CA2419644C - Method and kit for the transplantation of chondrocyte cells - Google Patents

Method and kit for the transplantation of chondrocyte cells Download PDF

Info

Publication number
CA2419644C
CA2419644C CA002419644A CA2419644A CA2419644C CA 2419644 C CA2419644 C CA 2419644C CA 002419644 A CA002419644 A CA 002419644A CA 2419644 A CA2419644 A CA 2419644A CA 2419644 C CA2419644 C CA 2419644C
Authority
CA
Canada
Prior art keywords
covering
patch
cell
free
collagen
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.)
Expired - Lifetime
Application number
CA002419644A
Other languages
French (fr)
Other versions
CA2419644A1 (en
Inventor
Henrik Vibe-Hansen
Charlotte Lundsgaard
Ahmed Idouraine
Kurt B. Osther
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Verigen Transplantation Services International AG
Original Assignee
Verigen Transplantation Services International AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27107401&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2419644(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US08/704,891 external-priority patent/US5759190A/en
Application filed by Verigen Transplantation Services International AG filed Critical Verigen Transplantation Services International AG
Publication of CA2419644A1 publication Critical patent/CA2419644A1/en
Application granted granted Critical
Publication of CA2419644C publication Critical patent/CA2419644C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61F2/28Bones
    • A61F2/2846Support means for bone substitute or for bone graft implants, e.g. membranes or plates for covering bone defects
    • 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
    • A61F2/30756Cartilage endoprostheses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/00491Surgical glue applicators
    • 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
    • A61F2/38Joints for elbows or knees
    • 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
    • A61F2/28Bones
    • A61F2002/2835Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
    • 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
    • A61F2002/30004Material related properties of the prosthesis or of a coating on the prosthesis the prosthesis being made from materials having different values of a given property at different locations within the same prosthesis
    • A61F2002/30016Material related properties of the prosthesis or of a coating on the prosthesis the prosthesis being made from materials having different values of a given property at different locations within the same prosthesis differing in hardness, e.g. Vickers, Shore, Brinell
    • 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
    • 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
    • A61F2002/30316The prosthesis having different structural features at different locations within the same prosthesis; Connections between prosthetic parts; Special structural features of bone or joint prostheses not otherwise provided for
    • A61F2002/30535Special structural features of bone or joint prostheses not otherwise provided for
    • 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
    • A61F2/30756Cartilage endoprostheses
    • A61F2002/30761Support means for artificial cartilage, e.g. cartilage defect covering membranes
    • 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
    • A61F2/30756Cartilage endoprostheses
    • A61F2002/30762Means for culturing cartilage
    • 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
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0014Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis
    • A61F2250/0019Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis differing in hardness, e.g. Vickers, Shore, Brinell
    • 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
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058Additional features; Implant or prostheses properties not otherwise provided for
    • 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
    • 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
    • A61L2430/00Materials or treatment for tissue regeneration
    • A61L2430/06Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus

Abstract

The present invention provides for articles, compositions and kits for use in the treatment of articulating joint cartilage defects. The articles and compositions of the present invention comprise a cell-free component or membrane and chondrocytes. The kits of the present invention may comprise a hemostatic barrier and a covering patch and may optionally further comprise organic glue, a surgical instrument or a matrix suitable for supporting chondrocytes.

Description

Method and Kit for the Transplantation of Chondrocyte Cells Field of the Invention The instant invention concems the field of chondrocyte transplantation, bone and cartilage grafting, healing, joint repair and the prevention of arthritic pathologies. In particular methods for the preparation of the graft site, instruments for such preparation and for the autologous transplantation of cells to the prepared graft site.

Background of the Invention More than 500,000 arthroplastic procedures and total joint replacements are performed each year in the United States. Approximately the same number of similar procedures are performed in Europe. Included in these numbers are about 90,000 total-knee replacements and around 50,000 procedures to repair defects in the knee per year in Europe.
The number of procedures are essentially the same in the U. S. (In: Praemer A., Fumer S., Rice, D.P., Musculoskeleta} conditions in the United States. American Academy of Orthopaedic Surgeons, Park Ridge, Ill., 1992, 125). A method for regeneration-treatment of cartilage would be most useful, and could be performed at an earlier stage of joint damage, thus reducing the number of patients needing artificial joint replacement surgery. With such preventative methods of treatment, the number of patients developing osteoarthritis would also decrease.

Techniques used for resurfacing the cartilage structure in joints have mainly attempted to induce the repair of cartilage using subchondral drilling, abrasion and other methods whereby there is excision of diseased cartilage and subchondral bone, leaving vascularized cancellous bone exposed (Insall, J., Clin. Orthop. I974,101,61;
Ficat R.P. et al, Clin Orthop. 1979, 144, 74; Johnson L.L., In: Operative Arthroscopy, McGinty J.B., Ed., Raven Press, New York, 1991, 341).

Coon and Cahn (Science 1966, 153, 1116) described a technique for the cultivation of cartilage synthesizing cells from chick embryo somites. Later Cahn and Lasher (PNAS
USA 1967, 58, 1131) used the system for analysis of the involvement of DNA
synthesis as a prerequisite for cartilage differentiation. Chondrocytes respond to both EFG
and FGF by growth (Gospodarowicz and Mescher, J. Cell Physiology 1977, 93, 117), but ultimately ta ti lose their differentiated function (Benya et al., Cell 1978, 15, 1313).
Methods for growing chondrocytes were described and are principally being used with minor adjustments by Brittberg, M. et al. (New Engi. J. Med. 1994, 331, 889). Cells grown using these methods were used as autologous transplants into knee joints of patients.
Additionally, Kolettas et al.
(J. Cell Science 1995, 108, 1991) examined the expression of cartilage-specific molecules such as collagens and proteoglycans under prolonged cell culturing. They found that despite morphological changes during culturing in monoiayer cultures (Aulthouse, A. et al., In Vitro Cell Dev. Biol., 1989,25,659; Archer, C. et al., J. Cell Sci.
1990,97,361; Hanselmann, H...et al., J. Cell Sci. 1994,107,17; Bonaventure, J. et al., Exp. Cell Res.
1994,212,97), when io compared to suspension cultures grown over agarose gels, alginate beads or as spinner cultures (retaining a round cell morphology) tested by various scientists did not change the chondrocyte - expressed markers such as types II and IX collagens and the large aggregating proteoglycans, aggrecan, versican and link protein did not change (Kolettas, E.
et al., J. Cell Science 1995,108,1991).

The articular chondrocytes are specialized mesenchymal derived cells found exclusively in cartilage. Cartilage is an avascular tissue whose physical properties depend on the extracellular matrix produced by the chondrocytes. During endochondral ossification chondrocytes undergo a maturation leading to cellular hypertrophy, characterized by the onset of expression of type X coilagen (Upholt, W.B. and Olsen, R.R., In:
CartilaEe Molecular Aspects (Hall, B & Newman, S, Eds.) CRC Boca Raton 1991, 43;
Reichenberger, E. et al., Dev. Biol. 1991, 148, 562; Kirsch, T. et al., Differentiation, 1992, 52, 89; Stephens, M. et al., J. Cell Sci. 1993, 103, 1111).

Excessive degredation of type II collagen in the outer layers or articular surfaces of joints is also caused by osteoarthritis. The collagen network is accordingly weakened and subsequently develops fibrillation whereby matrix substances such as proteoglycans are lost and eventually displaced entirely. Such fibrillation of weakened osteoarthritic cartilage can reach down to the calcified cartilage and into the subchondral bone (Kempson, G.E. et al., 3o Biochim. Biophys. Acta 1976, 428, 741; Roth, V. and Mow, V.C., J. Bone Joint Surgery, 1980, 62A, 1102; Woo, S.L.-Y. et al., in Handbook of Bioensineering (R. Skalak and S.
Chien eds.), McGraw-Hill, New York, 1987, pp. 4.1-4.44).
Descriptions of the basic development, histological and microscopic anatomy of bone, cartilage and other such connective tissues can be found for example in Wheater, Burkitt and Daniels, Functional Histology, 2n Edition, (Churchill Livingstone, London, 1987, Chp. 4). Descriptions of the basic histological anatomy of defects in bone, cartilage and other connective tissue can be found for example in Wheater, Burkitt, Stevens and Lowe, Basic Histopathologv, (Churchill Livingstone, London, 1985, Chp. 21).
Despite the advances in cultivating chondrocytes, and manipulating bone and cartilage, there has not been great success with the attempts to transplant cartilage or io chondrocytes for the repair of damaged articulating surfaces. The teachings of the instant invention provide for effective and efficient means of promoting the transplantation of cartilage and/or chondrocytes into a defect in an articulating joint or other cartilage covered bone surface, whereby cartilage is regenerated to fix the defect. The instant invention also provides for surgical instruments which are designed prepare the graft site so as to facilitate the efficient integration of grafted material to the graft site.
Brief Summary of the Invention The instant invention provides a method for the effective treatment of articulating joint surface cartilage by the transplantation of chondrocytes in a suitable matrix, to a surface to be treated, with a hemostatic barrier and a cell-free covering-patch comprising;
first placing a hemostatic barrier proximal to the surface to be treated, placing chondrocytes in a suitable matrix upon the surface to be treated distal to the hemostatic barrier, covering the surface to be treated with a cell-free covering-patch. A hemostatic barrier, as will be further described below, is a barrier which inhibits or prevents the penetration of vascularizing cells and tissue into the grafted material. In particular, the instant method provides for a hemostatic barrier that is a resorbable, semi-permeable material which inhibits or prohibits vascular infiltration through the barrier. In one embodiment the hemostatic barrier contains collagen. Cell-free, is used herein as in the art, and means a material that is substantially free from intact cells which are capable of further cell division, promulgation or biological activity. In a preferred embodiment, a cell-free material is free from all intact nucleated cells. In one embodiment, the instant method encompasses the use of a cell-free covering patch which contains a semi-permeable collagen matrix.
In one preferred embodiment of the method, the porous surface of the cell-free covering-patch is directed towards the implant material.

The instant invention further provides for the autologous transplantation of collagen or chondrocytes to a graft site, wherein the graft site has first been prepared by surgical manipulation to better accept the grafted material. In one embodiment, the graft site is sculpted such that the walls of the graft site are contoured in an undulating pattern such that the grafted material, when placed within the graft site and expanded to contact the graft site wall, there will be resistance against removal or expulsion of the entire graft from the graft io site. The instant invention further provides for surgical instruments designed to sculpt the graft site as taught by the method of the invention.

