Controlled Release of Mesenchymal Stem Cell-Conditioned Media from a Microsphere/Gel-Based Drug Delivery System for Wound Healing of Tympanic Membrane Perforations

Chronic tympanic membrane (TM) perforation increases patient susceptibility to infection, hearing loss, and other side effects. Current clinical treatment, surgical grafting, can result in detrimental side effects including nerve damage, dizziness, or hearing loss. Therefore, it is essential to develop novel therapeutic procedures that can induce or accelerate healing in minimally or noninvasive approaches. Cell-free therapies have safety advantages over stem cells and are logistically favorable for clinical use. The regenerative potential by mesenchymal stem cell-conditioned media (CM) has been promising. In this study, poly(lactic-co-glycolic acid) (PLGA) microspheres with CM encapsulated have been developed as a cell-free alternative regenerative treatment for TM perforation. The results suggest that the PLGA microspheres were capable of encapsulating and releasing CM for up to 21 days. The in vitro scratch wound proliferation assays showed increased wound healing ability of CM-loaded microspheres. In vivo guinea pig models treated with CM drops and CM-loaded microspheres using a thermoresponsive gel carrier demonstrated potential for wound healing in TM perforation. These studies provide a basis for further examination of the delivery of stem cell CM and investigation of time-dependent wound healing, long-term ototoxicity, and hearing restoration.