Surgical Angiogenesis with Short-Term Immunosuppression Maintains Bone Viability in Rabbit Allogenic Knee Joint Transplantation

Abstract

Background Vascularized Composite Allotransplantation (VCA) has potential for reconstruction of joint defects, but requires life-long immunosuppression (IS), with substantial risks. This study evaluates an alternative, using surgical angiogenesis from implanted autogenous vessels to maintain viability without long-term immunotherapy. Methods Vascularized knee joints were transplanted from Dutch Belted donors to New Zealand White rabbit recipients. Once positioned and revascularized microsurgically, a recipient-derived superficial inferior epigastric fascial (SIEF) flap and a saphenous AV bundle were placed within the transplanted femur and tibia, respectively, to develop a neoangiogenic, autogenous circulation. Ten transplants comprised Group 1. Group 2 (n=9) were no-angiogenesis controls with ligated flaps and AV bundles. Group 3 rabbits (n=10) were autotransplants with patent implants. Tacrolimus was used for 3 weeks to maintain nutrient flow during angiogenesis. At 16 weeks, we assessed bone healing, joint function, bone and cartilage mechanical properties and histology. Results Group 1 allotransplants had more robust angiogenesis, better healing, improved mechanical properties and better osteocyte viability than ligated controls (group 2). All 3 groups developed knee joint contractures and arthritic changes. Cartilage thickness and quality were poorer in allograft groups than autotransplant controls. Conclusions Surgical angiogenesis from implanted autogenous tissue improves bone viability, healing and material properties in rabbit allogenic knee transplants. However, joint contractures and degenerative changes occurred in all transplants, regardless of antigenicity or blood supply. Experimental studies in a larger animal model with improved methods to maintain joint mobility are needed before the merit of living joint allotransplantation can be judged.

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

“…As hypothesized, the implantation of an autogenous AV‐bundle within the tibial allotransplant improved endosteal static and dynamic remodeling parameters, implying a successful promotion of new bone formation and improved bone remodeling in bone VCAs with an implanted recipient‐derived AV bundle. These results support our previous studies in orthotopic rat and rabbit knee joint and femoral transplantation . The benefits at 16 weeks were significant only on the deep (endosteal) cortical bone surface, demonstrating no effect of an intramedullary pedicle on periosteal circulation at that point in time.…”

“…In our previous research, we have used this same strategy to maintain bone and joint VCA viability, coupled with short‐term immunosuppression to maintain the allogeneic nutrient pedicle blood flow during autogenous vessel angiogenesis. We have demonstrated surgical angiogenesis to revascularize necrotic structural allografts, maintain viability and promote bone remodeling in rat and rabbit skeletal defect models without the need of long‐term immunosuppression . This report is a progression of our previous work.…”

“…Currently, bone VCA depends on long‐term immunosuppression, often resulting in significant morbidity and the risk of graft‐versus‐host disease . Experimental bone VCA has focused until recently to small and large animal models, testing a variety of strategies to maintain viability …”

“…This study in a Yucatan mini pig tibia model, evaluates an alternative option to maintain bone VCA viability—using angiogenesis from implanted autogenous vessels to quickly develop a new, non‐rejectable circulation, requiring only short‐term immunosuppressive drug treatment. Previous work in the rat and rabbit has found this method to maintain VCA viability and promote bone remodeling . These results may well differ from clinical use in much larger human bone.…”

Neo‐Angiogenesis, Transplant Viability, and Molecular Analyses of Vascularized Bone Allotransplantation Surgery in a Large Animal Model

“…Previous studies have demonstrated that bone VCAs may be maintained in small animal models without the need of long‐term IS by switching the circulation of the transplant from allogenic to autogenous vessels, enabled by implantation of an arteriovenous bundle (AV bundle) elevated from adjacent soft tissue and placed within the allotransplant. The allogenic nutrient vessels are repaired microsurgically at the same time, but only short‐term immunosuppression is used . The immunosuppressive period allows nutrient pedicle to maintain transplant blood flow and cell viability.…”