The invention further provides for a kit for cartilage andlor chondrocyte transplantation onto the surface of an articular joint wherein said kit comprises a hemostatic barrier, cell-free semi-permeable covering-patch, and organic glue. In a further embodiment, the kit can optionally further provide one or more surgical instruments which can be used to sculpt the graft site in accordance with the methods of the instant invention.
Brief Description of the Drawings The present invention will be better understood by examining the following figures which illustrate certain properties of the instant invention wherein:
Figure lA is a drawing showing a typical articulating end of a bone.
Typically, the bone material is covered on the articulating surface with a cartilaginous.
Figure I B shows an example of where a defect or injury to the cartilaginous cap occurs (gap in cartilage), and such a defect can be treated directly, enlarged slightly, or sculpted to accept the grafted material by surgical procedures prior to treatment.
Figure 1 C shows how the hemostatic barrier (numbered 1) is placed within the defect in the cartilage cap to inhibit or prevent vascularization into regenerating cartilage, from the underlying bone. The chondrocytes to be implanted into the defect cavity are then layered on top of the hemostatic barrier.
Figure 2 is a drawing showing the treated defect (gap in cartilage) in the cartilaginous cap covered by a cell-free semi-permeable material (numbered 2) which is used to forrn a cap/patch or bandage over the defect site. This cap is fixed in place, either sutured to the edge of the cavity into healthy cartilage, or otherwise attached. This cap is covering the defective area of the joint into which the cultured chondrocytes/cartilage transplant has been placed, or will be placed under the partially attached cap.
Figure 3A is a diagram illustrating the differential response to compression and shearing forces by left side and right side cartilage with subsequent zone of demarcation.
Figure 3B illustrates the graft site, after the defect has been sculpted to have undulating walls.
Figure 3C illustrates the sculpted graft site with the hemostatic barrier (1), transplanted material (3), and cell-free covering-patch (2) in place within the articular 1o surface cartilage (4).
Figure 4A illustrates one embodiment of the surgical device of the instant invention showing cutting teeth (5) and protruding placement pin (6). The cross-section illustrations to the right show two possible configurations of the cutting blades.
Figure 4B illustrates a second embodiment of the surgical device of the instant I5 invention.
Figure 5 is a diagram illustrating the modified differential response to compression and shearing forces by harder cartilage and softer cartilage after sculpting the graft site.
Figure 6A is an MRI image of a pig knee showing cartilage defect in left (medial) condyle.
20 Figure 6B is an MRI image of the same pig knee three months after treatment.
Detailed Description of the Invention This invention concerns the use of certain products that inhibit the formation of vascular tissue, for instance such as capillary loops projecting into the cartilage being 25 established, during the process of autologous transplantation of chondrocytes into defects in the cartilage. The formation of vascular tissue from the underlying bone will tend to project into the new cartilage to be formed leading to appearance of cells other than the mesenchymal specialized chondrocytes desired.
The contaminating cells introduced by the vascularization may give rise to 30 encroachment and over-growth into the cartilage to be formed by the implanted chondrocytes_ One of the types of commercial products which can be used in -this invention is Surgicel (Ethicon Ltd., UK) which is absorbable after a period of 7 - 14 days. The use of this material in the method of the instant invention is contrary to the normal use of a hemostatic device, such as Surgicel' as it is described in the package insert from Ethicon Ltd.
Surprisingly, we have found that in a situation where you wish to inhibit re-vascularization into cartilage, a hemostatic material will act like a gel-like artificial coagulate. If red blood cells should be present within the full-thickness defect of articular cartilage that is capped by such a hemostatic barrier, these blood cells will be chemically changed to hematin, and thus rendered unable to induce vascular growth. Thus a hemostatic product used as a re-vascularization inhibitory barrier with or without fibrin adhesives, such as for example the Surgicel , is effective for the envisioned method as taught by the instant invention. Another part of this invention is the use of a cell-free component, that is used as a patch covering the defective area of the joint into which the cultured chondrocytes/cartilage are being transplanted, using autologous chondrocytes for the transplantation. The method of the invention also contemplates the use of suitable allogenic chondrocytes or xenogenic chondrocytes for the repair of a cartilage defect.
Thus the instant invention teaches methods for effective repair or treatment of cartilage defects in articular joint bone surfaces which comprises administering an agent or device to block vascular invasion into the cartilage site to be repaired, and also providing for a cell-free barrier which will isolate the repair site and keep transplanted cells in place.
Thus the instant invention also provides for a kit comprising a hemostatic barrier component for insertion into the site to be repaired, such that there is effective inhibition of vascularization into the site to be repaired; and once the chondrocytes to be transplanted are placed into the site to be repaired, a cell-free semi-permeable barrier is capped over the repair site such that the transplanted chondrocytes are held in place, but are still able to gain access to nutrients.
Certain aspects of the invention have been exemplified using an in vitro system to study the behavior of the chondrocytes when in contact with a certain product or a combination of certain products that inhibit the formation of vascular tissue.
This in vitro testing predicts the ability of certain tested materials to inhibit vascularization, as will occur in vivo where capillary loops project into the cartilage being established during the process of autologous transplantation of chondrocytes into defects in the cartilage.
Suitable hemostatic products will be characterized by having the ability to inhibit the growth, or invasion of vascular tissue, osteocytes, fibroblasts etc. into the developing cartilage. A suitable hemostatic material will achieve the goal of the method of the instant invention in that vascular and cellular invasion into developing cartilage should be prevented in order to optimize the formation of cartilage and achieve repair of the full-thickness of any defects in the articular cartilage. Ideally, the hemostatic barrier will be stable for an extended period of time sufficient to allow for full cartilage repair, and then be able to be resorbed or otherwise broken down over time. One material identified as suitable is called Surgicel W 1912 (an absorbable hemostat containing oxidized regenerated sterile cellulose; Lot GG3DH, Ethicon Ltd. UK). Another example of a suitable material is BioGide (a commercially available type I collagen matrix pad; Geistlich Sohne, Switzerland).
Suitable organic glue material can be found commercially, such as for example Tisseel or Tissucol (fibrin based adhesive; Immuno AG, Austria), Adhesive Protein (Cat.
#A-2707, Sigma Chemical, USA), and Dow Corning Medical Adhesive B (Cat. #895-3, Dow Corning, USA).
The surgical instruments contemplated by the instant invention can be manufactured from metal and/or plastic suitable for making single-use disposable, or multi-use reusable surgical instruments. The cutting instrument may contain cutting teeth that are fully circular or flat, or anything in between. As cartilage is a relatively soft material it may be advantageous to manufacture hardened plastic cutting edges which will be able to sculpt cartilage without being able to damage bone. Such cutting instruments can be manufactured to incorporate openings for administration of fluid, suction removal of cutting debris and fluid, and fiber optic threads for illumination and visualization of the defect site.
Certain aspects of the instant invention may be better understood as illustrated by the following examples, which are meant by way of illustration and not limitation.

Example 1 In order for the Surgicel to be used according to the invention for preventing development of blood vessels into autologous implanted cartilage or chondrocytes, Surgicel was first treated with a fixative, such as glutaric aldehyde.
Briefly, Surgicel was treated with 0.6% glutaric aldehyde for 1 minute, followed by several washings to eliminate glutaric aldehyde residues that may otherwise be toxic to tissue.
Alternatively, the Surgicel was treated with the fibrin adhesive called Tisseel prior to treatment with glutaric aldehyde as deScribed in Example 2. It was found that the Surgicel fixated for instance with a fixative such as glutaric aldehyde, washed with sterile physiological saline (0.9%) and stored in refrigerator, does not dissolve for I to 2 months.
Generally, Surgical is resorbed in a period between 7 and 14 days. This time would be too short, because a longer time is needed in preventing the development of blood vessels or vascularization as such from the bone structure into the implanted cartilage before the implanted chondrocytes have grown into a solid cartilage layer getting its nutrition requirements from the neighboring cartilage. In other words sufficient inhibition of the vascularization is needed for a longer time such as for instance one month. Therefore, the product should not be absorbed significantly prior to that time. On the other hand resorption is needed eventually. Hence, the organic material used as an inhibiting barrier shall have these capabilities, and it has io been found that the Surgicel treated in this manner provides that function.
Example 2 The Surgicel was also coated with an organic glue, in this example the glue used was Tisseel but others can also be used. This product, together with the Surgicel produces a useable barrier for the particular purpose of the invention. Any other hemostat or vascular inhibiting barrier could be used. The Tisseel was mixed as described below.
The Surgicel was then coated with Tisseel by spraying the Surgicel material on both sides until soaked.
The Tisseel (fibrin glue) was then allowed to solidify at room temperature.
Immediately prior to completed solidification, the coated Surgicel was then placed in 0.6% glutaric 2o aldehyde for 1 minute and then washed with sterile physiological (0.9%) saline. The pH
was then adjusted by PBS and/or with NaOH until pH was stable at 7.2 to 7.4.
Afterwards the thus treated Surgicel was then washed in tissue culture medium such as minimum essential rnedium/F 12 with 15 mM Hepes buffer.
As mentioned in this example we have used Tisseel as the fibrin adhesive to coat the Surgicel . Furthermore the fibrin adhesive or glue may also be applied directly on the bottom of the lesion towards the bone, on which the Surgicel is glued. The in vitro system used, in lieu of in vivo testing, consisted of a NUNCLON"" Delta 6-well sterile disposable plate for cell research work (NUNC, InterMed, Roskilde, Denmark). Each well measures approximately 4 cm in diameter.
In the invention the fibrin adhesive can be any adhesive which together with the fibrin component will produce a glue that can be tolerated in humans (Ihara, N, et al., Burns Incl. Therm. Inj., 1984, 10, 396). The invention also anticipates any other glue component that can be used in lieu of the fibrin adhesive. In this invention we used Tisseel or Tissucol (Imrnuno AG, Vienna, Austria). The Tisseel kit consists of the following components:
Tisseel , a lyophilized, virus-inactivated Sealer, containing clottable protein, thereof: fibrinogen, Plasma fibronectin (CIG) and Factor XIII, and Plasminogen.
s Aprotinin Solution (bovine) Thrombin 4 (bovine) Thrombin 500 (bovine) Calcium Chloride solution The ?'isseel kit contains a DUPLOJECT Application System. The fibrin adhesive io or the two-component sealant using Tisseel Kit is combined in the following manner according to the Immuno AG product insert sheet:

