US20020095218A1 - Tissue repair fabric - Google Patents

Tissue repair fabric Download PDF

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Publication number
US20020095218A1
US20020095218A1 US09/843,172 US84317201A US2002095218A1 US 20020095218 A1 US20020095218 A1 US 20020095218A1 US 84317201 A US84317201 A US 84317201A US 2002095218 A1 US2002095218 A1 US 2002095218A1
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US
United States
Prior art keywords
prosthesis
collagen
layers
icl
tissue
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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US09/843,172
Inventor
Robert Carr
Kimberlie Condon
Paul Termin
Janet Young
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Individual
Original Assignee
Individual
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Filing date
Publication date
Priority claimed from PCT/US1996/003336 external-priority patent/WO1996031157A1/en
Application filed by Individual filed Critical Individual
Priority to US09/843,172 priority Critical patent/US20020095218A1/en
Publication of US20020095218A1 publication Critical patent/US20020095218A1/en
Priority to US10/376,788 priority patent/US7060103B2/en
Priority to US11/277,406 priority patent/US7909886B2/en
Abandoned legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2/00Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0082Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
    • A61L2/0088Liquid substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/0063Implantable repair or support meshes, e.g. hernia meshes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/22Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24Collagen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3629Intestinal tissue, e.g. small intestinal submucosa
    • AHUMAN NECESSITIES
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    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3641Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3687Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
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    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58Materials at least partially resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/0077Special surfaces of prostheses, e.g. for improving ingrowth
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/02Prostheses implantable into the body
    • A61F2/04Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06Blood vessels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/02Prostheses implantable into the body
    • A61F2/10Hair or skin implants
    • A61F2/105Skin implants, e.g. artificial skin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/02Prostheses implantable into the body
    • A61F2/24Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
    • A61F2/2412Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/02Prostheses implantable into the body
    • A61F2/24Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
    • A61F2/2475Venous valves
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/44Joints for the spine, e.g. vertebrae, spinal discs
    • A61F2/442Intervertebral or spinal discs, e.g. resilient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2002/30001Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006Properties of materials and coating materials
    • A61F2002/30062(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
    • AHUMAN NECESSITIES
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    • A61F2/00Filters 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
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/30767Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2002/30929Special external or bone-contacting surface, e.g. coating for improving bone ingrowth having at least two superposed coatings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2210/00Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005The prosthesis being constructed from a particular material
    • A61F2310/00365Proteins; Polypeptides; Degradation products thereof
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S623/00Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
    • Y10S623/915Method or apparatus for preparing biological material
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S623/00Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
    • Y10S623/915Method or apparatus for preparing biological material
    • Y10S623/916Blood vessel
    • Y10S623/917Collagen

