WO1990013302A1 - Nouveaux materiaux et procedes de regeneration tissulaire guidee - Google Patents

Nouveaux materiaux et procedes de regeneration tissulaire guidee Download PDF

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Publication number
WO1990013302A1
WO1990013302A1 PCT/US1990/002406 US9002406W WO9013302A1 WO 1990013302 A1 WO1990013302 A1 WO 1990013302A1 US 9002406 W US9002406 W US 9002406W WO 9013302 A1 WO9013302 A1 WO 9013302A1
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Prior art keywords
membrane
tissue
composition
biodegradable
bioactive
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PCT/US1990/002406
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English (en)
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Stephen T. Sonis
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Brigham And Women's Hospital
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Publication of WO1990013302A1 publication Critical patent/WO1990013302A1/fr

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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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
    • 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
    • A61L31/044—Collagen
    • 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
    • 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
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006—Properties of materials and coating materials
    • A61F2002/30062—(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30667—Features concerning an interaction with the environment or a particular use of the prosthesis
    • A61F2002/30677—Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
    • 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
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices

Definitions

  • the present invention relates to novel materials, compositions and methods for guided tissue regeneration in animals including humans.
  • Regeneration or healing of diseased and injured tissue is of major practical clinical importance. With respect to periodontal and long bone defects especially, one of the most significant impediments to satisfactory regeneration is invasion of a wound site by tissue with little or no potential to differentiate into the appropriate skeletal or connective tissue type. Migration and proliferation of epithelial cells into a skeletal wound site, for example, can prevent re- population by osteogenic cells which migrate more slowly.
  • a passive non-resorbable membrane typically, this membrane will be composed of a biocompatible inert material, which is sutured in place.
  • GoreTex tm polytetrafluoroethylene
  • Millipore filters are two materials which have been used as membranes. The greatest drawback to the use of such inert materials is that they must be surgically removed. This procedure, of course, disrupts the healing process, and can lead to unwanted infection of the wound site.
  • United States Patent No. 4,752,294 describes an element for controlled growth of tissue which can may be used for attaching a prosthesis to the body or for controlled regeneration of tissue around teeth.
  • the element is stated to be a passive non-resorbable biocompatible material having perforated walls and cavities of defined size, and to function by mechanically directing growth of epithelial and connective tissue.
  • Gore- Tex tm membranes were stated to promote formation of new connective tissue attachment by preventing dentogingival epithelium and gingival connective tissue from interfering with cementum formation on surgically exposed and planed root surfaces in monkeys (Gottlow et al . , J. Dent. Res. 66 (Spec. Issue Mar.) :281, Abstr. 1394 (1987)). Pontoriero et al . , J. Dent. Res. 67(Spec. Issue Mar.):272, Abstr. 1277 (1988), covered Class II furcation defects in mandibular molars with Gore-Tex tm membranes which were removed 1-2 months later. They reported a reduction in probing depth after 3 and 6 months in treated versus untreated patients.
  • a porous (0.45 ⁇ m) polytetrafluoroethylene membrane was used to cover experimentally produced through-and-through osseous mandibular defects (5 mm diameter) in rats. Healing was observed on membrane-covered defects where membrane displacement had not occurred. The chemically inert Teflon membranes were not removed prior to sacrifice. The authors state that "[f]rom the clinical point of view, it might seem more advantageous to use some type of membrane which is eventually resorbed into the tissue," but that "this could introduce problems such as local inflammatory response with phagocytic activity and the need to maintain proper timing between completion of bone regeneration and degradation of the membrane.”
  • gingival fibroblasts migrate through a type I collagen barrier when fibroblast specific chemoattractants (PDGF) were placed on the dentin surface.
  • PDGF fibroblast specific chemoattractants
  • Implants Another reported approach to wound healing is the use of implants or grafts.
  • the general objective of such implants is to provide a base for cell migration and growth, rather than to guide migration or exclude certain cells.
  • Such methods typically involve injection of a collagen gel into the wound site.
  • Other substances, such as demineralized bone extracts, may be mixed throughout the gel.
  • Implant techniques suffer from the same potential for adverse inflammatory response as do collagen gel membrane techniques.
  • Lyodura a lyophilized, allogenic dura matter material
  • the authors report gains in probing attachment level and greater reduction in probing pocket depth as compared to non-implanted controls. It is stated that the Lyodura seemed to act as a barrier against epithelial downgrowth and inflammatory cell infiltration.
  • the Lyodura material is purified dura matter cerebri taken from human corpses.
