PROJECT SUMMARY Injured corneal nerves can regenerate but in general, the resulting nerve repair is incomplete or may take years to recover their original density and patterning. While several growth factors can enhance the recovery of damaged corneal nerves and one of them has been clinically approved to treat corneal injuries (nerve growth factor), patients still complain about discomfort, dryness, and pain. These observations indicate that more complete anatomical and sensory regeneration of injured nerves may need to occur for patients to recover. Most likely the type/site/time of nerve injury affects the anatomical, molecular, and functional regeneration of corneal nerves. Therefore, the administration of clinically validated factors that enhance nerve regeneration, not only accelerates the rate of healing but also induces differential effects on functional nerve sensation. Since regeneration of corneal nerves requires multiple wound healing processes, the use of single agents may not be the best therapeutic approach, and combination of factors with similar or complementary roles may be necessary to accomplish repair at the morphological and functional levels. In this proposal, we hypothesize that secreted extracellular vesicles (including exosomes) derived from different sources differentially regulate the anatomical, molecular, and functional aspects of regenerating corneal nerves. To identify these changes, we proposed the following: Aim 1 will characterize the ability of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) to promote the anatomic and molecular regeneration of corneal nerves following mechanical and chemical injury. Aim 2 will evaluate the functional and behavior recovery of corneal nerves following administration of EVs. Aim 3 will elucidate the bioactive components of the extracellular vesicle’s cargo, which can lead to new therapeutic approaches for complete corneal nerve repair.