Definitions

  • This invention is in the field of implantable biological prostheses.
  • the present invention is a non-antigenic, resilient, completely bioremodelable, biocompatible tissue prosthesis which can be engineered into a variety of shapes and used to repair, augment, or replace mammalian tissues and organs.
  • Each layer of the prosthesis is gradually degraded and remodeled by the host's cells which replace the implanted prosthesis in its entirety to restore structure and function and is useful for organ repair and reconstruction.
  • the prosthesis acts as a template by which the host's cells will remodel themselves through a process that will replace the prosthetic collagen molecules with the appropriate host cells in order to restore and replace the original host tissue or organ.
  • implantable prostheses are made from a number of synthetic and treated natural materials.
  • the ideal prosthetic material should be chemically inert, non-carcinogenic, capable of resisting mechanical stress, capable of being fabricated in the form required, and sterilizable, yet not be physically modified by tissue fluids, excite an inflammatory or foreign body reaction, induce a state of allergy or hypersensitivity, or, in some cases, promote visceral adhesions (Jenkins S.D., et al. Surgery 94(2):392-398, 1983).
  • absorbable synthetic meshes have the advantage of impermanence at the site of implantation, but often have the disadvantage of losing their mechanical strength, because of dissolution by the host, prior to adequate cell and tissue ingrowth.
  • GORE-TEX® is currently believed to be the most chemically inert polymer and has been found to cause minimal foreign body reaction when implanted.
  • Collagen first gained utility as a material for medical use because it was a natural biological prosthetic substitute that was in abundant supply from various animal sources.
  • the design objectives for the original collagen prosthetics were the same as for synthetic polymer prostheses; the prosthesis should persist and essentially act as an inert material.
  • purification and crosslinking methods were developed to enhance mechanical strength and decrease the degradation rate of the collagen (Chvapil, M., et al (1977) J. Biomed. Mater. Res. 11: 297-314; Kligman, A.M., et al (1986) J. DermatoL Surg. Oncol. 12 (4): 351-357; Roe, S.C., et al. (1990). Artif. Organs.
  • Crosslinking native collagen reduces the antigenicity of the material (Chvapil, M. (1980) Reconstituted collagen. pp. 313-324. In: Viidik, A., Vuust, J. (eds), Biology of Collagen. Academic Press, London; Harjula, A., et al. (1980) Ann. Chir. Gynaecol. 69: 256-262.) by linking the antigenic epitopes rendering them either inaccessible to phagocytosis or unrecognizable by the immune system.
  • U.S. Pat. No. 5,571,216 details several methods of achieving crosslinking through the heating and joining of free ends of collagen tendrils.
  • a prosthesis When such a prosthesis is implanted, it should immediately serve its requisite mechanical and/or biological function as a body part.
  • the prosthesis should also support appropriate host cellularization by ingrowth of mesenchymal cells, and in time, through isomorphous tissue replacement, be replaced with host tissue, wherein the host tissue is a functional analog of the original tissue.
  • the implant In order to do this, the implant must not elicit a significant humoral immune response or be either cytotoxic or pyrogenic to promote healing and development of the neo-tissue.
  • U.S. Pat. No. 4,787,900 to Yannas details a process for the creation of prosthetic blood vessels out of a collagenous composite formed, ex vivo, from individual collagen molecules in either powder or solution form.
  • the collagenous compound is a conglomerate of individual collagen molecules and does not retain any of the structural characteristics of the tissue from which the collagen was originally derived. Instead, this collagenous composite is a “tangled mass of collagen fibrils” that is later chemically tailored into the desired shape and thickness required for repairing the specific blood vessel.
  • Prostheses or prosthetic material derived from explanted mammalian tissue have been widely investigated for surgical repair or for tissue and organ replacement.
  • the tissue is typically processed to remove cellular components leaving a natural tissue matrix. Further processing, such as crosslinking, disinfecting or forming into shapes have also been investigated.
  • U.S. Pat. No. 3,562,820 to Braun discloses tubular, sheet and strip forms of prostheses formed from submucosa adhered together by use of a binder paste such as a collagen fiber paste or by use of an acid or alkaline medium.
  • 4,502,159 to Woodroof provides a tubular prosthesis formed from pericardial tissue in which the tissue is cleaned of fat, fibers and extraneous debris and then placed in phosphate buffered saline. The pericardial tissue is then placed on a mandrel and the seam is then closed by suture and the tissue is then crosslinked.
  • U.S. Pat. No. 4,703,108 to Silver provides a biodegradable matrix from soluble collagen solutions or insoluble collagen dispersions which are freeze dried and then crosslinked to form a porous collagen matrix.
  • 4,776,853 to Klement provides a process for preparing biological material for implant that includes extracting cells using a hypertonic solution at an alkaline pH followed by a high salt solution containing detergent; subjecting the tissue to protease free enzyme solution and then an anionic detergent solution.
  • U.S. Pat. No. 4,801,299 to Brendel discloses a method of processing body derived whole structures for implantation by treating the body derived tissue with detergents to remove cellular structures, nucleic acids, and lipids, to leave an extracellular matrix which is then sterilized before implantation.
  • 4,902,508 to Badylak discloses a three layer tissue graft composition derived from small intestine comprising tunica submucosa, the muscularis mucosa, and stratum compactum of the tunica mucosa.
  • the method of obtaining tissue graft composition comprises abrading the intestinal tissue followed by treatment with an antibiotic solution.
  • U.S. Pat. No. 5,336,616 to Livesey discloses a method of processing biological tissues by treatment of tissue to remove cells, treatment with a cryoprotectant solution, freezing, rehydration, and finally, innoculation with cells to repopulate the tissue.
  • U.S. Pat. No. 4,597,762 to Walter discloses a method of preparing collagenous prostheses through proteolysis, crosslinking with glutaraldehyde, welding and subsequent sterilization of animal hide or other mammalian tissues.
  • the present invention overcomes the difficulties of the materials currently available and provides a prosthetic device for use in the repair, augmentation, or replacement of damaged tissues and organs.
  • This invention is directed to a prosthetic material, which, when implanted into a mammalian host, undergoes controlled biodegradation accompanied by adequate living cell replacement, or neo-tissue formation, such that the original implanted prosthesis is ultimately remodeled and completely replaced by host derived tissue and cells.
  • the prosthesis of this invention a material for tissue repair, comprises a non-antigenic, sterile, completely bioremodelable collagenous material derived from mammalian tissue.
  • the prosthesis of this invention utilizes pre-existing, naturally-formed layers of biological collagen for surgical repair or for tissue and organ replacement.
  • the collagenous tissue of the present invention retains the structural characteristics of the tissue from which it has been derrived.
  • This collagenous tissue of the present invention is able to be layered and bonded together to form multilayer sheets, tubes, or complex shaped prostheses.
  • the bonded collagen layers of the invention are structurally stable, pliable, semi-permeable, and suturable.
  • Each layer of the prosthetic material of this invention are completely bioremodelable and is replaced by host cells to effectively become a host tissue.
  • the present invention is comprised of naturally-formed pre-existing collagen layers which have been harvested from other mammillian tissues, the risk of a significant humoral response has been greatly decreased. It is, therefore, an object of this invention to provide a tissue repair fabric that does not exhibit the above-mentioned shortcomings associated with many of the grafts now being used clinically.
  • Another object is the provision of a prosthetic material that will allow for and facilitate tissue ingrowth and/or organ regeneration at the site of implantation that is a sterile, non-pyrogenic, and non-antigenic material derived from mammalian collagenous tissue.
  • Prostheses prepared from this material when engrafted to a recipient host or patient, do not elicit a significant humoral immune response. Instead, the prostheses is accepted into the recipient host or patient as non-foreign material and the bioremodeling can proceed without interference from potential immune responses to foreign materials.
  • Prostheses formed from the material concomitantly undergoes controlled bioremodeling occurring with adequate living cell replacement such that the original implanted prosthesis is completely remodeled by the patient's living cells to form a regenerated organ or tissue.
  • a further object of the current invention is to provide a simple, repeatable method for manufacturing a tissue repair fabric.
  • Still another object of this invention is to provide a method for use of a novel multi-purpose tissue repair fabric in autografting, allografting, and heterografting indications.
  • Still a further object is to provide a novel tissue repair fabric that can be implanted using conventional surgical techniques.
  • This invention is directed to a tissue engineered prostheses, which, when implanted into a mammalian host, can serve as a functioning repair, augmentation, or replacement body part, or tissue structure, and will undergo controlled biodegradation occurring concomitantly with remodeling by the host's cells.
  • the prosthesis of this invention in its various embodiments, thus has dual properties: First, it functions as a substitute body part, and second, while still functioning as a substitute body part, it functions as a remodeling template for the ingrowth of host cells.
  • the prosthetic material of this invention a tissue repair fabric, was developed comprising mammalian derived collagenous tissue that is rendered non-antigenic and is able to be bonded to itself or another.
  • the prostheses will be illustrated through construction of various devices and constructs, the invention is not so limited. It will be appreciated that the device design in its shape and thickness is to be selected depending on the ultimate indication for the construct.
  • the collagenous material from which to form prostheses, or the prosthesis itself is rendered sterile, non-pyrogenic, and non-antigenic.
  • the prosthesis when engrafted to a recipient host or patient, does not elicit a significant humoral immune response.
  • An acceptable level of response is one that demonstrates no significant increase in antibody titer to collagenous tissue proteins from baseline titer levels when blood serum obtained from a recipient of a prosthesis is tested for antibodies to proteins in extracts of the collagenous tissue.
  • the tissue repair material or the prosthesis itself is rendered non-antigenic, while maintaining the ability for the prosthesis to concomitantly undergo controlled bioremodeling occurring with adequate living cell replacement.
  • the method of preparing a non-antigenic prosthetic collagen material comprises disinfection of the material by a method to prevent microbial degradation of the material, preferably by use of a solution comprising peracetic acid; and crosslinking the disinfected collagen material with a crosslinking agent, preferably 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC).
  • a crosslinking agent preferably 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC).
  • collagenous tissues derived from the mammalian body are used to make said collagen material.
  • Collagenous tissue sources include, but are not limited to intestine, fascia lata, pericardium, and dura mater.
  • the most preferred material for use is the tunica submucosa layer of the small intestine.
  • the tunica submucosa is preferably separated, or delaminated, from the other layers of the small intestine. This layer is referred to hereinafter as the Intestinal Collagen Layer (“ICL”).
  • ICL Intestinal Collagen Layer
  • the collagen layers of the prosthetic device may be from the same collagen material, such as two or more layers of ICL, or from different collagen materials, such as one or more layers of ICL and one or more layers of facia lata.
  • the tunica submucosa of the small intestine is harder and stiffer than the surrounding tissue, and the rollers squeeze the softer components from the submucosa.
  • the ICL was mechanically harvested from porcine small intestine using a Bitterling gut cleaning machine.
  • the mechanically cleaned submucosa may have some hidden, visibly nonapparent debris that affects the consistency of the mechanical properties
  • the submucosa may be chemically cleaned to remove debris and other substances, other than collagen, for example, by soaking in buffer solutions at 4° C., or by soaking with NaOH or trypsin, or other known cleaning techniques.
  • detergents such as TRITON X-100TM (Rohm and Haas) or sodium dodecylsulfate (SDS); enzymes such as dispase, trypsin, or thermolysin; and/or chelating agents such as ethylenediaminetetracetic acid (EDTA) or ethylenebis(oxyethylenitrilo)tetracetic acid (EGTA) may also be included in the chemical cleaning method.
  • EDTA ethylenediaminetetracetic acid
  • EGTA ethylenebis(oxyethylenitrilo)tetracetic acid
  • the (ICL) should be decontaminated or disinfected, preferably with the use of dilute peracetic acid solutions as described in U.S. Pat. No. 5,460,962, incorporated herein by reference.
  • Decontamination or disinfection of the material is done to prevent degradation of the collagenous matrix by bacteria or proteolytic enzymes.
  • Other disinfectant solutions and systems for use with collagen are known in the art and can be used so long as after the disinfection treatment there is no interference in the ability of the material to be remodeled.
  • the prosthetic device of this invention has two or more superimposed collagen layers that are bonded together.
  • bonded collagen layers means composed of two or more layers of the same or different collagen material treated in a manner such that the layers are superimposed on each other and are sufficiently held together by self-lamination.
  • the bonding of the collagen layers may be accomplished in a number of different ways: by heat welding or bonding, adhesives, chemical linking, or sutures.
  • the ICL is disinfected with a peracetic acid solution at a concentration between about 0.01 and 0.3% v/v in water, preferably about 0.1%, at a neutralized pH between about pH 6 and pH 8 and stored until use at about 4° C. in phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the ICL is cut longitudinally and flattened onto a solid, flat plate. One or more successive layers are then superimposed onto one another. A second solid flat plate is placed on top of the layers and the two plates are clamped tightly together.
  • the complete apparatus, clamped plates and collagen layers, are then heated for a time and under conditions sufficient to effect the bonding of the collagen layers together.
  • the amount of heat applied should be sufficiently high to allow the collagen to bond, but not so high as to cause the collagen to irreversibly denature.
  • the time of the heating and bonding will depend upon the type of collagen material layer used, the moisture content and thickness of the material, and the applied heat.
  • a typical range of heat is from about 50° C. to about 75° C., more typically 60° C. to 65° C. and most typically 62° C.
  • a typical range of times will be from about 7 minutes to about 24 hours, typically about one hour.
  • the degree of heat and the amount of time that the heat is applied can be readily ascertained through routine experimentation by varying the heat and time parameters.
  • the bonding step may be accomplished in a conventional oven, although other apparatus or heat applications may be used including, but not limited to, a water bath, laser energy, or electrical heat conduction.
  • the apparatus is cooled, in air or a water bath, at a range between room temperature at 20° C. and 1° C. Rapid cooling, termed quenching, will immediately, or almost immediately, stop the heating action.
  • the apparatus may be cooled, typically in a water bath, with a temperature preferably between about 1° C. to about 10° C., most preferably about 4° C.
  • cooling temperatures below 1° C. may be used, care will need to be taken not to freeze the collagen layers, which may cause structural damage.
  • temperatures above 10° C. may be used in quenching, but if the temperature of the quench is too high, then the heating may not be stopped in time to sufficiently fix the collagen layers in their current configuration.
  • the prosthetic material or multi-layered construct is preferably then crosslinked.
  • Crosslinking the bonded prosthetic device provides strength and some durability to the device to improve handling properties.
  • Crosslinking agents should be selected so as to produce a biocompatible material capable of being remodeled by host cells.
  • Various types of crosslinking agents are known in the art and can be used such as ribose and other sugars, oxidative agents and dehydrothermal (DHT) methods.
  • a preferred crosslinking agent is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC).
  • EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • the crosslinking solution containing EDC and water may also contain acetone.
  • sulfo-N-hydroxysuccinimide is added to the crosslinking agent (Staros, J. V., Biochem. 21, 3950-3955, 1982
  • a method comprising disinfection with peracetic acid and subsequent crosslinking with EDC of the ICL material is performed to reduce the antigenicity of the material.
  • the immunoreactive proteins present in non-sterilized, noncrosslinked ICL are either reduced or removed, or their epitopes have been modified such that they no longer elicit a significant humoral immune response. Graft implants of this material do, however, show an initial transient inflammatory response as a result of a wound healing response.
  • non-antigenic means not eliciting a significant humoral immune response in a host or patient in whom a prosthesis is implanted.
  • An acceptable level of response is one that demonstrates no significant increase in antibody titer to collagenous tissue proteins from baseline titer levels when blood serum obtained from a recipient of a prosthesis is tested for antibodies to proteins in extracts of the collagenous tissue.
  • the preferable serum antibody titer is 1:40 or less.
  • Prostheses of the preferred embodiment are also preferably non-pyrogenic.
  • a prosthesis that is pyrogenic, when engrafted to a recipient host or patient, will cause a febrile reaction in the patient, thus affecting the ability of the prosthesis to be remodeled.
  • Pyrogens are tested by intravenous injection of a solution containing a sample of material into three test rabbits.
  • a temperature sensing probe is positioned in the rectum of the rabbits to monitor temperature changes. If there is a rise in temperature in any rabbit above 0.5° C., then the test for that sample is continued in five more rabbits. If not more than three of the eight rabbits show individual rises in temperature of 0.5° C.
  • the tissue repair fabric of this invention functioning as a substitute body part, may be flat, tubular, or of complex geometry.
  • the shape of the tissue repair fabric will be decided by its intended use.
  • the mold or plate can be fashioned to accommodate the desired shape.
  • the tissue repair fabric can be implanted to repair, augment, or replace diseased or damaged organs, such as abdominal wall defects, pericardium, hernias, and various other organs and structures including, but not limited to, bone, periosteum, perichondrium, intervertebral disc, articular cartilage, dermis, epidermis, bowel, ligaments, and tendons.
  • the tissue repair fabric can be used as a vascular or intra-cardiac patch, or as a replacement heart valve.
  • Flat sheets may be used, for example, to support prolapsed or hypermobile organs by using the sheet as a sling for the organs.
  • This sling can support organs such as bladder or uterus.
  • Tubular grafts may be used, for example, to replace cross sections of tubular organs such as vasculature, esophagus, trachea, intestine, and fallopian tubes. These organs have a basic tubular shape with an outer surface and a luminal surface.
  • flat sheets and tubular structures can be formed together to form a complex structure to replace or augment cardiac or venous valves.
  • the second function of the prosthesis is that of a template or scaffold for bioremodeling.
  • Bioremodeling is used herein to mean the production of structural collagen, vascularization, and epithelialization by the ingrowth of host cells at a functional rate about equal to the rate of biodegradation of the implanted prosthesis by host cells and enzymes.
  • the tissue repair fabric retains the characteristics of the originally implanted prosthesis while it is remodeled by the host into all, or substantially all, host tissue, and as such, is functional as an analog of the tissue it repairs or replaces.
  • each layer of the prosthesis is completely bioremodelable and subsequently replaced by host cells.
  • the mechanical properties include mechanical integrity such that the tissue repair fabric resists creep during bioremodeling, and additionally is pliable and suturable.
  • the term “pliable” means good handling properties.
  • the term “suturable” means that the mechanical properties of the layer include suture retention which permits needles and suture materials to pass through the prosthesis material at the time of suturing of the prosthesis to sections of native tissue, a process known as anastomosis. During suturing, such prostheses must not tear as a result of the tensile forces applied to them by the suture, nor should they tear when the suture is knotted.
  • Suturability of tissue repair fabric i.e., the ability of prostheses to resist tearing while being sutured, is related to the intrinsic mechanical strength of the prosthesis material, the thickness of the graft, the tension applied to the suture, and the rate at which the knot is pulled closed.
  • non-creeping means that the biomechanical properties of the prosthesis impart durability so that the prosthesis is not stretched, distended, or expanded beyond normal limits after implantation. As is described below, total stretch of the implanted prosthesis of this invention is within acceptable limits.
  • the prosthesis of this invention acquires a resistance to stretching as a function of post-implantation cellular bioremodeling by replacement of structural collagen by host cells at a faster rate than the loss of mechanical strength of the implanted materials due from biodegradation and remodeling.
  • the tissue repair fabric of the present invention is “semi-permeable,” even though it has been crosslinked. Semi-permeability permits the ingrowth of host cells for remodeling or for deposition of the collagenous layer.
  • the “non-porous” quality of the prosthesis prevents the passage of fluids that are intended to be retained by the implantation of the prosthesis. Conversely, pores may be formed in the prosthesis if the quality is required for an application of the prosthesis.
  • the mechanical integrity of the prosthesis of this invention is also in its ability to be draped or folded, as well as the ability to cut or trim the prosthesis obtaining a clean edge without delaminating or fraying the edges of the construct.
  • mechanically sheared or chopped collagen fibers can be included between the collagen layers adding bulk to the construct and providing a mechanism for a differential rate of remodeling by host cells.
  • the properties of the construct incorporating the fibers may be altered by variations in the length and diameter of the fibers; variations on the proportion of the fibers used, and fully or partially crosslinking fibers.
  • the length of the fibers can range from 0.1 cm to 5.0 cm.
  • collagen threads such as those disclosed in U.S. Pat. No. 5,378,469 and incorporated herein by reference, can be incorporated into the multilayered tissue repair fabric for reinforcement or for different functional rates of remodeling.
  • a helix or “twist”, of a braid of 20 to 200 denier collagen thread may be applied to the surface of the tissue repair fabric.
  • the diameter size of the helix or braid of collagen thread can range from 50 to 500 microns, preferably 100 to 200 microns.
  • the properties of the tissue repair fabric layer can be varied by the geometry of the thread used for the reinforcement. The functionality of the design will be dependent on the geometry of the braid or twist.
  • collagen thread constructs such as a felt, a flat knitted or woven fabric, or a three-dimensional knitted, woven or braided fabric may be incorporated between the layers or on the surface of the construct.
  • Some embodiments may also include a collagen gel between the layers alone or with a drug, growth factor or antibiotic to function as a delivery system. Additionally, a collagen gel could be incorporated with a thread or a thread construct between the layers.
  • additional collagenous layers may be added to the outer or inner surfaces of the bonded collagen layers to create a smooth flow surface for its ultimate application as described in PCT International Publication No. WO 95/22301, the contents of which are incorporated herein by reference.
  • This smooth collagenous layer also promotes host cell attachment which facilitates ingrowth and bioremodeling.
  • this smooth collagenous layer may be made from acid-extracted fibrillar or non-fibrillar collagen, which is predominantly type I collagen, but may also include other types of collagen.
  • the collagen used may be derived from any number of mammalian sources, typically bovine, porcine, or ovine skin or tendons.
  • the collagen preferably has been processed by acid extraction to result in a fibril dispersion or gel of high purity.
  • Collagen may be acid-extracted from the collagen source using a weak acid, such as acetic, citric, or formic acid. Once extracted into solution, the collagen can be salt-precipitated using NaCl and recovered, using standard techniques such as centrifugation or filtration. Details of acid extracted collagen from bovine tendon are described, for example, in U.S. Pat. No. 5,106,949, incorporated herein by reference.
  • Collagen dispersions or gels for use in the present invention are generally at a concentration of about 1 to 10 mg/mL, preferably, from about 2 to 6 mg/mL, and most preferably at about 3 to 5 mg/mL and at pH of about 2 to 4.
  • a preferred solvent for the collagen is dilute acetic acid, e.g., about 0.05 to 0.1%.
  • Other conventional solvents for collagen may be used as long as such solvents are compatible.
  • the prosthetic device may be air dried, packaged, and sterilized with gamma irradiation, typically 2.5 Mrad, and stored. Terminal sterilization employing chemical solutions such as peracetic acid solutions as described in U.S. Pat. No. 5,460,962, incorporated herein, may also be used.
