Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Implantable prosthesis – Bone
Reexamination Certificate
1998-07-15
2001-05-08
Milano, Michael J. (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Implantable prosthesis
Bone
C623S023610
Reexamination Certificate
active
06228117
ABSTRACT:
The invention relates to a device facilitating cell growth, differentiation and subsequent osseous tissue generation in vitro and later in vivo, which comprises a porous, bioactive, osteoconductive and bone-bonding, polymer.
BACKGROUND
U.S. Pat. No. 5,226,914 (AI Caplan) discloses a method for treating connective tissue disorders by isolating and culturally expanding marrow-derived mesenchymal stem cells, adhering the cells onto the surface of a prosthetic device and implanting the prosthetic device containing the culturally expanded cells into the type of skeletal or connective tissue needed for implantation.
U.S. Pat. No. 5,399,665 (D Barrera) discloses the synthesis and applications of a hydrolytically degradable polymer useful in biomedical applications involving the interaction of cells with the polymer structure, by coupling peptides to the free amino groups of the polymers.
U.S. Pat. No. 5,041,138 (JP Vacanti) discloses methods and artificial matrices for the growth and implantation of cartilaginous structures and surfaces and the production of bioactive molecules manufactured by chondrocytes. Chondrocytes are grown in culture on biodegradable, biocompatible fibrous matrices until an adequate cell volume and density has developed for the cells to survive and proliferate in vivo, and the matrices are designed to allow adequate nutrient and gas exchange to the cells until engraftment and vascularisation at the site of engraftment occurs.
U.S. Pat. No. 5,522,895 (AG Mikos) discloses a biodegradable prosthetic template of a degradable polymer such as poly(lactic acid) or poly(lactic-co-glycolic acid) with a pore-former such as salt or gelatin, which template may be seeded with osteoblasts. The polymers used do not bind to bone and the osteoblasts are highly differentiated cells.
WO 96/28539 proposes a composition for growing cartilage or bone consisting of a biodegradable polymeric carrier such as polyglycolic acid or a polysaccharide containing mesenchymal stem cells. Mesenchymal stem cells are cells which are pluripotent, i.e. which can differentiate to various tissue types (muscle, cartilage, skin), while the polymers proposed do not bind to bone.
These prior art methods involve cells that are grown in the materials for the purpose of expansion or proliferation after which the materials containing the culturally expanded cells, are implanted at the site of engraftment. The prior art materials are degradable matrices, whether or not designed to couple peptides or biologically active moieties to serve to enhance binding of cells to the polymer, that mainly function as temporary devices for cell attachment. These prior methods therefore necessitate the production of connective tissues in vivo, while the prior materials function as a carrier for cell attachment and cell growth.
Surgical procedures related to bone tissue deficiencies vary from joint replacement, bone grafting and internal fixation, to maxillo-facial reconstructive surgery. From a biological perspective, the ideal material to reconstruct osseous tissues is auto-genous bone, because of its compatibility, osteoinductivity, osteoconductivity, and lack of immunologic response. However, the limitations of harvesting an adequate amount of autogenous bone, and the disadvantages of a secondary operation to harvest the auto-logous bone, make this “ideal” material far from ideal for many surgical procedures.
Alternatives are other bone-derived materials and man-made biomaterials. The first group concerns allogeneic and xenogeneic bone grafts. A problem is, that they exhibit the possibility of disease transfer such as HIV or hepatitis B, a higher immunogenic response, less revascularisation of the graft and manifest unreliable degradation characteristics.
The second group concerns man-made, alloplastic implant materials, or bio-materials, which are readily available in large quantities. The wide variety of biomaterials that are used in clinical applications can be divided into four major categories: metals, ceramics, polymers and composites, which all have their own characteristics. The most interesting alloplastic biomaterials for bone replacement are bioactive or osteoconductive materials, which means that they can bind to bone tissue. Bioactive materials can be found in all four of the above mentioned biomaterials categories and include polymers such as PEO/PBT copolymers, calcium phosphate ceramics such as hydroxyapatite and bioglasses or glass-ceramics.
Compared to autogenous bone, the main disadvantage of biomaterials is that, without added osteoinductive agents such as bone morphogenetic proteins, they are not osteoinductive and therefore do not have the ability to actively induce bone formation. Although this can be overcome by adding osteoinductive growth factors to the materials, difficulties still exist to gradually release these factors from the biomaterial surface over a prolonged time period, which is needed to have a sufficient biological response.
This is why there is a need for another approach for the treatment of osseous defects, which combines cultured autogenous tissues with biomaterials, in so-called biomaterial-tissue hybrid structures. Although the combination of cultured cells with biomaterials to form biomaterial-cell composites may also be advantageous in that the cultured cells, after implantation, can give rise to the formation of a tissue, we describe herein an invention of a device in which cells are cultured to produce an extracellular matrix, after which this biomaterial-tissue hybrid is implanted at the site of engraftment.
DESCRIPTION OF THE INVENTION
The present invention concerns a device made up from a polymeric material that is bicompatible, osteoconductive and bone-bonding (bioactive), that can be used to culture undifferentiated, differentiated, osteogenic or (osteo)progenitor cells that form a bone-like extracellular matrix in vitro, after which the polymer containing the biological extracellular matrix is placed or implanted at the site of engraftment. The uniqueness about the present invention is two-fold. In a first aspect, in contrast to the prior art methods, the material can calcify by itself during immersion in cell culture medium or post-operatively, or can be pre-calcified, thereby exhibiting bioactive and osteoconductive or bone-bonding properties that will improve tissue-material interaction. In the second aspect, undifferentiated, differentiated, osteogenic or (osteo)progenitor cells are grown in the bioactive, biodegradable polymeric matrix not only to expand, but to actively produce an extracellular matrix in vitro. Consequently, a hybrid structure encompassing a bioactive, biodegradable polymeric matrix and an already in vitro formed biological extracellular matrix is produced that can be used for engraftment in osseous defects or at sites where bone is needed. This invented hybrid structure can be seen as a flexible autogenous cultured bone graft which is unique.
The polymeric matrix can be constituted of a segmented thermoplastic bioactive, preferably biodegradable polymer, such as described in EP-A-357155 or WO-93/21858. The molecules of such segmented thermoplastic copolyester (polyesterether) consist essentially of segments of recurring long-chain ester units and segments with recurring short-chain ester units. The long-chain ester units preferably comprise 35-80% by weight of the copolytester (polyether) being represented by the formula
—OLO—CO—R—CO—
and the short chain ester units being represented by the formula
—OEO—CO—R—CO—
wherein
L is a divalent group remaining after removal of terminal hydroxyl groups from a poly(oxyalkylene) glycol with an average molecular weight of between 300 and 500 or between 500 and 3000;
R is a divalent group remaining after removal of carboxyl groups from a dicarboxylic acid having a molecular weight of less than 300; and
E is an alkylene group having 2-6 carbon atoms.
Examples of the alkylene group in the poly(oxyalkylene) glycol of L include ethylene, 1,2-propylene, 2-hydroxy-1,3-propylene and butylene, poly(oxyethylene) gl
Bovell Yvonne Pearl
De Bruijn Joost Dick
Van Blitterswijk Clemens Antoni
Van Den Brink Jennigje
Banner & Witcoff , Ltd.
IsoTis B.V.
Milano Michael J.
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