with buffered saline.
  • a guiding filament e.g. a suture thread
  • the gap between the nerve ends was 10 mm.
  • the siljcone tube was sutured to the perineurium of the inserted nerves with 9-0 "atraumatic" ophthalmic sutures (Ethicon).
  • the nerve and the tube with its gap were examined after 2 and 4 weeks with regard to the distribution, direction and coherence of the axons and of the Schwann cells, as visualised by immunohistochemistry with the aid of antibodies to neurofilaments (N 0142 & N 5389, Sigma) and to the neuroglial protein S-100 (S 2644, Sigma; Z 0311, Dakopatts). There was no regenerate bridging the gap. No axons or Schwann cells traversed the gap. Scattered amorphous protein strands and cells could be recognised in the gap fluid.
  • Nerve regeneration was thus blocked in absence of a mechanical guiding structure bridging the gap between the nerve ends, such as a filament covered with a fibrin network.
  • the sciatic nerve of adult rats was transected and the proximal end inserted 2mm into a silicone guide tube.
  • a single central guiding filament (10-0 monofilament nylon) was stitched through the proximal sciatic nerve end to extend into the lumen and the lumen was filled with PBS with the aid of an implanted osmotic minipump.
  • the distal end of the transected sciatic nerve was positioned among the thigh muscles so that it could not interfere with the growth in the silicone tube.
  • the regenerate formed in the gap was after 2 and 4 weeks examined with regard to the distribution and direction of the axons and of the Schwann cells, as visualised by immunohistochemistry.
  • the axons were sticking to the central guiding filament and many appeared to be parallel to it. Hpwever, the axons showed extensive aberration and loops were common.
  • the Schwann cells were to a large extent arranged parallel to the central guiding filament but many cells diverged from that direction. Fibroblasts formed an enclosing perineurium-like structure. There were numerous macrophages and blood cells outside the regenerate. Deficient repair of the nerve was thus achieved due to the nerve tissue regenerate following the path laid by the complex fibrin network formed in the early stages of the repair process.
  • the sciatic nerve of adult rats was transected and the proximal end inserted 2mm into a silicone guide tube.
  • a single central guiding filament (10-0 monofilament nylon) was stitched through the proximal sciatic nerve end to extend into the lumen, the lumen was filled with PBS and melagatran then infused systemically with the aid of an implanted osmotic minipump.
  • the distal end of the transected sciatic nerve was positioned among the thigh muscles so that it could not interfere with the growth in the silicone tube.
  • the regenerate formed in the gap was after 2 and 4 weeks examined with regard to the distribution and direction of the axons and of the Schwann cells, as visualised by immunohistochemistry.
  • the axons were arranged parallel to the central guiding filament and very few diverged. There was no axonal aberration and hardly any loops at all.
  • the Schwann cells were to a large extent arranged parallel to the central guiding filament Fibroblasts formed an enclosing perineurium-like structure. There were rarely any macrophages and blood cells outside the regenerate.
  • the sciatic nerve of adult rats was transected and the proximal end inserted 2mm into a silicone guide tube taking the form of the tube shown in Fig. 7.
  • a single central guiding filament (10-0 monofilament nylon) was stitched through the proximal sciatic nerve end to extend into the lumen, the lumen was filled with PBS and melagatran then infused locally with the aid of an implanted osmotic minipump.
  • the distal end of the transected sciatic nerve was positioned among the thigh muscles at a distance from the silicone tube and could thus not interfere with the regenerate.
  • the regenerate formed in the gap was after 2 and 4 weeks examined with regard to the distribution and direction of the axons and of the Schwann cells, as visualised by immunohistochemistry.
  • the axons were arranged parallel to the central guiding filament and very few diverged except in the immediate vicinity of the proximal nerve end. There was no axonal aberration and hardly any loops at all except for a few at the proximal nerve end.
  • the Schwann cells were mainly arranged parallel to the. central guiding filament Fibroblasts formed an enclosing perineurium-like structure. There were hardly any macrophages and blood cells outside the regenerate.