  • the ICL is cut longitudinally and flattened out onto a glass plate, although any inert non-insulated firm mold may be used.
  • the mold can be any shape: flat, rounded, or complex.
  • the bottom and upper mold pieces will be appropriately constructed so as to form the completed prosthesis into the desired shape. Once so constructed, the prosthesis will keep its shape.
  • the prosthesis is formed into a rounded shape, it can be used as a heart valve leaflet replacement.
  • the multi-layered tissue repair fabric may be tubulated by various alternative means or combinations thereof.
  • the multilayered tissue repair fabric may be formed into a tube in either the normal or the everted position.
  • the tube may be made mechanically by suturing, using interrupted sutures with suitable suture material and is advantageous as it allows the tube to be trimmed and shaped by the surgeon at the time of implantation without unraveling.
  • Other processes to seam the submucosa may include adhesive bonding, such as the use of fibrin-based glues or industrial-type adhesives such as polyurethane, vinyl acetate or polyepoxy.
  • heat bonding techniques may also be used including laser welding or heat welding of the seam, followed by quenching, to seal the sides of the thus formed tube.
  • tubulation techniques the ends of the sides may be either butt ended or overlapped. If the sides are overlapped, the seam may be trimmed once the tube is formed. In addition, these tubulation techniques are typically done on a mandrel so as to determine the desired diameter.
  • the thus formed structural tube can be kept on a mandrel or other suitable spindle for further processing.
  • the prosthesis is preferably crosslinked, using a suitable crosslinking agent, such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC).
  • EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • Crosslinking the prosthesis also aids in preventing luminal creep, in keeping the tube diameter uniform, and in increasing the burst strength.
  • the bond strength of a seam or multilayer prosthesis is increased when heat or dehydration bonding methods are used. It is believed that crosslinking the intestinal collagen layer also improves the suture retention strength by improving resistance to crack propagation.
  • Collagen may be deposited on the internal or external surface of the ICL as described in Example 5 of U.S. Pat. No. 5,256,418, incorporated herein by reference. Briefly, when the tissue repair fabric is to be tubulated, the multi-layered fabric is fitted at one end by luer fittings and the collagen dispersion fills the tube. This step may also be accomplished as described in the above-referenced patent application using a hydrostatic pressure head. The inner layer of collagen can also be deposited by flowing collagen into both ends of the tube simultaneously. The tube is then placed into a bath of 20% polyethylene glycol (PEG) in isotonic phosphate buffered saline (PBS), neutral pH.
  • PEG polyethylene glycol
  • PBS isotonic phosphate buffered saline
  • the osmotic gradient between the internal collagen solution and outer PEG solution in combination cause a simultaneous concentration and deposition of the collagen along the lumen of the internal structural layer wall.
  • the tube is then removed from the PEG bath, and a glass rod with a diameter desired diameter of the prosthesis lumen is inserted into the collagen solution, or alternatively, one end of the prosthesis is closed and air pressure is applied internally to keep the tube lumen open.
  • the prosthesis is then allowed to dry and subsequently is rehydrated in PBS.
  • the thus formed collagen coating in the form of a dense fibrillar collagen, fills slight irregularities in the intestinal structural layer, thus resulting in a prosthesis with both a smooth flow surface and a uniform thickness.
  • the procedure also facilitates the bonding of the collagen gel to the intestinal collagen layer.
  • a collagenous layer of varying thickness and density can be produced by changing the deposition conditions which can be determined by routine parameter changes. The same procedures can be used to apply the collagen to the outer surface of the ICL to create a three-layer prosthesis
  • the prosthesis construct is thrombogenic in small diameter blood vessel replacements. It can only be used in vascular applications in high flow (large diameter) vessels. Therefore, the prosthesis must be rendered non-thrombogenic if to be useful for small diameter blood vessel repair or replacement.
  • Heparin can be applied to the prosthesis, by a variety of well-known techniques.
  • heparin can be applied to the prosthesis in the following three ways.
  • BA-Hep benzalkonium heparin
  • EDC can be used to activate the heparin, then to covalently bond the heparin to the collagen fiber.
  • EDC can be used to activate the collagen, then covalently bond protamine to the collagen and then ionically bond heparin to the protamine.
  • Many other coating, bonding, and attachment procedures are well known in the art which could also be used.
  • the drugs may include for example, growth factors to promote vascularization and epithelialization, such as macrophage derived growth factor (MDGF), platelet derived growth factor (PDGF), endothelial cell derived growth factor (ECDGF); antibiotics to fight any potential infection from the surgery implant; or nerve growth factors incorporated into the inner collagenous layer when the prosthesis is used as a conduit for nerve regeneration.
  • growth factors to promote vascularization and epithelialization such as macrophage derived growth factor (MDGF), platelet derived growth factor (PDGF), endothelial cell derived growth factor (ECDGF); antibiotics to fight any potential infection from the surgery implant; or nerve growth factors incorporated into the inner collagenous layer when the prosthesis is used as a conduit for nerve regeneration.
  • matrix components such as proteoglycans or glycoproteins or glycosaminoglycans may be included within the construct.
  • the tissue repair fabric can be laser drilled to create micron sized pores through the completed prosthesis for aid in cell ingrowth using an excimer laser (e.g. at KrF or ArF wavelengths).
  • the pore size can vary from 10 to 500 microns, but is preferably from about 15 to 50 microns and spacing can vary, but about 500 microns on center is preferred.
  • the tissue repair fabric can be laser drilled at any time during the process to make the prosthesis, but is preferably done before decontamination or sterilization.
  • Voids or spaces can also be formed by the method of phase inversion.
  • crystalline particles that are insoluble in the liquid heat source for bonding but should be soluble in the quench bath or the crosslinking solution. If laser or dry heat is used to bond the layers then any soluble crystalline solid may be used as long as it is soluble in the quench bath or the crosslinking solution. When the crystalline solid is solubilized and has diffused out, there remains a space in which the solid had occupied.
  • the size of the particles may vary from 10 to 100 microns, but is preferably from about 15 to 50 microns and spacing can vary between particles when distributed between the layers. The number and size of the voids formed will also affect the physical properties (i.e., compliance, kink resistance, suture retention, pliability).
  • Example 1 Harvesting and Processing of The Intestinal Collagen Layer from Porcine Intestine
  • the small intestine of a pig was harvested and mechanically stripped, using a Bitterling gut cleaning machine (Nottingham, UK) which forcibly removes the fat, muscle and mucosal layers from the tunica submucosa using a combination of mechanical action and washing using hot water.
  • the mechanical action can be described as a series of rollers that compress and strip away the successive layers from the tunica submucosa when the intact intestine is run between them.
  • the tunica submucosa of the small intestine is harder and stiffer than the surrounding tissue, and the rollers squeeze the softer components from the submucosa.
  • the result of the machine cleaning was such that the submucosal layer of the intestine solely remained.
  • the submucosa was decontaminated with 0.3% peracetic acid for 18 hours at 4° C. and then washed in phosphate buffered saline.
  • the product that remained was an intestinal collagen layer (ICL).
  • ICL was inverted and stretched over a pair of mandrels which were inserted into an ICL mounting frame.
  • Mandrels were of stainless steel tubing with an external diameter of 4.75 mm.
  • the ICL and mandrels were then placed in a dehydration chamber set at 20% relative humidity at 4° C. for about 60 minutes. After dehydration, the ICL was removed from the chamber and the mandrels. The lymphatic tag areas were removed and the ICL was manually wrapped around the mandrel twice to form an ‘unwelded’ bilayer construct. The wrapped ICL was returned to the dehydration chamber and allowed to dry for another 90 minutes still at 20% relative humidity to about 50% moisture+/ ⁇ 10%. To determine the amount of moisture present in a sample construct, a CEMTM oven was used.
  • a THERMOCENTERTM oven was set for the designated temperature treatment for the constructs to be welded. Temperatures tested for welding ranged from 55° to 70° C. Once the constructs were placed in the oven, the oven was allowed to equilibrate before timing began. The constructs were allowed to remain in the chamber for the time required for that condition. Welding times ranged from 7 to 30 minutes. As soon as the time was completed the constructs were removed from the chamber and placed in a 4° C. water bath for about 2 to 5 minutes. The welded constructs were then returned to the dehydration chamber for about 30 minutes until dehydrated to about 20%+/ ⁇ 10%.
  • constructs were inserted into a vessel containing EDC in either deionized water or deionized water and acetone at the concentrations appropriate for the conditions tested.
  • EDC concentrations tested were 50, 100, and 200 mM.
  • Acetone concentrations tested were 0, 50, and 90% in water.
  • the time duration for crosslinking was determined by the conditions tested. Crosslinking times were 6, 12, and 24 hours.
  • the construct was removed from the solution and rinsed with physiological pH phosphate buffered saline (PBS) three times at room temperature. The welded and crosslinked construct was then removed from the mandrel and stored in PBS until testing.
  • PBS physiological pH phosphate buffered saline
  • two other bilayer constructs were prepared by welding at 62° C. for 15 minutes and crosslinked in 100 mM EDC in 100% H 2 O for 18 hours.
  • the suture retention test was used to determine the ability of a construct to hold a suture.
  • a piece of construct was secured in a CHATTILIONTM force measurement device and 1-2 mm bite was taken with a SURGILENETM 6-0 suture, pulled through one wall of the construct and secured. The device then pulls at the suture to determine the force required to tear the construct material.
  • the average suture breaks between 400-500 g of force; the surgeons pull tends to be 150 g of force.
  • the weld/material strength test was performed to determine the UTS of a construct. Sample rings of 5 mm lengths were excised from each tube and each was tested for their ultimate tensile strength (UTS) test using a mechanical testing system MTSTM. Three sample rings were excised from each tube for three test pulls done for each construct for a total of 90 pulls. A ring was placed in the grips of the MTSTM and is pulled at a rate of 0.02 kgforce/sec until the weld slips or breaks, or until the material (rather than the weld) breaks.
  • UTS ultimate tensile strength
  • Tubes were subjected to a temperature condition while wet for 3.5 hours. Temperatures conditions were: Room temperature (20° C.), 55° C., 62° C. and 62° C. then immediately quenched in 4° C. bath for one minute. All tubes were then crosslinked in EDC. Six tubes were placed together in 300 mL 100 mM EDC overnight at room temperature. Tubes were then rinsed with physiological strength phosphate buffered saline after crosslinking.
  • Sample rings of 5 mm lengths were excised from each tube and each was tested for ultimate tensile strength (UTS) test using a MTSTM. Five sample rings were taken from each tube for 5 test pulls on each of 6 tubes per condition for a total of 30 pulls.
  • UTS ultimate tensile strength
  • Fresh samples of porcine submucosal intestinal layer were obtained after the cleaning step as described in example 1. Samples were then left untreated and stored in water, soaked in physiological strength phosphate buffered saline, treated with 0.1% peracetic acid, or were treated with 0.1% peracetic acid and then crosslinked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). Samples were then extracted with a solution of 0.5 M NaCl/0.1 M tartaric acid for about 18 hours.
  • EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • the gel was blotted for about 2 hours with 1% dry non-fat milk (Carnation) in phosphate buffered saline. The gel was then washed three times with borate buffered saline/Tween with 200 ⁇ l of wash per lane. Primary antibody in 200 ⁇ l of Rb serum and borate buffered saline (100 mM boric acid: 25 mM sodium borate: 150 mM NaCl)/Tween was added to each lane at various titer range (1:40, 1:160, 1:640 and 1:2560). The gel was then incubated at room temperature for one hour on a rocker platform (Bellco Biotechnology) with the speed set at 10.
  • a rocker platform Bellco Biotechnology
  • the gel was then washed again three times with borate buffered saline/Tween.
  • Secondary antibody, goat anti-rabbit Ig-AP (Southern Biotechnology Associates Inc. cat# 4010-04) at a 1:1000 dilution was added to lanes at 200 ⁇ l per lane and the gel was incubated for one hour at room temperature on a rocker platform.
  • the nitrocellulose membrane was then immersed in AP color development solution while incubated at room temperature on a rocker platform until color development was complete. Development was stopped by washing the membrane in deionized water for ten minutes on a rocker platform while changing the water once during the ten minutes. The membrane was then air dried.
  • Example 5 Six Layered Tissue Repair Fabric as an Abdominal Wall Patch
  • the tissue repair fabric was sutured in a 3 cm ⁇ 5 cm defect in the midline of New Zealand White rabbits (4 kg) using a continuous 2-0 prolene suture. Animals were sacrificed at four weeks, ten weeks, and 16 weeks, and examined grossly, mechanically, and histologically. Gross examination showed minimal inflammation and swelling. The graft was covered with a glistening tissue layer which appeared to be continuous with the parietal peritoneum. Small blood vessels could be seen proceeding circumferentially from the periphery to the center of the patch. Mechanically the graft was stable with no reherniation observed. Histological examination revealed relatively few inflammatory cells and those that were observed were primarily near the margin of the graft (due to the presence of prolene suture material). The peritoneal surface was smooth and covered entirely by mesothelium.
  • Example 6 Two Layered Tissue Repair Fabric as a Pericardial Repair Patch
  • a 3 ⁇ 3 cm portion of New Zealand white rabbit pericardium was excised and replaced with a same size piece of tissue repair fabric (anastomosed with interrupted sutures of 7-0 prolene). Animals were sacrificed at four weeks and at 180 days, examined grossly, mechanically, and histologically. Gross examination showed minimal inflammation and swelling. Small blood vessels could be seen proceeding circumferentially from the periphery to the center to the graft. Mechanically, the graft was stable without adhesion to either the sternum or pericardial tissue. Histological examination revealed relatively few inflammatory cells and those that were observed were primarily near the margin of the graft (due to the presence of prolene suture material).
  • a prototype device for hernia repair was developed using ICL to have a hollow inner region.
  • the device when completed, had a round conformation bonded at the periphery and a swollen inner region rendered swollen by the inclusion of physiological strength phosphate buffered saline.
  • the inner region can optionally accommodate a wire coil for added rigidity or other substance for structural support or delivery of substance.
  • ICL multilayer sheets 15 cm lengths of ICL were trimmed of lymphatic tags and cut down the side with the tags to form a sheet. Sheets were patted dry with Texwipes. On a clean glass plate (6′′ ⁇ 8′′), sheets were layered mucosal side down. In this case, two two-layer and two four-layer patches were constructed by layering either two or four layers of ICL on the glass plates. A second glass plate (6′′ ⁇ 8′′) was placed on top of the last ICL layer and the plates were clamped together and then placed in a hydrated oven at 62° C. for one hour. Constructs were then quenched in deionized water at 4° C. for about ten minutes.
  • the glass plates were then removed from the bath and a plate removed from each patch.
  • the now bonded ICL layers were then smoothed out to remove any creases or bubbles.
  • the glass plate was replaced upon the ICL layers and returned to the hydrated oven for 30-60 minutes until dry. Patches were removed from the oven and partially rehydrated by spraying with physiological strength phosphate buffered saline.
  • Constructs were then quenched in deionized water at 4° C. for about fifteen minutes. Constructs were then crosslinked in 200 mL 100 mM EDC in 50% acetone for about 18 hours and then rinsed with deionized water. The constructs were then trimmed to shape with a razor blade to the size of the outer edge of the annular plate.
  • ICL dense fibrillar collagen and hyaluronic acid were configured to closely approximate the anatomic structure and composition of an intervertebral disc.
  • Dense fibrillar collagen diskettes containing hyaluronic acid were prepared. 9 mg hyaluronic acid sodium salt derived from bovine trachea (Sigma) was dissolved in 3 mL 0.5 N acetic acid. 15 mL of 5 mg/mL collagen (Antek) was added and mixed. The mixture was centrifuged to remove air bubbles. To three transwells (Costar) in a six well plate (Costar) was added 5 mL of the solution. To the area outside the transwell was added N600 PEG to cover the bottom of the membranes. The plate was maintained at 4° C. on an orbital shaker table at low speed for about 22 hours with one exchange of PEG solution after 5.5 hours. PEG solution was removed and the transwells dehydrated at 4° C./20% Rh overnight.
  • ICL multilayer sheets 15 cm lengths of ICL were trimmed of lymph tags and cut down the side with the tags to form a sheet. Sheets were patted dry with Texwipes. On a clean glass plate, sheets were layered mucosal side down to five layers thick and a second glass plate was laid on top of the fifth layer. Five five-layer patches were constructed. The plates with the ICL between were clamped together and placed in a hydrated oven at 62° C. for one hour. Constructs were then quenched in RODI water at 4 ° C. for about ten minutes then were removed form the quench bath and stored at 4° C. until assembly of the disc.
  • the thus formed device was placed in a hydrated oven at 62° C. for one hour and then quenched in RODI water at 4° C. for about ten mninutes.
  • the device was then crosslinked in 100 mM EDC (Sigma) in 90% acetone (Baxter) for about five hours and then rinsed with three exchanges of phosphate buffered saline. The edges of the device were then trimmed with a razor blade.
  • the proximal jejunum of a pig was harvested and processed with a Gut Cleaning Machine (Bitterling, Nottingham, UK) and then decontaminated with peracetic acid solution as described in example 1.
  • the peracetic acid treated ICL (PA-ICL) was cut open longitudinally and lymphatic tag areas were removed to form a sheet of ICL.
  • the ICL sheets were wrapped around a 6.0 mm diameter stainless steel mandrels to form bilayer constructs.
  • the constructs (on mandrels) were then placed in an equilibrated THERMOCENTERTM oven chamber set at 62° C. for about 1 hour.
  • the constructs were removed from the chamber and placed in a 4° C. water bath for about 2 to 5 minutes.
  • the constructs were chemically crosslinked in 50 mL of 100 mM 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) in 50/50 water/acetone solution for 18 hours to form peracetic acid treated, EDC crosslinked (PA/EDC-ICL) vascular graft constructs.
  • EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
  • PA/EDC-ICL peracetic acid treated, EDC crosslinked vascular graft constructs.
  • the constructs were removed from the mandrels and rinsed with water to remove residual EDC solution.
  • the collagen was allowed to fill the lumen of the ICL tube and was then placed into a stirring bath of 20% MW 8000 polyethylene glycol (Sigma Chemicals Co.) for 16 hours at 4° C.
  • the apparatus was then dismantled and a 4 mm diameter glass rod was placed into the collagen-filled ICL tube to fix the luminal diameter.
  • the prosthesis was then allowed to dry.
  • the luminal DFC layer was coated with benzalkonium chloride heparin (HBAC) by dipping the grafts three times into an 800 U/mL solution of HBAC and allowed to dry. Finally, the graft received a final chemical sterilization treatment in 0.1% v/v peracetic acid. The graft was stored in a dry state until the implant procedure.
  • HBAC benzalkonium chloride heparin
  • the grafts (6 mm ⁇ 8 cm) were placed between the distal infrarenal aorta (end-to-side anastomosis) and the aorta just proximal to the bifurcation (end-to-side anastomosis).
  • the aorta was ligated distal to the proximal anastomosis.
  • the incisions were closed and the dogs maintained on aspirin for 30 days post surgery.
  • the animals were opened bilaterally, the femoral arteries exposed, and a 5 cm length excised.
  • the grafts (4 mm ⁇ 5 cm) were anastomosed in end-to-end fashion to the femoral artery.
  • a control graft was placed on the contralateral side. The incisions were closed and the animals were maintained on aspirin for 30 days post surgery. Post operative follow-up ranged from 30 days to 360 days. Pre-implant, and four and eight weeks post-implant bloods were collected. Animals were sacrificed at various time points (30 days, 60 days, 90 days, 180 days, and 360 days).
  • Sections were examined on a JEOL Instruments JEM100S at 80 kV.
  • SEM scanning electron microscopy
  • samples were fixed for 18 hr in half strength Karnovsky's solution and rinsed five times in Sorensen's phosphate buffer prior to post fixation in 1.0% OsO4 for 1 hr.
  • Samples were then rinsed twice in Sorensen's phosphate buffer and three times in double distilled water. Dehydration was accomplished through an ethanol series (50%, 70%, 90%, and 100%), followed by critical point drying. Samples were mounted and coated with 60/40 gold/palladium.
  • ICL graft explants from dogs and rabbits were examined histologically to evaluate host cell ingrowth. Masson's trichrome staining of a 60 day explant showed significant host infiltrate. The darker blue staining showed collagen of the ICL while matrix surrounding the myofibroblasts, stained lighter blue, showed an abundance of host collagen. High power magnification of the section showed numerous cells intermingled within the ICL. The inflammatory response seen at 30 days had been resolved and the cellular response was predominantly myofibroblastic. The surface of the remodeled graft was lined by endothelial cells as demonstrated by SEM and Factor VIII staining. By 360 days, a mature ‘neo-artery’ had been formed. The neo-adventitia was composed of host collagen bundles populated by fibroblast-like cells. The cells and matrices of the remodeled construct appeared quite mature and tissue-like.
  • New Zealand White rabbits were immunized with 0.5 mg of any one of the three types of ICL samples (NC-ICL, PA-ICL, or PA/EDC-ICL) to generate anti-serum. Initially, rabbits were injected subcutaneously with 0.5 mL of homogenized untreated ICL in Freund's complete adjuvant (1:1, 1 mg/mL). Sham rabbits received 0.5 mL of phosphate buffered saline in Freund's complete adjuvant. Rabbits were boosted every 3 to 4 months with 0.5 mL of the appropriate form of ICL in Freund's incomplete adjuvant (0.25 mg/mL). Sera were collected 10-14 days after each boost.
  • Proteins were extracted from NC-ICL, PA-ICL, or PA/EDC-ICL using tartaric acid (Bellon, G., et al (1988) Anal. Biochem. 175: 263-273) or TRITON X-100 (Rohm and Haas).
  • Pulverized NC-ICL, PA-ICL, or PA/EDC-ICL (10% w/v) were mixed with either tartaric acid (0.1 M tartaric acid, 0.5 M NaCI) or TRITON X-100 (Rohm and Haas) extraction buffer (TEB; 1% TRITON X-100 in 20 mM Tris HCl (pH 7.2), 2 mM EGTA, 2 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, and 25 mg/mL each of aprotinin, leupeptin, and pepstatin (Sigma, St. Louis, Mo.)). The mixtures were incubated overnight at 4° C. The extracts were gauze filtered to remove debris, dialyzed against PBS and concentrated using Centriprep-30 (Amicon, Danvers, Mass.). Extracts were stored at ⁇ 80° C. until used.
  • Serum samples from animals or rabbit anti-collagen type I antibody (Southern Biotechnology, Birmingham, Ala.) were added to wells (100 mL/well) and incubated for 1 hr at room temperature. Plates were washed three times with PBS/Tween. Secondary antibodies: ALPH-labeled goat anti-rabbit Ig or ALPH-labeled goat anti-dog Ig (Southern Biotechnology) were added to the appropriate wells and incubated at room temperature for 1 hour. Plates were washed three times with PBS/Tween. P-nitrophenylphosphate (PNPP) substrate (1 mg/mL) was added to each well (100 niL/well). Absorbance was read at 405 nm on a SpectraMax microplate reader (Molecular Devices, Sunnydale, Calif.).
  • PNPP P-nitrophenylphosphate
  • Anti-collagen type I antibodies could not be detected in sera from rabbits immunized with any form of ICL, even at a 1:40 serum dilution. In contrast, rabbits immunized with purified type I collagen had antibody titer of 1:2560. These data suggest that crosslinking is not necessary to reduce the antigenicity to collagen type I, since rabbits immunized with NC-ICL did not generate anti-collagen type I antibodies. These data thus suggest that the immunodominant proteins in NC-ICL are non-collagenous proteins. Also, the effect of PA and EDC on reducing the antigenicity of ICL is directed toward the non-collagenous proteins.
  • Antibody response of PA-ICL or PA/EDC-ICL immunized rabbits was analyzed by immunoblotting, as described in Example 12. This approach was taken to ensure that the lack of reactivity of anti-NC-ICL sera with PA/EDC-ICL was due to the absence of proteins in ICL and not due to an inability to extract proteins which might be accessible to the immune system in vivo since crosslinking of collagenous materials with EDC could reduce the quantity and quality of protein extracted from ICL.
  • Anti-ICL antisera was generated using PA-ICL or PA/EDC-ICL to immunize rabbits. Sera from these rabbits were tested for antibodies specific for proteins in either tartaric acid or TEB protein extracts of NC-ICL.
  • Anti-PA-ICL recognized the 207, 170, and 38-24 kDa proteins recognized by anti-NC-ICL, but lost reactivity to the lower molecular weight proteins. No bands were detected by the anti-PA/EDC-ICL serum from 1 rabbit. Serum from another anti-PA/EDC-ICL rabbit reacted with the 24-38 kDa proteins. These data suggested that both PA-ICL and PA/EDC-ICL are less antigenic than NC-ICL. Either the antigenic epitopes of ICL are removed during the disinfecting and crosslinking process or they are modified to reduce their antigenicity. In either case, disinfection and crosslinking resulted in a material whose antigenicity was significantly reduced.

