CELLULAR BASED THERAPY FOR THE TREATMENT OF OSTEONECROSIS OF THE FEMORAL HEAD

Abstract

Introduction: Osteonecrosis of the femoral head, which involves the death of cells in trabecular bone and marrow, leads to fracture of subchondral bone and loss of the femur articulating surface in the hip and ultimately leads to total hip replacement (THR). Retrospective clinical studies show that osteonecrosis in 80–90% of affected patients inevitably progresses to destroy the femur head, usually within 2–3 years of diagnosis. None of the current treatment options are effective at terminating or reversing the disease process. Two reports (Hernigou and Beaujean, 2002 and Gangji, et al 2004) using fresh autologous bone marrow tissue injected directly into the necrotic femoral head, reported a high rate of success, especially in early stage osteonecrosis, in patients at most risk for disease progression. As a more standardized alternative to fresh bone marrow, Aastrom Biosciences has developed a proprietary automated process to expand autologous bone marrow cells. The ex vivo expanded cells referred to as Bone Repair Cells (BRC) are based on Aastrom Tissue Repair Cell (TRC) technology. BRC are a mixture of stem and early progenitor cells including cells of hematopoietic, mesenchymal, and endothelial lineages derived from a small sample of the patient’s own bone marrow.

Materials and Methods: Fresh bone marrow mononuclear cells from normal donors were purchased from Poietics Inc. (Gaithersburg, Maryland) for BRC culture. After ex vivo expansion, BRC viability and cell phenotype characterization was performed by flow cytometry. The frequency of mesenchymal and hematopoietic stem cells within BRC was determined using CFU-F and CFU-GM assays. The osteogenic and vascular in vitro potential of BRC was measured using standard osteogenic differentiation assays and tube formation assays. The bone formation potential of BRC was determined using an ectopic bone formation model involving subcutaneous implantation. Based on the in vitro and in vivo potential of BRC, a mixing procedure was developed to implant BRC and bone matrix into osteonecrotic sites during standard core decompression surgery. The viability of BRC within the bone matrix was measured using standard cell metabolic assays.

Results: BRC possess a diverse range of cell phenotypes with the potential to differentiate down the osteogenic and angiogenic lineage under the right conditions. BRC also has the potential for in vivo bone formation. In addition, examination of several cell-surface markers revealed a strong correlation between the frequency of cell surface markers CD105+, CD166+, CD90+ and in vivo bone formation scores when implanted with a ceramic matrix material. This BRC product can be mixed with a bone matrix for the implantation into long-bone defects or osteonecrotic sites without loss in cell viability.

Discussion: Aastrom BRCs have both in vivo and in vitro bone and vascular potential; thus, it is our intent to demonstrate clinical safety and efficacy in treating osteonecrosis patients with BRC. Aastrom’s ON-CORE trial is a 120 patient Phase III clinical trial for the treatment of University of Pennsylvania radiographic classification stage IIb and IIc osteonecrosis patients. The primary efficacy endpoint of this trial is to delay disease progression of osteonecrosis to fracture for at least 24 months post-treatment, and potentially prevent collapse of the femur head, which will be measured by a blinded third-party reviewer through magnetic resonance imaging. Patients will be followed for a total of 5 years, post-treatment.