  • Example 11 The set up for this Example was the same as that in Example 11 other than that streptokinase (Hoescht) was infused locally with the aid of a miniosmotic pump.
  • streptokinase Hoescht
  • Example 13 Results similar to those described above in Example 1 1 were obtained. However, the osmotic minipump was changed every second day to attain sufficient streptokinase activity during an 8 day period. Example 13
  • hrtPA human plasminogen activator Actilyse
  • Example 11 The set up for this Example was the same as that in Example 11 other than that urokinase was infused locally with the aid of an osmotic minipump.
  • the sciatic nerve was exposed unilaterally on the mid thigh of adult rats and transected.
  • the proximal and distal nerve ends were inserted 2 mm into a silicone tube prefilled with buffered saline and having through its centre a guiding filament, e.g. a suture thread.
  • the gap between the nerve ends was 10 mm.
  • the silicone tube was sutured to the perineurium of the inserted nerves with 9-0 "atraumatic" ophthalmic sutures (Ethicon).
  • the regenerate formed in the gap was after 2 and 4 weeks examined with regard to the distribution, direction and coherence of the axons and of the Schwann cells, as visualised by irnmunohistochemistry.
  • the axons were numerous and highly coherent, showing only minor aberrations, and were rarely arranged as loops.
  • the Schwann cells were identified in the central parts of the regenerate, and showed a high degree of coherence as well. Fibroblasts formed an enclosing perineurium-like structure. Rare macrophages were noticed in the gap region.
  • the sciatic nerve was exposed unilaterally on the mid thigh of adult rats and transected.
  • the proximal and distal nerve ends were inserted 2 mm into a silicone tube prefilled with buffered saline but having no guiding filament, e.g. a suture thread, in the centre of the silicone tube.
  • the gap between the nerve ends was 10 mm.
  • the silicone tube was sutured to the perineurium of the inserted nerves with 9-0 "atraumatic" ophthalmic sutures (Ethicon).
  • the nerve and the tube with its gap were examined after 2 and 4 weeks with regard to the -distribution, direction and coherence of the axons and of the Schwann cells, as visualised by irnmunohistochemistry with the aid of antibodies to neurofilaments (N 0142 & N 5389, Sigma) and to the neuroglial protein S- 100 (S 2644, Sigma; Z 0311 , Dakopatts). There was no regenerate bridging the gap. No axons or Schwann cells traversed the gap. Scattered amo ⁇ hous protein strands and cells could be recognised in the gap fluid.
  • Nerve regeneration was thus blocked in absence of a guiding structure, such as a filament covered with a fibrin network.
  • the sciatic nerve was exposed unilaterally on the mid thigh of adult rats and transected.
  • the proximal and distal nerve ends were inserted 2 mm into a silicone tube prefilled with buffered saline but not having a guiding filament e.g. a suture thread, in the centre of the silicone tube.
  • the gap between the nerve ends was 10 mm.
  • the silicone tube was sutured to the perineurium of the inserted nerves with 9-0 "atraumatic" ophthalmic sutures (Ethicon).
  • the nerve and the tube with its gap were examined after 2 and 4 weeks with regard to the distribution, direction and coherence of the axons and of the Schwann cells, as visualised by immunohistochemistry with the aid of antibodies to neurofilaments (N 0142 & N 5389, Sigma) and to the neuroglial protein S-100 (S 2644, Sigma; Z 0311, Dakopatts). There was no regenerate bridging the gap. No axons or Schwann cells traversed the gap. Scattered amo ⁇ hous protein strands and cells could be recognised in the gap fluid.
  • Nerve regeneration was thus blocked in absence of a mechanical guiding structure, such as a filament covered with a fibrin network.
  • a mechanical guiding structure such as a filament covered with a fibrin network.
  • Example parts of the Achilles tendon of adult rats were transected and the proximal and distal ends introduced 1mm into a silicone tube taking the form of that shown in Figs 1 to 6.
  • a single central guiding filament (10-0 monofilament nylon) was provided to extend through the lumen of the tube to connect the proximal and distal tendon stumps.