Abstract

This invention is directed to prosthesis, which, when implanted into a mammalian patient, serves as a functioning replacement for a body part, or tissue structure, and will undergo controlled biodegradation occurring concomitantly with bioremodeling by the patient's living cells. The prosthesis is treated so that it is rendered non-antigenic so as not to elicit a significant humoral immune response. The prosthesis of this invention, in its various embodiments, thus has dual properties. First, it functions as a substitute body part, and second, it functions as bioremodeling template for the ingrowth of host cells.

Description

    BACKGROUND OF THE INVENTION
  • 1. Field of the Invention: [0001]
  • This invention is in the field of implantable biological prostheses. The present invention is a non-antigenic, resilient, completely bioremodelable, biocompatible tissue prosthesis which can be engineered into a variety of shapes and used to repair, augment, or replace mammalian tissues and organs. Each layer of the prosthesis is gradually degraded and remodeled by the host's cells which replace the implanted prosthesis in its entirety to restore structure and function and is useful for organ repair and reconstruction. Thus, the prosthesis acts as a template by which the host's cells will remodel themselves through a process that will replace the prosthetic collagen molecules with the appropriate host cells in order to restore and replace the original host tissue or organ. [0002]
  • 2. Brief Description of the Background of the Invention: [0003]
  • Despite the growing sophistication of medical technology, repairing and replacing damaged tissues remains a frequent, costly, and serious problem in health care. Currently implantable prostheses are made from a number of synthetic and treated natural materials. The ideal prosthetic material should be chemically inert, non-carcinogenic, capable of resisting mechanical stress, capable of being fabricated in the form required, and sterilizable, yet not be physically modified by tissue fluids, excite an inflammatory or foreign body reaction, induce a state of allergy or hypersensitivity, or, in some cases, promote visceral adhesions (Jenkins S.D., et al. [0004] Surgery 94(2):392-398, 1983).
  • For example, body wall defects that cannot be closed with autogenous tissue due to trauma, necrosis or other causes require repair, augmentation, or replacement with synthetic mesh. In reinforcing or repairing abdominal wall defects, several prosthetic materials have been used, including tantalum gauze, stainless steel mesh, DACRON®, ORLON®, FORTISAN®, nylon, knitted polypropylene (MARLEX®), microporous expanded-polytetrafluoroethylene (GORE-TEX®), dacron reinforced silicone rubber (SILASTIC®), polyglactin 910 (VICRYL®), polyester (MERSILENE®), polyglycolic acid (DEXON®), processed sheep dermal collagen (PSDC®), crosslinked bovine pericardium (PERI-GUARD®), and preserved human dura (LYODURA®). No single prosthetic material has gained universal acceptance. [0005]
  • The major advantages of metallic meshes are that they are inert, resistant to infection and can stimulate fibroplasia. Their major disadvantage is the fragmentation that occurs after the first year of implantation as well as the lack of malleability. Synthetic meshes have the advantage of being easily molded and, except for nylon, retain their tensile strength in the body. European Patent No. 91122196.8 to Krajicek details a triple-layer vascular prosthesis which utilizes non-resorbable, synthetic mesh as the center layer. The synthetic textile mesh layer is used as a central frame to which layers of collagenous fibers can be added, resulting in the tri-layered prosthetic device. The major disadvantage of a non-resorbable synthetic mesh is lack of inertness, susceptibility to infection, and interference with wound healing. [0006]
  • In contrast to the non-resorbable mesh disclosed in Krajicek (E.P. No. 91122196.8), absorbable synthetic meshes have the advantage of impermanence at the site of implantation, but often have the disadvantage of losing their mechanical strength, because of dissolution by the host, prior to adequate cell and tissue ingrowth. [0007]
  • The most widely used material for abdominal wall replacement and for reinforcement during hernia repairs is MARLEX®; however, several investigators reported that with scar contracture, polypropylene mesh grafts became distorted and separated from surrounding normal tissue in a whorl of fibrous tissue. Others have reported moderate to severe adhesions when using MARLEX®. [0008]
  • GORE-TEX® is currently believed to be the most chemically inert polymer and has been found to cause minimal foreign body reaction when implanted. A major problem exists with the use of polytetrafluoroethylene in a contaminated wound as it does not allow for any macromolecular drainage, which limits treatment of infections. [0009]
  • Collagen first gained utility as a material for medical use because it was a natural biological prosthetic substitute that was in abundant supply from various animal sources. The design objectives for the original collagen prosthetics were the same as for synthetic polymer prostheses; the prosthesis should persist and essentially act as an inert material. With these objectives in mind, purification and crosslinking methods were developed to enhance mechanical strength and decrease the degradation rate of the collagen (Chvapil, M., et al (1977) [0010] J. Biomed. Mater. Res. 11: 297-314; Kligman, A.M., et al (1986) J. DermatoL Surg. Oncol. 12 (4): 351-357; Roe, S.C., et al. (1990). Artif. Organs. 14: 443-448. Woodroff, E.A. (1978). J. Bioeng. 2: 1-10). Crosslinking agents originally used include glutaraldehyde, formaldehyde, polyepoxides, diisocyanates (Borick P.M., et al. (1964) J. Phann. Sci. 52: 1273-1275), and acyl azides. Processed dermal sheep collagen has been studied as an implant for a variety of applications. Before implantation, the sheep dermal collagen is typically tanned with hexamethylenediisocyanate (van Wachem, P.B., et al. Biomaterials 12(March):215-223, 1991) or glutaraldehyde (Rudolphy, V.J., et al. Ann Thorac Surg 52:821-825, 1991). Glutaraldehyde, probably the most widely used and studied crosslinking agent, was also used as a sterilizing agent. In general, these crosslinking agents generated collagenous material which resembled a synthetic material more than a natural biological tissue, both mechanically and biologically.
  • Crosslinking native collagen reduces the antigenicity of the material (Chvapil, M. (1980) Reconstituted collagen. pp. 313-324. In: Viidik, A., Vuust, J. (eds), [0011] Biology of Collagen. Academic Press, London; Harjula, A., et al. (1980) Ann. Chir. Gynaecol. 69: 256-262.) by linking the antigenic epitopes rendering them either inaccessible to phagocytosis or unrecognizable by the immune system. There are many known methods of crosslinking collagenous materials. U.S. Pat. No. 5,571,216 details several methods of achieving crosslinking through the heating and joining of free ends of collagen tendrils. U.S. Pat. No. 5,263,983 to Yoshizato details crosslinking by treating collagenous composites with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride. Glutaraldehyde is also employed as a reagent in crosslinking (See U.S. Pat. No. 4,787,900 to Yannas; U.S. Pat. No. 4,597,762 to Walter). However, data from studies using glutaraldehyde as the crosslinking agent are hard to interpret since glutaraldehyde treatment is also known to leave behind cytotoxic residues (Chvapil, M. (1980), supra; Cooke, A., et al. (1983) Br. J. Exp. Path. 64: 172-176; Speer, D. P., et al. (1980) J. Biomed. Mater. Res. 14: 753-764; Wiebe, D., et al. (1988) Surgery. 104: 26-33). It is, therefore, possible that the reduced antigenicity associated with glutaraldehyde crosslinking is due to non-specific cytotoxicity rather than a specific effect on antigenic determinants. Glutaraldehyde treatment is an acceptable way to increase durability and reduce antigenicity of collagenous materials as compared to those that are non-crosslinked. However, glutaraldehyde crosslinking collagen materials significantly limits the body's ability to remodel the prosthesis (Roe, S.C., et al. (1990), supra).
  • All of the above problems associated with traditional materials stem, in part, from the inability of the body to recognize any implant as “inert”. Although biologic in origin, extensive chemical modification of collagen tends to render it as “foreign”. To improve the long term performance of implanted collagenous devices, it is important to retain many of the properties of the natural collagenous tissue. In this “tissue engineering” approach, the prosthesis is designed not as a permanent implant but as a scaffold or template for regeneration or remodeling. Tissue engineering design principles incorporate a requirement for isomorphous tissue replacement, wherein the biodegradation of the implant matrix occurs at about the same functional rate of tissue replacement (Yannas, I. V. (1995) Regeneration Templates. pp. 1619-1635. In: Bronzino, J. D. (ed.), The Biomedical Engineering Handbook, CRC Press, Inc., Boca Raton, Fla.). [0012]
  • When such a prosthesis is implanted, it should immediately serve its requisite mechanical and/or biological function as a body part. The prosthesis should also support appropriate host cellularization by ingrowth of mesenchymal cells, and in time, through isomorphous tissue replacement, be replaced with host tissue, wherein the host tissue is a functional analog of the original tissue. In order to do this, the implant must not elicit a significant humoral immune response or be either cytotoxic or pyrogenic to promote healing and development of the neo-tissue. [0013]
  • Prostheses or prosthetic material derived from isolated collagen molecules, either in powder form or in a solution, have been investigated for surgical repair or for tissue and organ replacement. The source of collagen used in these prosthetic deivces is determinate of the prostheses' form and function. U.S. Pat. No. 4,787,900 to Yannas details a process for the creation of prosthetic blood vessels out of a collagenous composite formed, ex vivo, from individual collagen molecules in either powder or solution form. The collagenous compound is a conglomerate of individual collagen molecules and does not retain any of the structural characteristics of the tissue from which the collagen was originally derived. Instead, this collagenous composite is a “tangled mass of collagen fibrils” that is later chemically tailored into the desired shape and thickness required for repairing the specific blood vessel. [0014]
  • Prostheses or prosthetic material derived from explanted mammalian tissue have been widely investigated for surgical repair or for tissue and organ replacement. The tissue is typically processed to remove cellular components leaving a natural tissue matrix. Further processing, such as crosslinking, disinfecting or forming into shapes have also been investigated. U.S. Pat. No. 3,562,820 to Braun discloses tubular, sheet and strip forms of prostheses formed from submucosa adhered together by use of a binder paste such as a collagen fiber paste or by use of an acid or alkaline medium. U.S. Pat. No. 4,502,159 to Woodroof provides a tubular prosthesis formed from pericardial tissue in which the tissue is cleaned of fat, fibers and extraneous debris and then placed in phosphate buffered saline. The pericardial tissue is then placed on a mandrel and the seam is then closed by suture and the tissue is then crosslinked. U.S. Pat. No. 4,703,108 to Silver provides a biodegradable matrix from soluble collagen solutions or insoluble collagen dispersions which are freeze dried and then crosslinked to form a porous collagen matrix. U.S. Pat. No. 4,776,853 to Klement provides a process for preparing biological material for implant that includes extracting cells using a hypertonic solution at an alkaline pH followed by a high salt solution containing detergent; subjecting the tissue to protease free enzyme solution and then an anionic detergent solution. U.S. Pat. No. 4,801,299 to Brendel discloses a method of processing body derived whole structures for implantation by treating the body derived tissue with detergents to remove cellular structures, nucleic acids, and lipids, to leave an extracellular matrix which is then sterilized before implantation. U.S. Pat. No. 4,902,508 to Badylak discloses a three layer tissue graft composition derived from small intestine comprising tunica submucosa, the muscularis mucosa, and stratum compactum of the tunica mucosa. The method of obtaining tissue graft composition comprises abrading the intestinal tissue followed by treatment with an antibiotic solution. U.S. Pat. No. 5,336,616 to Livesey discloses a method of processing biological tissues by treatment of tissue to remove cells, treatment with a cryoprotectant solution, freezing, rehydration, and finally, innoculation with cells to repopulate the tissue. U.S. Pat. No. 4,597,762 to Walter discloses a method of preparing collagenous prostheses through proteolysis, crosslinking with glutaraldehyde, welding and subsequent sterilization of animal hide or other mammalian tissues. [0015]
  • It is a continuing goal of researchers to develop implantable prostheses which can successfully be used to replace or to facilitate the repair of mammalian tissues, such as abdominal wall defects and vasculature, so that the intrinsic strength, resillience, and biocompatability of the host's own cells may be optimally exploited in the repair process. [0016]
  • SUMMARY OF THE INVENTION
  • The present invention overcomes the difficulties of the materials currently available and provides a prosthetic device for use in the repair, augmentation, or replacement of damaged tissues and organs. This invention is directed to a prosthetic material, which, when implanted into a mammalian host, undergoes controlled biodegradation accompanied by adequate living cell replacement, or neo-tissue formation, such that the original implanted prosthesis is ultimately remodeled and completely replaced by host derived tissue and cells. The prosthesis of this invention, a material for tissue repair, comprises a non-antigenic, sterile, completely bioremodelable collagenous material derived from mammalian tissue. The prosthesis of this invention utilizes pre-existing, naturally-formed layers of biological collagen for surgical repair or for tissue and organ replacement. Unlike the tissue repair fabrics that are currently available, which use collagenous composites formed from reconstituted individual collagen molecules, the collagenous tissue of the present invention retains the structural characteristics of the tissue from which it has been derrived. This collagenous tissue of the present invention is able to be layered and bonded together to form multilayer sheets, tubes, or complex shaped prostheses. The bonded collagen layers of the invention are structurally stable, pliable, semi-permeable, and suturable. [0017]
  • Each layer of the prosthetic material of this invention are completely bioremodelable and is replaced by host cells to effectively become a host tissue. Moreover, because the present invention is comprised of naturally-formed pre-existing collagen layers which have been harvested from other mammillian tissues, the risk of a significant humoral response has been greatly decreased. It is, therefore, an object of this invention to provide a tissue repair fabric that does not exhibit the above-mentioned shortcomings associated with many of the grafts now being used clinically. [0018]
  • Another object is the provision of a prosthetic material that will allow for and facilitate tissue ingrowth and/or organ regeneration at the site of implantation that is a sterile, non-pyrogenic, and non-antigenic material derived from mammalian collagenous tissue. Prostheses prepared from this material, when engrafted to a recipient host or patient, do not elicit a significant humoral immune response. Instead, the prostheses is accepted into the recipient host or patient as non-foreign material and the bioremodeling can proceed without interference from potential immune responses to foreign materials. Prostheses formed from the material concomitantly undergoes controlled bioremodeling occurring with adequate living cell replacement such that the original implanted prosthesis is completely remodeled by the patient's living cells to form a regenerated organ or tissue. [0019]
  • A further object of the current invention is to provide a simple, repeatable method for manufacturing a tissue repair fabric. [0020]
  • Still another object of this invention is to provide a method for use of a novel multi-purpose tissue repair fabric in autografting, allografting, and heterografting indications. [0021]
  • Still a further object is to provide a novel tissue repair fabric that can be implanted using conventional surgical techniques.[0022]
  • DETAILED DESCRIPTION OF THE INVENTION
  • This invention is directed to a tissue engineered prostheses, which, when implanted into a mammalian host, can serve as a functioning repair, augmentation, or replacement body part, or tissue structure, and will undergo controlled biodegradation occurring concomitantly with remodeling by the host's cells. The prosthesis of this invention, in its various embodiments, thus has dual properties: First, it functions as a substitute body part, and second, while still functioning as a substitute body part, it functions as a remodeling template for the ingrowth of host cells. In order to this, the prosthetic material of this invention, a tissue repair fabric, was developed comprising mammalian derived collagenous tissue that is rendered non-antigenic and is able to be bonded to itself or another. Although the prostheses will be illustrated through construction of various devices and constructs, the invention is not so limited. It will be appreciated that the device design in its shape and thickness is to be selected depending on the ultimate indication for the construct. [0023]
  • In the preferred embodiment, the collagenous material from which to form prostheses, or the prosthesis itself, is rendered sterile, non-pyrogenic, and non-antigenic. The prosthesis, when engrafted to a recipient host or patient, does not elicit a significant humoral immune response. An acceptable level of response is one that demonstrates no significant increase in antibody titer to collagenous tissue proteins from baseline titer levels when blood serum obtained from a recipient of a prosthesis is tested for antibodies to proteins in extracts of the collagenous tissue. [0024]
  • In the preferred method, the tissue repair material or the prosthesis itself is rendered non-antigenic, while maintaining the ability for the prosthesis to concomitantly undergo controlled bioremodeling occurring with adequate living cell replacement. The method of preparing a non-antigenic prosthetic collagen material, comprises disinfection of the material by a method to prevent microbial degradation of the material, preferably by use of a solution comprising peracetic acid; and crosslinking the disinfected collagen material with a crosslinking agent, preferably [0025] 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC).
  • Also in the preferred embodiment, collagenous tissues derived from the mammalian body are used to make said collagen material. Collagenous tissue sources include, but are not limited to intestine, fascia lata, pericardium, and dura mater. The most preferred material for use is the tunica submucosa layer of the small intestine. The tunica submucosa is preferably separated, or delaminated, from the other layers of the small intestine. This layer is referred to hereinafter as the Intestinal Collagen Layer (“ICL”). Further, the collagen layers of the prosthetic device may be from the same collagen material, such as two or more layers of ICL, or from different collagen materials, such as one or more layers of ICL and one or more layers of facia lata. [0026]
  • The submucosa, or the intestinal collagen layer (ICL), from a mammalian source, typically pigs, cows, or sheep, is mechanically cleaned by squeezing the raw material between opposing rollers to remove the muscular layers (tunica muscularis) and the mucosa (tunica mucosa). The tunica submucosa of the small intestine is harder and stiffer than the surrounding tissue, and the rollers squeeze the softer components from the submucosa. In the examples that follow, the ICL was mechanically harvested from porcine small intestine using a Bitterling gut cleaning machine. [0027]
  • As the mechanically cleaned submucosa may have some hidden, visibly nonapparent debris that affects the consistency of the mechanical properties, the submucosa may be chemically cleaned to remove debris and other substances, other than collagen, for example, by soaking in buffer solutions at 4° C., or by soaking with NaOH or trypsin, or other known cleaning techniques. Alternative means employing detergents such as TRITON X-100™ (Rohm and Haas) or sodium dodecylsulfate (SDS); enzymes such as dispase, trypsin, or thermolysin; and/or chelating agents such as ethylenediaminetetracetic acid (EDTA) or ethylenebis(oxyethylenitrilo)tetracetic acid (EGTA) may also be included in the chemical cleaning method. [0028]
  • After cleaning, the (ICL) should be decontaminated or disinfected, preferably with the use of dilute peracetic acid solutions as described in U.S. Pat. No. 5,460,962, incorporated herein by reference. Decontamination or disinfection of the material is done to prevent degradation of the collagenous matrix by bacteria or proteolytic enzymes. Other disinfectant solutions and systems for use with collagen are known in the art and can be used so long as after the disinfection treatment there is no interference in the ability of the material to be remodeled. [0029]
  • In a preferred embodiment, the prosthetic device of this invention has two or more superimposed collagen layers that are bonded together. As used herein, “bonded collagen layers” means composed of two or more layers of the same or different collagen material treated in a manner such that the layers are superimposed on each other and are sufficiently held together by self-lamination. The bonding of the collagen layers may be accomplished in a number of different ways: by heat welding or bonding, adhesives, chemical linking, or sutures. [0030]
  • In the preferred method, and in the examples that follow, the ICL is disinfected with a peracetic acid solution at a concentration between about 0.01 and 0.3% v/v in water, preferably about 0.1%, at a neutralized pH between about pH 6 and pH 8 and stored until use at about 4° C. in phosphate buffered saline (PBS). The ICL is cut longitudinally and flattened onto a solid, flat plate. One or more successive layers are then superimposed onto one another. A second solid flat plate is placed on top of the layers and the two plates are clamped tightly together. The complete apparatus, clamped plates and collagen layers, are then heated for a time and under conditions sufficient to effect the bonding of the collagen layers together. The amount of heat applied should be sufficiently high to allow the collagen to bond, but not so high as to cause the collagen to irreversibly denature. The time of the heating and bonding will depend upon the type of collagen material layer used, the moisture content and thickness of the material, and the applied heat. A typical range of heat is from about 50° C. to about 75° C., more typically 60° C. to 65° C. and most typically 62° C. A typical range of times will be from about 7 minutes to about 24 hours, typically about one hour. The degree of heat and the amount of time that the heat is applied can be readily ascertained through routine experimentation by varying the heat and time parameters. The bonding step may be accomplished in a conventional oven, although other apparatus or heat applications may be used including, but not limited to, a water bath, laser energy, or electrical heat conduction. Immediately following the heating and bonding, the apparatus is cooled, in air or a water bath, at a range between room temperature at 20° C. and 1° C. Rapid cooling, termed quenching, will immediately, or almost immediately, stop the heating action. To accomplish this step, the apparatus may be cooled, typically in a water bath, with a temperature preferably between about 1° C. to about 10° C., most preferably about 4° C. Although cooling temperatures below 1° C. may be used, care will need to be taken not to freeze the collagen layers, which may cause structural damage. In addition, temperatures above 10° C. may be used in quenching, but if the temperature of the quench is too high, then the heating may not be stopped in time to sufficiently fix the collagen layers in their current configuration. [0031]
  • The prosthetic material or multi-layered construct is preferably then crosslinked. Crosslinking the bonded prosthetic device provides strength and some durability to the device to improve handling properties. Crosslinking agents should be selected so as to produce a biocompatible material capable of being remodeled by host cells. Various types of crosslinking agents are known in the art and can be used such as ribose and other sugars, oxidative agents and dehydrothermal (DHT) methods. A preferred crosslinking agent is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). The crosslinking solution containing EDC and water may also contain acetone. In a preferred embodiment, sulfo-N-hydroxysuccinimide is added to the crosslinking agent (Staros, J. V., [0032] Biochem. 21, 3950-3955, 1982).
  • In a preferred embodiment, a method comprising disinfection with peracetic acid and subsequent crosslinking with EDC of the ICL material is performed to reduce the antigenicity of the material. The immunoreactive proteins present in non-sterilized, noncrosslinked ICL are either reduced or removed, or their epitopes have been modified such that they no longer elicit a significant humoral immune response. Graft implants of this material do, however, show an initial transient inflammatory response as a result of a wound healing response. As used herein, the term “non-antigenic” means not eliciting a significant humoral immune response in a host or patient in whom a prosthesis is implanted. An acceptable level of response is one that demonstrates no significant increase in antibody titer to collagenous tissue proteins from baseline titer levels when blood serum obtained from a recipient of a prosthesis is tested for antibodies to proteins in extracts of the collagenous tissue. For a patient or host previously non-sensitized to collagenous tissue proteins, the preferable serum antibody titer is 1:40 or less. [0033]