  • ECS enriched collagen solution
  • Porous hydroxyapatite is another substance which has been used as an implant. El Deeb et al . , J. Dent. Res. 65(Spec. Issue B) :822, Abstr. 864 (1986), used porous hydroxyapatite
  • Interpore 200 as a bone substitute to fill three wall iliac crest bone defects in monkeys. Histological examination revealed surrounding bone, muscle and connective tissue penetration of all implants. Kenney et al. , J. Dent. Res. 65(Spec. Issue B):82Z, Abstr. 867 (1986), used PHI to fill class II furcations in thirteen human patients. The authors report reduced pocket depths, increased attachment level gains, and increased vertical and horizontal bone level gains as compared to unfilled control defects.
  • novel membranes of the invention are characterized in being of a biodegradable material which is coated on one or more surfaces with one or more bioactive substances .
  • the biodegrad able bioactive membranes of the present invention are further characterized in that the specific bioactive substance or substances is chosen with reference to the particular tissue or cell type which it is desired to enhance or inhibit. Further, the choice of coating one or both sides of the bioactive biodegradable membranes of the invention is made with reference to the manner in which tissue regeneration may proceed with best therapeutic effect.
  • composition for guided tissue regeneration comprising a bioactive biodegradable membrane comprising a first and a second side, wherein said first side of said membrane comprises one or more biologically active substances not present on said second side.
  • the present invention provides for a composition for guided tissue regeneration comprising a biodegradable bioactive membrane comprising two sides, wherein a first and a second side of said membrane each comprises one or more biologically active substances, and wherein at least one of said one or more biologically active substances on said second side is not present on said first side.
  • compositions wherein said one or more biologically active substances is selected from the group consisting of drugs, peptides and proteins.
  • Biologically active substances may include hormones and growth factors.
  • biologically active substances according to the invention may be selected from, among others, epidermal growth factor, insulinlike growth factor, platelet derived growth factor, fibronectin, angiogenesis factor, and bone morphogenic protein, as well as those substances listed in Table II.
  • Additional embodiments comprise the preceding compositions, wherein the composition further permits the controlled release of BAS.
  • the release of BAS is controlled by covering at least part of the BAS-coated side of the membrane with a resorbable membrane layer.
  • BAS will be immediately available in areas of the membrane not covered by the resorbable membrane layer, whereas BAS availability in other areas of the membrane will require resorption of the resorbable membrane layer.
  • a resorbable membrane layer covering some or all of the BAS-coated side of the membrane may contain varying amounts of a component which may enhance or inhibit the rate of resorption, thereby controlling the rate at which BAS is released.
  • the BAS may be incorporated into a membrane comprising one or two layers.
  • the rate of BAS release may be further controlled by covering at least part of the BAS-coated membrane with a second resorbable membrane layer having a varying degree of cross-linked components.
  • the rate at which the membrane is resorbed will vary with the extent of cross-linking, thereby varying the rate of release of BAS.
  • compositions of the invention may additionally comprise an anti-microbial or other inhibitory agent on one or both sides, as appropriate for a given therapeutic application.
  • Non-limiting examples of suitable biodegradable membrane components according to the invention include polylactic acid, polyethylene oxide/polylactic acid (PELA), collagens, laminin and fibronectin.
  • PELA polyethylene oxide/polylactic acid
  • collagens include collagens, laminin and fibronectin.
  • tissue compositions such as those described above.
  • tissues which may be appropriate for guided tissue regenera tion according to the methods of the invention include epithelial tissue, bone tissue, ophthalmic tissue, vascular tissue and endothelial tissue.
  • a process for preparing a composition for guided tissue regeneration comprising conjugating to one or more sides of a biodegradable membrane a biologically active material.
  • the membrane may be desirable to affix the membrane to the tissue.
  • the means for affixing the membrane will depend upon, for example, the site of placement of the membrane and the size of the membrane.
  • the membrane may be affixed by suturing.
  • FIGURE Figure 1 is a representation of a biodegradable bioactive membrane having a bioactive substance. Some of the bioactive substance is covered by a resorbable membrane layer composed of one or more resorbable membranes assembled in a stepwise fashion.
  • guided tissue regeneration is meant the placement of a biodegradable membrane which is coated on one or more surfaces with one or more BAS at or in close apposition to the site of tissue loss or deficit, by means of which the migration, proliferation, or maturation of certain tissue or cell types may be enhanced or, if desired, inhibited. Such enhancement or inhibition will be understood by those of skill to be included within the definition of tissue guidance for the purposes of the present invention.
  • the biodegradable membrane may have one or more BAS incorporated within it.