  • PBS or melagatran were then infused systemically with the aid of an osmotic minipump.
  • the Achilles tendon was exposed unilaterally on adult rats and a portion of it transected.
  • the transected and isolated proximal and distal tendon ends were inserted 2 mm into a silicone tube prefilled with buffered saline and having through its centre a guiding filament, e.g. a suture thread.
  • the gap between the tendon ends was 4-6 mm.
  • the silicone tube was sutured to the paratenon with 9-0 "atraumatic" ophthalmic sutures (Ethicon).
  • the regenerate formed in the silicone tube was examined after 2 and 4 weeks with regard to -the distribution, direction and coherence of collagen fibres and cells.
  • the gap was filled with collagen fibres showing high degrees of coherence. Randomly organised collagen structures were rare. Fibroblasts and vascular wall cells were common while macrophages and inflammatory cells were rare. A paratenon-like structure could be recognised. Good regeneration of the tendon was thus achieved.
  • the Achilles tendon was exposed unilaterally on adult rats and a portion of it transected.
  • the transected and isolated proximal and distal tendon ends were inserted 2 mm into a silicone tube prefilled with buffered saline but lacking a guiding filament such as a suture thread inserted in the centre of the silicone tube.
  • the gap between the tendon ends was 4 - 6 mm.
  • the silicone tube was sutured to the paratenon with 9-0 "atraumatic" ophthalmic sutures (Ethicon).
  • the regenerate formed in the silicone tube was examined after 2 and 4 weeks with regard to the distribution, direction and coherence of collagen fibres and cells.
  • the gap was incompletely filled with randomly organised collagen filaments, highly variable in size and direction. There was a lack of good coherence. Randomly organised collagen structures thus dorninated. Fibroblasts and vascular wall cells were common while macrophages and inflammatory cells were rare.
  • the sciatic nerve was exposed unilaterally on the mid thigh of adult rats and transected.
  • the proximal and distal nerve ends were then each inserted 2 mm into a 10mm silicone tube (inner diameter 1.8mm) of the type shown in Figs 1 to 6 to leave a gap in the lumen between the nerve ends of 6 mm prefilled with a homogeneous 1% agar gel.
  • the silicone tube was sutured to the epineurium of the inserted nerves ends with 10-0 "atraumatic"
  • the nerve and the tube with its gap were examined after 2 and 4 weeks with regard to the distribution, direction and coherence of the axons and of the Schwann cells, as visualised by immunohistochemistry with the aid of antibodies to neurofilaments (N 0142 & N 5389, Sigma) and to the neuroglial protein S-100 (S 2644, Sigma; Z 0311, Dakopatts).
  • a positive pinch test was elicited after 4 weeks at a distance of 15 mm in one out of 4 animals, the other 3 being negative.
  • the sciatic nerve was exposed unilaterally on the mid thigh of adult rats and transected.
  • the proximal and distal nerve ends were then each inserted 2 mm into a 10mm silicone tube (inner diameter 1.8mm) to leave a gap in the lumen between the nerve ends of 6 mm prefilled with a 1% agar gel having 3 or 5 longitudinal channels of nominal diameter of 0.4mm formed by temporary insertion of filaments during the gelation procedure, for example as shown in Fig. 8.
  • the silicone tube was sutured to the epineurium of the inserted
  • the nerve and the tube with its gap were examined after 2 and 4 weeks with regard to the distribution, direction and coherence of the axons and of the Schwann cells, as visualised for example by immunohistochemistry with the aid of antibodies to neurofilaments (N 0142 & N 5389, Sigma) and to the neuroglial protein S-100 (S 2644, Sigma; Z 0311, Dakopatts). 5
  • the interfaces between the nerve ends and the gel and between the gel and the enclosing silicone tube were filled with tissue, rebuilt and restructured in a regular manner over time. Macroscopic inspection after 1 week revealed that a fibrin network was converging towards the opening of each one of the channels, proximally as well as distally. 0
  • the nerve tissue bridging the conduit gap from the proximal to the distal nerve end through o the intermediate channels were arranged in minifascicles. mainly composed of axons and Schwann cells enclosed by a thin perineurium. The axons and the Schwann cells were arranged in distinct fascicle bundles, bridging between the nerve ends through the channels. In addition, randomly orientated Schwann cells could be recognised between the fairly coherent cell bundles in the gap region. The number of axons per channel increased by a factor in the order of at least 3 from 2 weeks to 4 weeks. The perineural connective tissue enclosing the minifascicles was less abundant than that observed in the regenerates from PBS filled tubes, e.g. Example 1.
