Host‐derived neoangiogenesis with short‐term immunosuppression allows incorporation and remodeling of vascularized diaphyseal allogeneic rabbit femur transplants

Abstract

The purpose of this study was to demonstrate that living bone allotransplants can incorporate, remodel, and maintain mechanical properties without long-term immunosuppression in a fashion comparable to living autotransplants. For this, viability is maintained by repair of nutrient vessels and neovascularization from implanted host-derived vasculature. Microsurgically revascularized femoral diaphysis allotransplants were transferred from young male New-Zealand-White (NZW) into 4 groups of male Dutch-Belted (DB) rabbits. Short-term immunosuppression by tacrolimus (IS, groups 4 and 5) and host-derived neovascularization (NV) from implanted fascial flaps was used to maintain viability (groups 3 and 5) as independent variables. Group 2 received neither IS nor NV. Vascularized pedicled autotransplants were orthotopically transplanted in group 1. After 16 weeks, transplants were evaluated using radiologic, histologic, biomechanical, and histomorphometric parameters. Vascularized bone allotransplants treated with both short-term IS and host-derived NV (group 5) healed in a fashion similar to pedicled autotransplants (group 1). Their radiographic scores were higher than other groups. Groups with patent fascial flaps (3 and 5) showed significantly greater neoangiogenesis than ligated controls (2 and 4). Tacrolimus administration did not affect neoangiogenesis. Elastic modulus and ultimate stress were significantly greater in autogenous bone than in allotransplanted femora. Biomechanical properties were not significantly different among allotransplants. Bone turnover was decreased with IS, but increased with NV by the implanted fascial flaps. Living allogeneic femoral allotransplants treated with short-term IS and host-derived neoangiogenesis can lead to stable transplant incorporation in this rabbit model. The reconstruction of skeletal defects remains a challenging reconstructive problem, for which vascularized bone autotransplants are among the best options. They heal more reliably and quickly, remodel more effectively, and resist infection better than nonviable allografts. 1 Limited donor sites, potential donor site morbidity, and poor geometric matching to defects create surgical challenges. 2 Prosthetic replacement and distraction osteogenesis also have significant rates of hardware failure or sepsis. 2 Avascular structural bone allografts do not fully incorporate and demonstrate little remodeling.Living bone allotransplantation is intriguing, given absence of donor morbidity, close geometric matching, and potentially similar healing/remodeling to living autotransplant bone. A few reports of clinical use, however, have demonstrated poor viability and mechanical properties, and problems with infections. [3][4][5] The need to maintain long-term immunosuppression (IS) raises concerns for potential severe side-effects, which are difficult to justify for extremity-preserving procedures.We previously have described a method of living allogeneic bone transplantation in the rat not requiring long-term IS, made poss...

Knee joint transplantation combined with surgical angiogenesis in rabbits—A new experimental model

“…Therefore, we included a sufficient amount of fascia in the SIEF-flap and the saphenous arteriovenous bundle to fill the intramedullary canal of femur and tibia, respectively. One of the main questions was if neoangiogenesis occurs from these tissues in joints similar to previous studies that successfully applied these techniques to segmental diaphyseal bone 31–33 .…”

“…We have previously reported a novel method to maintain viability of bone allotransplants without long-term immunosuppression, using neoangiogenesis from autogenous tissue implanted within the bone at the time of transplantation and microvascular repair of the allogeneic nutrient circulation 31–34 . A short two-week period of postoperative immunosuppression maintains viability of the allograft through the nutrient pedicle.…”

“…Additionally, we implanted a superficial inferior epigastric facial flap in the femur and a saphenous arteriovenous bundle in the tibia (figure 1), to promote angiogenesis as we have described previously for bone allotransplantation 31–34 . Anesthesia was induced with intramuscular injection of ketamine (Ketaset1, Fort Dodge Animal Health; 40 mg/kg IM), xylazine hydrochloride (VetTek, Bluesprings, MO; 7 mg/kg IM) and acepromazine maleate (Boehringer Ingelheim Vetmedica, Inc., St. Joseph, MO; 1 mg/kg IM).…”

“…Osseous healing was evaluated radiographically using a scoring system (no bone healing [0 points] to complete healing and remodeling [24 points]) based on that described by Taira et al and Giessler et al 31, 36 . Additionally, arthrosis was evaluated using a score from 0 (no arthrosis) to 5 (complete joint destruction).…”

“…We have previously described the use of angiogenesis to replace the allogeneic circulation with autogenous vessels. This method allows long-term bone allotransplant survival in rat and rabbit models, 31–33 and requires only short term immunosuppression. Here, immunosuppression is only used to maintain patency of the microsurgical nutrient pedicle and thereby allows bone survival for a short period.…”