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Living Bone Allotransplants Survive by Surgical Angiogenesis Alone: Development of a Novel Method of Composite Tissue Allotransplantation
Mikko Larsen, MD1; Michael Pelzer, MD2; Patricia F. Friedrich, AAS1; Christina M. Wood, MS1; Allen T. Bishop, MD1
1 Departments of Orthopedic Surgery (M.L., P.F.F., and A.T.B.) and Biostatistics (C.M.W.), Mayo Clinic, 200 First Street S.W., Rochester, MN 55905. E-mail address for A.T. Bishop: bishop.allen@mayo.edu
2 Department of Hand, Plastic and Reconstructive Surgery—Burn Center, BG-Unfallklinik Ludwigshafen, Ludwig-Guttmann-Strasse 13, 67071 Ludwigshafen, Germany
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Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the National Institutes of Health (AR49718). Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

Investigation performed at the Department of Orthopedic Surgery, Microvascular Research Laboratory, and Department of Biostatistics, Mayo Clinic, Rochester, Minnesota

Copyright © 2011 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2011 Feb 02;93(3):261-273. doi: 10.2106/JBJS.G.01152
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Segmental bone defects pose reconstructive challenges. Composite tissue allotransplantation offers a potential solution but requires long-term immunosuppression with attendant health risks. This study demonstrates a novel method of composite-tissue allotransplantation, permitting long-term drug-free survival, with use of therapeutic angiogenesis of autogenous vessels to maintain circulation.


Ninety-three rats underwent femoral allotransplantation, isotransplantation, or allografting. Group-1 femora were transplanted across a major histocompatibility complex barrier, with microsurgical pedicle anastomoses. The contralateral saphenous artery and vein (termed the AV bundle) of the recipient animal were implanted within the medullary canal to allow development of an autogenous circulation. In Group 2, allotransplantation was also performed, but with AV bundle ligation. Group 3 bones were frozen allografts rather than composite-tissue allotransplantation femora, and Group 4 bones were isotransplants. Paired comparison allowed evaluation of AV bundle effect, bone allogenicity (isogeneic or allogeneic), and initial circulation and viability (allotransplant versus allograft). Two weeks of immunosuppression therapy maintained blood flow initially, during development of a neoangiogenic autogenous blood supply from the AV bundle in patent groups. At eighteen weeks, skin grafts from donor, recipient, and third-party rats were tested for immunocompetence and donor-specific tolerance. At twenty-one weeks, bone circulation was quantified and new bone formation was measured.


Final circulatory status depended on both the initial viability of the graft and the successful development of neoangiogenic circulation. Median cortical blood flow was highest in Group 1 (4.6 mL/min/100 g), intermediate in Group 4 isotransplants (0.4 mL/min/100 g), and absent in others. Capillary proliferation and new bone formation were generally highest in allotransplants (15.0%, 6.4 µm3/µm2/yr) and isotransplants with patent AV bundles (16.6%, 50.3 µm3/µm2/yr) and less in allotransplants with ligated AV bundles (4.4%, 0.0 µm3/µm2/yr) or allografts (8.1%, 24.1 µm3/µm2/yr). Donor and third-party-type skin grafts were rejected, indicating immunocompetence without donor-specific tolerance.


In the rat model, microvascular allogeneic bone transplantation in combination with short-term immunosuppression and AV bundle implantation creates an autogenous neoangiogenic circulation, permitting long-term allotransplant survival with measurable blood flow.

Clinical Relevance: 

These methods may allow future composite-tissue allotransplantation of bone without the appreciable health risks that are associated with long-term immunosuppression or immune tolerance induction.

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    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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