Single injection of tacrolimus-loaded thermosensitive hydrogel improves outcomes in vascularized composite allotransplantation

Background: Thermosensitive hydrogels are promising for sustained immunosuppressive drug release, but the efficacy of a single local injection of mixed thermosensitive hydrogel-carried tacrolimus in preventing rejection and maintaining allograft survival with minimal systemic effects needs further investigation. Methods: In this study, Lewis rats were injected daily with tacrolimus (2 mg/kg intraperitoneally) or single injection of thermosensitive hydrogel loaded with tacrolimus (10 mg) after receiving full-thickness tail skin or vascularized composite allografts. We observed tacrolimus concentration and kidney function, peripheral immune response, allograft survival, and histopathological changes. Results: Tacrolimus concentration was maintained at sub-therapeutic levels for at least 90 days without signs of kidney failure and systemic adverse effects. With this, 4 of 6 skin allograft recipients had significantly prolonged allograft survival (>90 days vs ≈ 40.5 days, p < 0.05). Additionally, recipients of vascularized bone marrow and mystacial pad allotransplantation also demonstrated an improvement in allograft outcome, including prolonged allograft survival (5/6, >90 days and 6/6, MST ≈75.5 days), increased chimerism, and improved nerve regeneration after injection received. Conclusion: Encapsulating tacrolimus in in situ gelling mixed hydrogels efficiently delivers immunosuppressive drugs to skin or vascularized composite allograft recipients, reducing administration frequency, increasing local concentration, and minimizing systemic effects.