Bone Quality and Healing in a Swine Vascularized Bone Allotransplantation Model Using Cyclosporine-Based Immunosuppression Therapy

Abstract

Although vascularized bone and joint allotransplantation is a promising new treatment option for reconstructing large bone defects, the need for immunosuppressive agents to prevent rejection in these procedures poses a major problem. This problem stems from the fact that several of these agents can cause harmful side effects, such as alterations in bone quality and healing. Therefore, the purpose of this study was to determine what effect the commonly used immunosuppressant regimen cyclosporine A-based combination therapy has on bone quality and healing. In 10 pigs, vascularized bone allografts with skin and muscle components (osteomyocutaneous free flaps) were transplanted from size-matched donor animals. Recipient animals received oral cyclosporine A/mycophenolate mofetil/prednisone therapy for 90 days. Bone quality was studied before and after transplantation by measuring the bone's acoustic velocity and density and calculating the bone's elastic coefficient. Bone healing was assessed using radiographic analysis. Four animals were lost as a result of graft rejection or immunosuppression-related complications before the 90-day endpoint of the study. Although bone specimens taken from the six animals that completed the 90-day protocol had histological signs of rejection, they all seemed to have normal bone healing. Posttransplant bone density values were significantly decreased (p < 0.05) (1544.7 +/- 47.5 kg/m3) as compared with pretransplant values (1722.7 +/- 44.1 kg/m3). Results of the acoustic velocity and elastic coefficients measurements showed a significant decrease (p < 0.05) in posttransplant values (from 3503.0 +/- 165.1 meters/sec to 2963.0 +/- 54.6 meters/sec and from 21.6 +/- 2.2 GPa to 13.6 +/- 0.5 GPa, respectively), indicating diminished bone quality. The findings indicate that cyclosporine A/mycophenolate mofetil/prednisone combination therapy is ineffective in preventing bone rejection, that it decreases bone quality, and that it is associated with systemic toxicity, suggesting that this immunosuppressive regimen at the doses used in this study is not ideal for vascularized bone allotransplantation procedures.

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

“…With axial compression testing, we found the elastic modulus to be less than normal bone at 16 weeks. Vossen et al demonstrated a similar finding at 12 weeks after bone VCA, although direct comparison with our study is not possible due to differences in methodology . Interestingly, on the microscale the allotransplant elastic modulus and hardness proved not to be significantly different than contralateral tibias.…”

“…As both blood type and the major histocompatibility haplotypes (the swine leucocyte antigen or SLA complex) have been well defined, the mini pig is proving of value for study of many VCA tissues . A limitation of the swine model is its rapid growth .…”

“…Experimental bone VCA investigations are sparse . In this report, we describe both the gross mechanical strength (compressive loading of bone cross‐sections) as well as nanoindentation characterization of porcine tibial allotransplants.…”

Nonhuman Primate Model of Fibula Vascularized Composite Tissue Allotransplantation Demonstrates Donor-Recipient Bony Union

“…Similar results have been reported previously in rodent and porcine models of long-bone allotransplantation using tacrolimus immunosuppression. 28,29,31,63 Our findings additionally support reconstructive clinical applications of isolated vascularized bone allografts using a potentially limited course of tacrolimus immunosuppression. 41 The dose and duration of tacrolimus therapy to achieve stable bony union is unknown, as is whether bone quality could be maintained in the absence of immunosuppression in our model.…”

“…[60][61][62] Indeed, similar studies of vascularized long-bone transplantation in large-animal models have found that prednisone administration impaired bone healing/bone quality, and may have been responsible for immunosuppression-related complications leading to animal loss. 29,31 In contrast, tacrolimus-based therapy, whether alone or in combination with CD28 costimulatory blockade, provided adequate immunosuppression to prolong vascularized bone allograft survival without impaired physiologic healing in our model. Similar results have been reported previously in rodent and porcine models of long-bone allotransplantation using tacrolimus immunosuppression.…”