  • biodegradable membrane is meant generally any relatively thin layer of tissue, such as that which may cover a surface, line a cavity, or divide a space or organ, which is susceptible of degradation by biological processes. Such membranes may be derived from natural or synthetic sources, or may comprise a combination of natural and synthetic elements. It will be appreciated, of course, that biodegradable membranes according to the present invention will preferably also be biocompatible, i.e., they will not have uncontrolled or uncontrollable inherent toxic or injurious effects upon biological functions.
  • biodegradable membranes will vary, depending upon the type of tissue(s) which it is desired to regenerate.
  • Such membranes could include, but not be limited to, collagen membranes prepared commercially from a molecular solution of purified bovine collagen, cross-linked with glutaraldehyde under sterile conditions.
  • Such membranes have been shown to successfully guide connective tissue attachment and generally last between 6 and 8 weeks before being resorbed by the host (Pitaru et al . , J. Dent. Res. 65(Spec. Issue B) :822, Abstr. 870 (1986); Blumenthal, J. Periodontol. 59(12) :830-836 (1988)).
  • biodegradable membranes of the present invention it will be generally preferable to design membranes having resorption rates which are slightly too slow, rather than too fast.
  • desirable resorption rates will vary as a function of, inter al ia, the rate of migration, proliferation and maturation of the predominant cell type involved.
  • composition of the biodegradable membranes of the invention will be chosen and the membranes assembled with reference to the particular target tissue, with the exercise of no more than routine skill.
  • Another suitable biodegradable membrane may be composed of polylactic acid.
  • Polylactic acid is a biodegradable ester polymer, synthesized from cyclic lactides. It contains no peptide linkages.
  • Polylactic acid membranes are available commercially, and have been used successfully for guided tissue regeneration and as a surgical mesh to treat facial deformities, arterial defects, dural defects and dental surgical defects (Kulkarni et al . , Arch. Surg. 9:839 (1966); Kulkarni et al . , J. Biomed. Mater. Res. 5:169-181 (1971); Magnusson et al . , J. Dent. Res. 65(Spec. Issue B) :822, Abstr. 866 (1986)).
  • a variant of the polylactic acid membrane is the polyethylene oxide/polylactic acid (PELA) membrane.
  • PELA polyethylene oxide/polylactic acid
  • This membrane is a co-polymer of polylactic acid and may be more efficacious in certain applications, since it exhibits a relatively more rapid resorption rate (Younes et al . , Biomat. , Art. Cells, Art. Organs 16:705-719 (1988)).
  • a preferred biodegradable membrane for use in accordance with the present invention will be composed, in major part, of collagen.
  • collagen Several different collagenous proteins have been isolated from connective tissues.
  • the collagen family of proteins presently comprises 11 different types, designated types I-XI. Different collagen types often are characteristically associated with different natural connective tissues. Accordingly, it will be evident to those of skill that the composition of a collagen-based biodegradable bioactive membrane may be adjusted with respect to the type and relative proportion of collagen used, so as to provide an optimal membrane for guided tissue regeneration of a given tissue.
  • the fibril-forming collagens are types I, II and III. Of these, type I is most abundant. Type II is the main collagenous protein of cartilage. Type III accompanies type I in different ratios in almost all tissues. Type IV collagen differs markedly in structure from the fiber-forming col lagens, forming a non-fibrillar network, and is found in basement membranes.
  • the glycoprotein fibronectin can serve as a mediator between collagen and the cell surface. As such, it is another constituent which those of skill will recognize as a desirable component of biodegradable membranes according to the present invention, for many tissue applications. Fibronectin has particularly high affinity for denatured collagens, Jilek et al . , Hoppe-Seyler's Z. Physiol . Chem. 359:247-250 (1978), and contains binding sites for collagen and for the cell surface. Fibronectin is reviewed, for example, in Yamada, Ann. Rev. Biochem. 52:761-799 (1983), and Yamada et al . , J. Cell Biochem. 28:79-97 (1985).
  • Plasma fibronectin shares antigenic expression and forms precipitant lines of identity on double immunodiffusion against polyclonal antisera prepared to any other fibronectin species, and has been described as a form of fibronectin distinct from extracellular or cell-associated fibronectin. See, J. McDonagh, ed., "Plasma Fibronectin: Structure and Function," Marcel Dekker, Inc., New York (1985). Those of skill will recognize that plasma fibronectin may be a desirable component of the biodegradable membranes according to the present invention. Alternatively, plasma fibronectin may be coated on the surface of a biodegradable membrane as a bioactive substance in keeping with the present invention.
