Revascularized Intercalary Bone Allografts with Short-Term Immunosuppression with Cyclosporine in the Canine

Abstract

To study the healing process of vascularized intercalary bone allograft after withdrawal of immunosuppressive drugs, allotransplantation of the tibia diaphysis with a vascular pedicle was performed in eight adult mongrel dogs (group 2) and assessments were made both during administration and after discontinuation of cyclosporin A. As controls, similar grafts with the vascular pedicles were removed and reimplanted back to the same animals (five dogs, group 1). Allotransplantation of frozen stored bone without a vascular pedicle (10 dogs, groups 3A and 3B) were also compared. No union occurred in most cases of frozen stored bone allotransplant because the transplanted bone was resorbed, leading to loosening and subsequent failure of osteosynthesis with the plate and screws used. Under cyclosporin A immunosuppression, bony union (i.e., when trabeculae were seen crossing the graft-recipient junction with obliteration of the junction line) occurred at almost similar time intervals in all dogs of group 2 (bone allotransplant with a vascular pedicle) by 3 months postoperatively, which was similar to those of group 1. No systemic side effects of cyclosporin A were observed. Cyclosporin A was discontinued 3 months following graft implantation. The bone graft became avascular within a week following withdrawal of cyclosporin A. However, bone union was maintained, and the transplanted bone never showed bone resorption, sclerosis, or fracture on serial radiographs up to the time the animals were sacrificed, between 5 and 14 months later. Histology at sacrifice showed that the transplanted allografts were being replaced at both ends by fresh bone derived from the transplantation bed. We conclude on the basis of the results of this study that solid bony union can be obtained in allotransplanted bone with a vascular pedicle if cyclosporin A is given for a brief period. After cyclosporin A is withdrawn, although the bone becomes nonviable secondary to rejection occurring in the blood vessels, its skeletal structure remains intact, enabling it to maintain its structural support while awaiting replacement by bony ingrowth from both ends of the graft.

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

“…Biomechanical testing further supported donor-recipient bony union. Also consistent with other models, 28,40,41,58,59 transplanted bone marrow was completely replaced by recipient cells.…”

“…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. The use of isolated vascularized bone allografts to heal continuity defects in patients with other reconstructive options would spare patients donor-site morbidity of autologous reconstruction and preserve future options should allogeneic reconstruction fail.…”

Host‐derived angiogenesis maintains bone blood flow after withdrawal of immunosuppression

“…The percentage rate of viable osteocytes were slightly less than previous similar allogenic limb transplant reports in experimental animals. 1,[18][19][20] Most of the viable osteocytes were found in the outer cortex, the inner layer being largely necrotic (empty osteocyte lacunae). This can be explained by the medullary canal reaming necessary to allow AV bundle insertion, thus damaging bone endosteal circulation.…”

“…Some authors have claimed that a short course of immunosuppressant treatment maintains structural integrity of grafts, but with loss of tissue viability within a few weeks after withdrawal of immunosuppression. 1,2 Angiogenesis is the growth and proliferation of blood vessels from existing vascular structures and is fundamental to reproduction, development, and repair of tissue. In bone, such vessels play an important role in osteogenesis.…”

Xenotransplantation model for vascularized musculoskeletal tissues in rodents

“…[7][8][9][10] Long-term allograft survival has been reported in rodents with satisfactory function. 1,11 Limb tissue allografts, however, are rapidly rejected in the same manner as solid organ allografts unless sustained systemic immunosuppressive agents, such as cyclosporine or FK506, are used in the host.…”