  • Axons were as well observed along the interface between the gel and the tube. The vast majority of these axons were randomly orientated, lacking the high degree of axonal coherence demonstrable in the gel channels.
  • the axons in the 5 channel system showed good coherence even when entering the distal nerve.
  • an encasement structure such as the guide tubes of the Examples
  • mechanical guide means for the tissue regenerate such as the central guide filaments of the Examples
  • a fibrin network formation inhibiting agent such as a fibrinolytic agents and/or a thrombin inhibitor
  • the materials which may be used as a carrier matrix for the fibrin network formation inhibiting agent includes any material or system in which the agent can be inserted into or conveyed into the encased wound area such as any biocompatible material into which the agent can be suspended, dissolved or released from.
  • carrier materials may include, but are not Hmited to, collagen, methylcellulose gel, chitosan and other polysaccharides, fibrin or other proteins, extracellular matrix materials such a MatrigelTM (Collaborative Research, Inc., Waltham, MA, USA), Biomatrix TM (Biomedical Technologies, Inc., Stoughton, MA) or other related materials.
  • the carrier may also comprise saline, water or, as in the Examples described above, buffered solutions which may be delivered to the encased wound area using a continuous delivery system, such as an osmotic mini-pump or externally accessible catheter connected to the device for continuous delivery.
  • a continuous delivery system such as an osmotic mini-pump or externally accessible catheter connected to the device for continuous delivery.
  • the fibrin network formation inhibiting agent could also be immobilised in the encasement structure.
  • the present invention also provides for growth-stimulating agents to be placed or delivered into the encased wound area.
  • agents include trophic, chemotactic, mitogenic, or similar substances, or combinations or mixtures thereof, which are capable of stimulating growth, directly or indirectly.
  • these agents include insulin like growth factors-I, insulin-like growth factors-D, platelet derived growth factors, interleukines, cytokines, fibroblast growth factors, transforming growth factors- ⁇ , transforming growth factors-a, epidermal growth factors, brain-derived neurotrophic factors, neurotrophines, ciliary neurotrophic factors, EGF and glial growth factors.
  • Therapeutic agents may also include whole cells or their parts which may be delivered to the encased wound area. These include Schwann cells, endothelial cells, fibroblasts, monocytes, macrophages, inflammatory cells or genetically altered cells or mixtures thereof.
  • the growth- stimulating agent may be inco ⁇ orated in the carrier matrix for the fibrin network formation inhibiting agent or in its own carrier, for example genetically altered or unaltered cells capable of delivering growth- stimulating agents may be inco ⁇ orated as a delivery system for the growth-stimulating agents to the encased injured structure.
  • the growth-stimulating agent may also be immobilised in the encasement structure for slow release thereof.

Abstract

Système, procédé et dispositif utiles pour activer la croissance d'un régénérat tissulaire dans une zone blessée située dans une structure de tissus organisés d'un corps humain ou animal à partir d'une surface de la zone blessée dans un sens prédéterminé. Une structure de protection (5) enferme la surface blessée pour empêcher des tissus de granulation d'y pénétrer, des guides mécaniques (11) pour le régénérat tissulaire en pleine croissance étant disposés dans la zone blessée de manière à s'étendre dans le sens prédéterminé. Selon un aspect de l'invention, on administre de manière concomittante un agent inhibant la formation d'un réseau de fibrine sur la surface blessée de la zone blessée enfermée. Selon un autre aspect, le guide mécanique se présente sous forme d'une structure de gel associée à une ou plusieurs rainures de guides destinées au régénérat tissulaire en pleine croissance, qui s'étendent dans le sens prédéterminé.