  • Variations in the macromolecular structure of collagen types are believed to modify the biomechanical properties of the extracellular matrix to the various physiological functions of different connective tissues.
  • the ability of the fiber-forming collagens to vary their macromolecular organization is not enough to build stabilizing scaffolds for all of the different extracellular matrices.
  • triple-helical elements are believed to be combined with globular domains on the one hand, and on the other hand, the length and some structural features of the triple-helical domain itself often may be altered.
  • type IV collagen is found only in basement membranes.
  • the molecules of type IV collagen do not form fibrils, but form instead a network in which they are connected to one another via their like ends. Flexibility is introduced by frequent interruption of the triple helix by non-helical areas.
  • type IV collagen differs from the fiber- forming collagens.
  • Type VI collagen is particularly rich in the cornea.
  • Type VII is the major and perhaps sole component of anchoring fibrils, and cornea demonstrates the most extensive anchoring fibril network visualized thus far.
  • Type VIII collagen also known as endothelial collagen, is secreted by most endothelial cells in culture. Highest type VIII levels are observed in rapidly proliferating or migrating cells plated at low density.
  • Type VIII collagen also is found in high concentrations in Descemet's membrane, which is the basement membrane which separated cornea! endothelial cells from corneal stroma.
  • a collagen-based membrane intended for use in guiding tissue regeneration of corneal tissue might contain relatively greater amounts of type VI, type VII, and type VIII collagens.
  • These collagen types might not be included in the preparation of a biodegradable membrane according to the present invention which was intended for use in guiding regeneration of skin, tendon, muscle, bone, etc., which might contain relatively larger proportions of type I and type III collagens.
  • a biodegradable collagen-based membrane which was intended for use in regeneration of hyaline cartilage, might contain a relatively higher proportion of type IX collagen.
  • This collagen is a proteoglycan, predominantly present in the pericell ular matrix which immediately surrounds chondrocytes.
  • Type XI collagen might also be included for such purposes according to the present invention.
  • preparation of a biodegradable membrane according to the invention could preferably include relatively larger amounts of type X collagen. It is known, for example, that accumulation of type X collagen precedes calcification of tissue. It is the major collagen type synthesized in most mature chondrocytes involved in endochondral bone formation. Thus, type X collagen bridges the spatial and temporal transition from cartilage to bone.
  • Laminin is a multi-functional protein with diverse biological activities. Like fibronectin, it is believed to influence cell adhesion, growth, morphology, differentiation, migration, and agglutination, as well as the assembly of the extra-cellular matrix. Laminin primarily affects cells of epithelial origin, and the response varies depending upon the cell. Laminin is a large glycoprotein present in all basement membranes, where it is the most abundant constituent. It binds to various components of basement membrane and probably links these to one another to form an integrated complex. A specific cell surface receptor to laminin has been identified. Laminin and its biological activities are described in Kleinman et al . , J. Cell Biochem.
  • Laminin binds to matrix components, including type IV collagen, heparin sulfate proteoglycan, entactin, and nidogen, which those of skill will recognize as other elements which it may be desirable to incorporate into the biodegradable bioactive membranes of the invention.
  • Laminin promotes attachment of various epithelial cells to type IV collagen-coated substrates. Unlike fibronectin, laminin is able to bind either to the cell surface or to collagen, although laminin appears to be most effective as an attachment protein for epithelial cells when bound to type IV collagen.
  • fibronectin modulates the function of platelets, neutrophils, monocytes, fibroblasts, endothelial cells, and keratinocytes.
  • the plasma enzyme transglutaminase (factor VIII) cross-links the fibrin polymer which is a major structural component of the blood clot that fills a skin wound defect.
  • factor VIII which also covalently links fibronectin to the fibrin polymer, may be a desirable bioactive substance for use in the biodegradable membranes of the present invention.
  • Elastin is an important component of the extracellular matrix in tissues that undergo repeated elastic recoil. It thus may be an especially desirable component of the biodegradable bioactive membranes of the invention when guided regeneration of such tissues is indicated. Together with glycoprotein microfibrils, elastin forms extracellular fibers that provide resiliency essential for normal tissue function. Cell types that synthesize elastin include smooth muscle cells, fibroblasts and myofibroblasts, endothelial cells, and chondrocytes in elastic cartilage. The elastic properties of many tissues of the vertebrate body, such as the lung and larger arteries, are due mainly to the presence in the extracellular matrix of elastic fibers composed primarily of the protein elastin.
  • Proteoglycans are a diverse group of heterogeneous macromolecu!es that are most abundant in the extracellular matrix of connective tissues.
