Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Implantable prosthesis – Bone
Reexamination Certificate
1999-09-17
2002-04-02
McDermott, Corrine (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Implantable prosthesis
Bone
C623S023580, C623S908000, C424S426000
Reexamination Certificate
active
06364912
ABSTRACT:
This invention relates to implantable biocompatible compositions that induce the repair of damaged or diseased bone, cartilage or other connective tissues upon contact of the damaged or diseased tissues with the composition in vivo. The invention also relates methods of inducing repair. More particularly the present invention is directed to the use of a composition comprising an effective amount of pleiotrophin to induce repair of damaged or diseased connective tissues.
BACKGROUND OF THE INVENTION
Currently, bone defects are typically repaired by autografts or banked bone. Autografts have a good ability to unify the bone, and physicians often prefer to use bone from sources such as the iliac crest. However, procedures using autografts suffer from several drawbacks. First, autografts require a separate harvest operation, resulting in increased operative time and the use of blood transfusions. Secondly, patients often lack adequate amounts of material for harvesting and often experience donation site morbidity. Implantation of banked bone does not require the harvest operation, but its bone healing capability is not as high as that of autografts. Therefore, it is undesirable to use banked bone in severe conditions such as nonunion.
Because of these drawbacks, researchers have searched for compositions and methods for promoting bone growth without necessitating the use of autografts or banked bones. One potential source for bone growth promoting factors is the extracellular matrices of healthy bone and cartilage tissues. Extracellular bone matrix contains predominantly mineral (hydroxyapatite) and an organic matrix, where the major component of the organic matrix is collagen type I. The remaining components of bone matrices include a number of less abundant non-collagenous proteins and growth factors. For example, since the mid-1960's the osteoinductive activity of both demineralized bone matrix (DBM) and bone morphogenetic protein (BMP) has been studied (Ijiri, 1992). In addition to DBM and BMP, many non-collagenous bone matrix protein components possess biological activity and find wide use in medical applications such as prosthetic devices, drugs, blood components, and the like.
One non-collagenous protein found in bone matrix is pleiotrophin (also known as HB-GAM, HARP, P18, and OSF-1). Pleiotrophin is a heparin-binding protein belonging to a recently described family of developmentally regulated cytokines. Pleiotrophin has been reported to exhibit both neurite outgrowth-promoting activity, on embryonic rat brain neurons in culture, and mitogenic activity toward rat and mouse fibroblasts. The biological activity of recombinant human pleiotrophin is measured by its ability to enhance neurite outgrowth of cerebral cortical neurons of E10 chicken embryos. The EC
50
is defined as the effective concentration of growth factor that elicits a 50% increase of neurite outgrowth from E10 chicken embryos.
Pleiotrophin protein was initially isolated from early postnatal rat brain and bovine uterus, and can be isolated from warm-blooded vertebrate bone and cartilage tissues using standard extraction techniques known to those skilled in the art, including extracting with guanidine hydrochloride. Human pleiotrophin protein is initially produced as a 168 amino acid residue precursor that is processed to remove the 32 amino acid residue signal peptide and produce the 136 amino acid mature protein. DNA sequences encoding the protein have been recently cloned and recombinant pleiotrophin protein is commercially available from Sigma chemical company (St. Louis, Mo.). Gene sequences (cDNA clones) encoding for pleiotrophin have been prepared from rat, bovine and human cell mRNAs. The predicted amino acid sequence of pleiotrophin is highly conserved between these three species, and each encoded protein contains a signal sequence, suggesting that the protein is secreted.
Pleiotrophin binds strongly to bone extracellular matrix in vitro and may have an autocrine or paracrine action. Pleiotrophin shares some chemical similarities with the family of fibroblast growth factors (FGF), namely the heparin-binding ability, however pleiotrophin does not belong chemically to the FGF family. The deduced amino acid sequence of pleiotrophin is distinct from any other known growth factor family. Pleiotrophin is known to be expressed by osteoblasts, cartilage and osteosarcoma cells, and has been isolated from bone and cartilage. The expression of pleiotrophin has been associated with bone and cartilage progenitor cells, as well the mesenchyme of lung, gut, kidney, and reproductive tract of developing rat tissues.
Numerous compounds have been isolated from biological sources and have been identified as having potential bone growth enhancing activities based on the response of cultured cells to those compounds. In particular, due to the association of pleiotrophin with developing bone in animal tissues, and the response of various cultured cells to pleiotrophin in vitro, it has been suggested that this molecule may play a role in bone and/or cartilage development. However, in vitro results may vary due to a variety of factors, including cell type, cell density, cell isolation procedures, and type of growth medium. Therefore, while useful, in vitro studies are not always predictive of in vivo activity.
For example over the last two decades prostaglandins had been reported as both increasing bone resorption as well as increasing bone formation. Analysis of the literature references reporting the conflicting activities of prostaglandins reveals that almost all reports of bone resorption were performed in vitro and almost all the studies reporting bone formation were done in vivo (Mark and Miller, 1993). Previous studies of bone growth in vitro were performed with tissue/organ cultures of bone or relatively pure isolated bone cell populations. The apparent conflicting reports of the predominant skeletal affects of the prostaglandins can be explained on the basis of the limitations of the cell culture systems used to study those effects. Similarly, initial reports of TGF- activity based on cell culture assays failed to correlate with observed in vivo activities. Therefore, skilled artisans appreciate that in vitro activity does not always predict in vivo results.
What is needed are compositions shown to repair connective tissue in vivo.
SUMMARY OF THE INVENTION
In accordance with the present invention, compositions comprising pleiotrophin are used to induce growth of bone or cartilage at an in vivo site in need of repair. The disclosed composition is administered to a warm-blooded species, either by implanting or injecting the composition, for in vivo contact with the site in need of repair. This invention is the first demonstration that pleiotrophin alone is capable of enhancing the repair of bone or cartilage tissues by endogenous tissues.
Another aspect of this invention is a method for inducing new bone or cartilage growth at a predetermined in vivo site of a vertebrate species comprising the steps of contacting the site with a composition comprising substantially purified pleiotrophin, in an amount effective to induce endogenous tissue growth, and a pharmaceutically acceptable carrier. In a preferred embodiment, the composition is in liquid form and the site is contacted by injection of the composition. In another preferred embodiment, the carrier is a polymer matrix comprising a polymer selected from the group consisting of polyesters, ionomers, poly(amino acids), polyvinyl acetate, polyacrylates, polyorthoesters, polyanhydrides, collagens, fibrins, starches, alginate, and hyaluronic acid. Alternatively, the carrier may be a metal, glass, or mineral salt. Preferred mineral salts include tricalcium phosphate, hydroxyapatite, and gypsum.
Still another aspect of this invention is a method of treating a bone or cartilage pathogenic condition in a warm-blooded vertebrate by administering a composition systemically to the warm-blooded vertebrate, wherein the composition comprises substantially purified pleiotrophin,
Nousek-Goebl Nancy
Peterson Dale R.
Barnes & Thornburg
DePuy Orthopeaedics, Inc.
Martin Alice O.
McDermott Corrine
Pellegrino Brian E.
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