Example 3 Chondrocytes were grown in minimal essential culture medium containing HAM
15 F12 and 15 mM Hepes buffer and 5 to 7.5% autologous serum in a CO2 incubator at 37 C
and handled in a Class 100 laboratory at Verigen Europe A/S, Symbion Science Park, Copenhagen, Denmark. Other compositions of culture medium may be used for culturing the chondrocytes. The cells were trypsinized using trypsin EDTA for 5 to 10 minutes and counted using Trypan Blue viability staining in a Bilrker-Turk chamber. The cell count was 2o adjusted to 7.5 x 105 cells per ml. One NUNCLONTM plate was uncovered in the Class 100 laboratory.
The Surgicel' hemostatic barrier was cut to a suitable size fitting into the bottom of the well in the NUNCLONT'" tissue culture tray. In this case a circle, of a size of approximately 4 cm (but could be of any possible size) and placed under aseptic conditions 25 on the bottom in well in a NUNCLONTM Delta 6-well sterile disposable plate for cell research work (NUNC, InterMed, Roskilde, Denmark). The hemostatic barrier to be placed on the bottom of the well was pre-treated as described in Example 1. This treatment delays the absorption of the Surgicel significantly. This hemostatic barrier was then washed several times in distilled water and subsequently several times until non-reacted 30 glutaraldehyde was washed out. A small amount of the cell culture medium containing serum was applied to be absorbed into the hemostatic barrier and at the same time keeping the hemostatic barrier wet at the bottom of the well.
Approximately 10 cells in I ml culture medium were placed directly on top of the hemostatic barrier, dispersed over the surface of the hemostatic barrier pre-treated with 0.4% glutaraldehyde as described above. The plate was then incubated in a CO2 incubator at 37 C for 60 minutes. An amount of 2 to 5 ml of tissue culture medium containing 5 to 7.5%
serum was carefully added to the well containing the cells avoiding splashing the cells by holding the pipette tip tangential to the side of the well when expelling the medium. It appeared that the pH of the medium was too low (pH -6.8). The pH was then adjusted to 7.4 to 7.5. The next day some chondrocytes had started to grow on the hemostatic bamer, ananged in clusters. Some of the cells had died due to the low pH exposure prior to the adjustment of the pH. The plate was incubated for 3 to 7 days with medium change at day 1o 3.
At the end of the incubation period the medium was decanted and cold refrigerated 2.5% glutaraidehyde containing 0.1M sodium salt of dimethylarsinic acid, (also called sodium cacodylate, pH is adjusted with HCI to 7.4), was added as fixative for preparation of the cell and supporter (hemostatic barrier) for later preparation for electron microscopy.
Example 4 Chondrocytes were grown in minimal essential culture medium containing HAM
F12 and 15 mM Hepes buffer and 5 to 7.5% autologous serum in a CO, incubator at 37 C
and handled in a Class 100 laboratory at Verigen Europe A/S, Symbion Science Park, Copenhagen, Denmark. Other compositions of culture medium may be used for culturing the chondrocytes. The cells were trypsinized using trypsin EDTA for 5 to 10 minutes and counted using Trypan Blue viability staining in a Burker-Turk chamber. The cell count was adjusted to 7.5 x 105 cells per ml. One NUNCLONTM plate was uncovered in the Class 100 laboratory.
The Surgicel (for use as the hemostatic barrier) was treated with 0.6%
glutaric aldehyde for one minute as described in Example 1, and washed with 0.9%
sterile sodium chloride solution or, preferably, with a buffer such as a PBS buffer or the culture medium such as MEM/F12, because pH after the glutaric aldehyde treatment is 6.8 and should preferably be 7.0 to 7.5. The Tisseel was applied on both side of the Surgicel using the 3o DUPLOJECT system, thus coating both sides of the Surgicel , the patch intended to be used, with fibrin adhesive. The glue is left to dry under aseptic condition for at least 3 to 5 minutes. The "coated" hemostatic barrier was placed on the bottom of the well in a NUNCLONTM Delta 6-well sterile disposable plate for cell research work. A
small amount of tissue culture medium containing serum was applied to be absorbed into the hemostatic barrier. Approximately 106 cells in 1 ml tissue culture medium containing serum was placed directly on top of the Hemostat, dispersed over the surface of the hemostatic barrier.
The plate was then incubated in a COZ incubator at 37 C for 60 minutes. An amount of 2 to 5 ml of tissue culture medium containing 5 to 7.5 % serum was carefully added to the well containing the cells avoiding splashing the cells by holding the pipette tip tangential to the side of the well when expelling the medium. After 3 to 6 days, microscopic examination showed that the cells were adhering to and growing into the Surgicel in a satisfactory way suggesting that Surgicel' did not show toxicity to the chondrocytes and that the lo chondrocytes grew in a satisfactory manner into the Surgicel .
The plate was incubated for 3 to 7 days with medium change at day 3. At the end of the incubation period the medium was decanted and cold refrigerated 2.5%
glutaraldehyde containing 0.1 M sodium salt of dimethylarsinic acid, also called sodium cacodylate, pH is adjusted with HCI to 7.4, was added as fixative for preparation of the cell and supporter (hemostatic barrier) for later preparation for electron microscopy.
Example 5 Chondrocytes were grown in minimal essential culture medium containing HAM
F12 and 15 mM Hepes buffer and 5 to 7.5% autologous serum in a COZ incubator at 37 C
and handled in a Class 1001aboratory at Verigen Europe A/S, Symbion Science Park, Copenhagen, Denmark. The cells were trypsinized using trypsin EDTA for 5 to 10 minutes and counted using Trypan Blue viability staining in a Burker-Turk chamber. The cell count was adjusted to 7.5 x 105 to 2 x 10 cells per ml. One NtTNCLONTm plate was uncovered in the Class 100 laboratory.
It has been found that the Bio-Gide'' can be used as a resorbable bilayer membrane which will be used as the patch or bandage covering the defective area of the joint into which the cultured chondrocytes are being transplanted as well as the hemostatic barrier.
The Bio-Gide is a pure collagen membrane obtained by standardized, controlled manufacturing processes (by E.D. Geistlich Sohne AG, Ck-i-6110 VlTolhusen).
The collagen is extracted from veterinary certified pigs and is carefully purified to avoid antigenic reactions, and sterilized in double blisters by y-irradiation. The bilayer membrane has a porous surface and a dense surface. The membrane is made of collagen type I
and type III
without further cross-linking or chemical treatment. The collagen is resorbed within 24 ~t weeks. The membrane retains its structural integrity even when wet and it can be fixed by sutures or nails. The membrane may also be "glued" using fibrin adhesive such as Tisseel to the neighboring cartilage or tissue either instead of sutures or together with sutures.
The Bio-Gide was un-covered in a class 100 laboratory and placed under aseptic conditions on the bottom of the wells in a NUNCLONT"" Delta 6-well sterile disposable plate for cell research work, - either with the porous surface of the bilayer membrane facing up or with the dense surface facing up. Approximately I Obcells in I ml tissue culture medium containing serum was placed directly on top of the Bio-Gide , dispersed either over the porous or the dense surface of the Bio-Gide. The plate was then incubated in a 1 o COZ incubator at 37 C for 60 minutes. An amount of 2 to 5 ml of tissue culture medium containing 5 to 7.5 % serum was carefully added to the well containing the cells avoiding splashing the cells by holding the pipette tip tangential to the side of the well when expelling the medium.
On day 2 after the chondrocytes were placed in the well containing the Bio-Gide the cells were examined in a Nikon Inverted microscope. It was noticed that some chondrocytes had adhered to the edge of the Bio-Gide. It was of course not possible to be able to look through the Bio-Gide itself using this microscope.
The plate was incubated for 3 to 7 days with medium change at day 3. At the end of the incubation period the medium was decanted and cold refrigerated 2.5%
glutaraldehyde containing 0.11v1 sodium salt of dimethylarsinic acid, also called sodium cacodylate, pH is adjusted with HCI to 7.4, was added as fixative for preparation of the cell and the Bio-Gide supporter with the cells either cultured on the porous surface or the dense surface.
The Bio-Gide patches were then sent for electron microscopy at Department of Pathology, Herlev Hospital, Denmark.
The electron microscopy showed that the chondrocytes cultured on the dense surface of the Bio-Gide did not grow into the collagen structure of the Bio-Gide , whereas the cells cultured on the porous surface did indeed grow into the collagen structure and furthermore, showed presence of proteoglycans and no signs of fibroblast structures. This result shows that when the collagen patch, as for instance a Bio-Gide patch is sewn as a patch covering a cartilage defect the porous surface shall be facing down towards the defect in which the cultured chondrocytes are to be injected. They will then be able to penetrate the collagen and produce a smooth cartilage surface in line with the intact surface, and in this area a smooth layer of proteoglycans will be built up. Whereas, if the dense surface of the collagen is facing down into the defect the chondrocytes to be implanted will not integrate with the collagen, and the cells will not produce the same smooth surface as described above.

Example 6 Chondrocytes were grown in minimal essential culture medium containing HAM
F12 and 15 mM Hepes buffer and 5 to 7.5% autologous serum in a CO, incubator at 37 C
and handled in a Class 100 laboratory at Verigen Europe A/S, Symbion Science Park, Copenhagen, Denmark. The cells were trypsinized using trypsin EDTA for 5 to 10 minutes 1 o and counted using Trypan Blue viability staining in a Biirker-Tiirk chamber. The cell count was adjusted to 7.5 x 205 to 2 x 10b cells per ml. One NUNCLONT"' plate was uncovered in the Class 100 laboratory.
The Bio-Gide used as a resorbable bilayer membrane may also be used together with an organic glue such as Tisseel with additional, significantly higher content of Aprotinin than normally found in Tisseel , as described in the product insert.
By increasing the content of Aprotinin to about 25,000 KIiT/ml, the resorption of the material will be delayed by weeks instead of the normai span of days.
To test this feature in vitro, the Tisseel is applied to the bottom of the well of the NUNCLONTm plate, and allowed to solidify incompletely. A collagen patch such as a Bio-2o Gide is then applied over the Tisseel and glued to the bottom of the well. This combination of Bio-Gide and Tisseel is designed to be a hemostatic barrier that will inhibit or prevent development or infiltration of blood vessels into the chondrocyte transplantation area. This hybrid collagen patch can now be used for both as a hemostatic barrier at the bottom of the lesion (most proximal to the surface to be repaired) but also as a support for cartilage formation because the distal surface can be the porous side of the collagen patch and thus encourage infiltration of chondrocytes and cartilage matrix. Thus this hybrid coliagen patch can also be used to cover the top of the implant with the collagen porous surface directed down towards the implanted chondrocytes and the barrier forming the top. The hybrid collagen patch, with elevated Aprotinin component may also be used without any organic glue such as Tisseel and placed within the defect directly, adhering by natural forces. Thus the collagen patch can be used both as the hemostatic barrier, and the cell-free covering of the repair/transplant site, with the porous surfaces of the patches oriented towards the transplanted chondrocytes/cartilage. Another variant would use a collagen patch which consists of type II collagen (ie. from Geistlich Sohne AG, CH-6I 10 Wolhusen).
Thus the instant invention provides for a hybrid collagen patch where said patch is a collagen matrix with elevated levels of aprotinin component, preferably about 25,000 KIU/ml, in association with an organic matrix glue, where the coliagen component is similar to the Bio-Gide resorbable bilayer material or Type II collagen, and the organic glue is similar to the Tisseel material. In another embodiment, the hybrid collagen patch does not use any organic glue to adhere to the site of the repair.

Example 7 Because of the weakened structure of osteoarthritic cartilage, adherence of cultured autologous chondrocytes transplanted to a graft site in defective cartilage may be inhibited, thus creating a marginal zone (zone of demarcation) between the newly implanted cartilage/chondrocytes and the surrounding established cartilage. This marginal zone will be most pronounced if the graft site is prepared for the graft by creating straight, smooth walls cut in a linear fashion. The shearing and compression forces across such a marginal zone (as illustrated in Figure 3A) will exert great force to dislodge the graft when the graft site is cut in a linear fashion. This marginal zone, and differential movement of materials along this zone will inhibit confluent healing between the grafted material and the surrounding material. This marginal zone shearing is exacerbated when the hardness of the abutting material is different. In many cases the graft material is softer than the surrounding material, however, in some instances of osteoarthritis disease, the surrounding cartilage may in fact be softer than the implanted chondrocytes/cartilage.
Therefore, in order to solve this problem, the method of the invention teaches the use of surgical instruments to sculpt the walls of the graft site such that the walls are non-linear, and thus provide for undulated surfaces which will reduce marginal zone shearing and provide anchorage for grafted material. It is also possible to shape the graft site such that the diameter of the site proximal to the bone surface is of a greater dimension then the opening distal to the bone and at the surface of the cartilage to be repaired such that there is 3o a "reverse funnel" effect. A narrowed opening at the surface will aid in reducing marginal zone shearing and the expulsion of graft material from the graft site. A
preferred embodiment describes the sculpting of the walls of the graft site in an fashion similar to a threaded opening for receiving a bolt or screw (as illustrated in Figure 3B), thus providing mechanical resistance to the compression and or ejection of the grafted material from the graft site which can be described as "male" and "female" threading.
The surgical instruments contemplated by the instant invention can be manufactured from metal and/or plastic suitable for making single-use disposable, or multi-use reusable surgical instruments. As cartilage is a relatively soft material it may be advantageous to manufacture hardened plastic cutting edges which will be able to sculpt cartilage without being able to damage bone. Such cutting instruments can be manufactured to incorporate openings for administration of fluid, suction removal of cutting debris and fluid, and fiber optic threads for illumination and visualization of the defect site. In certain embodiments of lo the instrument, the base of the instrument may have protruding point or pin-like structure which will assist in guiding and placing the instrument in the graft site. Of course such a pin would be designed to minimized damage to the underlying bone.
While the cutting surface of the instrument may be single toothed, or multi-toothed, or describe a screw-like pattern such as that in a metal tap used to generate threaded holes in metal parts, the characteristic required of the cutting instrument is that the resulting sculpted sides of the graft site is undulated, and non-linear. For example, in certain embodiments, the cutting edge of the instrument can be shaped similar to that shown in Figure 4A, or as in Figure 4B. The cutting edge maybe flat, or circular in that it wraps around the diameter of the cutting instrument. Many other shapes can be designed to 2o accomplish the purpose of the method of the invention to create an interface which provides for mechanical resistance to differential reaction to compression and shearing forces on the transplanted material and the surrounding material.

Example 8 A four month old mixed Yorkshire breed pig was subjected to general anesthesia and placed on its back. The pig was washed and draped in a surgical suite at Harrington Arthritis Research Center, Phoenix, Arizona. The entire surgical procedure was performed aseptically. The left hind-leg and adjacent abdomen and inguinal area was cleaned with iodine. The knee joint was localized, and the patella localized. A medial incision was performed approximately 3 cm from the posterior part of the patella and the several subcutis, muscle layers and ligaments was cut approximately in order to get access to the medial femoral condyle. Using a circular cutter a lesion was prepared in the white cartilage on the medial part of the medial condyle, leaving a 0.5 to 1 cm margin to the edge of the cartilage covering the posterior-medial part of the condyle (left condyle, Figure 6A). The 0.5 to 1 cm defect was placed in a caudal weight bearing part of the medial condyle. The entire surgical procedure was done without tourniquet on the lefft femur. The different layers and skin was sutured appropriately.
On day 3 the animal was again brought to the surgical suite and positioned as above on the operating table and given general anesthesia. The left hind leg, abdomen and inguinal region was ionized as described above. Sutures were cut and the area opened. It was noticed that a moderate hematoma was present in the knee joint. The blood clot was removed and the defect inspected. There was a blood clot in the defect which was removed.
to A sterile surgical instrument designed with a male thread cutting edge, with a size corresponding to, or slightly bigger than the circumference of the lesion was caref'ully screwed down into the defect. A BioGide pad was cut to a size equal to the bottom of the defect. The first glue used, called Adhesive Protein (A-2707, Sigma Chemical, USA) was applied on the dense side of the trimmed hemostatic barrier pad, and the pad was placed dense side down into the bottom of the lesion, using it as a barrier as described above. It was found that this glue did not seem to dry very fast. The slight bleeding from the bottom of the defect stopped immediately. A second BioGide was cut somewhat bigger in circumference than the lesion and was placed with dense side up (thus the porous side down towards the graft) as described above.
This non-cellular covering-pad was then sutured over the cavity, leaving one edge open, where the chondrocyte to be explanted could be injected into the graft site. The surrounding part of the edge of the pad was covered with the second glue, Dow Corning Medical Adhesive B (Cat. #895-3, Dow Corning, USA). This second glue dried much faster and more efficiently than the first glue. It was found that during this particular procedure, the first glue had not dried sufficiently to hold the hemostatic barrier in place when suturing of the cap was attempted. The main barrier formed on the proximal surface of the graft site was by the glue itself.

