Local Immunosuppression for Vascularized Composite Allografts: Application of Topical FK506-TyroSpheres in a Nonhuman Primate Model. Issue 6 (30th November 2020)

• Record Type: Journal Article
• Authors: Gama, Amon-Ra; Ng, Zhi Yang; Shanmugarajah, Kumaran; Mastroianni, Melissa; Randolph, Mark A; Lellouch, Alexandre G; Kohn, Joachim; Cetrulo, Curtis L
• Is Part Of: Journal of burn care & research. Volume 41:Issue 6(2020)
• Page Start: 1172
• Page End: 1178
• Publication Date: 2020-11-30
• Subjects: Burns and scalds -- Treatment -- Periodicals; Burns and scalds -- Periodicals; Burns -- Periodicals; Burns -- rehabilitation -- Periodicals; Research -- Periodicals; Brûlés -- Réadaptation -- Périodiques; Brûlures -- Prévention -- Périodiques; Burns and scalds -- Patients; Periodicals; 617.11005
• DOI: 10.1093/jbcr/iraa062
• Languages: English
• ISSNs: 1559-047X

Abstract

Abstract: Transplantation of vascularized composite allografts (VCAs) provides a means of restoring complex anatomical and functional units following burns and other disfigurement otherwise not amenable to conventional autologous reconstructive surgery. While short- to intermediate-term VCA survival is largely dependent on patient compliance with medication, the myriad of side effects resulting from lifelong systemic immunosuppression continue to pose a significant challenge. Topical immunosuppression is therefore a logical and attractive alternative for VCA. Current formulations are limited though, by poor skin penetration but this may be mitigated by conjugation of immunosuppressive drugs to TyroSpheres for enhanced delivery. Therefore, we investigated the topical application of FK506-TyroSpheres (in the form of a gel dressing) in a clinically relevant nonhuman primate VCA model to determine if allograft survival could be prolonged at reduced levels of maintenance systemic immunosuppression. Six Major Histocompatibility Complex (MHC)-mismatched cynomolgus macaques ( Macaca fascicularis ) served as reciprocal donors and recipients of radial forearm fasciocutaneous flaps. Standard Bacitracin ointment and FK506-TyroSpheres were applied every other day to the VCAs of animals in groups 1 (controls, n = 2) and 2 (experimental, n = 4), respectively, before gradual taper of systemic FK506. Clinical features of VCA rejection still developed when systemic FK506 fell below 10 ng/ml despite application of FK506-TyroSpheres and prolonged VCA survival was not achieved. However, unwanted systemic FK506 absorption was avoided with TyroSphere technology. Further refinement to optimize local drug delivery profiles to achieve and maintain therapeutic delivery of FK506 with TyroSpheres is underway, leveraging significant experience in controlled drug delivery to mitigate acute rejection of VCAs.