  • Proteoglycans contain core proteins to which one or more glycosaminoglycan side chains are covalently attached.
  • Glycosaminoglycans are linear anionic polysaccharides with repeating disaccharide units containing a hexosamine residue and usually, but not always, a hexuronic acid residue.
  • Proteoglycans, and especially chondroitin sulfate are found in high concentrations in cartilage. Most of the proteoglycans within the cartilage matrix seem to be present as aggregates.
  • proteoglycans are central to the proper functioning of cartilage, which is to be able to reversibly absorb loading forces. There are experimental data which suggest that proteoglycans play an active role in the mineralization process. Thus, those of skill will appreciate that proteoglycans may be desirable constituents of biodegradable bioactive membranes according to the present invention, especially with respect to guided regeneration of cartilage tissue. Proteoglycans are reviewed, for example, by Kuttner et al . , J. Cell Biochem. 27:327-336 (1985); and T.N. Wight and R.P. Mecham, eds., "Biology of Proteoglycans," Academic Press, Inc., Orlando (1987).
  • biodegradable bioactive membranes of the present invention may be incorporated into the biodegradable bioactive membranes of the present invention in their mature forms, as well as in known precursor forms, and further, that synthetic analogues of these components also may be advantageously used.
  • synthetic analogues of these components also may be advantageously used.
  • bioactive agents to coat one or more surfaces of the membrane, rather than as constituents of the membrane matrix itself.
  • biodegradable bioactive membrane comprising two sides
  • the biodegradable bioactive membrane will have coated onto at least one of said sides one or more bioactive agents.
  • incorpororation of such bioactive agents onto the surface of the biodegradable bioactive membranes of the present invention results in selective enhancement or, if desired, inhibition of host or foreign cell or tissue migration, proliferation, or maturation which has not previously been possible.
  • bioactive agents for use according to the present invention will be made with reference to the particular types of host or foreign cell or tissues which it is desired to enhance or inhibit.
  • bioactive agents will thus be made by those of skill, keeping in mind general principles of cell migration, proliferation, and maturation.
  • the principal bioactive agents which may be employed in accordance with the present invention include, but are not limited to, drugs, hormones and peptide growth factors.
  • drugs any chemical compound that may be used on or administered to humans or animals as an aid in the diagnosis, treatment, or prevention of disease or other abnormal condition, for the relief of pain or suffering, or to control or improve any physiologic or pathologic condition.
  • drugs useful in the present invention may act to enhance or inhibit host or foreign cellular or tissue function, and that the choice of such drugs will be made in accordance with generally accepted principles of clinical therapeutics. Such principles are set forth, for example, in A. G. Gilman et al . , eds., “Goodman and Gilman's The Pharmacological Basis of Therapeutics," 7th Ed., MacMillan Publishing Co., New York (1985).
  • a first side of the biodegradable bioactive membrane will be coated with one or more agents which enhance the migration, proliferation or maturation of a particular cell type.
  • This first side will be placed at the site of a wound or defect such that it faces said wound or defect, in order to achieve the optimal enhancing effects of the agent or agents which coat this first side.
  • a second side of said membrane will be uncoated, or, preferably, coated with one or more inhibiting agents.
  • agents might include, for example, anti-microbial agents, in order to reduce the incidence of undesirable inflammation and infection.
  • Suitable anti-microbials which may be used in accordance with the invention will be selected by those of skill in accordance with accepted principles of clinical antimicrobial treatment.
  • the general goal in choosing an anti-microbial is to select a drug or other agent which is selectively active for the most likely infecting microorganism(s), and that has the least potential to cause toxicity or allergic reactions in the individual being treated.
  • anti-microbial agents which may be selected for use in accordance with the invention may be mentioned the sulfonamides, trimethorprim-sulfamethoxazole, penicillins, cephalosporins, and other ⁇ -lactam antibiotics, aminoglycosides, tetracyclines, chloramphenicol, erythromycin, and other anti-bacterial agents, as well as anti -fungal and anti-viral agents.
  • the second side of the biodegradable bioactive membrane of the invention may, in another embodiment, be coated with an enhancing agent.
  • This agent may be the same as that which is used to coated the first side of the membrane. In a preferred embodiment, however, it will be a different agent, and may be chosen with the object of enhancing a different host cell or tissue type than that which is the object of the first agent coating the first side of the membrane. In this manner, it will be possible according to the invention to differentially enhance and guide regeneration of different cell or tissue types on each side of the membrane.
  • the second side of the membrane may be coated with factors to regulate epithelial growth.
  • factors to regulate epithelial growth are EGF, and other examples will be apparent to one of skill in the art.