Using a 1 mi syringe and a 16 gauge needle, the chondrocyte cell suspension (about 0.6 ml) was drawn up into the barrel of the syringe. A 23 gauge short needle was switched for the 16 gauge needle, and the cell suspension was injected under the sutured covering-patch into the graft site (about 10 x 10b cells). The open edge of the cap was then glued prior to removal of the needle, and the needle carefully withdrawn. No leakage of cells was seen. The wound was sutured and as above, no tourniquet was used, no bleeding was observed. The final skin layers were sutured. No protrusion of the skin occurred after suturing, which indicates that there was no hematoma. Postoperative recovery was uneventful.
As expected, the grafted chondrocytes produced cartilage matrix sufficient to repair the defect made in the articular cartilage surface of the knee joint of the test pig. Figure 6A
is an IVIRI image of a pig knee showing the cartilage defect created in the knee (left condyle, the medial condyle), and Figure 6B is an MRI image of the same pig knee three months after treatment showing repair of the defect.
Example 9 A kit comprising the components useful for practicing the method of the invention, will allow for the convenient practice of the method of the invention in a surgical setting.. In a preferred embodiment, a kit of the invention will provide sterile components suitable for easy use in the surgical environment, and will provide a suitable hemostatic barrier, suitable covering patch, and if needed organic glue. A kit of the invention may also provide sterile, cell-free matrix material suitable for supporting autologous chondrocytes that are to be implanted into an articular joint surface defect. In one embodiment, a kit of the invention contains a Surgicel hemostatic barrier and a Bio-Gide covering patch with suitable coating of Tisseel organic glue, where the Surgicel and Bio-Gide have been treated according to the teachings of the invention to increase the time till resorption. In instances where Tisseel is pre-coated, in one embodiment the Tisseel is supplemented with additional aprotinin to increase time till resorption.
In another preferred embodiment, the hemostatic barrier and covering-patch are both a semi-permeable collagen matrix which is treated to extend the time till resorption of the material. It is also possible to provide Tisseel glue in enhanced fonn as a separate component to be applied as needed because of the inherent variability and unique circumstances every repair/transplantation procedure will encounter.
A further embodiment of a kit of the invention will include a surgical instrument as described in Example 7 above, or suitable variations thereof.
It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention shown in the specific embodiments without departing form the spirit and scope of the invention as described.

Claims (77)

THE EMBODIMENTS OF THE INVENTION FOR WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An article comprising a cell-free component and chondrocyte cells adjacent to said cell-free component, wherein said cell-free component comprises Type II
collagen.
2. An article comprising a cell-free component and chondrocyte cells adjacent to said cell-free component, wherein said cell-free component comprises collagen.
3. The article of claim 2, wherein said cell-free component comprises collagen Type I, collagen Type II, collagen Type III or combinations thereof.
4. The article of claim 2, wherein said cell-free component comprises Type I
and Type III collagen.
5. The article of claim 2, wherein said cell-free component comprises Type II
collagen.
6. The article of any one of claims 1 to 5, wherein said chondrocyte cells are xenogenic.
7. The article of any one of claims 1 to 5, wherein said chondrocyte cells are allogenic.
8. The article of any one of claims 1 to 5, wherein said chondrocyte cells are autologous.
9. The article of any one of claims 1 to 8, wherein said cell-free component is a membrane.
10. The article of claim 9, wherein said membrane is semi-permeable.
11. The article of claim 1, further comprising a biocompatible adhesive adjacent to said cell-free component.
12. The article of any one of claims 1 to 11, wherein said cell-free component is resorbable.
13. The article of any one of claims 1 to 12, wherein said cell-free component is configured to be disposed over an articular cartilage defect.
14. The article of any one of claims 1 to 12, wherein said cell-free component is configured to be disposed in an articular cartilage defect.
15. The article of any one of claims 1 to 12, wherein said chondrocyte cells are adhered to said cell-free component.
16. A composition comprising a multilayer cell-free membrane having a porous surface; a biocompatible adhesive adjacent to said membrane; and chondrocyte cells adjacent to said porous surface of said membrane wherein at least one layer of said multilayer cell-free membrane comprises collagen.
17. A composition comprising a multilayer cell-free membrane having a porous surface and chondrocyte cells adjacent to said porous surface of said membrane, wherein said membrane comprises Type I and Type III collagen.
18. A composition according to claim 16 or 17, wherein said chondrocyte cells are adhered to said porous surface.
19. A composition according to claim 16, wherein all layers of said multilayer membrane comprise collagen.
20. A composition according to claim 16, wherein at least one of layer of said multilayer membrane comprises Type I and Type III collagen.
21. A composition according to any one of claims 16 to 20, wherein said membrane is resorbable.
22. A composition according to any one of claims 16 to 21, wherein said chondrocyte cells are autologous.
23. A composition according to any one of claims 16 to 21, wherein said chondrocyte cells are allogenic.
24. A composition according to any one of claims 16 to 21, wherein said chondrocyte cells are xenogenic.
25. A composition according to claim 17, further comprising a biocompatible adhesive adjacent to said membrane.
26. A composition according to any one of claims 16 to 25, wherein said membrane is configured to be disposed over an articular cartilage defect.
27. A composition according to any one of claims 16 to 25, wherein said membrane is configured to be disposed in an articular cartilage defect.
28. Use of chondrocytes in a suitable matrix, a hemostatic barrier and a cell-free covering patch for treatment of articulating joint surface cartilage, wherein said hemostatic barrier is for placement proximal to the articulating joint surface cartilage to be treated, said chondrocytes are for placement upon the articulating joint surface cartilage to be treated distal to the hemostatic barrier, and adjacent to said cell-free covering-patch, wherein said cell-free covering-patch is for covering said articulating joint surface cartilage to be treated.
29. The use according to claim 28, wherein said covering-patch is for adherence to the surface of the cartilage covering a graft site, and said chondrocytes are for placement under said covering-patch into said graft site.
30. The use according to claim 28 or 29, wherein said covering-patch comprises a semi-permeable collagen matrix.
31. The use according to claim 30, wherein said semi-permeable collagen matrix has a porous surface.
32. The use according to claim 31, wherein said porous surface contacts the grafted chondrocytes.
33. The use according to any one of claims 28 to 32, wherein said hemostatic barrier is a resorbable semi-permeable material which inhibits or prohibits vascular infiltration through the barrier.
34. The use according to any one of claims 28 to 33, wherein said hemostatic barrier comprises collagen.
35. Use of chondrocytes in a suitable matrix, a hemostatic barrier and a cell-free covering-patch for transplantation of said chondrocytes to a sculpted graft site in a surface to be treated, said graft site comprising non-linear and/or undulating walls, wherein said hemostatic barrier is for placement proximal to the surface to be treated within the sculpted graft site, said chondrocytes are for placement within the graft site upon the hemostatic barrier and adjacent to the cell-free covering patch, and wherein said covering-patch is for covering the surface to be treated.
36. The use according to claim 35, wherein said covering-patch is for partial attachment prior to placing said chondrocytes within said graft site, upon said hemostatic barrier.
37. The use according to claim 35 or 36, wherein said hemostatic barrier is a resorbable semi-permeable material which inhibits or prohibits vascular infiltration through the barrier.
38. The use according to any one of claims 35 to 37, wherein said hemostatic barrier comprises collagen.
39. The use according to any one of claims 35 to 37, wherein said covering-patch is a cell-free semi-permeable collagen matrix.
40. A kit for chondrocyte and optionally cartilage transplantation onto the surface of an articular joint wherein said kit comprises a hemostatic barrier pre-treated to resist resorption which can be configured for placing on said surface, a covering-patch pre-treated to resist resorption which can be configured for covering said surface, and optionally organic glue for attaching said hemostatic barrier and/or said covering-patch to said surface, wherein said covering-patch is substantially free of viable cells and said patch comprises a collagen matrix with elevated levels of aprotinin component.
41. A kit comprising a hemostatic barrier treated to inhibit resorption, a covering-patch treated to inhibit resorption, optionally an organic glue, optionally a surgical instrument for sculpting at least a wall of a graft site to be sculpted, and optionally a matrix material suitable for supporting chondrocytes placed within said graft site, wherein said covering-patch is substantially free of viable cells and said patch comprises a collagen matrix with elevated levels of aprotinin component.
42. Use of chondrocytes in a suitable matrix and a cell-free covering-patch which is a semi-permeable collagen matrix with a porous surface for treatment of articulating joint surface cartilage, wherein said chondrocytes are for placement upon the surface to be treated and adjacent to the cell-free covering patch, and wherein said cell-free covering patch is for covering the surface to be treated.
43. The use according to claim 42, wherein the porous surface of the covering-patch is for placement toward the articulating joint surface cartilage to be treated.
44. The use according to claim 42 or 43, wherein the covering-patch is resorbable.
45. The use according to any one of claims 42 to 44, wherein the covering-patch is for partial attachment to the articulating joint surface cartilage to be treated prior to placement of the chondrocytes
46. Use of chondrocytes in a suitable matrix and a cell-free covering patch for treatment of a sculpted articulating joint surface cartilage, wherein said chondrocytes are for placement upon the sculpted articulating joint surface cartilage to be treated and adjacent to the cell-free covering patch, and wherein said covering-patch is for covering the sculpted articulating joint surface cartilage to be treated.
47. The use according to claim 46, wherein the matrix is cell-free.
48. The use according to claim 46 or 47, wherein the covering-patch is a semi-permeable collagen matrix with a porous surface.
49. The use according to claim 48, wherein the porous surface of the covering-patch is for placement toward the sculpted articulating joint surface cartilage to be treated.
50. The use according to any one of claims 46 to 49, wherein the covering-patch is a semi-permeable collagen matrix which is substantially free of intact cells.
51. The use according to any one of claims 46 to 50, wherein the covering-patch is resorbable.
52. The use according to any one of claims 46 to 51, wherein the covering-patch is for partial attachment to the sculpted articulating joint surface cartilage to be treated prior to placement of the chondrocytes.
53. A kit for chondrocyte transplantation comprising a covering-patch comprising collagen, an organic glue, and a surgical instrument for sculpting a surface to be treated.
54. The kit according to claim 53, further comprising a matrix suitable for the placement of chondrocytes.
55. The kit according to claim 54, wherein the matrix is cell-free.
56. A kit for chondrocyte transplantation comprising a covering-patch which is a semi-permeable collagen matrix with a porous surface and an organic glue.
57. The kit according to claim 56, further comprising a matrix suitable for the placement of chondrocytes.
58. The kit according to claim 57, wherein the matrix is cell-free.
59. Use of an article for repair of a defect in articular cartilage, said article comprising a cell-free membrane having a porous surface and a dense surface and chondrocyte cells adjacent to said porous surface.
60. The use according to claim 59, wherein said chondrocyte cells are adhered to said porous surface.
61. The use according to claim 60, wherein said chondrocyte cells are grown on said porous surface.
62. The use according to any one of claims 59 to 61, wherein said membrane is collagen.
63. The use according to any one of claims 59 to 61, wherein said membrane is Type I and Type III collagen.
64. The use according to any one of claims 59 to 62, wherein said membrane is resorbable.
65. The use according to any one of claims 59 to 64, wherein said chondrocyte cells are autologous.
66. The use according to any one of claims 59 to 64, wherein said chondrocyte cells are allogenic.
67. The use according to any one of claims 59 to 64, wherein said chondrocyte cells are xenogenic.
68. The use according to any one of claims 59 to 67, wherein said article further comprises a biocompatible adhesive adjacent to said membrane.
69. The use according to any one of claims 59 to 67, wherein said membrane is configured to be disposed over the articular cartilage defect.
70. The use according to any one of claims 59 to 67, wherein said membrane is configured to be disposed in the articular cartilage defect.
71. A kit for chondrocyte or cartilage transplantation into a graft site on a surface of an articular joint, said kit comprises a hemostatic barrier pre-treated to inhibit resorption, a cell-free covering patch which is a semi-permeable collagen-matrix with a porous surface and which is pre-treated to inhibit resorption, an organic glue for attaching said hemostatic barrier and/or said covering-patch to said surface, and chondrocytes in a suitable matrix for being placed under and adjacent to the cell-free covering-patch into said graft site.
72. The kit according to claim 71, further comprising a surgical instrument for sculpting walls of said graft site.
73. The kit according to claim 71 or 72, wherein said covering-patch is resorbable.
74. The kit according to any one of claims 71 to 73, wherein said hemostatic barrier is a resorbable semi-permeable material which inhibits or prohibits vascular infiltration through the barrier.
75. The kit according to any one of claims 71 to 74, wherein said hemostatic barrier comprises collagen.
76. The Article of claim 2, wherein said cell-free component comprises collagen Type I and collagen Type III.
77. The Article of claim 2, wherein said article further comprises a biocompatible adhesive adjacent to said cell-free component
CA002419644A 1996-08-30 1997-08-29 Method and kit for the transplantation of chondrocyte cells Expired - Lifetime CA2419644C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US08/704,891 US5759190A (en) 1996-08-30 1996-08-30 Method and kit for autologous transplantation
US08/704,891 1996-08-30
US08/857,090 1997-05-15
US08/857,090 US5989269A (en) 1996-08-30 1997-05-15 Method, instruments and kit for autologous transplantation
CA002264138A CA2264138C (en) 1996-08-30 1997-08-29 Method, instruments and kit for autologous transplantation