PCT/SE1997/000565 1996-03-29 1997-04-01 Stimulation de la regeneration de tissus organises WO1997037002A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
IL12609397A IL126093A0 (en) 1996-03-29 1997-04-01 Promotion of regeneration of organized tissues
IL13843697A IL138436A0 (en) 1996-03-29 1997-04-01 An implantable device for the promotion of regeneration of organized tissues
BR9708459A BR9708459A (pt) 1996-03-29 1997-04-01 Sistema dispositivo implantável e processo para promover o crescimento em uma direção predeterminada de regenerado de tecido e uso do sistema e do dispositivo
NZ331710A NZ331710A (en) 1996-03-29 1997-04-01 Regeneration of growth tissue in wound using an encasement, mechanical guide and thrombin inhibitor
EP97915831A EP0942960A1 (fr) 1996-03-29 1997-04-01 Stimulation de la regeneration de tissus organises
AU23157/97A AU717648B2 (en) 1996-03-29 1997-04-01 Promotion of regeneration of organized tissues
PL97329483A PL329483A1 (en) 1996-03-29 1997-04-01 Stimulation of organised tissue regeneration
JP09535213A JP2000510712A (ja) 1996-03-29 1997-04-01 生体組織の再生促進
IS4849A IS4849A (is) 1996-03-29 1998-09-18 Hvött endurmyndun skipulagðra vefja
NO984534A NO984534L (no) 1996-03-29 1998-09-28 Promovering av regenerering av organiserte vev

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9601243A SE9601243D0 (sv) 1996-03-29 1996-03-29 Promotion of regeneration of organized tissues
SE9601243-0 1996-03-29

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WO1997037002A1 true WO1997037002A1 (fr) 1997-10-09

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EP (1) EP0942960A1 (fr)
JP (1) JP2000510712A (fr)
KR (1) KR20000005068A (fr)
CN (1) CN1219965A (fr)
AU (1) AU717648B2 (fr)
BR (1) BR9708459A (fr)
CA (1) CA2248729A1 (fr)
CZ (1) CZ306798A3 (fr)
HU (1) HUP9902451A3 (fr)
IL (2) IL138436A0 (fr)
IS (1) IS4849A (fr)
NO (1) NO984534L (fr)
NZ (1) NZ331710A (fr)
PL (1) PL329483A1 (fr)
SE (1) SE9601243D0 (fr)
TR (1) TR199801931T2 (fr)
WO (1) WO1997037002A1 (fr)

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WO2000033746A1 (fr) * 1998-12-08 2000-06-15 Orthofix Inc Dispositif et procede de passage d'un tendon
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EP1466561A1 (fr) * 1998-12-08 2004-10-13 Brian D. Adams Dispositif de passage d'un tendon
EP1586285A1 (fr) * 2002-12-27 2005-10-19 Nipro Corporation Tube d'induction de regeneration de nerfs
GB2417904A (en) * 2004-09-14 2006-03-15 Spinox Ltd Tubular prosthesis for nerve regeneration
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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6339074B1 (en) * 1994-03-23 2002-01-15 Fidia Advanced Biopolymers, Srl Sulfated hyaluronic acid and esters thereof
US6322571B1 (en) 1998-06-05 2001-11-27 Brian D. Adams Apparatus and method for placing sutures in the lacerated end of a tendon and similar body tissues
WO2000001439A1 (fr) * 1998-07-01 2000-01-13 University Of Pittsburgh Of The Commonwealth System Of Higher Education Applicateur non occlusif de fermeture coaxiale d'un vaisseau
WO2000033746A1 (fr) * 1998-12-08 2000-06-15 Orthofix Inc Dispositif et procede de passage d'un tendon