  • Prostheses of the preferred embodiment are also preferably non-pyrogenic. A prosthesis that is pyrogenic, when engrafted to a recipient host or patient, will cause a febrile reaction in the patient, thus affecting the ability of the prosthesis to be remodeled. Pyrogens are tested by intravenous injection of a solution containing a sample of material into three test rabbits. A temperature sensing probe is positioned in the rectum of the rabbits to monitor temperature changes. If there is a rise in temperature in any rabbit above 0.5° C., then the test for that sample is continued in five more rabbits. If not more than three of the eight rabbits show individual rises in temperature of 0.5° C. or more and the sum of the eight individual maximum temperature rises does not exceed 3.3° C., the material under examination meets the requirements for the absence of pyrogens. (Pyrogen Test (151), pp. 1718-1719. In: [0034] The United States Pharmacopeia (USP) 23 The United States Pharmacopeial Convention, Inc., Rockville, Md.)
  • The tissue repair fabric of this invention, functioning as a substitute body part, may be flat, tubular, or of complex geometry. The shape of the tissue repair fabric will be decided by its intended use. Thus, when forming the bonding layers of the prosthesis of this invention, the mold or plate can be fashioned to accommodate the desired shape. The tissue repair fabric can be implanted to repair, augment, or replace diseased or damaged organs, such as abdominal wall defects, pericardium, hernias, and various other organs and structures including, but not limited to, bone, periosteum, perichondrium, intervertebral disc, articular cartilage, dermis, epidermis, bowel, ligaments, and tendons. In addition, the tissue repair fabric can be used as a vascular or intra-cardiac patch, or as a replacement heart valve. [0035]
  • Flat sheets may be used, for example, to support prolapsed or hypermobile organs by using the sheet as a sling for the organs. This sling can support organs such as bladder or uterus. [0036]
  • Tubular grafts may be used, for example, to replace cross sections of tubular organs such as vasculature, esophagus, trachea, intestine, and fallopian tubes. These organs have a basic tubular shape with an outer surface and a luminal surface. [0037]
  • In addition, flat sheets and tubular structures can be formed together to form a complex structure to replace or augment cardiac or venous valves. [0038]
  • In addition to functioning as a substitute body part or support, the second function of the prosthesis is that of a template or scaffold for bioremodeling. “Bioremodeling” is used herein to mean the production of structural collagen, vascularization, and epithelialization by the ingrowth of host cells at a functional rate about equal to the rate of biodegradation of the implanted prosthesis by host cells and enzymes. The tissue repair fabric retains the characteristics of the originally implanted prosthesis while it is remodeled by the host into all, or substantially all, host tissue, and as such, is functional as an analog of the tissue it repairs or replaces. Thus, each layer of the prosthesis is completely bioremodelable and subsequently replaced by host cells. [0039]
  • The mechanical properties include mechanical integrity such that the tissue repair fabric resists creep during bioremodeling, and additionally is pliable and suturable. The term “pliable” means good handling properties. The term “suturable” means that the mechanical properties of the layer include suture retention which permits needles and suture materials to pass through the prosthesis material at the time of suturing of the prosthesis to sections of native tissue, a process known as anastomosis. During suturing, such prostheses must not tear as a result of the tensile forces applied to them by the suture, nor should they tear when the suture is knotted. Suturability of tissue repair fabric, i.e., the ability of prostheses to resist tearing while being sutured, is related to the intrinsic mechanical strength of the prosthesis material, the thickness of the graft, the tension applied to the suture, and the rate at which the knot is pulled closed. [0040]
  • As used herein, the term “non-creeping” means that the biomechanical properties of the prosthesis impart durability so that the prosthesis is not stretched, distended, or expanded beyond normal limits after implantation. As is described below, total stretch of the implanted prosthesis of this invention is within acceptable limits. The prosthesis of this invention acquires a resistance to stretching as a function of post-implantation cellular bioremodeling by replacement of structural collagen by host cells at a faster rate than the loss of mechanical strength of the implanted materials due from biodegradation and remodeling. The tissue repair fabric of the present invention is “semi-permeable,” even though it has been crosslinked. Semi-permeability permits the ingrowth of host cells for remodeling or for deposition of the collagenous layer. The “non-porous” quality of the prosthesis prevents the passage of fluids that are intended to be retained by the implantation of the prosthesis. Conversely, pores may be formed in the prosthesis if the quality is required for an application of the prosthesis. [0041]
  • The mechanical integrity of the prosthesis of this invention is also in its ability to be draped or folded, as well as the ability to cut or trim the prosthesis obtaining a clean edge without delaminating or fraying the edges of the construct. [0042]
  • Additionally, in another embodiment of the invention, mechanically sheared or chopped collagen fibers can be included between the collagen layers adding bulk to the construct and providing a mechanism for a differential rate of remodeling by host cells. The properties of the construct incorporating the fibers may be altered by variations in the length and diameter of the fibers; variations on the proportion of the fibers used, and fully or partially crosslinking fibers. The length of the fibers can range from 0.1 cm to 5.0 cm. [0043]
  • In another embodiment of the invention, collagen threads, such as those disclosed in U.S. Pat. No. 5,378,469 and incorporated herein by reference, can be incorporated into the multilayered tissue repair fabric for reinforcement or for different functional rates of remodeling. For example, a helix or “twist”, of a braid of 20 to 200 denier collagen thread may be applied to the surface of the tissue repair fabric. The diameter size of the helix or braid of collagen thread can range from 50 to 500 microns, preferably 100 to 200 microns. Thus, the properties of the tissue repair fabric layer can be varied by the geometry of the thread used for the reinforcement. The functionality of the design will be dependent on the geometry of the braid or twist. Additionally, collagen thread constructs such as a felt, a flat knitted or woven fabric, or a three-dimensional knitted, woven or braided fabric may be incorporated between the layers or on the surface of the construct. Some embodiments may also include a collagen gel between the layers alone or with a drug, growth factor or antibiotic to function as a delivery system. Additionally, a collagen gel could be incorporated with a thread or a thread construct between the layers. [0044]
  • As will be appreciated by those of skill in the art, many of the embodiments incorporating collagen gel, thread or a thread construct will also affect the physical properties, such as compliance, radial strength, kink resistance, suture retention, and pliability. Physical properties of the thread or the thread construct may also be varied by crosslinking the threads. [0045]
  • In some embodiments, additional collagenous layers may be added to the outer or inner surfaces of the bonded collagen layers to create a smooth flow surface for its ultimate application as described in PCT International Publication No. WO 95/22301, the contents of which are incorporated herein by reference. This smooth collagenous layer also promotes host cell attachment which facilitates ingrowth and bioremodeling. As described in PCT International Publication No. WO 95/22301, this smooth collagenous layer may be made from acid-extracted fibrillar or non-fibrillar collagen, which is predominantly type I collagen, but may also include other types of collagen. The collagen used may be derived from any number of mammalian sources, typically bovine, porcine, or ovine skin or tendons. The collagen preferably has been processed by acid extraction to result in a fibril dispersion or gel of high purity. Collagen may be acid-extracted from the collagen source using a weak acid, such as acetic, citric, or formic acid. Once extracted into solution, the collagen can be salt-precipitated using NaCl and recovered, using standard techniques such as centrifugation or filtration. Details of acid extracted collagen from bovine tendon are described, for example, in U.S. Pat. No. 5,106,949, incorporated herein by reference. [0046]
  • Collagen dispersions or gels for use in the present invention are generally at a concentration of about 1 to 10 mg/mL, preferably, from about 2 to 6 mg/mL, and most preferably at about 3 to 5 mg/mL and at pH of about 2 to 4. A preferred solvent for the collagen is dilute acetic acid, e.g., about 0.05 to 0.1%. Other conventional solvents for collagen may be used as long as such solvents are compatible. [0047]
  • Once the prosthetic device has been produced, it may be air dried, packaged, and sterilized with gamma irradiation, typically 2.5 Mrad, and stored. Terminal sterilization employing chemical solutions such as peracetic acid solutions as described in U.S. Pat. No. 5,460,962, incorporated herein, may also be used. [0048]
  • In the examples that follow, the ICL is cut longitudinally and flattened out onto a glass plate, although any inert non-insulated firm mold may be used. In addition, the mold can be any shape: flat, rounded, or complex. In a rounded or complex mold, the bottom and upper mold pieces will be appropriately constructed so as to form the completed prosthesis into the desired shape. Once so constructed, the prosthesis will keep its shape. Thus, for example, if the prosthesis is formed into a rounded shape, it can be used as a heart valve leaflet replacement. [0049]
  • The multi-layered tissue repair fabric may be tubulated by various alternative means or combinations thereof. The multilayered tissue repair fabric may be formed into a tube in either the normal or the everted position. The tube may be made mechanically by suturing, using interrupted sutures with suitable suture material and is advantageous as it allows the tube to be trimmed and shaped by the surgeon at the time of implantation without unraveling. Other processes to seam the submucosa may include adhesive bonding, such as the use of fibrin-based glues or industrial-type adhesives such as polyurethane, vinyl acetate or polyepoxy. Preferably heat bonding techniques may also be used including laser welding or heat welding of the seam, followed by quenching, to seal the sides of the thus formed tube. Other mechanical means are possible, such as using pop rivets or staples. With these tubulation techniques, the ends of the sides may be either butt ended or overlapped. If the sides are overlapped, the seam may be trimmed once the tube is formed. In addition, these tubulation techniques are typically done on a mandrel so as to determine the desired diameter. [0050]
  • The thus formed structural tube can be kept on a mandrel or other suitable spindle for further processing. To control functional rates of biodegradation and therefore the rate of prosthesis strength decrease during bioremodeling, the prosthesis is preferably crosslinked, using a suitable crosslinking agent, such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). Crosslinking the prosthesis also aids in preventing luminal creep, in keeping the tube diameter uniform, and in increasing the burst strength. The bond strength of a seam or multilayer prosthesis is increased when heat or dehydration bonding methods are used. It is believed that crosslinking the intestinal collagen layer also improves the suture retention strength by improving resistance to crack propagation. [0051]
  • Collagen may be deposited on the internal or external surface of the ICL as described in Example 5 of U.S. Pat. No. 5,256,418, incorporated herein by reference. Briefly, when the tissue repair fabric is to be tubulated, the multi-layered fabric is fitted at one end by luer fittings and the collagen dispersion fills the tube. This step may also be accomplished as described in the above-referenced patent application using a hydrostatic pressure head. The inner layer of collagen can also be deposited by flowing collagen into both ends of the tube simultaneously. The tube is then placed into a bath of 20% polyethylene glycol (PEG) in isotonic phosphate buffered saline (PBS), neutral pH. The osmotic gradient between the internal collagen solution and outer PEG solution in combination cause a simultaneous concentration and deposition of the collagen along the lumen of the internal structural layer wall. The tube is then removed from the PEG bath, and a glass rod with a diameter desired diameter of the prosthesis lumen is inserted into the collagen solution, or alternatively, one end of the prosthesis is closed and air pressure is applied internally to keep the tube lumen open. The prosthesis is then allowed to dry and subsequently is rehydrated in PBS. The thus formed collagen coating, in the form of a dense fibrillar collagen, fills slight irregularities in the intestinal structural layer, thus resulting in a prosthesis with both a smooth flow surface and a uniform thickness. The procedure also facilitates the bonding of the collagen gel to the intestinal collagen layer. A collagenous layer of varying thickness and density can be produced by changing the deposition conditions which can be determined by routine parameter changes. The same procedures can be used to apply the collagen to the outer surface of the ICL to create a three-layer prosthesis. [0052]
  • The prosthesis construct is thrombogenic in small diameter blood vessel replacements. It can only be used in vascular applications in high flow (large diameter) vessels. Therefore, the prosthesis must be rendered non-thrombogenic if to be useful for small diameter blood vessel repair or replacement. [0053]
  • Heparin can be applied to the prosthesis, by a variety of well-known techniques. For illustration, heparin can be applied to the prosthesis in the following three ways. First, benzalkonium heparin (BA-Hep) solution can be applied to the prosthesis by dipping the prosthesis in the solution and then air-drying it. This procedure treats the collagen with an ionically bound BA-Hep complex. Second, EDC can be used to activate the heparin, then to covalently bond the heparin to the collagen fiber. Third, EDC can be used to activate the collagen, then covalently bond protamine to the collagen and then ionically bond heparin to the protamine. Many other coating, bonding, and attachment procedures are well known in the art which could also be used. [0054]
  • Treatment of the tissue repair fabric with drugs in addition to or in substitution for heparin may be accomplished. The drugs may include for example, growth factors to promote vascularization and epithelialization, such as macrophage derived growth factor (MDGF), platelet derived growth factor (PDGF), endothelial cell derived growth factor (ECDGF); antibiotics to fight any potential infection from the surgery implant; or nerve growth factors incorporated into the inner collagenous layer when the prosthesis is used as a conduit for nerve regeneration. In addition to or in substitution for drugs, matrix components such as proteoglycans or glycoproteins or glycosaminoglycans may be included within the construct. [0055]
  • The tissue repair fabric can be laser drilled to create micron sized pores through the completed prosthesis for aid in cell ingrowth using an excimer laser (e.g. at KrF or ArF wavelengths). The pore size can vary from 10 to 500 microns, but is preferably from about 15 to 50 microns and spacing can vary, but about 500 microns on center is preferred. The tissue repair fabric can be laser drilled at any time during the process to make the prosthesis, but is preferably done before decontamination or sterilization. [0056]
  • Voids or spaces can also be formed by the method of phase inversion. At the time of layering the ICL, between layers is distributed crystalline particles that are insoluble in the liquid heat source for bonding but should be soluble in the quench bath or the crosslinking solution. If laser or dry heat is used to bond the layers then any soluble crystalline solid may be used as long as it is soluble in the quench bath or the crosslinking solution. When the crystalline solid is solubilized and has diffused out, there remains a space in which the solid had occupied. The size of the particles may vary from 10 to 100 microns, but is preferably from about 15 to 50 microns and spacing can vary between particles when distributed between the layers. The number and size of the voids formed will also affect the physical properties (i.e., compliance, kink resistance, suture retention, pliability). [0057]
  • The following examples are provided to better elucidate the practice of the present invention and should not be interpreted in any way to limit the scope of the present invention. Those skilled in the art will recognize that various modifications, can be made to the methods described herein while not departing from the spirit and scope of the present invention. [0058]
  • EXAMPLES Example 1: Harvesting and Processing of The Intestinal Collagen Layer from Porcine Intestine
  • The small intestine of a pig was harvested and mechanically stripped, using a Bitterling gut cleaning machine (Nottingham, UK) which forcibly removes the fat, muscle and mucosal layers from the tunica submucosa using a combination of mechanical action and washing using hot water. The mechanical action can be described as a series of rollers that compress and strip away the successive layers from the tunica submucosa when the intact intestine is run between them. The tunica submucosa of the small intestine is harder and stiffer than the surrounding tissue, and the rollers squeeze the softer components from the submucosa. The result of the machine cleaning was such that the submucosal layer of the intestine solely remained. Finally, the submucosa was decontaminated with 0.3% peracetic acid for 18 hours at 4° C. and then washed in phosphate buffered saline. The product that remained was an intestinal collagen layer (ICL). [0059]
  • Example 2: Various Welding Temperatures and EDC Concentrations of ICL
  • The effects of welding temperature (followed by quenching), weld time, 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) concentration, acetone concentration and crosslinking time, after welding on weld strength were examined for the ICL two layered tube application. ICL was porcine derived as described in the Example 1. Strength qualities were measured using a suture retention test and a ultimate tensile strength (UTS) test. [0060]
  • ICL was inverted and stretched over a pair of mandrels which were inserted into an ICL mounting frame. Mandrels were of stainless steel tubing with an external diameter of 4.75 mm. The ICL and mandrels were then placed in a dehydration chamber set at 20% relative humidity at 4° C. for about 60 minutes. After dehydration, the ICL was removed from the chamber and the mandrels. The lymphatic tag areas were removed and the ICL was manually wrapped around the mandrel twice to form an ‘unwelded’ bilayer construct. The wrapped ICL was returned to the dehydration chamber and allowed to dry for another 90 minutes still at 20% relative humidity to about 50% moisture+/−10%. To determine the amount of moisture present in a sample construct, a CEM™ oven was used. [0061]
  • A THERMOCENTER™ oven was set for the designated temperature treatment for the constructs to be welded. Temperatures tested for welding ranged from 55° to 70° C. Once the constructs were placed in the oven, the oven was allowed to equilibrate before timing began. The constructs were allowed to remain in the chamber for the time required for that condition. Welding times ranged from 7 to 30 minutes. As soon as the time was completed the constructs were removed from the chamber and placed in a 4° C. water bath for about 2 to 5 minutes. The welded constructs were then returned to the dehydration chamber for about 30 minutes until dehydrated to about 20%+/−10%. [0062]
  • After dehydration, constructs were inserted into a vessel containing EDC in either deionized water or deionized water and acetone at the concentrations appropriate for the conditions tested. EDC concentrations tested were 50, 100, and 200 mM. Acetone concentrations tested were 0, 50, and 90% in water. The time duration for crosslinking was determined by the conditions tested. Crosslinking times were 6, 12, and 24 hours. After crosslinking, the construct was removed from the solution and rinsed with physiological pH phosphate buffered saline (PBS) three times at room temperature. The welded and crosslinked construct was then removed from the mandrel and stored in PBS until testing. In addition to the thirty constructs that were prepared, two other bilayer constructs were prepared by welding at 62° C. for 15 minutes and crosslinked in 100 mM EDC in 100% H[0063] 2O for 18 hours.
  • The suture retention test was used to determine the ability of a construct to hold a suture. A piece of construct was secured in a CHATTILION™ force measurement device and 1-2 mm bite was taken with a SURGILENE™ 6-0 suture, pulled through one wall of the construct and secured. The device then pulls at the suture to determine the force required to tear the construct material. The average suture breaks between 400-500 g of force; the surgeons pull tends to be 150 g of force. [0064]
  • The weld/material strength test was performed to determine the UTS of a construct. Sample rings of 5 mm lengths were excised from each tube and each was tested for their ultimate tensile strength (UTS) test using a mechanical testing system MTS™. Three sample rings were excised from each tube for three test pulls done for each construct for a total of 90 pulls. A ring was placed in the grips of the MTS™ and is pulled at a rate of 0.02 kgforce/sec until the weld slips or breaks, or until the material (rather than the weld) breaks. [0065]
  • Example 3: Various Welding Temperatures of ICL
  • The effect of welding temperature and quenching after welding on weld strength were examined for the ICL two layered tube application. [0066]
  • An ICL sample of 10 feet long was cut along its length and prepared as in the procedure outlined in Example 2. Six 6 mm diameter tubes ranging between 15-20 cm in length were prepared for each temperature condition. [0067]
  • Tubes were subjected to a temperature condition while wet for 3.5 hours. Temperatures conditions were: Room temperature (20° C.), 55° C., 62° C. and 62° C. then immediately quenched in 4° C. bath for one minute. All tubes were then crosslinked in EDC. Six tubes were placed together in 300 mL 100 mM EDC overnight at room temperature. Tubes were then rinsed with physiological strength phosphate buffered saline after crosslinking. [0068]
  • Sample rings of 5 mm lengths were excised from each tube and each was tested for ultimate tensile strength (UTS) test using a MTS™. Five sample rings were taken from each tube for 5 test pulls on each of [0069] 6 tubes per condition for a total of 30 pulls.
  • Weld strength was less consistent for tubes bonded by dehydration at room temperature as compared to the other temperature treatments when tested using the UTS test. One of the six tubes welded at room temperature had UTS measurements comparable to those of the other treatments. For the tubes welded at other temperatures either with or without quenching, there were no differences in weld strength. After UTS testing, it was determined that the breaking of the material was not a separation of the weld but a material failure in all instances. [0070]
  • Example 4: The Antigenicity of Crosslinked Intestinal Collagen Layer
  • Fresh samples of porcine submucosal intestinal layer were obtained after the cleaning step as described in example 1. Samples were then left untreated and stored in water, soaked in physiological strength phosphate buffered saline, treated with 0.1% peracetic acid, or were treated with 0.1% peracetic acid and then crosslinked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). Samples were then extracted with a solution of 0.5 M NaCl/0.1 M tartaric acid for about 18 hours. [0071]
  • Two 12% Tris-glycine sodium dodecylsulfate-polyacrylamide gels (Novex Precast Gels cat# EC6009) were run and then transferred after about 18 hours to 0.45 μnitrocellulose paper. Tartaric acid extracts of either untreated or treated ICL were run against a control standard lane containing: 10 μl Kaleidoscope Prestained Standards (Bio-Rad cat# 161-0324): 2 μl biotinylated SDS-PAGE low range molecular weight standards (Bio-Rad cat# 161-0306): 6 μ[0072] 1 loading buffer; 10 μl of control standard were loaded to each lane. The gel was blotted for about 2 hours with 1% dry non-fat milk (Carnation) in phosphate buffered saline. The gel was then washed three times with borate buffered saline/Tween with 200 μl of wash per lane. Primary antibody in 200 μl of Rb serum and borate buffered saline (100 mM boric acid: 25 mM sodium borate: 150 mM NaCl)/Tween was added to each lane at various titer range (1:40, 1:160, 1:640 and 1:2560). The gel was then incubated at room temperature for one hour on a rocker platform (Bellco Biotechnology) with the speed set at 10. The gel was then washed again three times with borate buffered saline/Tween. Secondary antibody, goat anti-rabbit Ig-AP (Southern Biotechnology Associates Inc. cat# 4010-04) at a 1:1000 dilution was added to lanes at 200 μl per lane and the gel was incubated for one hour at room temperature on a rocker platform. The nitrocellulose membrane was then immersed in AP color development solution while incubated at room temperature on a rocker platform until color development was complete. Development was stopped by washing the membrane in deionized water for ten minutes on a rocker platform while changing the water once during the ten minutes. The membrane was then air dried.