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CA002264138A Division CA2264138C (en) 1996-08-30 1997-08-29 Method, instruments and kit for autologous transplantation

Publications (2)

Publication Number Publication Date
CA2419644A1 CA2419644A1 (en) 1998-03-05
CA2419644C true CA2419644C (en) 2009-10-13

Family

ID=27107401

Family Applications (2)

Application Number Title Priority Date Filing Date
CA002264138A Expired - Lifetime CA2264138C (en) 1996-08-30 1997-08-29 Method, instruments and kit for autologous transplantation
CA002419644A Expired - Lifetime CA2419644C (en) 1996-08-30 1997-08-29 Method and kit for the transplantation of chondrocyte cells

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CA002264138A Expired - Lifetime CA2264138C (en) 1996-08-30 1997-08-29 Method, instruments and kit for autologous transplantation

Country Status (27)

Country Link
US (9) US5989269A (en)
EP (4) EP1181908B1 (en)
JP (3) JP2002502272A (en)
KR (2) KR20030097603A (en)
CN (2) CN1200656C (en)
AT (3) ATE428376T1 (en)
AU (1) AU731162B2 (en)
BR (1) BR9711967A (en)
CA (2) CA2264138C (en)
CZ (1) CZ297248B6 (en)
DE (4) DE69726896T2 (en)
DK (5) DK1384452T3 (en)
ES (3) ES2325206T3 (en)
HK (2) HK1025035A1 (en)
HU (2) HUP0002980A3 (en)
IL (1) IL128580A (en)
MX (1) MXPA99001794A (en)
NO (1) NO990933L (en)
NZ (3) NZ518474A (en)
PL (1) PL331834A1 (en)
PT (3) PT1006950E (en)
RU (2) RU2214197C2 (en)
SG (2) SG120854A1 (en)
SI (2) SI1006950T1 (en)
SK (1) SK285075B6 (en)
TR (3) TR199900437T2 (en)
WO (1) WO1998008469A2 (en)