US6342060B1 (en) 1998-12-08 2002-01-29 Brian D. Adams Tendon passing device and method
EP1466561A1 (fr) * 1998-12-08 2004-10-13 Brian D. Adams Dispositif de passage d'un tendon
WO2002047557A1 (fr) * 2000-12-15 2002-06-20 The University Of Nottingham Regeneration de nerf
US7700819B2 (en) 2001-02-16 2010-04-20 Kci Licensing, Inc. Biocompatible wound dressing
US7763769B2 (en) 2001-02-16 2010-07-27 Kci Licensing, Inc. Biocompatible wound dressing
US8735644B2 (en) 2001-02-16 2014-05-27 Kci Licensing, Inc. Biocompatible wound dressing
US8163974B2 (en) 2001-02-16 2012-04-24 Kci Licensing, Inc. Biocompatible wound dressing
US8084664B2 (en) 2001-02-16 2011-12-27 Kci Licensing, Inc. Biocompatible wound dressing
EP1586285A1 (fr) * 2002-12-27 2005-10-19 Nipro Corporation Tube d'induction de regeneration de nerfs
EP1586285A4 (fr) * 2002-12-27 2008-04-02 Nipro Corp Tube d'induction de regeneration de nerfs
US8911761B2 (en) 2004-03-05 2014-12-16 Oxford Biomaterials Limited Composite materials
GB2417904A (en) * 2004-09-14 2006-03-15 Spinox Ltd Tubular prosthesis for nerve regeneration
US8216602B2 (en) 2005-11-17 2012-07-10 Gelita Ag Nerve guide
DE102005054941A1 (de) * 2005-11-17 2007-05-31 Gelita Ag Nervenleitschiene
WO2008040260A1 (fr) * 2006-10-03 2008-04-10 Centro De Ingeniería Genética Y Biotecnología Utilisation du facteur de croissance épidermique pour la restauration morphofonctionnelle de nerfs périphériques dans la neuropathie diabétique
US8642552B2 (en) 2006-10-03 2014-02-04 Centro De Ingenieria Genetica Y Biotecnologia Use of epidermal growth factor for the morphofunctional restoration of peripheral nerves in diabetic neuropathy
US9034826B2 (en) 2006-10-03 2015-05-19 Centro De Ingenieria Genetica Y Biotecnologia Use of epidermal growth factor for the morphofunctional restoration of peripheral nerves in diabetic neuropathy
DE102009057962B4 (de) * 2009-12-11 2012-09-20 Karlsruher Institut für Technologie Nervenprothese und Verfahren zur Herstellung einer Nervenprothese
WO2011069670A3 (fr) * 2009-12-11 2011-10-13 Karlsruher Institut für Technologie Prothèse nerveuse et procédé de fabrication d'une prothèse nerveuse
DE102009057962A1 (de) * 2009-12-11 2011-06-16 Karlsruher Institut für Technologie Nervenprothese und Verfahren zur Herstellung einer Nervenprothese
US9877725B2 (en) 2009-12-11 2018-01-30 Karlsruher Institut Fur Technologie Neural prosthesis and method for producing a neural prosthesis
CN105013015B (zh) * 2014-04-20 2018-04-24 上海市第一人民医院 一种组织工程学修复神经缺损的方法

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Publication number Publication date
NZ331710A (en) 2000-08-25
PL329483A1 (en) 1999-03-29
AU717648B2 (en) 2000-03-30
IL138436A0 (en) 2001-10-31
JP2000510712A (ja) 2000-08-22
NO984534L (no) 1998-11-25
EP0942960A1 (fr) 1999-09-22
HUP9902451A3 (en) 2001-05-28
HUP9902451A2 (hu) 1999-11-29
AU2315797A (en) 1997-10-22
NO984534D0 (no) 1998-09-28
CZ306798A3 (cs) 1999-01-13
CA2248729A1 (fr) 1997-10-09
CN1219965A (zh) 1999-06-16
TR199801931T2 (xx) 1999-01-18
KR20000005068A (ko) 2000-01-25
IL126093A0 (en) 1999-05-09
SE9601243D0 (sv) 1996-03-29
IS4849A (is) 1998-09-18
BR9708459A (pt) 1999-04-13

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