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Allogeneic Mesenchymal Stem Cells Regenerate Bone in a Critical-Sized Canine Segmental Defect

Investigation performed at Osiris Therapeutics, Baltimore, Maryland

Treena Livingston Arinzeh, PhD
Department of Biomedical Engineering, New Jersey Institute of Technology, University Heights, Newark, NJ 07102. E-mail address: arinzeh{at}njit.edu

Susan J. Peter, PhD
Medtronic Sofamor Danek, 1800 Pyramid Place, Memphis, TN 38132

Michael P. Archambault, MS
Christian van den Bos, PhD
Steve Gordon, PhD
Karl Kraus, VMD
Department of Surgery, Tufts University School of Veterinary Medicine, 200 Westboro Road, North Grafton, MA 01536

Alan Smith, PhD
Sudha Kadiyala, PhD
DePuy-Acromed, Incorporated, 325 Paramount Drive, Raynham, MA 02767

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from Osiris Therapeutics, Inc. In addition, one or more of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity (Osiris Therapeutics, Inc.). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Background: Mesenchymal stem cells from adult bone marrow are multipotent cells capable of forming bone, cartilage, and other connective tissues. In a previous study, we demonstrated that autologous mesenchymal stem cells could repair a critical-sized bone defect in the dog. The objective of this study was to determine whether the use of allogeneic mesenchymal stem cells could heal a critical-sized bone defect in the femoral diaphysis in dogs without the use of immunosuppressive therapy.

Methods: A critical-sized segmental bone defect, 21 mm in length, was created in the mid-portion of the femoral diaphysis of twelve adult dogs that weighed between 22 and 25 kg. Each defect was treated with allogeneic mesenchymal stem cells loaded onto a hollow ceramic cylinder consisting of hydroxyapatite-tricalcium phosphate. A complete mismatch between donor stem cells and recipient dogs was identified by dog leukocyte antigen typing prior to implantation. The healing response was evaluated histologically and radiographically at four, eight, and sixteen weeks after implantation. The radiographic and histological results at sixteen weeks were compared with the historical data for the control defects, which included defects that had been treated with a cylinder loaded with autologous mesenchymal stem cells, defects treated with a cylinder without mesenchymal stem cells, and defects that had been left untreated (empty). The systemic immune response was evaluated by the analysis of recipient serum for production of antibodies against allogeneic cells.

Results: For defects treated with allogeneic mesenchymal stem cell implants, no adverse host response could be detected at any time-point. Histologically, no lymphocytic infiltration occurred and no antibodies against allogeneic cells were detected. Histologically, by eight weeks, a callus spanned the length of the defect, and lamellar bone filled the pores of the implant at the host bone-implant interface. Fluorescently labeled allogeneic cells were also detected. At sixteen weeks, new bone had formed throughout the implant. These results were consistent with those seen in implants loaded with autologous cells. Implants loaded with allogeneic or autologous stem cells had significantly greater amounts of bone within the available pore space than did cell-free implants at sixteen weeks (p < 0.05).

Conclusions: The results of this study demonstrated that allogeneic mesenchymal stem cells loaded on hydroxyapatite-tricalcium phosphate implants enhanced the repair of a critical-sized segmental defect in the canine femur without the use of immunosuppressive therapy. No adverse immune response was detected in this model.

Clinical Relevance: The use of allogeneic mesenchymal stem cells for the repair of large defects may be an alternative to autologous and allogeneic bone-grafting procedures. An allogeneic approach would enable mesenchymal stem cells to be isolated from any donor, expanded, and cryopreserved, providing a readily available source of cells for bone tissue engineering.

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