  • the second side may be coated with a fibroblast proliferation regulator, an example of which is TGF ⁇ or ⁇ .
  • Drugs and other bioactive agents used in accordance with the present invention may be coated on the surface of the biodegradable bioactive membranes of the invention by any known methods, including the use of cross-linking molecules such as proteins.
  • the enzyme factor VIII is one non-limiting example of a protein cross-linking molecule which may be employed in this regard.
  • Cross-linkage also may be performed in some systems using irradiation at low temperatures.
  • Other techniques for coating one or both surfaces of the biodegradable bioactive membranes of the present invention will be determined by those of skill with reference to the particular agent, the composition of the membrane, and other factors, with the exercise of routine skill. It will thus be appreciated that the term “coated” as used herein refers broadly to any method or process which allows the achievement of the desired result as herein described.
  • drugs and other active substances may be employed in the form of pharmaceutical compositions, and, of course, that many combinations of active agents may be beneficially used on one or both sides of the biodegradable bioactive membranes of the invention. Accordingly, such pharmaceutical compositions may be administered to any animal which may experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited.
  • the dosage of the active agents administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • the pharmaceutical preparations may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilit- ate processing of the active compounds into preparations which can be used pharmaceutically.
  • the pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary.
  • Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrol idone.
  • fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose,
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrol idone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Suitable formulations include aqueous solutions of the active compounds in water-soluble form, for example, water- soluble salts.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides.
  • Aqueous suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • hormones generally chemical messengers normally synthesized in the endocrine glands of multicellular organisms and secreted into the extracellular body fluids. Hormones typically are recognized by and bind to specific cellular receptors of their respective target tissues.
  • peptide growth factors or “growth factors” is meant generally hormone-related substances which play an important role in the control mechanisms of growth and development in a diversity of organs and tissues. Unlike classical hormones, growth factors typically are not synthesized in specialized endocrine organs, but are produced and secreted by cells from different tissues in a steady flow to diffuse to responsive cells, frequently located not far from the site of release.
  • Growth factors usually are identified by their ability to induce stimulation of target cell multiplication, and their activity is measured by, for example, assays in which either the increase in cell populations or the incorporation of labeled thymidine into DNA is determined.
  • a listing of growth factors, hormones, and other growth-regulating agents of exogenous cellular origin which are suitable for use as biologically active substances in accordance with the present invention is provided in Table II. It will be appreciated, of course, that this listing is merely exemplary of suitable agents, and is not intended to be limiting. Further, those of skill will recognize that certain of the listed agents may, in certain circumstances, be unsuitable for use in accordance with the invention.
  • biodegradable bioactive membranes of the present invention include, but are not limited to, periodontology, craniofacial defects, orthodontics, ophthalmology and plastic surgery.
  • novel materials, compositions and methods of the invention will be useful in virtually any application in which tissue repair or regeneration is desired or desirable.
  • a preferred clinical therapeutic application of the present invention is in the treatment of wounds, including ulcerations and burn wounds. Effective management and healing such wounds presents a significant challenge to clinicians, in large part because of the risk of complications resulting from infection at the wound site.
  • the biodegradable bioactive membranes of the present invention may be employed as occlusive wet dressings. Such dressings primarily protect the wound site from bacterial contamination and prevent post- burn contractures, and are often employed during the initial treatment phases while the patient is being readied for skin or skin substitute grafts.
  • the biodegradable bioactive membranes of the invention may have a first side, which will be placed in contact with the wound surface, coated with a suitable topical bactericide, bacterio stat, or anti-microbial agent, or a combination thereof.
  • This first side may also include other agents selected to enhance migration of cells into the wound site from adjacent intact tissues, as well as suitable growth factors, such as epidermal growth factor, known to be involved in wound repair.
  • the second side of the membrane may be uncoated, or may preferably be coated with a bactericide, bacteriostat, anti-microbial, or other agent.
  • the advantages of the biodegradable bioactive membranes of the invention in this application will include the guidance and enhancement of the rate of migration and proliferation of cells into the wound site and reduced risk of infection. This may allow healing of many wounds without the need for grafting.
  • the biodegradable bioactive membranes of the present invention will be well suited for use as skin substitutes.
  • the choice of membrane composition and bioactive agents will follow the same general principles as those which apply when the membrane is to be used as a wet occlusive dressing.
  • the biodegradable bioactive membrane may be sutured into place using appropriate methods known to those of skill. General applicable surgical principles of burn wound treatment and maintenance are set forth, for example, in MacMillanm, Surgical Clinics N. America 58(6) : (1978); and Parks et al . , Surgical Cl inics N. America 57(5) : (1977).