Families Citing this family (205)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050186673A1 (en) * 1995-02-22 2005-08-25 Ed. Geistlich Soehne Ag Fuer Chemistrie Industrie Collagen carrier of therapeutic genetic material, and method
US5940807A (en) * 1996-05-24 1999-08-17 Purcell; Daniel S. Automated and independently accessible inventory information exchange system
US20020173806A1 (en) * 1996-08-30 2002-11-21 Verigen Transplantation Service International (Vtsi) Ag Method for autologous transplantation
US6569172B2 (en) * 1996-08-30 2003-05-27 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US20060025786A1 (en) * 1996-08-30 2006-02-02 Verigen Transplantation Service International (Vtsi) Ag Method for autologous transplantation
US5989269A (en) * 1996-08-30 1999-11-23 Vts Holdings L.L.C. Method, instruments and kit for autologous transplantation
US9603711B2 (en) 2001-05-25 2017-03-28 Conformis, Inc. Patient-adapted and improved articular implants, designs and related guide tools
US8480754B2 (en) 2001-05-25 2013-07-09 Conformis, Inc. Patient-adapted and improved articular implants, designs and related guide tools
US8545569B2 (en) 2001-05-25 2013-10-01 Conformis, Inc. Patient selectable knee arthroplasty devices
US7618451B2 (en) 2001-05-25 2009-11-17 Conformis, Inc. Patient selectable joint arthroplasty devices and surgical tools facilitating increased accuracy, speed and simplicity in performing total and partial joint arthroplasty
US8771365B2 (en) 2009-02-25 2014-07-08 Conformis, Inc. Patient-adapted and improved orthopedic implants, designs, and related tools
US8556983B2 (en) 2001-05-25 2013-10-15 Conformis, Inc. Patient-adapted and improved orthopedic implants, designs and related tools
US8617242B2 (en) 2001-05-25 2013-12-31 Conformis, Inc. Implant device and method for manufacture
US7534263B2 (en) 2001-05-25 2009-05-19 Conformis, Inc. Surgical tools facilitating increased accuracy, speed and simplicity in performing joint arthroplasty
US8882847B2 (en) 2001-05-25 2014-11-11 Conformis, Inc. Patient selectable knee joint arthroplasty devices
US10085839B2 (en) 2004-01-05 2018-10-02 Conformis, Inc. Patient-specific and patient-engineered orthopedic implants
US20070100462A1 (en) 2001-05-25 2007-05-03 Conformis, Inc Joint Arthroplasty Devices
US8234097B2 (en) 2001-05-25 2012-07-31 Conformis, Inc. Automated systems for manufacturing patient-specific orthopedic implants and instrumentation
US7468075B2 (en) 2001-05-25 2008-12-23 Conformis, Inc. Methods and compositions for articular repair
US8735773B2 (en) 2007-02-14 2014-05-27 Conformis, Inc. Implant device and method for manufacture
US8083745B2 (en) 2001-05-25 2011-12-27 Conformis, Inc. Surgical tools for arthroplasty
US20030180263A1 (en) * 2002-02-21 2003-09-25 Peter Geistlich Resorbable extracellular matrix for reconstruction of bone
US20050186283A1 (en) * 1997-10-10 2005-08-25 Ed. Geistlich Soehne Ag Fuer Chemistrie Industrie Collagen carrier of therapeutic genetic material, and method
US8858981B2 (en) * 1997-10-10 2014-10-14 Ed. Geistlich Soehne Fuer Chemistrie Industrie Bone healing material comprising matrix carrying bone-forming cells
US9034315B2 (en) * 1997-10-10 2015-05-19 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Cell-charged multi-layer collagen membrane
US8563232B2 (en) 2000-09-12 2013-10-22 Lifenet Health Process for devitalizing soft-tissue engineered medical implants, and devitalized soft-tissue medical implants produced
US20080077251A1 (en) * 1999-06-07 2008-03-27 Chen Silvia S Cleaning and devitalization of cartilage
US6293970B1 (en) 1998-06-30 2001-09-25 Lifenet Plasticized bone and soft tissue grafts and methods of making and using same
US20100030340A1 (en) * 1998-06-30 2010-02-04 Wolfinbarger Jr Lloyd Plasticized Grafts and Methods of Making and Using Same
TR200100482T2 (en) * 1998-08-14 2001-06-21 Verigen Transplantation Service International(Vtsi)Ag Methods for chondrocyte cell transplantation; instruments and items
EP1656960A1 (en) * 1998-08-14 2006-05-17 Verigen AG Methods, instruments and materials for chondrocyte cell transplantation
JP2002532126A (en) 1998-09-14 2002-10-02 スタンフォード ユニバーシティ Joint condition evaluation and damage prevention device
US7239908B1 (en) 1998-09-14 2007-07-03 The Board Of Trustees Of The Leland Stanford Junior University Assessing the condition of a joint and devising treatment
US20020081732A1 (en) 2000-10-18 2002-06-27 Bowlin Gary L. Electroprocessing in drug delivery and cell encapsulation
US7615373B2 (en) 1999-02-25 2009-11-10 Virginia Commonwealth University Intellectual Property Foundation Electroprocessed collagen and tissue engineering
US7476250B1 (en) * 1999-04-06 2009-01-13 Mansmann Kevin A Semi-permeable membranes to assist in cartilage repair
US20020095157A1 (en) 1999-07-23 2002-07-18 Bowman Steven M. Graft fixation device combination
US6179840B1 (en) 1999-07-23 2001-01-30 Ethicon, Inc. Graft fixation device and method
DE60018576T2 (en) * 1999-07-28 2006-04-13 Interface Biotech A/S IN VITRO HEALING OF BONE AND / OR TROUBLE DAMAGE
US20020116063A1 (en) * 1999-08-02 2002-08-22 Bruno Giannetti Kit for chondrocyte cell transplantation
CA2391819A1 (en) * 1999-08-02 2001-02-08 Verigen Transplantation Service International Ag Kit for chondrocyte cell transplantation
EP1233707B1 (en) * 1999-12-03 2007-08-08 The University Of Leeds Repair of damaged tissue
US6626945B2 (en) * 2000-03-14 2003-09-30 Chondrosite, Llc Cartilage repair plug
US7678151B2 (en) 2000-05-01 2010-03-16 Ek Steven W System and method for joint resurface repair
AU2001259327B2 (en) * 2000-05-01 2005-02-17 Arthrosurface, Inc. System and method for joint resurface repair
US7713305B2 (en) * 2000-05-01 2010-05-11 Arthrosurface, Inc. Articular surface implant
US6520964B2 (en) * 2000-05-01 2003-02-18 Std Manufacturing, Inc. System and method for joint resurface repair
US6610067B2 (en) 2000-05-01 2003-08-26 Arthrosurface, Incorporated System and method for joint resurface repair
US8177841B2 (en) 2000-05-01 2012-05-15 Arthrosurface Inc. System and method for joint resurface repair
US7163541B2 (en) 2002-12-03 2007-01-16 Arthrosurface Incorporated Tibial resurfacing system
US8366787B2 (en) 2000-08-04 2013-02-05 Depuy Products, Inc. Hybrid biologic-synthetic bioabsorbable scaffolds
US6638312B2 (en) 2000-08-04 2003-10-28 Depuy Orthopaedics, Inc. Reinforced small intestinal submucosa (SIS)
AU2001288692A1 (en) 2000-09-01 2002-03-13 Virginia Commonwealth University Intellectual Property Foundation Electroprocessed fibrin-based matrices and tissues
EP1322224B1 (en) 2000-09-14 2008-11-05 The Board Of Trustees Of The Leland Stanford Junior University Assessing condition of a joint and cartilage loss
WO2002022014A1 (en) 2000-09-14 2002-03-21 The Board Of Trustees Of The Leland Stanford Junior University Assessing the condition of a joint and devising treatment
US6852330B2 (en) * 2000-12-21 2005-02-08 Depuy Mitek, Inc. Reinforced foam implants with enhanced integrity for soft tissue repair and regeneration
US20020127265A1 (en) * 2000-12-21 2002-09-12 Bowman Steven M. Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration
CA2365376C (en) 2000-12-21 2006-03-28 Ethicon, Inc. Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration
US6599323B2 (en) * 2000-12-21 2003-07-29 Ethicon, Inc. Reinforced tissue implants and methods of manufacture and use
US20040151705A1 (en) * 2002-03-22 2004-08-05 Shuichi Mizuno Neo-cartilage constructs and a method for preparation thereof
US6713085B2 (en) 2001-04-27 2004-03-30 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Method and membrane for mucosa regeneration
US8951260B2 (en) 2001-05-25 2015-02-10 Conformis, Inc. Surgical cutting guide
AU2002310193B8 (en) 2001-05-25 2007-05-17 Conformis, Inc. Methods and compositions for articular resurfacing
US8439926B2 (en) 2001-05-25 2013-05-14 Conformis, Inc. Patient selectable joint arthroplasty devices and surgical tools
US6723102B2 (en) * 2001-06-14 2004-04-20 Alexandria Research Technologies, Llc Apparatus and method for minimally invasive total joint replacement
US6482209B1 (en) * 2001-06-14 2002-11-19 Gerard A. Engh Apparatus and method for sculpting the surface of a joint
AU2002322567B2 (en) 2001-07-16 2007-09-06 Depuy Products, Inc. Devices form naturally occurring biologically derived
WO2003007787A2 (en) 2001-07-16 2003-01-30 Depuy Products, Inc. Cartilage repair and regeneration device and method
WO2003007786A2 (en) 2001-07-16 2003-01-30 Depuy Products, Inc. Porous delivery scaffold and method
US8025896B2 (en) 2001-07-16 2011-09-27 Depuy Products, Inc. Porous extracellular matrix scaffold and method
US7361195B2 (en) 2001-07-16 2008-04-22 Depuy Products, Inc. Cartilage repair apparatus and method
EP1416879A4 (en) * 2001-07-16 2007-04-25 Depuy Products Inc Unitary surgical device and method
EP1416888A4 (en) 2001-07-16 2007-04-25 Depuy Products Inc Meniscus regeneration device and method
US7819918B2 (en) 2001-07-16 2010-10-26 Depuy Products, Inc. Implantable tissue repair device
US7914808B2 (en) 2001-07-16 2011-03-29 Depuy Products, Inc. Hybrid biologic/synthetic porous extracellular matrix scaffolds
CN1592635A (en) * 2001-09-24 2005-03-09 维里根股份公司 Autologous growth factor cocktail composition, method of production and use
JP4330991B2 (en) * 2001-10-01 2009-09-16 スキャンディウス・バイオメディカル・インコーポレーテッド Apparatus and method for repairing articular cartilage defects
CA2412012C (en) * 2001-11-20 2011-08-02 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Resorbable extracellular matrix containing collagen i and collagen ii for reconstruction of cartilage
BR0307033A (en) * 2002-01-22 2004-12-07 Pfizer 3- (imidazolyl) -2-aminopropanoic acids for use as tafi-a inhibitors for the treatment of thrombotic diseases
US7537780B2 (en) * 2002-03-22 2009-05-26 Histogenics Corporation Method for preparing and implanting a cartilage construct to treat cartilage lesions
CA2483660A1 (en) * 2002-05-01 2003-11-13 Verigen Ag Injectable chondrocyte implant
SE0201479D0 (en) * 2002-05-16 2002-05-16 Pharmacia Groningen Bv Kit and method in eye surgery
US20040166169A1 (en) * 2002-07-15 2004-08-26 Prasanna Malaviya Porous extracellular matrix scaffold and method
US20040136968A1 (en) * 2002-09-27 2004-07-15 Verigen Ag Autologous cells on a support matrix for tissue repair
ATE497740T1 (en) * 2002-10-07 2011-02-15 Conformis Inc MINIMALLY INVASIVE JOINT IMPLANT WITH A THREE-DIMENSIONAL GEOMETRY ADAPTED TO THE JOINT SURFACES
US20040078090A1 (en) 2002-10-18 2004-04-22 Francois Binette Biocompatible scaffolds with tissue fragments
US7824701B2 (en) 2002-10-18 2010-11-02 Ethicon, Inc. Biocompatible scaffold for ligament or tendon repair
US7799084B2 (en) 2002-10-23 2010-09-21 Mako Surgical Corp. Modular femoral component for a total knee joint replacement for minimally invasive implantation
EP3075356B1 (en) 2002-11-07 2023-07-05 ConforMIS, Inc. Method of selecting a meniscal implant
US20060147332A1 (en) 2004-12-30 2006-07-06 Howmedica Osteonics Corp. Laser-produced porous structure
EP1418013B1 (en) 2002-11-08 2005-01-19 Howmedica Osteonics Corp. Laser-produced porous surface
US7901408B2 (en) 2002-12-03 2011-03-08 Arthrosurface, Inc. System and method for retrograde procedure
AU2003900620A0 (en) * 2003-02-12 2003-02-27 Australian Surgical Design And Manufacture Pty Limited Arthroscopic chondrocyte implantation method and device
US8388624B2 (en) 2003-02-24 2013-03-05 Arthrosurface Incorporated Trochlear resurfacing system and method
US8197837B2 (en) 2003-03-07 2012-06-12 Depuy Mitek, Inc. Method of preparation of bioabsorbable porous reinforced tissue implants and implants thereof
US7067123B2 (en) 2003-04-29 2006-06-27 Musculoskeletal Transplant Foundation Glue for cartilage repair
US20050064042A1 (en) * 2003-04-29 2005-03-24 Musculoskeletal Transplant Foundation Cartilage implant plug with fibrin glue and method for implantation
US7488348B2 (en) 2003-05-16 2009-02-10 Musculoskeletal Transplant Foundation Cartilage allograft plug
US7901457B2 (en) 2003-05-16 2011-03-08 Musculoskeletal Transplant Foundation Cartilage allograft plug
CA2528399A1 (en) * 2003-06-12 2004-12-23 Interface Biotech A/S A method for cell implantation
US8226715B2 (en) 2003-06-30 2012-07-24 Depuy Mitek, Inc. Scaffold for connective tissue repair
US10583220B2 (en) 2003-08-11 2020-03-10 DePuy Synthes Products, Inc. Method and apparatus for resurfacing an articular surface
US20050046915A1 (en) * 2003-08-22 2005-03-03 Fuji Photo Film Co., Ltd. Hologram recording material composition, hologram recording material and hologram recording method
DE10349722A1 (en) 2003-10-23 2005-06-16 Beschorner, Katharina, Dr. Composition for arthritis / arthritis treatment, in particular of joints
GB0325141D0 (en) * 2003-10-28 2003-12-03 Xiros Plc Repair of damaged tissue on a bone site
US7951163B2 (en) 2003-11-20 2011-05-31 Arthrosurface, Inc. Retrograde excision system and apparatus
WO2005051231A2 (en) 2003-11-20 2005-06-09 Arthrosurface, Inc. Retrograde delivery of resurfacing devices
CA2593182A1 (en) 2003-11-20 2006-07-13 Arthrosurface, Inc. System and method for retrograde procedure
US7316822B2 (en) 2003-11-26 2008-01-08 Ethicon, Inc. Conformable tissue repair implant capable of injection delivery
US7901461B2 (en) 2003-12-05 2011-03-08 Ethicon, Inc. Viable tissue repair implants and methods of use
ATE515245T1 (en) 2003-12-11 2011-07-15 Isto Technologies Inc PARTICLE CARTILAGE SYSTEM
US11395865B2 (en) 2004-02-09 2022-07-26 DePuy Synthes Products, Inc. Scaffolds with viable tissue
EP1576957A1 (en) * 2004-03-18 2005-09-21 Universiteit Twente Tissue repair using pluripotent cells
US8221780B2 (en) 2004-04-20 2012-07-17 Depuy Mitek, Inc. Nonwoven tissue scaffold
US8657881B2 (en) 2004-04-20 2014-02-25 Depuy Mitek, Llc Meniscal repair scaffold
US8137686B2 (en) 2004-04-20 2012-03-20 Depuy Mitek, Inc. Nonwoven tissue scaffold
US7569233B2 (en) * 2004-05-04 2009-08-04 Depuy Products, Inc. Hybrid biologic-synthetic bioabsorbable scaffolds
CA2470463C (en) * 2004-06-09 2012-09-18 Lornamead Brands, Inc. Tooth whitening products and methods of making the same
JP2008504107A (en) 2004-06-28 2008-02-14 アースロサーフィス・インコーポレーテッド Joint surface replacement system
CA2541827C (en) * 2004-07-30 2013-05-14 Histogenics Corporation Method for in situ repair of injured, damaged, diseased or aged articular cartilage using neo-cartilage constructs and a method for preparation thereof
US8697139B2 (en) 2004-09-21 2014-04-15 Frank M. Phillips Method of intervertebral disc treatment using articular chondrocyte cells
US7837740B2 (en) 2007-01-24 2010-11-23 Musculoskeletal Transplant Foundation Two piece cancellous construct for cartilage repair
US7513866B2 (en) 2004-10-29 2009-04-07 Depuy Products, Inc. Intestine processing device and associated method
US20060111778A1 (en) * 2004-10-29 2006-05-25 Michalow Alexander E Methods of promoting healing of cartilage defects and method of causing stem cells to differentiate by the articular chondrocyte pathway
US7828853B2 (en) 2004-11-22 2010-11-09 Arthrosurface, Inc. Articular surface implant and delivery system
US7354627B2 (en) * 2004-12-22 2008-04-08 Depuy Products, Inc. Method for organizing the assembly of collagen fibers and compositions formed therefrom
CN100384390C (en) * 2005-01-13 2008-04-30 中国人民解放军第三军医大学第一附属医院 Complex tissue of tissue-engineered bone and cartilage and external constructing method thereof
US7815926B2 (en) 2005-07-11 2010-10-19 Musculoskeletal Transplant Foundation Implant for articular cartilage repair
WO2007025290A2 (en) 2005-08-26 2007-03-01 Isto Technologies, Inc. Implants and methods for repair, replacement and treatment of joint disease
EP1924146A4 (en) * 2005-09-02 2012-05-02 Interface Biotech As A method for cell implantation
EP1926459B1 (en) 2005-09-19 2015-01-07 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
CN101384230A (en) 2005-11-21 2009-03-11 福特真公司 Devices and methods for treating facet joints, uncovertebral joints, costovertebral joints and other joints
US8728387B2 (en) 2005-12-06 2014-05-20 Howmedica Osteonics Corp. Laser-produced porous surface
EP1803513B1 (en) * 2005-12-30 2017-03-29 Howmedica Osteonics Corp. Method of manufacturing implants using laser
US8623026B2 (en) 2006-02-06 2014-01-07 Conformis, Inc. Patient selectable joint arthroplasty devices and surgical tools incorporating anatomical relief
CN101420911B (en) 2006-02-06 2012-07-18 康复米斯公司 Patient selectable arthroplasty device and surjical tool
US20070288021A1 (en) * 2006-06-07 2007-12-13 Howmedica Osteonics Corp. Flexible joint implant
US8147861B2 (en) * 2006-08-15 2012-04-03 Howmedica Osteonics Corp. Antimicrobial implant
DE07825069T1 (en) * 2006-09-07 2010-04-08 Ed Geistlich Söhne Ag Für Chemische Industrie METHOD FOR THE TREATMENT OF BONE CANCER
KR20080037883A (en) * 2006-10-27 2008-05-02 세원셀론텍(주) Using method and medical kit
EP2136717B1 (en) 2006-12-11 2013-10-16 Arthrosurface Incorporated Retrograde resection apparatus
US7871440B2 (en) 2006-12-11 2011-01-18 Depuy Products, Inc. Unitary surgical device and method
US8163549B2 (en) 2006-12-20 2012-04-24 Zimmer Orthobiologics, Inc. Method of obtaining viable small tissue particles and use for tissue repair
US7758643B2 (en) * 2007-02-26 2010-07-20 Biomet Sports Medicine, Llc Stable cartilage defect repair plug
US8435551B2 (en) 2007-03-06 2013-05-07 Musculoskeletal Transplant Foundation Cancellous construct with support ring for repair of osteochondral defects
WO2008128075A1 (en) 2007-04-12 2008-10-23 Isto Technologies, Inc. Compositions and methods for tissue repair
US8685107B2 (en) 2007-07-03 2014-04-01 Histogenics Corporation Double-structured tissue implant and a method for preparation and use thereof
US20090054984A1 (en) 2007-08-20 2009-02-26 Histogenics Corporation Method For Use Of A Double-Structured Tissue Implant For Treatment Of Tissue Defects
US9125743B2 (en) * 2007-07-16 2015-09-08 Lifenet Health Devitalization and recellularization of cartilage
US20090024224A1 (en) 2007-07-16 2009-01-22 Chen Silvia S Implantation of cartilage
WO2009014718A1 (en) 2007-07-24 2009-01-29 Porex Corporation Porous laser sintered articles
WO2009026392A1 (en) 2007-08-20 2009-02-26 Histogenics Corporation A method for improvement of differentiation of mesenchymal stem cells using a double-structured tissue implant
CA2701884A1 (en) * 2007-10-15 2009-04-23 Wake Forest University Health Sciences Methods and compositions for printing biologically compatible nanotube composites of autologous tissue
EP2291205A2 (en) * 2008-02-29 2011-03-09 Coloplast A/S Compositions and methods for augmentation and regeneration of living tissue in a subject
CA2713118A1 (en) * 2008-02-29 2009-09-03 Interface Biotech A/S Biosynthetic cartilaginous matrix and methods for their production
WO2009111481A1 (en) 2008-03-03 2009-09-11 Arthrosurface Incorporated Bone resurfacing system and method
EP2265220A1 (en) 2008-03-05 2010-12-29 Musculoskeletal Transplant Foundation Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles
WO2009111626A2 (en) 2008-03-05 2009-09-11 Conformis, Inc. Implants for altering wear patterns of articular surfaces
JP2011519713A (en) 2008-05-12 2011-07-14 コンフォーミス・インコーポレイテッド Devices and methods for treatment of facet joints and other joints
GB0812631D0 (en) * 2008-07-10 2008-08-20 Imp Innovations Ltd Modular knee implants
US8808297B2 (en) 2009-02-24 2014-08-19 Microport Orthopedics Holdings Inc. Orthopedic surgical guide
US9017334B2 (en) 2009-02-24 2015-04-28 Microport Orthopedics Holdings Inc. Patient specific surgical guide locator and mount
US8808303B2 (en) 2009-02-24 2014-08-19 Microport Orthopedics Holdings Inc. Orthopedic surgical guide
JP2012523897A (en) 2009-04-16 2012-10-11 コンフォーミス・インコーポレイテッド Patient-specific joint replacement device for ligament repair
US9662126B2 (en) 2009-04-17 2017-05-30 Arthrosurface Incorporated Glenoid resurfacing system and method
WO2010121246A1 (en) 2009-04-17 2010-10-21 Arthrosurface Incorporated Glenoid resurfacing system and method
WO2016154393A1 (en) 2009-04-17 2016-09-29 Arthrosurface Incorporated Glenoid repair system and methods of use thereof
AU2011222404A1 (en) 2010-03-05 2012-09-27 Arthrosurface Incorporated Tibial resurfacing system and method
US8895291B2 (en) 2010-10-08 2014-11-25 Terumo Bct, Inc. Methods and systems of growing and harvesting cells in a hollow fiber bioreactor system with control conditions
EP2754419B1 (en) 2011-02-15 2024-02-07 ConforMIS, Inc. Patient-adapted and improved orthopedic implants
US9066716B2 (en) 2011-03-30 2015-06-30 Arthrosurface Incorporated Suture coil and suture sheath for tissue repair
WO2013081071A1 (en) * 2011-12-02 2013-06-06 テルモ株式会社 Device for cell transplantation
EP2804565B1 (en) 2011-12-22 2018-03-07 Arthrosurface Incorporated System for bone fixation
US9364896B2 (en) 2012-02-07 2016-06-14 Medical Modeling Inc. Fabrication of hybrid solid-porous medical implantable devices with electron beam melting technology
US9180010B2 (en) 2012-04-06 2015-11-10 Howmedica Osteonics Corp. Surface modified unit cell lattice structures for optimized secure freeform fabrication
US9135374B2 (en) 2012-04-06 2015-09-15 Howmedica Osteonics Corp. Surface modified unit cell lattice structures for optimized secure freeform fabrication
US9486226B2 (en) 2012-04-18 2016-11-08 Conformis, Inc. Tibial guides, tools, and techniques for resecting the tibial plateau
US9186053B2 (en) * 2012-05-03 2015-11-17 Covidien Lp Methods of using light to repair hernia defects
US9675471B2 (en) 2012-06-11 2017-06-13 Conformis, Inc. Devices, techniques and methods for assessing joint spacing, balancing soft tissues and obtaining desired kinematics for joint implant components
US9468448B2 (en) 2012-07-03 2016-10-18 Arthrosurface Incorporated System and method for joint resurfacing and repair
US10016527B2 (en) 2012-10-23 2018-07-10 Orthovita, Inc. Materials and methods for repair of cartilage defects
US20140178343A1 (en) 2012-12-21 2014-06-26 Jian Q. Yao Supports and methods for promoting integration of cartilage tissue explants
US9492200B2 (en) 2013-04-16 2016-11-15 Arthrosurface Incorporated Suture system and method
PL2853384T3 (en) * 2013-09-27 2017-06-30 Skulle Implants Oy A method for coating and a coated surface
EP3068867B1 (en) 2013-11-16 2018-04-18 Terumo BCT, Inc. Expanding cells in a bioreactor
US10624748B2 (en) 2014-03-07 2020-04-21 Arthrosurface Incorporated System and method for repairing articular surfaces
US20150250472A1 (en) 2014-03-07 2015-09-10 Arthrosurface Incorporated Delivery System for Articular Surface Implant
US11607319B2 (en) 2014-03-07 2023-03-21 Arthrosurface Incorporated System and method for repairing articular surfaces
JP6783143B2 (en) 2014-03-25 2020-11-11 テルモ ビーシーティー、インコーポレーテッド Passive replenishment of medium
US20160090569A1 (en) 2014-09-26 2016-03-31 Terumo Bct, Inc. Scheduled Feed
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
CA2985398C (en) * 2015-05-08 2021-08-03 Reoss Gmbh Device for covering and/or reconstructing a bone defect site; method for producing a cap of a covering device for a bone defect site
US20160331539A1 (en) * 2015-05-12 2016-11-17 Elwha Llc Modifiable implants
WO2017004592A1 (en) 2015-07-02 2017-01-05 Terumo Bct, Inc. Cell growth with mechanical stimuli
US11104874B2 (en) 2016-06-07 2021-08-31 Terumo Bct, Inc. Coating a bioreactor
US11685883B2 (en) 2016-06-07 2023-06-27 Terumo Bct, Inc. Methods and systems for coating a cell growth surface
US11624046B2 (en) 2017-03-31 2023-04-11 Terumo Bct, Inc. Cell expansion
EP3656841A1 (en) 2017-03-31 2020-05-27 Terumo BCT, Inc. Cell expansion
AU2018203479A1 (en) 2017-05-18 2018-12-06 Howmedica Osteonics Corp. High fatigue strength porous structure
WO2019028344A1 (en) 2017-08-04 2019-02-07 Arthrosurface Incorporated Multicomponent articular surface implant
GB2567173A (en) * 2017-10-04 2019-04-10 Univ Oxford Innovation Ltd Cartilage plug
DE102018113580A1 (en) * 2018-06-07 2019-12-12 Christoph Karl METHOD AND DEVICE FOR PRODUCING AN IMPLANT
GB2609338B (en) 2019-03-12 2023-06-14 Arthrosurface Inc Humeral and glenoid articular surface implant systems and methods
US11523834B1 (en) 2022-06-20 2022-12-13 University Of Utah Research Foundation Cartilage and bone harvest and delivery system and methods
US11660194B1 (en) 2022-06-20 2023-05-30 University Of Utah Research Foundation Cartilage and bone harvest and delivery system and methods