  • The results obtained from analysis of the gel suggest that the antigenicity of the porcine derived ICL treated with peracetic acid and EDC has greatly reduced antigenicity as compared to the other treatments. [0073]
  • Example 5: Six Layered Tissue Repair Fabric as an Abdominal Wall Patch
  • Six layers of porcine intestinal collagen were superimposed onto one another on a glass plate. A second plate of glass was then placed on top of the intestinal collagen layers and clamped tightly to the first plate. The apparatus was placed into a conventional type oven at 62° C. for one hour. Immediately following heating, the apparatus was placed into a 4° C. water bath for ten minutes. The apparatus was disassembled, the intestinal collagen layers removed, and treated with 100 mM 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) in 50% acetone for four hours at 25° C. The material was bagged and sterilized by gamma irradiation (2.5 Mrad). [0074]
  • The tissue repair fabric was sutured in a 3 cm×5 cm defect in the midline of New Zealand White rabbits (4 kg) using a continuous 2-0 prolene suture. Animals were sacrificed at four weeks, ten weeks, and 16 weeks, and examined grossly, mechanically, and histologically. Gross examination showed minimal inflammation and swelling. The graft was covered with a glistening tissue layer which appeared to be continuous with the parietal peritoneum. Small blood vessels could be seen proceeding circumferentially from the periphery to the center of the patch. Mechanically the graft was stable with no reherniation observed. Histological examination revealed relatively few inflammatory cells and those that were observed were primarily near the margin of the graft (due to the presence of prolene suture material). The peritoneal surface was smooth and covered entirely by mesothelium. [0075]
  • Example 6: Two Layered Tissue Repair Fabric as a Pericardial Repair Patch
  • Two layers of porcine intestinal collagen were superimposed onto one another on a glass plate. A second plate of glass was then placed on top of the intestinal collagen layers and clamped tightly to the first plate. The apparatus was placed into a conventional type oven at 62° C. for one hour. Immediately following heating, the apparatus was placed into a 4° C. water bath for ten minutes. The apparatus was disassembled, the intestinal collagen layers removed, and treated with 10 mM 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) in 50% acetone for four hours at 25° C. The material was bagged and sterilized by gamma irradiation (2.5 Mrad). [0076]
  • A 3×3 cm portion of New Zealand white rabbit pericardium was excised and replaced with a same size piece of tissue repair fabric (anastomosed with interrupted sutures of 7-0 prolene). Animals were sacrificed at four weeks and at 180 days, examined grossly, mechanically, and histologically. Gross examination showed minimal inflammation and swelling. Small blood vessels could be seen proceeding circumferentially from the periphery to the center to the graft. Mechanically, the graft was stable without adhesion to either the sternum or pericardial tissue. Histological examination revealed relatively few inflammatory cells and those that were observed were primarily near the margin of the graft (due to the presence of prolene suture material). [0077]
  • Example 7: Hernia Repair Device
  • A prototype device for hernia repair was developed using ICL to have a hollow inner region. The device, when completed, had a round conformation bonded at the periphery and a swollen inner region rendered swollen by the inclusion of physiological strength phosphate buffered saline. The inner region can optionally accommodate a wire coil for added rigidity or other substance for structural support or delivery of substance. [0078]
  • To assemble ICL multilayer sheets, 15 cm lengths of ICL were trimmed of lymphatic tags and cut down the side with the tags to form a sheet. Sheets were patted dry with Texwipes. On a clean glass plate (6″×8″), sheets were layered mucosal side down. In this case, two two-layer and two four-layer patches were constructed by layering either two or four layers of ICL on the glass plates. A second glass plate (6″×8″) was placed on top of the last ICL layer and the plates were clamped together and then placed in a hydrated oven at 62° C. for one hour. Constructs were then quenched in deionized water at 4° C. for about ten minutes. The glass plates were then removed from the bath and a plate removed from each patch. The now bonded ICL layers were then smoothed out to remove any creases or bubbles. The glass plate was replaced upon the ICL layers and returned to the hydrated oven for 30-60 minutes until dry. Patches were removed from the oven and partially rehydrated by spraying with physiological strength phosphate buffered saline. [0079]
  • For the construction of a bi-layer construct, one bi-layer patch was removed from the glass plates and placed upon the other bi-layer patch still on the other glass plate. An annular plate (d[0080] out=8.75 cm; din=6 cm) was placed upon the second patch. About 10 cc of physiological strength phosphate buffered saline was then injected through a 25 gauge needle between the two bilayer patches. A second glass plate was then placed on top of the annular plate and were then clamped together. For the construction of a four-layer construct, the same steps were followed except that two four-layer patches were used rather than two bi-layer patches. The constructs were placed in a hydrated oven at 62° C. for one hour. Constructs were then quenched in deionized water at 4° C. for about fifteen minutes. Constructs were then crosslinked in 200 mL 100 mM EDC in 50% acetone for about 18 hours and then rinsed with deionized water. The constructs were then trimmed to shape with a razor blade to the size of the outer edge of the annular plate.
  • Example 8: Intervertebral Disc Replacement
  • ICL, dense fibrillar collagen and hyaluronic acid were configured to closely approximate the anatomic structure and composition of an intervertebral disc. [0081]
  • Dense fibrillar collagen diskettes containing hyaluronic acid were prepared. 9 mg hyaluronic acid sodium salt derived from bovine trachea (Sigma) was dissolved in 3 mL 0.5 N acetic acid. 15 mL of 5 mg/mL collagen (Antek) was added and mixed. The mixture was centrifuged to remove air bubbles. To three transwells (Costar) in a six well plate (Costar) was added 5 mL of the solution. To the area outside the transwell was added N600 PEG to cover the bottom of the membranes. The plate was maintained at 4° C. on an orbital shaker table at low speed for about 22 hours with one exchange of PEG solution after 5.5 hours. PEG solution was removed and the transwells dehydrated at 4° C./20% Rh overnight. [0082]
  • To assemble ICL multilayer sheets, 15 cm lengths of ICL were trimmed of lymph tags and cut down the side with the tags to form a sheet. Sheets were patted dry with Texwipes. On a clean glass plate, sheets were layered mucosal side down to five layers thick and a second glass plate was laid on top of the fifth layer. Five five-layer patches were constructed. The plates with the ICL between were clamped together and placed in a hydrated oven at 62° C. for one hour. Constructs were then quenched in RODI water at 4 ° C. for about ten minutes then were removed form the quench bath and stored at 4° C. until assembly of the disc. [0083]
  • To another glass plate, one large patch was laid. A slightly smaller patch was laid upon the first patch aligned to one edge of the larger patch. One patch was cut in half and a hole was cut in the center of each approximating the size of the DFC diskettes. With the center holes aligned, the two halves were laid upon the second patch aligned to the same edge. Three rehydrated DFC/HA diskettes were placed within the center hole. Another slightly smaller patch was laid upon the two halves containing the DFC diskettes and a larger patch laid upon the smaller patch, both aligned to the same edge. A second glass plate was placed on top of the construct. The resultant shape was that of a wedge with the thicker side being the one with the aligned edges tapering to the opposite side. The thus formed device was placed in a hydrated oven at 62° C. for one hour and then quenched in RODI water at 4° C. for about ten mninutes. The device was then crosslinked in 100 mM EDC (Sigma) in 90% acetone (Baxter) for about five hours and then rinsed with three exchanges of phosphate buffered saline. The edges of the device were then trimmed with a razor blade. [0084]
  • Example 9: The Formation of Vascular Graft Construct
  • The proximal jejunum of a pig was harvested and processed with a Gut Cleaning Machine (Bitterling, Nottingham, UK) and then decontaminated with peracetic acid solution as described in example 1. The peracetic acid treated ICL (PA-ICL) was cut open longitudinally and lymphatic tag areas were removed to form a sheet of ICL. The ICL sheets were wrapped around a 6.0 mm diameter stainless steel mandrels to form bilayer constructs. The constructs (on mandrels) were then placed in an equilibrated THERMOCENTER™ oven chamber set at 62° C. for about 1 hour. The constructs were removed from the chamber and placed in a 4° C. water bath for about 2 to 5 minutes. The constructs were chemically crosslinked in 50 mL of 100 mM 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) in 50/50 water/acetone solution for 18 hours to form peracetic acid treated, EDC crosslinked (PA/EDC-ICL) vascular graft constructs. The constructs were removed from the mandrels and rinsed with water to remove residual EDC solution. [0085]
  • After removal from the mandrels, a layer (approximately 200 μm thick) of type I collagen extracted from bovine tendon, was deposited on the luminal surface of the constructs according to the method described in U.S. Pat. No. 5,256,418, incorporated herein. Polycarbonate barbs (luer lock fittings that are conically shaped on one end) were sealably fixed at either end of the constructs and the constructs were placed horizontally in a deposition fixture. A 50 mL reservoir of 2.5 mg/mL acid-extracted collagen, prepared by the method described in U.S. Pat. No. 5,106,949, incorporated herein, was attached via the barbs. The collagen was allowed to fill the lumen of the ICL tube and was then placed into a stirring bath of 20% MW 8000 polyethylene glycol (Sigma Chemicals Co.) for 16 hours at 4° C. The apparatus was then dismantled and a 4 mm diameter glass rod was placed into the collagen-filled ICL tube to fix the luminal diameter. The prosthesis was then allowed to dry. [0086]
  • The luminal DFC layer was coated with benzalkonium chloride heparin (HBAC) by dipping the grafts three times into an 800 U/mL solution of HBAC and allowed to dry. Finally, the graft received a final chemical sterilization treatment in 0.1% v/v peracetic acid. The graft was stored in a dry state until the implant procedure. [0087]
  • Example 10: Implant Studies on Animal Models
  • Twenty-five mongrel dogs weighing 15-25 kg were fasted overnight and then anesthetized with intravenous thiopental (30 mg/kg), entubated, and maintained with halothane and nitrous oxide. Cefazolin (1000 mg) was administered intravenously preoperatively as well as postoperatively. Each dog received either an aortic bypass grafts or a femoral interposition graft. For the aortic bypass grafts, a midline abdominal incision was made and the aorta exposed from the renal arteries to the bifurcation, followed by the administration of intravenous heparin (100 U/kg). The grafts (6 mm×8 cm) were placed between the distal infrarenal aorta (end-to-side anastomosis) and the aorta just proximal to the bifurcation (end-to-side anastomosis). The aorta was ligated distal to the proximal anastomosis. The incisions were closed and the dogs maintained on aspirin for 30 days post surgery. For the femoral interposition grafts, the animals were opened bilaterally, the femoral arteries exposed, and a 5 cm length excised. The grafts (4 mm×5 cm) were anastomosed in end-to-end fashion to the femoral artery. On the contralateral side, a control graft was placed. The incisions were closed and the animals were maintained on aspirin for 30 days post surgery. Post operative follow-up ranged from 30 days to 360 days. Pre-implant, and four and eight weeks post-implant bloods were collected. Animals were sacrificed at various time points (30 days, 60 days, 90 days, 180 days, and 360 days). [0088]
  • New Zealand White rabbits weighing 3.5-4.5 kg were fasted overnight, and then anesthetized with acepromazine (20 mg) and ketamine (40 mg), entubated, and maintained with ketamine (50 mg/mL), injected intravenously as needed. Penicillin (60,000 U) was administered intramuscularly preoperatively. A midline abdominal incision was made and the aorta exposed from the renal arteries to the bifurcation, followed by the administration of intravenous heparin (100 U/kg). A 3 cm length of aorta was excised, and the grafts (2.5 mm×3 cm) were anastomosed in end-to-end fashion to the aorta. The incisions were closed and the animals were maintained with no anticoagulant therapy post surgery. Post operative follow-up ranged from 30 days to 360 days. Animals were sacrificed at various time points (30 days, 60 days, 90 days, 180 days, and 360 days). [0089]
  • The implants along with adjacent vascular tissues obtained from sacrificed animals were fixed for transmission electron microscopy (TEM) analysis for 4 hr in a solution of 2.0% paraformaldehyde, 2.5% glutaraldehyde in 0.1 M sodium cacodylate, pH 7.4. Samples were then post-fixed in 1.0% OsO4 (in 0.1 M sodium cacodylate) and stained en bloc with 2.0% uranyl acetate (aqueous). After secondary fixation all specimens were dehydrated in a graded ethanol series and propylene oxide and embedded in Epox 812 (Ernest F. Fullam, Rochester, N.Y., USA). Ultrathin (˜700 nm) sections were stained with uranyl acetate and lead citrate. Sections were examined on a JEOL Instruments JEM100S at 80 kV. For scanning electron microscopy (SEM), samples were fixed for 18 hr in half strength Karnovsky's solution and rinsed five times in Sorensen's phosphate buffer prior to post fixation in 1.0% OsO4 for 1 hr. Samples were then rinsed twice in Sorensen's phosphate buffer and three times in double distilled water. Dehydration was accomplished through an ethanol series (50%, 70%, 90%, and 100%), followed by critical point drying. Samples were mounted and coated with 60/40 gold/palladium. [0090]
  • ICL graft explants from dogs and rabbits were examined histologically to evaluate host cell ingrowth. Masson's trichrome staining of a 60 day explant showed significant host infiltrate. The darker blue staining showed collagen of the ICL while matrix surrounding the myofibroblasts, stained lighter blue, showed an abundance of host collagen. High power magnification of the section showed numerous cells intermingled within the ICL. The inflammatory response seen at 30 days had been resolved and the cellular response was predominantly myofibroblastic. The surface of the remodeled graft was lined by endothelial cells as demonstrated by SEM and Factor VIII staining. By 360 days, a mature ‘neo-artery’ had been formed. The neo-adventitia was composed of host collagen bundles populated by fibroblast-like cells. The cells and matrices of the remodeled construct appeared quite mature and tissue-like. [0091]
  • Example 11: Generation of Anti-ICL Antibodies
  • Fresh samples of porcine submucosal intestinal layer were obtained after the cleaning step as described in example 1 but were not peracetic acid treated. Samples were then left untreated (NC-ICL), treated with 0.1% peracetic acid (PA-ICL), or treated with 0.1% peracetic acid and then crosslinked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (PA/EDC-ICL). [0092]
  • New Zealand White rabbits were immunized with 0.5 mg of any one of the three types of ICL samples (NC-ICL, PA-ICL, or PA/EDC-ICL) to generate anti-serum. Initially, rabbits were injected subcutaneously with 0.5 mL of homogenized untreated ICL in Freund's complete adjuvant (1:1, 1 mg/mL). Sham rabbits received 0.5 mL of phosphate buffered saline in Freund's complete adjuvant. Rabbits were boosted every 3 to 4 months with 0.5 mL of the appropriate form of ICL in Freund's incomplete adjuvant (0.25 mg/mL). Sera were collected 10-14 days after each boost. [0093]
  • Example 12: Generation of ICL Extracts and Characterization of Potentially Antigenic Proteins Associated With Native Collagen
  • Proteins were extracted from NC-ICL, PA-ICL, or PA/EDC-ICL using tartaric acid (Bellon, G., et al (1988) [0094] Anal. Biochem. 175: 263-273) or TRITON X-100 (Rohm and Haas). Pulverized NC-ICL, PA-ICL, or PA/EDC-ICL (10% w/v) were mixed with either tartaric acid (0.1 M tartaric acid, 0.5 M NaCI) or TRITON X-100 (Rohm and Haas) extraction buffer (TEB; 1% TRITON X-100 in 20 mM Tris HCl (pH 7.2), 2 mM EGTA, 2 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, and 25 mg/mL each of aprotinin, leupeptin, and pepstatin (Sigma, St. Louis, Mo.)). The mixtures were incubated overnight at 4° C. The extracts were gauze filtered to remove debris, dialyzed against PBS and concentrated using Centriprep-30 (Amicon, Danvers, Mass.). Extracts were stored at−80° C. until used.
  • Tartaric acid and TEB extracts of were separated on 10% polyacrylamide gels by SDS-PAGE according to Laemmli (Laemrnli, U.K. (1970) [0095] Nature 227: 680-685). Gels were either silver stained (Bio-Rad, Hercules, Calif.) or transferred to nitrocellulose membranes (Amersham, Arlington Heights, Ill.). Multiple protein bands were visualized in the NC-ICL extracts by silver staining. In contrast, only two bands were visible in the PA-ICL extracts and no protein bands were seen in the lanes containing PA/EDC-ICL. These results suggest that peracetic acid and EDC treatment, in combination, leads to a decrease in the extractable non-collagenous proteins in ICL.
  • Immunoblot transfer was done overnight using a Trans-Blot Cell (Bio-Rad) in Tris-Glycine 20% methanol transfer buffer. Nitrocellulose membranes containing ICL transferred proteins were blocked with Blotto buffer (1% non-fat dry milk in borate buffered saline with 0.1% Tween-20 (BBS/Tween)) for one hour at room temperature. The nitrocellulose membranes were transferred to a multiscreen apparatus containing 12 individual lanes. The membranes were washed three times with BBS/Tween. Positive control or test sera (100 μL/lane) were added to the membrane and rocked at room temperature for 1 hour. Each lane was washed three times with BBS/Tween. Secondary antibodies: ALPH-labeled goat anti-rabbit Ig or ALPH-labeled goat anti-dog Ig (Southern Biotechnology) were added to the appropriate lanes (100 μL/lane) and streptavidin-AP (100 μL) was added to one of the lanes containing the Kaleidoscope molecular weight standards (Bio-Rad). An alkaline phosphatase conjugate substrate kit (Bio-Rad) was used to visualize the immunoblots. [0096]
  • Rabbit anti-NC-ICL serum, generated by repeated immunization with NC-ICL, was used to detect potentially immunoreactive proteins. Sera from immunized rabbits recognized antigens with molecular weights in the range of<30, 40-70, and>100 kDa in the tartaric acid extract. These same sera were tested on immunoblots of TEB extracts from NC-ICL. Immunoreactive proteins were detected with molecular weights ranges similar to those detected in the tartaric acid extract, with additional reactivity detected in the 70-100 kDa range. The results indicated that NC-ICL contains multiple proteins which are immunoreactive and these proteins can be extracted by tartaric acid or TEB. The greater number of immunoreactive proteins present in the TEB extract correlated with the increase in proteins extracted using TEB as compared to tartaric acid. [0097]
  • Example 13: Effect of PA or EDC Treatment of ICL on the Antigenicity of Type I Collagen in ICL
  • Sera from rabbits immunized with NC-ICL, PA-ICL, or PA/EDC-ICL (sera prepared as described in example 11) or acid extracted type I collagen (Organogenesis, Canton, MA) were tested for type I collagen specific antibodies by ELISA. ELISA plates (Immulon II, NUNC, Bridgeport, N.J.) were coated with 200 mL/well of 1 mg/mL acid extracted type I collagen in 0.05 M carbonate buffer (pH 9.6) overnight at 4° C. Plates were washed twice with PBS/Tween-20 (0.1%). Serum samples from animals or rabbit anti-collagen type I antibody (Southern Biotechnology, Birmingham, Ala.) were added to wells (100 mL/well) and incubated for 1 hr at room temperature. Plates were washed three times with PBS/Tween. Secondary antibodies: ALPH-labeled goat anti-rabbit Ig or ALPH-labeled goat anti-dog Ig (Southern Biotechnology) were added to the appropriate wells and incubated at room temperature for 1 hour. Plates were washed three times with PBS/Tween. P-nitrophenylphosphate (PNPP) substrate (1 mg/mL) was added to each well (100 niL/well). Absorbance was read at 405 nm on a SpectraMax microplate reader (Molecular Devices, Sunnydale, Calif.). [0098]
  • Anti-collagen type I antibodies could not be detected in sera from rabbits immunized with any form of ICL, even at a 1:40 serum dilution. In contrast, rabbits immunized with purified type I collagen had antibody titer of 1:2560. These data suggest that crosslinking is not necessary to reduce the antigenicity to collagen type I, since rabbits immunized with NC-ICL did not generate anti-collagen type I antibodies. These data thus suggest that the immunodominant proteins in NC-ICL are non-collagenous proteins. Also, the effect of PA and EDC on reducing the antigenicity of ICL is directed toward the non-collagenous proteins. [0099]
  • Example 14: Effects of Disinfecting and Crosslinking on Antigenicity of ICL.
  • The effect of PA and EDC treatment on the antigenicity of ICL was determined by using anti-NC-ICL antiserum to probe for immunoreactive proteins present in tartaric acid or TEB extracts of PA or PA/EDC treated ICL. [0100]
  • Tartaric acid extracts of PA-ICL and TEB extracts of PA/EDC-ICL were separated on 10% SDS-PAGE gels and transferred to nitrocellulose membranes for immunoblot analysis, as described in Example 12. NC-ICL specific antisera were used to probe for immunoreactive proteins in each extract. Even when immunoblots of PA-ICL and PA/EDC-ICL were overexposed, no reactivity could be detected in lanes containing anti-NC-ICL antibodies thus suggesting that the immunoreactive proteins detected in the NC-ICL are either missing or their epitopes have been modified such that they are no longer recognized by anti-NC-ICL anti-serum. To address this latter issue, serum from rabbits immunized with either PA-ICL or PA/EDC-ICL was also tested. No antibody binding was detected in any of the lanes above background. These data indicate that even when rabbits were immunized with modified ICL they did not generate antibodies which could recognize modified ICL extracted proteins. These results suggest that the proteins removed or modified during the process of disinfecting and crosslinking are the same proteins responsible for the antigenicity of NC-ICL. [0101]
  • Antibody response of PA-ICL or PA/EDC-ICL immunized rabbits was analyzed by immunoblotting, as described in Example 12. This approach was taken to ensure that the lack of reactivity of anti-NC-ICL sera with PA/EDC-ICL was due to the absence of proteins in ICL and not due to an inability to extract proteins which might be accessible to the immune system in vivo since crosslinking of collagenous materials with EDC could reduce the quantity and quality of protein extracted from ICL. Anti-ICL antisera was generated using PA-ICL or PA/EDC-ICL to immunize rabbits. Sera from these rabbits were tested for antibodies specific for proteins in either tartaric acid or TEB protein extracts of NC-ICL. Anti-PA-ICL recognized the 207, 170, and 38-24 kDa proteins recognized by anti-NC-ICL, but lost reactivity to the lower molecular weight proteins. No bands were detected by the anti-PA/EDC-ICL serum from 1 rabbit. Serum from another anti-PA/EDC-ICL rabbit reacted with the 24-38 kDa proteins. These data suggested that both PA-ICL and PA/EDC-ICL are less antigenic than NC-ICL. Either the antigenic epitopes of ICL are removed during the disinfecting and crosslinking process or they are modified to reduce their antigenicity. In either case, disinfection and crosslinking resulted in a material whose antigenicity was significantly reduced. [0102]
  • Example 15: Determination of Humoral Immune Response in Graft Recipients
  • Dogs were tested for a humoral immune response to ICL graft components to determine if ICL must retain its antigenicity to stimulate cell ingrowth into the graft. Pre-implant, and four and eight weeks post-implant blood samples were collected from fifteen dogs that received PA/EDC-ICL vascular grafts. Serum from each blood sample was tested for antibodies to proteins in both the tartaric acid and TEB extracts of NC-ICL. Even at a 1:40 dilution of serum, none of the dogs tested had antibodies which reacted with ICL proteins. These same serum samples were tested for the presence of anti-collagen type I antibodies by ELISA. All serum samples were negative for antibodies to type I collagen at a serum dilution of 1:40. Masson's trichrome staining of explant paraffin sections from these dogs did shown infiltration of host cells. These results demonstrate that PA/EDC-ICL does not elicit an antibody response when the host is actively remodeling the material. [0103]
  • Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be obvious to one of skill in the art that certain changes and modifications may be practiced within the scope of the appended claims. [0104]

