Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Implantable prosthesis – Bone
Reexamination Certificate
2000-11-22
2003-08-05
Philogene, Pedro (Department: 3732)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Implantable prosthesis
Bone
C623S023610
Reexamination Certificate
active
06602294
ABSTRACT:
The invention relates to implantable substrates for the healing and protection of connecting tissue, preferably cartilage in the state of athrosis, more specifically, the latter relates to an implantable substrate for the healing and protection of connecting tissue, prefeerably cartilage, comprising at least one structure for the invasion of cells in vivo and/or for the formation of cell matrix and/or for the release of constituents of the employed means and at least one means for the activation of locally present cells for the regeneration of tissue, a method for the production of the latter, a method for the healing and/or protection of connecting tissue, preferably cartilage in the state of arthrosis, employing the substrates according to the invention, as well as the use of the latter in the field of surgical medicine and tissue engineering.
Arthrosis
Osteoarthrosis is the most common joint disease worldwide, the majority of humans older than 65 are affected by the latter. As a necessary consequence, there is an enormous clinical, health-political and economical relevancy of methods directed to the treatment of osteoarthrosis. During the course of this primarily degenerative joint disease, which is dependent on the age, a stepwise focal destruction of the surface of the joint occurs, and, as a reaction, an misregulated regional growth of the neighboring and subchondral bone structures (osteophytes) happens. The consequence is pain and restricted function and mobility. Systemic factors which influence the emergence of osteoarthrosis are age, gender, weight, osteoporosis, hereditary factors and an excess of mechanical stress. Local factors comprise the specific shape of the joint, distortions, traumata, as well as specifically acting biomechanical factors. Although the primary genesis is degenerative, during the course of osteoarthrosis, there are inflammatory degenerations to be observed, such as synovitis (inflammation of the endothelium of the joint) and the production of biological messenger substances, which promote the inflammation, occurs (cytokines and growth factors). These ongoing changes embody an ill-regulated regulation of tissue homeostasis, which occurs in the area of load-carrying cartilage and bone structures, i.e., there is a lack of balance between degenerative processes and repair processes (W B van den Berg: The role of cytokines and growth factors in cartilage destruction in osteoarthritis, Z Rheumatol. 58:136-141, 1999).
The disease is a consequence of malfunctions in the area of the entire joint including the bone, the muscle and the innervation of the joint, which finally leads to an excessive mechanical stress and a biochemically mediated destruction of the affected joints. Furthermore, it is important that there has yet not been any possibility of healing the latter disease: Very often, physiotherapeutic measures and pain-reducing, anti-inflammatory medicaments (non-steroidal anti-rheumatic drugs) are insufficient symptomatic kinds of treatments. Conventional orthopedic measures (debridement, joint-shaving, microfracture, drilling) are also only effective in an insufficient manner. If extensive degenerations occur, often a surgical reconstructive measure with endoprothetic exchange of the joint remains as the only option (J A Buckwalter, H J Mankin: Articular Cartilage Repair and Transplantation: Arthritis & Rheumatism 41:1131-1342, 1998).
Regeneration of Cartilage by Tissue Engineering with Cells and Growth Factors
Tissue engineering offers promising new technologies by transplantation of functionally active autologous cells and optionally of biomaterials creating a desired shape of the material.
Using the latter technology, new cartilage and bone tissue is actively built up or bred, respectively. Usually, tissue engineering is based on the breeding of autologous cells which are subsequently transplanted into the patient, for example as a solution or as a matured graft. Unfortunately, the proliferative potential of these cells is limited and the breeding over many cell passages in vitro substantially reduces the functional quality of the cells.
A further approach in tissue engineering is embodied by the stimulation of tissue regeneration itself or at least the differentiation of cells which were yielded from the patient beforehand, for example by addition of growth factors. In this context, especially the factors of the TGF-&bgr;-superfamily are of interest, because they play a major role during the development of tissues and organs. Concerning tissue engineering, there are substantially different principles to employ these factors. For example, a part of the cells may be transfected with the genes of the TGF-&bgr;-family to achieve an improved maturation, but also in order to protect the tissue of an, e.g., chronically inflammated joint from being destroyed again (Evans C H, Robbins P D: Gene therapy for arthritis, Gene therapeutics: Methods and applications of direct gene transfer, edited by J A Wolff, Boston, Birkhäuser, 321, (1994); Kalden J R, Geiler T, Hermann M, Bertling W: Gentherapie der rheumatoiden Arthritis—ein bereits anwendbares Therapieprinzip?—Z Rheumatol 57:139-47, (1988); Herndon J H, Robbins P D, Evans C H: Arthritis: is the cure in your genes? J Bone Joint Surg Am, 81:152-7, (1999)).
A further possibility lies in the use of release systems (U.S. Pat. No. 5,910,489), i.e., the transient release of factors from resorbable microparticles or cell carriers, e.g., to stabilize a graft during the critical phase of wound healing. Finally, the direct regeneration of tissue may be achieved without cells by using growth factors and biomaterials (Kübler, Osteoinduktion und-reparation, Mund-Kiefer-Gesichtschir., 1, 2-25, (1997)).
The discovery and characterization of new factors, which are capable of influencing the maturation and differentiation of somatic cells, tools are available which allow for the manufacture of a full-fledged replacement cartilage or bone, starting with only a few autologous cells.
However, the major disadvantage of the latter technology is the necessity to yield a tissue sample from the patient at first and also the comparably sophisticated cultivation of the cells.
Recruitment of Stem Cells, Growth Factors
During a naturally-occurring tissue healing process, normally cells from the surrounding of the defect or lesion are attracted in order to fill that lesion. They are mainly precursor cells which at a later stage develop into tissue cells with their particular properties. Accordingly, when a bone fracture happens, precursor cells from the periostium and the bone marrow migrate into the defect and form new bones via the “detour” of a cartilage tissue. Natural regeneration of cartilage by means of invading precursor cells does finally not work in humans at all. Certain methods of treatment, such as methods of microfracture, are aimed at opening the way into the joint space for cells originating from bone marrow.
In the are of cartilage healing also bioactive substances have been developed, which posses chemotactic, anti-inflammatory, anti-angiogenetic, differentiating or anti-adhesive properties (U.S. Pat. No. 5,853,746: Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone using functional barrier; U.S. Pat. No. 5,817,773: Stimulation, production, culturing and transplantation of stem cells by fibroblast growth factors; U.S. Pat. No. 5,910,489: Topical composition containing hyaluronic acid and NSAIDs).
The invention is based on the problem of developing a substrate which can be used in the process of the healing and/or protection of connecting tissue, preferably cartilage. The problem was solved by the provision of implantable substrates for the healing and/or protection of connecting tissue, particularly for the healing and/or protection of cartilage in the state of arthrosis.
The present invention is particularly based on the use or stimulation, respectively, of pluripotent precursor cells or mesenchymal stem cells for the regeneration of tissue, the potent
Burmester Gerd-Rudiger
Schultz Olaf
Sittinger Michael
Jones Day
Philogene Pedro
TransTissue Technologies GmbH
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