Family Cites Families (94)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH632922A5 (en) 1978-10-06 1982-11-15 Sulzer Ag Anchorage pin for bone implants
ATE4440T1 (en) 1980-02-21 1983-08-15 J. & P. Coats, Limited DEVICE FOR TREATMENT OF DAMAGED SURFACES OF HUMAN JOINTS.
US4649918A (en) * 1980-09-03 1987-03-17 Custom Medical Devices, Inc. Bone core removing tool
US4553272A (en) 1981-02-26 1985-11-19 University Of Pittsburgh Regeneration of living tissues by growth of isolated cells in porous implant and product thereof
US4393874A (en) 1982-04-26 1983-07-19 Telectronics Pty. Ltd. Bradycardia event counting and reporting pacer
IL68218A (en) * 1983-03-23 1985-12-31 Univ Ramot Compositions for cartilage repair comprising embryonal chondrocytes
US4559936A (en) * 1983-09-29 1985-12-24 Hill Edward B Bone plugging apparatus
WO1985001651A1 (en) * 1983-10-20 1985-04-25 Vettivetpillai Ketharanathan Biomaterial
US4620327A (en) 1984-07-05 1986-11-04 Caplan Arnold I Process of adapting soluble bone protein for use in stimulating osteoinduction
US4789663A (en) * 1984-07-06 1988-12-06 Collagen Corporation Methods of bone repair using collagen
US4877020A (en) * 1984-11-30 1989-10-31 Vich Jose M O Apparatus for bone graft
US4642117A (en) 1985-03-22 1987-02-10 Collagen Corporation Mechanically sheared collagen implant material and method
US5902741A (en) 1986-04-18 1999-05-11 Advanced Tissue Sciences, Inc. Three-dimensional cartilage cultures
US5041138A (en) 1986-11-20 1991-08-20 Massachusetts Institute Of Technology Neomorphogenesis of cartilage in vivo from cell culture
US5736372A (en) 1986-11-20 1998-04-07 Massachusetts Institute Of Technology Biodegradable synthetic polymeric fibrous matrix containing chondrocyte for in vivo production of a cartilaginous structure
NL8700113A (en) * 1987-01-19 1988-08-16 Groningen Science Park INK, SUITABLE FOR TREATMENT BY RECONSTRUCTIVE SURGERY, WITH TISSUE-SPECIFIC POROSITY, AND METHOD FOR MANUFACTURING THE ENTAGMENT.
GB8705985D0 (en) 1987-03-13 1987-04-15 Geistlich Soehne Ag Dressings
US4846835A (en) * 1987-06-15 1989-07-11 Grande Daniel A Technique for healing lesions in cartilage
US5306311A (en) * 1987-07-20 1994-04-26 Regen Corporation Prosthetic articular cartilage
US5158574A (en) 1987-07-20 1992-10-27 Regen Corporation Prosthetic meniscus
US5258043A (en) 1987-07-20 1993-11-02 Regen Corporation Method for making a prosthetic intervertebral disc
US5116374A (en) 1989-03-02 1992-05-26 Regen Corporation Prosthetic meniscus
CA1329089C (en) 1987-09-02 1994-05-03 Russell Warren Surgical fastener
NZ226170A (en) 1987-09-18 1990-07-26 Ethicon Inc Stable freeze-dried pharmaceutical composition containing epidermal growth factor
WO1989004646A1 (en) 1987-11-13 1989-06-01 Jefferies Steven R Bone repair material and delayed drug delivery
JP2645098B2 (en) * 1988-09-06 1997-08-25 テルモ株式会社 Antibacterial agent-containing artificial skin and method for producing the same
JP2820415B2 (en) * 1988-03-14 1998-11-05 ティーエイチエム・バイオメディカル・インコーポレイテッド Biodegradable and osteogenic graft bone graft substitute composition
US5201745A (en) * 1988-03-15 1993-04-13 Imedex Visceral surgery patch
US4975526A (en) 1989-02-23 1990-12-04 Creative Biomolecules, Inc. Bone collagen matrix for zenogenic implants
US4904259A (en) * 1988-04-29 1990-02-27 Samuel Itay Compositions and methods for repair of cartilage and bone
US5053050A (en) * 1988-04-29 1991-10-01 Samuel Itay Compositions for repair of cartilage and bone
US5108436A (en) 1988-09-29 1992-04-28 Collagen Corporation Implant fixation
IE61346B1 (en) 1988-11-02 1994-11-02 Genentech Inc A permeable material to fit around the teeth or gums of a mammal
US5162430A (en) 1988-11-21 1992-11-10 Collagen Corporation Collagen-polymer conjugates
US5510418A (en) 1988-11-21 1996-04-23 Collagen Corporation Glycosaminoglycan-synthetic polymer conjugates
US5092883A (en) * 1988-12-28 1992-03-03 Eppley Barry L Method for promoting soft connective tissue growth and repair in mammals
WO1990009783A1 (en) 1989-02-22 1990-09-07 Massachusetts Institute Of Technology Delivery system for controlled release of bioactive factors
AU5654990A (en) 1989-04-28 1990-11-29 Brigham And Women's Hospital Novel materials and methods for guided tissue regeneration
US5015255A (en) * 1989-05-10 1991-05-14 Spine-Tech, Inc. Spinal stabilization method
US5129906A (en) 1989-09-08 1992-07-14 Linvatec Corporation Bioabsorbable tack for joining bodily tissue and in vivo method and apparatus for deploying same
US5067964A (en) * 1989-12-13 1991-11-26 Stryker Corporation Articular surface repair
US5019108A (en) * 1990-02-02 1991-05-28 Bertin Kim C Modular implant
US6413511B1 (en) * 1990-12-20 2002-07-02 University Of Pittsburgh Of The Commonwealth System Of Higher Education Cartilage alterations by administering to joints chondrocytes comprising a heterologous polynucleotide
US5206023A (en) * 1991-01-31 1993-04-27 Robert F. Shaw Method and compositions for the treatment and repair of defects or lesions in cartilage
US5853746A (en) * 1991-01-31 1998-12-29 Robert Francis Shaw Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone using functional barrier
US5206028A (en) 1991-02-11 1993-04-27 Li Shu Tung Dense collagen membrane matrices for medical uses
SE9101853D0 (en) * 1991-06-17 1991-06-17 Jonas Wadstroem IMPROVED TISSUE ASHESIVE
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.
US5259835A (en) * 1991-08-29 1993-11-09 Tri-Point Medical L.P. Wound closure means and method using flowable adhesive
US5270300A (en) * 1991-09-06 1993-12-14 Robert Francis Shaw Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone
IL100721A (en) * 1992-01-21 1996-12-05 Milo Simcha Punch for opening passages between two compartments
DE69307299T2 (en) * 1992-02-14 1997-04-30 Univ Texas MULTI-PHASE, BIODEGRADABLE IMPLANT / CARRIER AND METHOD FOR THE PRODUCTION THEREOF
US5326357A (en) 1992-03-18 1994-07-05 Mount Sinai Hospital Corporation Reconstituted cartridge tissue
AU4543193A (en) * 1992-06-22 1994-01-24 Henry E. Young Scar inhibitory factor and use thereof
WO1994009118A1 (en) 1992-10-13 1994-04-28 The General Hospital Corporation Immortalized human chondrocytes
US5455597A (en) * 1992-12-29 1995-10-03 Canon Kabushiki Kaisha Image-forming apparatus, and designation of electron beam diameter at image-forming member in image-forming apparatus
DE4300039C1 (en) 1993-01-04 1994-06-09 Imz Fertigung Vertrieb Fixture nail for attachment of cover membrane to bone surrounding defect point filled with bone structural material - has nail head of large dia. and shaft of smaller dia. which has cylindrical retention part and conical point part
US5514378A (en) * 1993-02-01 1996-05-07 Massachusetts Institute Of Technology Biocompatible polymer membranes and methods of preparation of three dimensional membrane structures
DE4431598C2 (en) 1993-03-03 1997-03-20 Michael Sittinger Process for producing an implant from cell cultures
DE4306661C2 (en) 1993-03-03 1995-04-20 Michael Dipl Biol Sittinger Process for producing an implant from cell cultures
US5709854A (en) * 1993-04-30 1998-01-20 Massachusetts Institute Of Technology Tissue formation by injecting a cell-polymeric solution that gels in vivo
DE4317448A1 (en) * 1993-05-19 1994-11-24 Gross Ulrich Joint replacement
CA2130295A1 (en) 1993-08-26 1995-02-27 Richard A. Berg Ionically crosslinked glycosaminoglycan gels for soft tissue augmentation and drug delivery
US5423858A (en) 1993-09-30 1995-06-13 United States Surgical Corporation Septoplasty fasteners and device for applying same
GB9400163D0 (en) 1994-01-06 1994-03-02 Geistlich Soehne Ag Membrane
US5354283A (en) 1994-01-07 1994-10-11 Little Rapids Corporation Trocar retention apparatus
CA2142209A1 (en) 1994-03-29 1995-09-30 George H. Chu Collagen implants having improved tensile properties
WO1995030742A1 (en) * 1994-05-05 1995-11-16 Genzyme Corporation Methods and compositions for the repair of articular cartilage defects in mammals
US5858781A (en) * 1994-05-13 1999-01-12 Matyas; John R. Method of tissue transfer and retrieval
EP0692227A1 (en) 1994-07-11 1996-01-17 SULZER Medizinaltechnik AG Sheet implant
ZA956249B (en) 1994-07-28 1996-05-10 Ivan Vesely Bioprosthetic implants and method of making and using same
US5769899A (en) 1994-08-12 1998-06-23 Matrix Biotechnologies, Inc. Cartilage repair unit
DE4425456A1 (en) * 1994-09-07 1996-03-21 Matthias Dr Med Honl Bone saw for concentric cylindrical or part spherical cuts
US5569252A (en) 1994-09-27 1996-10-29 Justin; Daniel F. Device for repairing a meniscal tear in a knee and method
US6080194A (en) 1995-02-10 2000-06-27 The Hospital For Joint Disease Orthopaedic Institute Multi-stage collagen-based template or implant for use in the repair of cartilage lesions
US5713374A (en) * 1995-02-10 1998-02-03 The Hospital For Joint Diseases Orthopaedic Institute Fixation method for the attachment of wound repair materials to cartilage defects
GB9721585D0 (en) 1997-10-10 1997-12-10 Geistlich Soehne Ag Chemical product
GB9503492D0 (en) 1995-02-22 1995-04-12 Ed Geistlich S Hne A G F R Che Chemical product
US6132463A (en) * 1995-05-19 2000-10-17 Etex Corporation Cell seeding of ceramic compositions
WO1997004665A1 (en) 1995-07-31 1997-02-13 Alta Spinner Australia Pty. Limited Surface moisture removal from food products
US5659252A (en) * 1995-08-25 1997-08-19 Sony Corporation Apparatus and method for detecting arcing in a CRT
DE19540487A1 (en) 1995-10-20 1997-04-24 Olaf Schultz Cell interaction system for induction of artificial 3-dimensional tissue
WO1997015655A2 (en) 1995-10-20 1997-05-01 Michael Sittinger New artificial tissue, method for the production and the use thereof
DE19601477C2 (en) 1996-01-17 1999-12-16 Axel Kirsch Fastening nail
US5842477A (en) 1996-02-21 1998-12-01 Advanced Tissue Sciences, Inc. Method for repairing cartilage
DE19654884C2 (en) 1996-03-04 1999-07-29 Kirsch Axel Molded body
ES2210526T3 (en) 1996-06-04 2004-07-01 Centerpulse Biologics Inc. CARTILAGO PRODUCTION PROCEDURE.
US5989269A (en) * 1996-08-30 1999-11-23 Vts Holdings L.L.C. Method, instruments and kit for autologous transplantation
EP0842670A1 (en) 1996-11-13 1998-05-20 Katsunari Nishihara Biomedical materials
US6187053B1 (en) 1996-11-16 2001-02-13 Will Minuth Process for producing a natural implant
DE19648876C2 (en) 1996-11-16 1999-10-07 Will Minuth Method of making a natural implant
AU6654598A (en) 1997-02-13 1998-09-08 Benedict, James A. Implantable collagen-containing putty material
DE19957388A1 (en) 1999-11-24 2001-06-13 Michael Sittinger Chondroinductive and implantable substrates for cartilage healing and protection
DE10006822A1 (en) 2000-02-08 2001-08-23 Michael Sittinger Artificial bone chips, processes for their production and their use