Claims (33)

What is claimed:
1. A prosthesis comprising two or more superimposed, bonded layers of collagenous tissue which have been crosslinked with a crosslinking agent that permits bioremodeling and sterilized, wherein all of the layers of the prosthesis are completely bioremodelable, and which, when implanted into a mammalian patient, undergoes controlled biodegradation occurring with adequate living cell replacement such that the original implanted prosthesis is remodeled by the patient's living cells.
2. The prosthesis of claim 1 wherein the shape of said prosthesis is flat, tubular, or complex.
3. The prosthesis of claim 1 wherein said collagen material is sourced from a mammalian source and is intestinal material, fascia lata, dura mater, and pericardium.
4. The prosthesis of claim 3 wherein said collagen material is the tunica submucosa of the small intestine.
5. The prosthesis of claim 1 wherein said collagen layers are bonded together by heat welding for a time and under conditions sufficient to effect the bonding of the collagenous tissue layers.
6. The prosthesis of claim 1 wherein said prosthesis is crosslinked with the crosslinking agent 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride.
7. The prosthesis of claim 6 wherein sulfo-N-hydroxysuccinimide is added to the crosslinking agent.
8. The prosthesis of claim 6 wherein acetone is added to the crosslinking agent.
9. The prosthesis of claim 1 wherein the prosthesis is sterilized with peracetic acid.
10. The prosthesis of claim 10 wherein said prosthesis is non-antigenic.
11. The prosthesis of claim 1 wherein one or more surfaces of said prosthesis is coated with a collagenous material which acts as a smooth flow surface.
12. The prosthesis of claim 1 wherein said prosthesis further contains pores.
13. The prosthesis of claim 1 wherein said prosthesis is further composed of chopped collagen fibers.
14. The prosthesis of claim 1 wherein said prosthesis is further composed of collagen threads.
15. The prosthesis of claim 14 wherein said collagen threads are arranged to form a felt, a bundle, a weave or a braid.
16. The prosthesis of any of claims 13-15 wherein said collagen fibers or threads are partially or completely crosslinked.
17. The prosthesis of claim 1 wherein said prosthesis additionally contains an anticoagulant; one or more antibiotics, or one or more growth factors.
18. A method of preparing a prosthesis having two or more superimposed, bonded layers of collagen material, comprising:
(a) bonding the two or more collagen layers together using heat welding by heating said collagenous tissue layers for a time and under conditions sufficient to effect the bonding of the collagen layers and to form a prosthesis;
(b) cooling said heated prosthesis; and,
(c) crosslinking said prosthesis with a crosslinking agent that permits bioremodeling, wherein said thus formed prosthesis when implanted into a mammalian patient, undergoes controlled biodegradation occurring with adequate living cell replacement such that the original implanted prosthesis is remodeled by the patient's living cells;
wherein the collagenous tissue layers are sterilized with peracetic acid before bonding in step (a) or the prosthesis is sterilized after crosslinking in step (c).
19. The method of claim 18 wherein said collagen layers are formed from two or more layers of collagenous tissue sourced from a mammalian source and is intestinal material, fascia lata, dura mater, and pericardium.
20. The method of claim 19 wherein said collagen material is the tunica submucosa of the small intestine.
21. The method of claim 18 wherein said heat welding is from about 50° C. to about 75° C., more preferably from about 60° to 65° C. and most preferably at about 62° C.
22. The method of claim 18 wherein said cooling is accomplished by quenching.
23. The method of claim 18 wherein said heat welding is accomplished for a time from about 7 minutes to about 24 hours, preferably about 1 hour.
24. The method of claim 18 wherein said prosthesis is crosslinked with the crosslinking agent 1-ethyl-3-(3-dimethylaminopropyl) carbodimide hydrochloride.
25. The method of claim 18 wherein said prosthesis is non-antigenic.
26. A method of repairing or replacing a damaged tissue comprising implanting a prosthesis in a patient comprising two or more superimposed, bonded layers of collagenous tissue which have been sterilized with peracetic acid and crosslinked with a crosslinking agent that permits bioremodeling, wherein all of the layers of the prosthesis are completely bioremodelable, and which, when implanted into a mammalian patient, undergoes controlled biodegradation occurring with adequate living cell replacement such that the original implanted prosthesis is remodeled by the patient's living cells.
27. A sterile, non-pyrogenic, and non-antigenic prosthesis formed from mammalian derived collagenous tissue for engraftment to a recipient patient, whereby said engrafted prosthesis does not elicit a humoral immune response to components in said collagenous tissue and wherein said prosthesis concomitantly undergoes bioremodeling occurring with adequate living cell replacement such that the original implanted prosthesis is remodeled by the patient's living cells.
28. The prosthesis if claim 27 wherein said humoral immune response to components derived from said collagenous tissue demonstrates no significant increase in antibody titer for antibodies from baseline titer levels when blood serum obtained from a recipient of a prosthesis is tested for antibodies to proteins in extracts of the collagenous tissue..
29. The prosthesis of claim 28 wherein said antibody titer levels is 1:40 or less for a patient or host previously non-sensitized to collagenous tissue proteins.
30. A method of preparing a non-antigenic prosthesis prepared from collagenous tissue derived from a mammalian source selected from the group consisting of intestinal material, fascia lata, dura mater, and pericardium, comprising:
(a) disinfecting the collagen material with peracetic acid at a concentration between about 0.01 and 0.3% v/v in water; and,
(b) crosslinking said sterilized collagenous tissue with a crosslinking agent that permits bioremodeling;
wherein the prosthesis isformed from two or more superimposed, bonded layers of collagenous tissue, wherein all of the layers of the prosthesis are bioremodelable, and wherein the prosthesis when implanted into a mammalian patient, undergoes controlled bioremodeling occurring with adequate living cell replacement such that the original implanted prosthesis is remodeled by the patient's living cells without eliciting a significant humoral immune response.
31. The method of claim 30 wherein said collagenous tissue is the tunica submucosa of the small intestine.
32. The method of claim 30 wherein said collagen material is formed from two or more layers of superimposed, bonded layers of collagen material.
33. The method of claim 30 wherein the prosthesis is sterilized with peracetic acid prior to implantation into the mammalian patient.
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Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1389450A1 (en) * 2002-08-16 2004-02-18 Tutogen Medical GmbH Hernia implant
US20040132365A1 (en) * 2002-11-04 2004-07-08 Sofradim Production Intermediate composite part for forming reinforcement prosthesis
US20060025786A1 (en) * 1996-08-30 2006-02-02 Verigen Transplantation Service International (Vtsi) Ag Method for autologous transplantation
US20060029633A1 (en) * 2004-08-03 2006-02-09 Arthrotek, Inc Biological patch for use in medical procedures
US20060159641A1 (en) * 2002-01-25 2006-07-20 Biomedical Design, Inc. Variably crosslinked tissue
US20070027529A1 (en) * 2005-07-29 2007-02-01 Guo-Feng Xu Biological artificial blood vessel and method of making
US20070032806A1 (en) * 2005-08-04 2007-02-08 Song-Tao Qi Biological membrane-carrying aneurysm clip
US20070038299A1 (en) * 2005-08-12 2007-02-15 Arthrotek, Inc Multilayer microperforated implant
US20080051888A1 (en) * 2005-02-18 2008-02-28 Anthony Ratcliffe Synthetic structure for soft tissue repair
US20080147198A1 (en) * 2006-10-19 2008-06-19 C.R. Bard, Inc. Prosthetic repair fabric
US20090069838A1 (en) * 2004-12-06 2009-03-12 Paul Ram H Inflatable occlusion devices, methods, and systems
US7790945B1 (en) 2004-04-05 2010-09-07 Kci Licensing, Inc. Wound dressing with absorption and suction capabilities
USRE42834E1 (en) 2001-11-20 2011-10-11 Kci Licensing Inc. Personally portable vacuum desiccator
US20140172096A1 (en) * 2011-03-08 2014-06-19 Mimedx Group, Inc. Collagen fiber ribbons with integrated fixation sutures and methods of making the same
US20150005869A1 (en) * 2012-02-14 2015-01-01 Neograft Technologies, Inc. Kink Resistant Graft Devices and Related Systems and Methods
US9242026B2 (en) 2008-06-27 2016-01-26 Sofradim Production Biosynthetic implant for soft tissue repair
US9308068B2 (en) 2007-12-03 2016-04-12 Sofradim Production Implant for parastomal hernia
US9445883B2 (en) 2011-12-29 2016-09-20 Sofradim Production Barbed prosthetic knit and hernia repair mesh made therefrom as well as process for making said prosthetic knit
US9499927B2 (en) 2012-09-25 2016-11-22 Sofradim Production Method for producing a prosthesis for reinforcing the abdominal wall
US9526603B2 (en) 2011-09-30 2016-12-27 Covidien Lp Reversible stiffening of light weight mesh
US9554887B2 (en) 2011-03-16 2017-01-31 Sofradim Production Prosthesis comprising a three-dimensional and openworked knit
US9622843B2 (en) 2011-07-13 2017-04-18 Sofradim Production Umbilical hernia prosthesis
US9750837B2 (en) 2012-09-25 2017-09-05 Sofradim Production Haemostatic patch and method of preparation
US9839505B2 (en) 2012-09-25 2017-12-12 Sofradim Production Prosthesis comprising a mesh and a strengthening means
US9877820B2 (en) 2014-09-29 2018-01-30 Sofradim Production Textile-based prosthesis for treatment of inguinal hernia
US9932695B2 (en) 2014-12-05 2018-04-03 Sofradim Production Prosthetic porous knit
US9931198B2 (en) 2015-04-24 2018-04-03 Sofradim Production Prosthesis for supporting a breast structure
US9980802B2 (en) 2011-07-13 2018-05-29 Sofradim Production Umbilical hernia prosthesis
US10080639B2 (en) 2011-12-29 2018-09-25 Sofradim Production Prosthesis for inguinal hernia
US10159555B2 (en) 2012-09-28 2018-12-25 Sofradim Production Packaging for a hernia repair device
US10184032B2 (en) 2015-02-17 2019-01-22 Sofradim Production Method for preparing a chitosan-based matrix comprising a fiber reinforcement member
US10213283B2 (en) 2013-06-07 2019-02-26 Sofradim Production Textile-based prosthesis for laparoscopic surgery
US10327882B2 (en) 2014-09-29 2019-06-25 Sofradim Production Whale concept—folding mesh for TIPP procedure for inguinal hernia
US10363690B2 (en) 2012-08-02 2019-07-30 Sofradim Production Method for preparing a chitosan-based porous layer
US10405960B2 (en) 2013-06-07 2019-09-10 Sofradim Production Textile-based prothesis for laparoscopic surgery
US10549015B2 (en) 2014-09-24 2020-02-04 Sofradim Production Method for preparing an anti-adhesion barrier film
US10646321B2 (en) 2016-01-25 2020-05-12 Sofradim Production Prosthesis for hernia repair
US10675137B2 (en) 2017-05-02 2020-06-09 Sofradim Production Prosthesis for inguinal hernia repair
US10682215B2 (en) 2016-10-21 2020-06-16 Sofradim Production Method for forming a mesh having a barbed suture attached thereto and the mesh thus obtained
US10743976B2 (en) 2015-06-19 2020-08-18 Sofradim Production Synthetic prosthesis comprising a knit and a non porous film and method for forming same
US10865505B2 (en) 2009-09-04 2020-12-15 Sofradim Production Gripping fabric coated with a bioresorbable impenetrable layer
US11471257B2 (en) 2018-11-16 2022-10-18 Sofradim Production Implants suitable for soft tissue repair
US11589973B2 (en) 2018-05-16 2023-02-28 Mimedx Group, Inc. Methods of making collagen fiber medical constructs and related medical constructs, including patches
US11925543B2 (en) 2011-12-29 2024-03-12 Sofradim Production Barbed prosthetic knit and hernia repair mesh made therefrom as well as process for making said prosthetic knit

Families Citing this family (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020026244A1 (en) * 2000-08-30 2002-02-28 Trieu Hai H. Intervertebral disc nucleus implants and methods
US7833283B2 (en) * 2001-08-16 2010-11-16 Purdue Research Foundation Material and method for promoting tissue growth
US7622129B1 (en) 2002-08-05 2009-11-24 Purdue Research Foundation Nano-structured polymers for use as implants
US20040254640A1 (en) * 2002-03-01 2004-12-16 Children's Medical Center Corporation Needle punched textile for use in growing anatomical elements
US20040054414A1 (en) 2002-09-18 2004-03-18 Trieu Hai H. Collagen-based materials and methods for augmenting intervertebral discs
US7744651B2 (en) * 2002-09-18 2010-06-29 Warsaw Orthopedic, Inc Compositions and methods for treating intervertebral discs with collagen-based materials
CN100394989C (en) * 2002-11-15 2008-06-18 华沙整形外科股份有限公司 Collagen-based materials and methods for augmenting intervertebral discs
US20040186471A1 (en) * 2002-12-07 2004-09-23 Sdgi Holdings, Inc. Method and apparatus for intervertebral disc expansion
US7993412B2 (en) * 2003-03-27 2011-08-09 Purdue Research Foundation Nanofibers as a neural biomaterial
US8545386B2 (en) 2003-08-14 2013-10-01 Boston Scientific Scimed, Inc. Surgical slings
US7056337B2 (en) * 2003-10-21 2006-06-06 Cook Incorporated Natural tissue stent
JP4207224B2 (en) * 2004-03-24 2009-01-14 富士ゼロックス株式会社 Image forming method
WO2006026731A1 (en) 2004-08-30 2006-03-09 Spineovations, Inc. Method of treating spinal internal disk derangement
US8127770B2 (en) * 2004-08-30 2012-03-06 Spineovations, Inc. Method of using an implant for treament of ligaments and tendons
US7402172B2 (en) * 2004-10-13 2008-07-22 Boston Scientific Scimed, Inc. Intraluminal therapeutic patch
WO2006044832A2 (en) * 2004-10-15 2006-04-27 The Cleveland Clinic Foundation Device for tissue engineering
US8329202B2 (en) 2004-11-12 2012-12-11 Depuy Products, Inc. System and method for attaching soft tissue to an implant
WO2006060546A2 (en) * 2004-12-01 2006-06-08 Cook Incorporated Valve with leak path
WO2006138718A2 (en) 2005-06-17 2006-12-28 Drexel University Three-dimensional scaffolds for tissue engineering made by processing complex extracts of natural extracellular matrices
CN1903144A (en) * 2005-07-29 2007-01-31 广东冠昊生物科技有限公司 Biological artificial ligamentum and method for preparing same
AU2006275350A1 (en) 2005-08-04 2007-02-08 C.R. Bard, Inc. Pelvic implant systems and methods
AU2006295080A1 (en) * 2005-09-21 2007-04-05 Medtronic, Inc. Composite heart valve apparatus manufactured using techniques involving laser machining of tissue
WO2007059199A2 (en) 2005-11-14 2007-05-24 C.R. Bard, Inc. Sling anchor system
DE102005054940A1 (en) * 2005-11-17 2007-05-24 Gelita Ag Composite material, in particular for medical use, and method for its production
CN1986001B (en) * 2005-12-20 2011-09-14 广东冠昊生物科技股份有限公司 Biological wound-protecting film
CN1986006A (en) 2005-12-20 2007-06-27 广州知光生物科技有限公司 Biological nerve duct
CN1985778B (en) * 2005-12-20 2010-10-13 广东冠昊生物科技股份有限公司 Artificial biological cornea
CN1986007B (en) * 2005-12-20 2011-09-14 广东冠昊生物科技股份有限公司 Biological surgical patch
US20080004703A1 (en) * 2006-06-30 2008-01-03 Warsaw Orthopedic, Inc. Method of treating a patient using a collagen material
US8118779B2 (en) 2006-06-30 2012-02-21 Warsaw Orthopedic, Inc. Collagen delivery device
US20080004431A1 (en) * 2006-06-30 2008-01-03 Warsaw Orthopedic Inc Method of manufacturing an injectable collagen material
US8399619B2 (en) 2006-06-30 2013-03-19 Warsaw Orthopedic, Inc. Injectable collagen material
CN101332314B (en) * 2008-07-22 2012-11-14 广东冠昊生物科技股份有限公司 Biotype articular cartilage repair piece
US20100023129A1 (en) * 2008-07-22 2010-01-28 Guo-Feng Xu Jawbone prosthesis and method of manufacture
CN101332316B (en) * 2008-07-22 2012-12-26 广东冠昊生物科技股份有限公司 Biotype nose bridge implantation body
US20080058779A1 (en) * 2006-09-05 2008-03-06 Ace Vision Usa Method for Affecting Biomechanical Properties of Biological Tissue
US20080063627A1 (en) * 2006-09-12 2008-03-13 Surmodics, Inc. Tissue graft materials containing biocompatible agent and methods of making and using same
WO2008033950A2 (en) 2006-09-13 2008-03-20 C. R. Bard, Inc. Urethral support system
CN101616698A (en) * 2006-10-23 2009-12-30 库克生物科技公司 The ECM material of the enhanced processing of component characteristic
US20080299172A1 (en) * 2007-06-04 2008-12-04 Stuart Young Tissue repair implant
US20090036996A1 (en) * 2007-08-03 2009-02-05 Roeber Peter J Knit PTFE Articles and Mesh
US20090187197A1 (en) * 2007-08-03 2009-07-23 Roeber Peter J Knit PTFE Articles and Mesh
ITBO20070702A1 (en) * 2007-10-19 2009-04-20 A U S L Azienda Unita Sanitari METHOD OF TREATMENT OF CONNECTIVE FABRIC AND RELATED APPLICATIONS OF USE OF SUCH TISSUE.
US8206280B2 (en) 2007-11-13 2012-06-26 C. R. Bard, Inc. Adjustable tissue support member
JP2011505904A (en) * 2007-12-07 2011-03-03 シー・アール・バード・インコーポレーテッド Implantable prosthesis
US8679176B2 (en) 2007-12-18 2014-03-25 Cormatrix Cardiovascular, Inc Prosthetic tissue valve
US8257434B2 (en) 2007-12-18 2012-09-04 Cormatrix Cardiovascular, Inc. Prosthetic tissue valve
US20100004700A1 (en) * 2008-03-05 2010-01-07 Neville Alleyne Method of treating tissue with a suspenson of tricalcium hydroxyapatite microspheres
US8469961B2 (en) * 2008-03-05 2013-06-25 Neville Alleyne Methods and compositions for minimally invasive capsular augmentation of canine coxofemoral joints
EP2113262B1 (en) 2008-04-29 2013-11-06 Proxy Biomedical Limited A Tissue Repair Implant
US8298584B2 (en) * 2008-12-30 2012-10-30 Collagen Matrix, Inc. Biopolymeric membrane for wound protection and repair
US9150318B1 (en) * 2009-01-02 2015-10-06 Lifecell Corporation Method for sterilizing an acellular tissue matrix
US9271925B2 (en) 2013-03-11 2016-03-01 Bioinspire Technologies, Inc. Multi-layer biodegradable device having adjustable drug release profile
EP2477617B1 (en) 2009-09-18 2018-01-31 Bioinspire Technologies Inc. Free-standing biodegradable patch
WO2011094313A1 (en) * 2010-01-28 2011-08-04 Boston Scientific Scimed, Inc. Composite surgical implants for soft tissue repair
WO2011119845A1 (en) 2010-03-24 2011-09-29 Tyco Healthcare Group Lp Combination three-dimensional surgical implant
FR2962646B1 (en) 2010-07-16 2012-06-22 Sofradim Production PROSTHETIC WITH RADIO OPAQUE ELEMENT
KR20140024905A (en) 2011-05-27 2014-03-03 코매트릭스 카디오바스컬라 인코포레이티드 Sterilized, acellular extracellular matrix compositions and methods of making thereof
US9005308B2 (en) 2011-10-25 2015-04-14 Covidien Lp Implantable film/mesh composite for passage of tissue therebetween
US10206769B2 (en) 2012-03-30 2019-02-19 Covidien Lp Implantable devices including a film providing folding characteristics
CN102716516B (en) * 2012-05-11 2014-02-26 天津大学 Polydatin modified collagen scaffold, and preparation method and application thereof
FR2992662B1 (en) 2012-06-28 2014-08-08 Sofradim Production KNIT WITH PICOTS
FR2992547B1 (en) 2012-06-29 2015-04-24 Sofradim Production PROSTHETIC FOR HERNIA
US9238090B1 (en) 2014-12-24 2016-01-19 Fettech, Llc Tissue-based compositions
EP3137058B1 (en) 2015-01-16 2018-09-05 SpineOvations, Inc. Method of treating spinal disk
AU2018351351B2 (en) 2017-10-19 2022-09-29 C.R.Bard, Inc. Self-gripping hernia prosthesis
US11285177B2 (en) 2018-01-03 2022-03-29 Globus Medical, Inc. Allografts containing viable cells and methods thereof
RU2714200C1 (en) * 2018-12-29 2020-02-13 Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) Method for producing a bioresorbable tube based on methacrylized gelatine and methacrylized fibroin and a method for reconstructing a small intestine wall experimentally using such a tube

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3919411A (en) * 1972-01-31 1975-11-11 Bayvet Corp Injectable adjuvant and compositions including such adjuvant
US4148664A (en) * 1976-05-10 1979-04-10 Avicon, Inc. Preparation of fibrous collagen product having hemostatic and wound sealing properties
US4703108A (en) * 1984-03-27 1987-10-27 University Of Medicine & Dentistry Of New Jersey Biodegradable matrix and methods for producing same
US5219576A (en) * 1988-06-30 1993-06-15 Collagen Corporation Collagen wound healing matrices and process for their production
US5487895A (en) * 1993-08-13 1996-01-30 Vitaphore Corporation Method for forming controlled release polymeric substrate
US5866414A (en) * 1995-02-10 1999-02-02 Badylak; Stephen F. Submucosa gel as a growth substrate for cells
US5893888A (en) * 1992-08-07 1999-04-13 Tissue Engineering, Inc. Method and construct for producing graft tissue from extracellular matrix
US6090995A (en) * 1989-09-15 2000-07-18 Surmodics, Inc. Surface modifying composition and method