  • a square or roughly rectangular-shaped BAS-coated membrane may be visualized as having two opposite edges.
  • the membrane near one edge would have no overlying second resorbable membrane layer, thus allowing immediate availability of the BAS.
  • the membrane near the second edge would be coated with a plurality of second resorbable membranes.
  • the second resorbable membranes are built up across the BAS-coated membrane in a stepwise fashion.
  • the second edge of the membrane may have 20 layers of second resorbable membranes, whereas the center of the membrane may have less than 20 layers of second resorbable membranes and BAS-coated membrane closest to the first edge of the membrane would have immediately available BAS.
  • This "staggered" layering of second resorbable membranes is shown in Figure 1.
  • Staggered second resorbable membranes would be applied to one or both sides of the biodegradable bioactive membrane. Application to a side previously coated with, for example, a growth factor, would allow release of the growth factor at different sites at different times, depending on the thickness of the second resorbable membrane layer and the rate of its resorbtion.
  • staggered second resorbable membrane layer to a second side of the biodegradable bioactive membrane, coated with, for example, a bacteriostatic agent, would likewise allow release of the bacteriostatic agent at different sites at different times.
  • a roughly circular or rounded BAS- coated membrane may have a region with immediately available BAS, surrounded by a separate region in which the availability of the BAS is delayed by a resorbable membrane layer covering the BAS.
  • the layer may contain a gradient of a component which renders the membrane resistant to enzymatic action. Membrane having little or none of this component would permit immediate release of BAS, whereas membrane having a higher concentration of the component would allow delayed release of BAS.
  • Controlled release of BAS from the membrane may also be accomplished by the incorporation of BAS into the membrane itself.
  • the membrane comprises two sides.
  • the membrane layer adjacent to one side has incorporated within it one or more BAS.
  • the membrane layer adjacent to the second side has incorporated within it one or more BAS, at least one of which differs from BAS in the membrane layer adjacent to the first side.
  • the membrane adjacent to the first side may have primary osteogenic factor incorporated within it.
  • the membrane adjacent to the second side may contain a factor to slow epithelial proliferation, such as TGF ⁇ .
  • the membrane would consist of a biodegradable material as described herein, thus allowing controlled release of the BAS as the membrane is degraded.
  • controlled release may be accomplished using a membrane comprising two layers. Each layer has incorporated within it one or more BAS, and at least one BAS of one layer differs from the BAS of the second layer. For example, one layer may have primary osteogenic factor incorporated within it. The second layer may contain a factor to slow epithelial growth, such as TGF ⁇ .
  • the membrane layers would consist of biodegradable materials to allow controlled release of the BAS.
  • the membranes described above may be used to treat a periodontal bony defect. Using the method as described herein, the membrane would be located in the patient's mouth in such a manner that the osteogenic factor-containing side of the membrane faced and covered the defect.
  • the resorbable membrane as described above may contain other BAS as described herein. Use of such membranes is in accordance with the methods described herein and will depend upon the particular BAS incorporated within the membrane.
  • the controlled release of BAS can be further accomplished by varying the cross-linking of the polymers in the resorbable membrane.
  • biodegradable bioactive membrane it may be desirable or advantageous to affix the biodegradable bioactive membrane to the tissue.
  • the means of affixing the membrane will depend upon the composition of the membrane, the site at which the membrane is to be placed, the size of the membrane, and other parameters which will be taken into account by one skilled in the art.
  • Bioadhesion may be accomplished using, for example, the materials disclosed in U.S. Patent No. Re. 33,093, which is incorporated herein by reference in its entirety.
  • the membranes of the invention may also be affixed by suturing. Suitable methods of suturing are well-known to one of skill in the art.
  • a biodegradable bioactive membrane according to the invention is employed to guide regeneration of human periodontal bony defects.
  • a human subject suffering from interdental bony craters two-wall lesions
  • An experimental lesion and a comparable lesion which will act as a control are identified.
  • Subgingival curettage at the sites of bony defects is performed fourteen days prior to scheduled surgery. Baseline recordings of gingival recession, probing bone level and probing pocket depth are measured immediately prior to surgery.
  • the interdental craters are exposed through the modified Widman technique.
  • the biodegradable bioactive membrane is composed of a purified commercially available bovine collagen preparation.
  • the first side of this membrane which will be placed against the alveolar bone and will cover the defect, is coated with primary osteogenic factor.
  • Primary osteogenic factor is described, for example, in U.S. Patent 4,804,744.