Also Published As

Publication number Publication date
DK1181908T3 (en) 2004-04-13
CZ297248B6 (en) 2006-10-11
EP1181908A1 (en) 2002-02-27
EP1006950A2 (en) 2000-06-14
DE69726896T2 (en) 2004-10-28
AU4171097A (en) 1998-03-19
SG119137A1 (en) 2006-02-28
PT1384452E (en) 2009-07-02
NZ334400A (en) 2001-01-26
HU225952B1 (en) 2008-01-28
SK285075B6 (en) 2006-05-04
KR100686412B1 (en) 2007-02-23
DE69728569T2 (en) 2005-04-07
TR200102871T2 (en) 2002-06-21
MXPA99001794A (en) 2002-05-06
EP1006950B1 (en) 2004-04-07
CA2264138C (en) 2003-05-27
ES2325206T3 (en) 2009-08-28
NO990933D0 (en) 1999-02-26
TR199900437T2 (en) 1999-05-21
US20030195532A1 (en) 2003-10-16
CN1500447A (en) 2004-06-02
US6599300B2 (en) 2003-07-29
PT1006950E (en) 2004-08-31
EP1181908B1 (en) 2003-12-17
US20020091396A1 (en) 2002-07-11
US5989269A (en) 1999-11-23
EP1384452B1 (en) 2009-04-15
SG120854A1 (en) 2006-04-26
CZ58799A3 (en) 2000-05-17
US6283980B1 (en) 2001-09-04
WO1998008469A2 (en) 1998-03-05
IL128580A (en) 2007-09-20
IL128580A0 (en) 2000-01-31
US20060195122A1 (en) 2006-08-31
SI1384452T1 (en) 2009-10-31
DK200200178U1 (en) 2002-06-04
DK1384452T3 (en) 2009-07-27
RU2002103570A (en) 2003-10-10
WO1998008469A3 (en) 1998-04-23
DE29724585U1 (en) 2002-05-16
JP2007296371A (en) 2007-11-15
CN1200656C (en) 2005-05-11
BR9711967A (en) 2000-01-18
JP2002502272A (en) 2002-01-22
DE69739363D1 (en) 2009-05-28
RU2214197C2 (en) 2003-10-20
EP1459709A1 (en) 2004-09-22
ATE263524T1 (en) 2004-04-15
CA2419644A1 (en) 1998-03-05
ES2218697T3 (en) 2004-11-16
JP2003159266A (en) 2003-06-03
NO990933L (en) 1999-02-26
DE69726896D1 (en) 2004-01-29
US6599301B2 (en) 2003-07-29
KR20000035886A (en) 2000-06-26
AU731162B2 (en) 2001-03-22
EP1384452A1 (en) 2004-01-28
HK1063003A1 (en) 2004-12-10
US7048750B2 (en) 2006-05-23
ATE428376T1 (en) 2009-05-15
HUP0002980A2 (en) 2001-01-29
US6592598B2 (en) 2003-07-15
SI1006950T1 (en) 2004-12-31
PL331834A1 (en) 1999-08-02
PT1181908E (en) 2004-04-30
DK200200177U1 (en) 2002-06-04
US20020151912A1 (en) 2002-10-17
US6379367B1 (en) 2002-04-30
US20020116015A1 (en) 2002-08-22
KR20030097603A (en) 2003-12-31
CN1241918A (en) 2000-01-19
NZ508145A (en) 2002-07-26
US6592599B2 (en) 2003-07-15
DK1006950T3 (en) 2004-07-19
HU0400358D0 (en) 2004-05-28
ATE256443T1 (en) 2004-01-15
NZ518474A (en) 2003-09-26
TR200102883T2 (en) 2002-06-21
DE69728569D1 (en) 2004-05-13
SK24099A3 (en) 2001-03-12
ES2211722T3 (en) 2004-07-16
HUP0002980A3 (en) 2001-02-28
CA2264138A1 (en) 1998-03-05
US20020116014A1 (en) 2002-08-22
HK1025035A1 (en) 2000-11-03

Similar Documents

Publication Publication Date Title
CA2419644C (en) Method and kit for the transplantation of chondrocyte cells
US7137989B2 (en) Method, instruments, and kit for autologous transplantation
AU2002334852A1 (en) Method, instruments, and kit for autologous transplantation
AU781214B2 (en) Method, instruments and kit for autologous transplantation
AU775219B2 (en) Method, instruments and kit for autologous transplantation
AU2007234527A1 (en) Method, instruments and kit for autologous transplantation

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry

Effective date: 20170829