Family Cites Families (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2127903A (en) 1936-05-05 1938-08-23 Davis & Geck Inc Tube for surgical purposes and method of preparing and using the same
FR1358465A (en) 1963-02-21 1964-04-17 Process for the treatment of animal tissues, in particular with a view to the separation of polysaccharides
US3366440A (en) 1964-11-03 1968-01-30 Ethicon Inc Process for manufacturing a collagen fabric-film laminate
US3272204A (en) 1965-09-22 1966-09-13 Ethicon Inc Absorbable collagen prosthetic implant with non-absorbable reinforcing strands
AT261800B (en) 1966-08-22 1968-05-10 Braun Internat Gmbh B Process for the manufacture of tubular, smooth or threaded tissue-blood vessel prostheses
US3551560A (en) 1967-10-02 1970-12-29 Heinrich F Thiele Process of reconstructing tendons,cartilage,nerve sheaths,and products
JPS5141794B2 (en) 1972-07-12 1976-11-11
US3974526A (en) 1973-07-06 1976-08-17 Dardik Irving I Vascular prostheses and process for producing the same
US3914802A (en) 1974-05-23 1975-10-28 Ebert Michael Non-thrombogenic prosthetic material
US4082507A (en) 1976-05-10 1978-04-04 Sawyer Philip Nicholas Prosthesis and method for making the same
DE2960875D1 (en) 1978-04-19 1981-12-10 Ici Plc A method of preparing a tubular product by electrostatic spinning
AU516741B2 (en) 1978-05-23 1981-06-18 Bio Nova Neo Technics Pty. Ltd. Vascular prostheses
US4252759A (en) 1979-04-11 1981-02-24 Massachusetts Institute Of Technology Cross flow filtration molding method
US4378224A (en) 1980-09-19 1983-03-29 Nimni Marcel E Coating for bioprosthetic device and method of making same
DE3042860A1 (en) 1980-11-13 1982-06-09 Heyl & Co Chemisch-Pharmazeutische Fabrik, 1000 Berlin COLLAGEN PREPARATIONS, METHODS FOR THEIR PRODUCTION AND THEIR USE IN HUMAN AND VETERINE MEDICINE
US4539716A (en) 1981-03-19 1985-09-10 Massachusetts Institute Of Technology Fabrication of living blood vessels and glandular tissues
US4420339A (en) 1981-03-27 1983-12-13 Kureha Kagaku Kogyo Kabushiki Kaisha Collagen fibers for use in medical treatments
US4629456A (en) * 1981-09-18 1986-12-16 Edwards David L Target ring for an eye dropper bottle
US4475972A (en) 1981-10-01 1984-10-09 Ontario Research Foundation Implantable material
US4902289A (en) 1982-04-19 1990-02-20 Massachusetts Institute Of Technology Multilayer bioreplaceable blood vessel prosthesis
US4787900A (en) 1982-04-19 1988-11-29 Massachusetts Institute Of Technology Process for forming multilayer bioreplaceable blood vessel prosthesis
US4502159A (en) 1982-08-12 1985-03-05 Shiley Incorporated Tubular prostheses prepared from pericardial tissue
JPS59177042A (en) 1983-03-29 1984-10-06 マ−セル・イ−・ニムニ Film for biological dental prosthesis and production thereof
US4801299A (en) 1983-06-10 1989-01-31 University Patents, Inc. Body implants of extracellular matrix and means and methods of making and using such implants
JPS6034450A (en) 1983-08-03 1985-02-22 テルモ株式会社 Artificial blood vessel
IL74180A (en) 1984-01-30 1992-06-21 Meadox Medicals Inc Drug delivery collagen-impregnated synthetic vascular graft
US5197977A (en) 1984-01-30 1993-03-30 Meadox Medicals, Inc. Drug delivery collagen-impregnated synthetic vascular graft
US5108424A (en) 1984-01-30 1992-04-28 Meadox Medicals, Inc. Collagen-impregnated dacron graft
US4842575A (en) 1984-01-30 1989-06-27 Meadox Medicals, Inc. Method for forming impregnated synthetic vascular grafts
FR2559666B1 (en) 1984-02-21 1986-08-08 Tech Cuir Centre PROCESS FOR THE MANUFACTURE OF COLLAGEN TUBES, ESPECIALLY LOW-DIAMETER TUBES, AND APPLICATION OF THE TUBES OBTAINED IN THE FIELD OF VASCULAR PROSTHESES AND NERVOUS SUTURES
US4889120A (en) 1984-11-13 1989-12-26 Gordon Robert T Method for the connection of biological structures
US5037377A (en) 1984-11-28 1991-08-06 Medtronic, Inc. Means for improving biocompatibility of implants, particularly of vascular grafts
US4629458A (en) 1985-02-26 1986-12-16 Cordis Corporation Reinforcing structure for cardiovascular graft
IL76079A (en) 1985-08-13 1991-03-10 Univ Ramot Collagen implants
CA1292597C (en) 1985-12-24 1991-12-03 Koichi Okita Tubular prothesis having a composite structure
DE3608158A1 (en) 1986-03-12 1987-09-17 Braun Melsungen Ag VESSELED PROSTHESIS IMPREGNATED WITH CROSSLINED GELATINE AND METHOD FOR THE PRODUCTION THEREOF
US5061276A (en) 1987-04-28 1991-10-29 Baxter International Inc. Multi-layered poly(tetrafluoroethylene)/elastomer materials useful for in vivo implantation
DE3717076A1 (en) 1987-05-21 1988-12-08 Wacker Chemie Gmbh METHOD FOR PRODUCING MOLDED BODIES OR COATING
US5007934A (en) 1987-07-20 1991-04-16 Regen Corporation Prosthetic meniscus
US5263984A (en) 1987-07-20 1993-11-23 Regen Biologics, Inc. Prosthetic ligaments
US5131908A (en) 1987-09-01 1992-07-21 Herbert Dardik Tubular prosthesis for vascular reconstructive surgery and process for preparing same
AU632273B2 (en) 1988-03-09 1992-12-24 Terumo Kabushiki Kaisha Medical material permitting cells to enter thereinto and artificial skin
ES2060614T3 (en) 1988-03-11 1994-12-01 Chemokol G B R Ing Buro Fur Ko PROCEDURE FOR THE MANUFACTURE OF COLLAGEN MEMBRANES FOR HEMOSTASIS, WOUND TREATMENT AND IMPLANTS.
US5201745A (en) * 1988-03-15 1993-04-13 Imedex Visceral surgery patch
US4956178A (en) 1988-07-11 1990-09-11 Purdue Research Foundation Tissue graft composition
US4902508A (en) 1988-07-11 1990-02-20 Purdue Research Foundation Tissue graft composition
US5024671A (en) 1988-09-19 1991-06-18 Baxter International Inc. Microporous vascular graft
US4863668A (en) 1988-09-22 1989-09-05 University Of Utah Method of forming fibrin-collagen nerve and body tissue repair material
US5026381A (en) 1989-04-20 1991-06-25 Colla-Tec, Incorporated Multi-layered, semi-permeable conduit for nerve regeneration comprised of type 1 collagen, its method of manufacture and a method of nerve regeneration using said conduit
US4990158A (en) 1989-05-10 1991-02-05 United States Surgical Corporation Synthetic semiabsorbable tubular prosthesis
US5084065A (en) 1989-07-10 1992-01-28 Corvita Corporation Reinforced graft assembly
US5106949A (en) 1989-09-15 1992-04-21 Organogenesis, Inc. Collagen compositions and methods for preparation thereof
JPH067410B2 (en) * 1989-10-02 1994-01-26 伊藤忠商事株式会社 Recording disk substrate and method of manufacturing magnetic recording disk
US5256418A (en) 1990-04-06 1993-10-26 Organogenesis, Inc. Collagen constructs
US5378469A (en) 1990-04-06 1995-01-03 Organogenesis, Inc. Collagen threads
US5336616A (en) 1990-09-12 1994-08-09 Lifecell Corporation Method for processing and preserving collagen-based tissues for transplantation
CS277367B6 (en) 1990-12-29 1993-01-13 Krajicek Milan Three-layered vascular prosthesis
WO1992014419A1 (en) 1991-02-14 1992-09-03 Baxter International Inc. Pliable biological graft materials and their methods of manufacture
FR2679778B1 (en) 1991-08-02 1995-07-07 Coletica USE OF CROLAGEN CROSSLINKED BY A CROSSLINKING AGENT FOR THE MANUFACTURE OF A SLOW RESORPTIVE, BIOCOMPATIBLE, SUTURABLE MEMBRANE, AS WELL AS SUCH A MEMBRANE.
US5281422A (en) 1991-09-24 1994-01-25 Purdue Research Foundation Graft for promoting autogenous tissue growth
US5500013A (en) 1991-10-04 1996-03-19 Scimed Life Systems, Inc. Biodegradable drug delivery vascular stent
US5376376A (en) 1992-01-13 1994-12-27 Li; Shu-Tung Resorbable vascular wound dressings
US6653291B1 (en) * 1992-11-13 2003-11-25 Purdue Research Foundation Composition and method for production of transformed cells
US5374515A (en) 1992-11-13 1994-12-20 Organogenesis, Inc. In vitro cornea equivalent model
US5523291A (en) 1993-09-07 1996-06-04 Datascope Investment Corp. Injectable compositions for soft tissue augmentation
US5713950A (en) 1993-11-01 1998-02-03 Cox; James L. Method of replacing heart valves using flexible tubes
US5480424A (en) 1993-11-01 1996-01-02 Cox; James L. Heart valve replacement using flexible tubes
US5460962A (en) 1994-01-04 1995-10-24 Organogenesis Inc. Peracetic acid sterilization of collagen or collagenous tissue
US5571216A (en) 1994-01-19 1996-11-05 The General Hospital Corporation Methods and apparatus for joining collagen-containing materials
JP3765828B2 (en) 1994-02-18 2006-04-12 オーガノジェネシス インコーポレイテッド Biologically reorganizable collagen graft prosthesis
US6334872B1 (en) 1994-02-18 2002-01-01 Organogenesis Inc. Method for treating diseased or damaged organs
CA2186375A1 (en) 1994-04-29 1995-11-09 William Carl Bruchman Improved blood contact surfaces using endothelium on a subendothelial extracellular matrix
CA2188563C (en) * 1994-04-29 2005-08-02 Andrew W. Buirge Stent with collagen
JPH09512463A (en) 1994-04-29 1997-12-16 ダブリュ.エル.ゴア アンド アソシエイツ,インコーポレイティド Improved blood contact surface utilizing natural subendothelial matrix and method of making and using same
EP0698396B1 (en) 1994-08-12 2001-12-12 Meadox Medicals, Inc. Vascular graft impregnated with a heparin-containing collagen sealant
US5948654A (en) 1996-08-28 1999-09-07 Univ Minnesota Magnetically oriented tissue-equivalent and biopolymer tubes comprising collagen
US6110212A (en) * 1994-11-15 2000-08-29 Kenton W. Gregory Elastin and elastin-based materials
US5554389A (en) 1995-04-07 1996-09-10 Purdue Research Foundation Urinary bladder submucosa derived tissue graft
DE69622548T2 (en) 1995-04-07 2003-09-18 Purdue Research Foundation West Lafayette TISSUE TRANSPLANT FOR BUBBLE RECONSTRUCTION
US5733337A (en) 1995-04-07 1998-03-31 Organogenesis, Inc. Tissue repair fabric
US5711969A (en) 1995-04-07 1998-01-27 Purdue Research Foundation Large area submucosal tissue graft constructs
US5788625A (en) 1996-04-05 1998-08-04 Depuy Orthopaedics, Inc. Method of making reconstructive SIS structure for cartilaginous elements in situ
US5755791A (en) 1996-04-05 1998-05-26 Purdue Research Foundation Perforated submucosal tissue graft constructs
AU742457B2 (en) 1996-08-23 2002-01-03 Cook Biotech, Incorporated Graft prosthesis, materials and methods
US6241981B1 (en) 1996-09-16 2001-06-05 Purdue Research Foundation Composition and method for repairing neurological tissue
CA2267449C (en) 1996-11-05 2008-10-14 Purdue Research Foundation Myocardial graft constructs
BR9712671A (en) 1996-12-10 1999-10-19 Purdue Research Foundation Tubular submucosal graft constructions
JP4302188B2 (en) 1996-12-10 2009-07-22 パーデュー・リサーチ・ファウンデーション Gastric submucosa-derived tissue graft
DK1671604T3 (en) 1996-12-10 2009-11-09 Purdue Research Foundation Synthetic tissue valve
US5993844A (en) 1997-05-08 1999-11-30 Organogenesis, Inc. Chemical treatment, without detergents or enzymes, of tissue to form an acellular, collagenous matrix
JP4356053B2 (en) 1998-06-05 2009-11-04 オルガノジェネシス インク. Bioengineered vascular graft support prosthesis

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3919411A (en) * 1972-01-31 1975-11-11 Bayvet Corp Injectable adjuvant and compositions including such adjuvant
US4148664A (en) * 1976-05-10 1979-04-10 Avicon, Inc. Preparation of fibrous collagen product having hemostatic and wound sealing properties
US4703108A (en) * 1984-03-27 1987-10-27 University Of Medicine & Dentistry Of New Jersey Biodegradable matrix and methods for producing same
US5219576A (en) * 1988-06-30 1993-06-15 Collagen Corporation Collagen wound healing matrices and process for their production
US6090995A (en) * 1989-09-15 2000-07-18 Surmodics, Inc. Surface modifying composition and method
US5893888A (en) * 1992-08-07 1999-04-13 Tissue Engineering, Inc. Method and construct for producing graft tissue from extracellular matrix
US5487895A (en) * 1993-08-13 1996-01-30 Vitaphore Corporation Method for forming controlled release polymeric substrate
US5866414A (en) * 1995-02-10 1999-02-02 Badylak; Stephen F. Submucosa gel as a growth substrate for cells

Cited By (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060025786A1 (en) * 1996-08-30 2006-02-02 Verigen Transplantation Service International (Vtsi) Ag Method for autologous transplantation
USRE42834E1 (en) 2001-11-20 2011-10-11 Kci Licensing Inc. Personally portable vacuum desiccator
US20060159641A1 (en) * 2002-01-25 2006-07-20 Biomedical Design, Inc. Variably crosslinked tissue
US7918899B2 (en) 2002-01-25 2011-04-05 Biomedical Design, Inc. Variably crosslinked tissue
EP1389450A1 (en) * 2002-08-16 2004-02-18 Tutogen Medical GmbH Hernia implant
US20040034374A1 (en) * 2002-08-16 2004-02-19 Tutogen Medical Gmbh Implant
US20040132365A1 (en) * 2002-11-04 2004-07-08 Sofradim Production Intermediate composite part for forming reinforcement prosthesis
US8084663B2 (en) 2004-04-05 2011-12-27 Kci Licensing, Inc. Wound dressing with absorption and suction capabilities
US7790945B1 (en) 2004-04-05 2010-09-07 Kci Licensing, Inc. Wound dressing with absorption and suction capabilities
US20060029633A1 (en) * 2004-08-03 2006-02-09 Arthrotek, Inc Biological patch for use in medical procedures
US20090069838A1 (en) * 2004-12-06 2009-03-12 Paul Ram H Inflatable occlusion devices, methods, and systems
US20080051888A1 (en) * 2005-02-18 2008-02-28 Anthony Ratcliffe Synthetic structure for soft tissue repair
US9820847B2 (en) * 2005-02-18 2017-11-21 Synthasome Inc. Synthetic structure for soft tissue repair
US20070027529A1 (en) * 2005-07-29 2007-02-01 Guo-Feng Xu Biological artificial blood vessel and method of making
US8292799B2 (en) * 2005-07-29 2012-10-23 Grandhope Biotech Co., Ltd. Biological artificial blood vessel and method of making
US20070032806A1 (en) * 2005-08-04 2007-02-08 Song-Tao Qi Biological membrane-carrying aneurysm clip
US8197500B2 (en) 2005-08-04 2012-06-12 Grandhope Biotech Co., Ltd. Biological membrane-carrying aneurysm clip
US20070038299A1 (en) * 2005-08-12 2007-02-15 Arthrotek, Inc Multilayer microperforated implant
US20080147198A1 (en) * 2006-10-19 2008-06-19 C.R. Bard, Inc. Prosthetic repair fabric
US7900484B2 (en) 2006-10-19 2011-03-08 C.R. Bard, Inc. Prosthetic repair fabric
US10368971B2 (en) 2007-12-03 2019-08-06 Sofradim Production Implant for parastomal hernia
US9308068B2 (en) 2007-12-03 2016-04-12 Sofradim Production Implant for parastomal hernia
US10070948B2 (en) * 2008-06-27 2018-09-11 Sofradim Production Biosynthetic implant for soft tissue repair
US9242026B2 (en) 2008-06-27 2016-01-26 Sofradim Production Biosynthetic implant for soft tissue repair
US10865505B2 (en) 2009-09-04 2020-12-15 Sofradim Production Gripping fabric coated with a bioresorbable impenetrable layer
US20140172096A1 (en) * 2011-03-08 2014-06-19 Mimedx Group, Inc. Collagen fiber ribbons with integrated fixation sutures and methods of making the same
US9636209B2 (en) * 2011-03-08 2017-05-02 Mimedx Group, Inc. Collagen fiber ribbons with integrated fixation sutures and methods of making the same
US10653514B2 (en) 2011-03-08 2020-05-19 Mimedx Group, Inc. Collagen fiber ribbons with integrated fixation sutures and methods of making the same
US11612472B2 (en) 2011-03-16 2023-03-28 Sofradim Production Prosthesis comprising a three-dimensional and openworked knit
US10472750B2 (en) 2011-03-16 2019-11-12 Sofradim Production Prosthesis comprising a three-dimensional and openworked knit
US9554887B2 (en) 2011-03-16 2017-01-31 Sofradim Production Prosthesis comprising a three-dimensional and openworked knit
US11039912B2 (en) 2011-07-13 2021-06-22 Sofradim Production Umbilical hernia prosthesis
US9622843B2 (en) 2011-07-13 2017-04-18 Sofradim Production Umbilical hernia prosthesis
US11903807B2 (en) 2011-07-13 2024-02-20 Sofradim Production Umbilical hernia prosthesis
US10709538B2 (en) 2011-07-13 2020-07-14 Sofradim Production Umbilical hernia prosthesis
US9980802B2 (en) 2011-07-13 2018-05-29 Sofradim Production Umbilical hernia prosthesis
US9526603B2 (en) 2011-09-30 2016-12-27 Covidien Lp Reversible stiffening of light weight mesh
US11266489B2 (en) 2011-12-29 2022-03-08 Sofradim Production Barbed prosthetic knit and hernia repair mesh made therefrom as well as process for making said prosthetic knit
US11471256B2 (en) 2011-12-29 2022-10-18 Sofradim Production Prosthesis for inguinal hernia
US11925543B2 (en) 2011-12-29 2024-03-12 Sofradim Production Barbed prosthetic knit and hernia repair mesh made therefrom as well as process for making said prosthetic knit
US9445883B2 (en) 2011-12-29 2016-09-20 Sofradim Production Barbed prosthetic knit and hernia repair mesh made therefrom as well as process for making said prosthetic knit
US10342652B2 (en) 2011-12-29 2019-07-09 Sofradim Production Barbed prosthetic knit and hernia repair mesh made therefrom as well as process for making said prosthetic knit
US10080639B2 (en) 2011-12-29 2018-09-25 Sofradim Production Prosthesis for inguinal hernia
US20150005869A1 (en) * 2012-02-14 2015-01-01 Neograft Technologies, Inc. Kink Resistant Graft Devices and Related Systems and Methods
US10363690B2 (en) 2012-08-02 2019-07-30 Sofradim Production Method for preparing a chitosan-based porous layer
US9750837B2 (en) 2012-09-25 2017-09-05 Sofradim Production Haemostatic patch and method of preparation
US9499927B2 (en) 2012-09-25 2016-11-22 Sofradim Production Method for producing a prosthesis for reinforcing the abdominal wall
US9839505B2 (en) 2012-09-25 2017-12-12 Sofradim Production Prosthesis comprising a mesh and a strengthening means
US10159555B2 (en) 2012-09-28 2018-12-25 Sofradim Production Packaging for a hernia repair device
US11622845B2 (en) 2013-06-07 2023-04-11 Sofradim Production Textile-based prothesis for laparoscopic surgery
US11304790B2 (en) 2013-06-07 2022-04-19 Sofradim Production Textile-based prothesis for laparoscopic surgery
US10213283B2 (en) 2013-06-07 2019-02-26 Sofradim Production Textile-based prosthesis for laparoscopic surgery
US10405960B2 (en) 2013-06-07 2019-09-10 Sofradim Production Textile-based prothesis for laparoscopic surgery
US10549015B2 (en) 2014-09-24 2020-02-04 Sofradim Production Method for preparing an anti-adhesion barrier film
US10327882B2 (en) 2014-09-29 2019-06-25 Sofradim Production Whale concept—folding mesh for TIPP procedure for inguinal hernia
US10653508B2 (en) 2014-09-29 2020-05-19 Sofradim Production Textile-based prosthesis for treatment of inguinal hernia
US9877820B2 (en) 2014-09-29 2018-01-30 Sofradim Production Textile-based prosthesis for treatment of inguinal hernia
US11589974B2 (en) 2014-09-29 2023-02-28 Sofradim Production Textile-based prosthesis for treatment of inguinal hernia
US11291536B2 (en) 2014-09-29 2022-04-05 Sofradim Production Whale concept-folding mesh for TIPP procedure for inguinal hernia
US11359313B2 (en) 2014-12-05 2022-06-14 Sofradim Production Prosthetic porous knit
US10745835B2 (en) 2014-12-05 2020-08-18 Sofradim Production Prosthetic porous knit
US11713526B2 (en) 2014-12-05 2023-08-01 Sofradim Production Prosthetic porous knit
US9932695B2 (en) 2014-12-05 2018-04-03 Sofradim Production Prosthetic porous knit
US10815345B2 (en) 2015-02-17 2020-10-27 Sofradim Production Method for preparing a chitosan-based matrix comprising a fiber reinforcement member
US10184032B2 (en) 2015-02-17 2019-01-22 Sofradim Production Method for preparing a chitosan-based matrix comprising a fiber reinforcement member
US9931198B2 (en) 2015-04-24 2018-04-03 Sofradim Production Prosthesis for supporting a breast structure
US11439498B2 (en) 2015-04-24 2022-09-13 Sofradim Production Prosthesis for supporting a breast structure
US10660741B2 (en) 2015-04-24 2020-05-26 Sofradim Production Prosthesis for supporting a breast structure
US10743976B2 (en) 2015-06-19 2020-08-18 Sofradim Production Synthetic prosthesis comprising a knit and a non porous film and method for forming same
US11826242B2 (en) 2015-06-19 2023-11-28 Sofradim Production Synthetic prosthesis comprising a knit and a non porous film and method for forming same
US10646321B2 (en) 2016-01-25 2020-05-12 Sofradim Production Prosthesis for hernia repair
US11389282B2 (en) 2016-01-25 2022-07-19 Sofradim Production Prosthesis for hernia repair
US10682215B2 (en) 2016-10-21 2020-06-16 Sofradim Production Method for forming a mesh having a barbed suture attached thereto and the mesh thus obtained
US11696819B2 (en) 2016-10-21 2023-07-11 Sofradim Production Method for forming a mesh having a barbed suture attached thereto and the mesh thus obtained
US11672636B2 (en) 2017-05-02 2023-06-13 Sofradim Production Prosthesis for inguinal hernia repair
US10675137B2 (en) 2017-05-02 2020-06-09 Sofradim Production Prosthesis for inguinal hernia repair
US11589973B2 (en) 2018-05-16 2023-02-28 Mimedx Group, Inc. Methods of making collagen fiber medical constructs and related medical constructs, including patches
US11471257B2 (en) 2018-11-16 2022-10-18 Sofradim Production Implants suitable for soft tissue repair

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