Abstract
Orofacial clefts are the most common congenital craniofacial anomaly. Adverse healing following cleft palate repair can lead to oronasal fistula (ONF), a persistent connection between the oral and nasal cavities. Although human allograft tissues are currently the gold standard for ONF repair, these methods carry risks of infection and rejection, often requiring surgical revision. Immunoregenerative therapies present a novel alternative approach to harness the body's immune response and enhance the wound healing environment. An FDA-approved immunomodulatory drug, FTY720, is repurposed to reduce lymphocyte egress and induce immune cell fate switching toward pro-regenerative phenotypes. In this study, a bilayer biomaterial system is engineered using Tegaderm to secure and control the delivery of FTY720-nanofiber scaffolds (FTY720-NF). The release kinetics of the bilayer FTY720-NF is optimized to maintain drug release for up to 7 days, ensuring safe transdermal absorption and tissue biodistribution. The comprehensive immunophenotyping results demonstrate a regenerative state transition in hybrid immune cells recruited to the wound site. Further, histological evaluations reveal a significant ONF closure in mice by day 7 following bilayer FTY720-NF implantation. These findings demonstrate the utility of immunomodulatory strategies for oral wound healing, better positing the field to develop more efficacious treatment options in pediatric patients.