A Modified Heterotopic Swine Hind Limb Transplant Model for Translational Vascularized Composite Allotransplantation (VCA) Research

Abstract

Vascularized Composite Allotransplantation (VCA) such as hand and face transplants represent a viable treatment option for complex musculoskeletal trauma and devastating tissue loss. Despite favorable and highly encouraging early and intermediate functional outcomes, rejection of the highly immunogenic skin component of a VCA and potential adverse effects of chronic multi-drug immunosuppression continue to hamper widespread clinical application of VCA. Therefore, research in this novel field needs to focus on translational studies related to unique immunologic features of VCA and to develop novel immunomodulatory strategies for immunomodulation and tolerance induction following VCA without the need for long term immunosuppression.This article describes a reliable and reproducible translational large animal model of VCA that is comprised of an osteomyocutaneous flap in a MHC-defined swine heterotopic hind limb allotransplantation. Briefly, a well-vascularized skin paddle is identified in the anteromedial thigh region using near infrared laser angiography. The underlying muscles, knee joint, distal femur, and proximal tibia are harvested on a femoral vascular pedicle. This allograft can be considered both a VCA and a vascularized bone marrow transplant with its unique immune privileged features. The graft is transplanted to a subcutaneous abdominal pocket in the recipient animal with a skin component exteriorized to the dorsolateral region for immune monitoring.Three surgical teams work simultaneously in a well-coordinated manner to reduce anesthesia and ischemia times, thereby improving efficiency of this model and reducing potential confounders in experimental protocols. This model serves as the groundwork for future therapeutic strategies aimed at reducing and potentially eliminating the need for chronic multi-drug immunosuppression in VCA. Video LinkThe video component of this article can be found at

Ancillary Procedures Necessary for Translational Research in Experimental Craniomaxillofacial Surgery

“…The dorsal tunneling was effective in preventing self-induced trauma by the swine (11). However, as the Le Fort-based facial alloflap was being designed, it was noted that the alloflap's inflow/outflow design and necessary anastomoses were dependent on the neck's venous drainage system.…”

“…The use of near-infrared laser angiography was found to be critical for flap design given the swine's skin thickness, and played a vital role in pre-operative planning and intra-operative assessment (11). Although the vascular network of a human's face is well-described and understood, the arterial and venous descriptions of a swine's face are poorly detailed.…”

“…Regular discussions followed prior to the first live surgery. Original planning included the use of a human Shiley tracheostomy device for airway management (9), an esophagostomy tube for feeding based on previous investigations in feline (10), and a tunneled intravenous external jugular vein catheter (11). Intra-operative near-infrared laser angiography was needed for assistance with alloflap design and concern over facial vascularity (12).…”

“…After surgery, the tracheostomy tube was suctioned both on an hourly schedule and as-needed. Feeding PEG tubes and tunneled femoral vein Hickman catheters were placed using standard technique (11,14). …”

Surgical and Logistical Aspects of Donor Limb Procurement in Hand and Upper Extremity Transplantation

“…[3][4][5][6][7] Strides toward inducing long-term allograft tolerance have shown great promise in both translational animal models and clinical trials. [10][11][12] For continued improvement, standardized protocols are required to facilitate the widespread use of this novel reconstructive modality.…”