Recipient‐derived angiogenesis with short term immunosuppression increases bone remodeling in bone vascularized composite allotransplantation: A pilot study in a swine tibial defect model

• Published in: Journal of orthopaedic research 2017-06, Vol.35 (6), p.1242-1249
• Main Authors: Kotsougiani, Dimitra, Hundepool, Caroline A., Bulstra, Liselotte F., Friedrich, Patricia F., Shin, Alexander Y., Bishop, Allen T.
• Format: Article
• Language: English
• Subjects: angiogenesis; Animals; bone; Bone Remodeling; Bone Transplantation - methods; Neovascularization, Physiologic; pig; Pilot Projects; segmental bone defects; Swine; Swine, Miniature; Vascularized Composite Allotransplantation - methods; VCA; X-Ray Microtomography
• ISSN: 0736-0266; 1554-527X
• DOI: 10.1002/jor.23378

ABSTRACT Current vascularized composite allotransplantation (VCA) transplantation protocols rely upon life‐long immune modulation to maintain tissue perfusion. Alternatively, bone‐only VCA viability may be maintained in small animal models using surgical angiogenesis from implanted autogenous vessels to develop a neoangiogenic bone circulation that will not be rejected. This study tests the method's efficacy in a large animal model as a bridge to clinical practice, quantifying the remodeling and mechanical properties of porcine tibial VCAs. A segmental tibial defect was reconstructed in Yucatan miniature swine by transplantation of a matched tibia segment from an immunologically mismatched donor. Microsurgical repair of nutrient vessels was performed in all pigs, with simultaneous intramedullary placement of an autogenous arteriovenous (AV) bundle in Group 2. Group 1 served as a no‐angiogenesis control. All received 2 weeks of immunosuppression. After 16 weeks, micro‐CT and histomorphometric analyses were used to evaluate healing and remodeling. Axial compression and nanoindentation studies evaluated bone mechanical properties. Micro‐CT analysis demonstrated significantly more new bone formation and bone remodeling at the distal allotransplant/recipient junction and on the endosteal surfaces of Group 2 tibias (p = 0.03). Elastic modulus and hardness were not adversely affected by angiogenesis. The combination of 2 weeks of immunosuppression and autogenous AV‐bundle implantation within a microsurgically transplanted tibial allotransplant permitted long‐term allotransplant survival over the study period of 16 weeks in this large animal model. Angiogenesis increased bone formation and remodeling without adverse mechanical effects. The method may allow future composite‐tissue allotransplantation of bone without the risks associated with long‐term immunosuppression. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1242–1249, 2017. Segmental tibial defects in swine were reconstructed by microsurgical transplantation of a matched tibia segment from an immunologically mismatched donor. All pigs received 2 weeks of immunosuppression. In Group 2 an autogenous arteriovenous (AV) bundle was placed intramedullary for development of a neoangiogenic bone circulation that will not be rejected. Group 1 served as a no‐angiogenesis control. The neoangiogenic bone circulation from the implanted AV bundle increased bone formation and re