  • the second side of the membrane is coated with erythromycin. The membrane is applied so as to bridge the interdental crater and cover the alveolar bone for a minimum of three millimeters on each side of the defect.
  • the flaps are sutured and dressed with a commercially available periodontal pack.
  • the control defect is treated in an identical fashion, except that the collagen membrane applied is not bioactive.
  • the evaluation parameters are measured at 12, 24 and 48 weeks. Although no significant differences in gingival recession are observed, there is a noticeable decrease in inflammatory response on the experimental side. Probing bone level and probing pocket depth values, however, reveal a significant improvement in alveolar bone regeneration on the experimental side.
  • a biodegradable bioactive membrane is employed as in Example 1.
  • the first side of this membrane which will be placed against the alveolar bone and will cover the defect, is coated with primary osteogenic factor.
  • Primary osteogenic factor is described, for example, in U.S. Patent 4,804,744.
  • a second material having antimicrobial properties, such as tetracycline, is also incorporated on this first side.
  • the second side of the membrane is coated with a factor, TGF ⁇ , to slow epithelial proliferation.
  • TGF ⁇ factor
  • a biodegradable bioactive membrane having at least one side coated with a staggered resorbable membrane according to the invention is employed to guide regeneration of human periodontal bony defects.
  • a human subject is selected and presurgical procedures carried out according to Example 1.
  • the interdental craters are exposed through the modified Widman technique. Thorough curettage is performed, followed by application of a biodegradable bioactive membrane to the interdental crater at the experimental site.
  • the biodegradable bioactive membrane is composed of a purified commercially available bovine collagen preparation.
  • the first side of this membrane which will be placed against the alveolar bone and will cover the defect, is coated with primary osteogenic factor.
  • Some of the primary osteogenic factor is located between the biodegradable bioactive membrane and at least one layer of a second resorbable membrane, in the following manner.
  • the primary osteogenic factor remains uncovered.
  • the primary osteogenic factor is covered with 20 layers of second resorbable membrane. These layers are built up in a staggered manner between the first and second edge of the biodegradable bioactive membrane.
  • the second side of the biodegradable bioactive membrane is coated with EGF.
  • the membrane is applied so as to bridge the interdental crater and cover the alveolar bone for a minimum of three millimeters on each side of the defect.
  • the first edge of the membrane, having no second resorbable membrane overlay is placed in proximity to the site of regeneration.
  • the second edge of the membrane, having the maximum thickness of second resorbable membrane overlay, is placed farther from the site of regeneration.
  • the flaps are sutured and dressed with a commercially available periodontal pack.
  • a biodegradable bioactive membrane is employed as in example 3, except that in this example the second side of the biodegradable bioactive membrane is coated with TGF ⁇ .
  • EXAMPLE 5 As a fifth non-limiting example of the use of the present invention, a bioactive, biodegradable membrane is used as an occlusive wet dressing for the treatment of a skin wound.
  • a biodegradable bioactive membrane composed primarily of collagen is prepared and one side of the membrane is coated with epidermal growth factor.
  • the epidermal growth factor layer is at least partially covered with a second resorbable membrane.
  • the epidermal growth factor will be fully exposed and available to the wound sites where immediate regeneration is desired. Delayed or guided regeneration in other areas of the wound sites can be accomplished by controlling release of growth factor to those sites. Release of the growth factor to those sites occurs only after resorption of the resorbable layer protecting the growth factor. Epidermal growth factor is thus immediately available in areas of the wound where immediate regeneration is desired, and sustained or guided regeneration is achieved by delaying the release of growth factor to other sites of the wound.

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Abstract

L'invention concerne des matériaux et des procédés nouveaux de régénération tissulaire guidée. Les compositions de l'invention comprennent une membrane biodégradable comportant des première et seconde faces, ladite première face de ladite membrane comprenant une ou plusieurs substances biologiquement actives, non présentes sur ou dans ladite seconde face. Dans un autre mode de réalisation, les deux faces de la membrane peuvent comprendre une ou plusieurs surfaces biologiquement actives. Une face ou les deux faces de ladite membrane peuvent être au moins recouvertes d'une seconde couche de membrane résorbable d'épaisseur et/ou de composition variable, permettant ainsi la libération régulée de ladite ou desdites substances biologiquement actives. Les compositions, les matériaux et les procédés de l'invention présentent une utilité thérapeutique afin de guider la régénération tissulaire chez l'animal et chez l'homme.
PCT/US1990/002406 1989-04-28 1990-04-30 Nouveaux materiaux et procedes de regeneration tissulaire guidee WO1990013302A1 (fr)

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