Local delivery of epigenetically stimulating folic acid for peripheral nerve regeneration

Folic acid is an essential source of the single carbon group used in DNA methylation and plays a pivotal role in the development, function, regeneration, and repair of the central nervous system (CNS). The mandate of folic acid supplementation in grained products has reduced the occurrence of neural tube defects by one third in the U.S since its introduction by the Food and Drug Administration in 1998. However, the advantages and possible mechanisms of action of using folic acid for peripheral nerve engineering and neurological diseases still remain largely elusive. Herein, we designed nerve guidance conduits out of biodegradable crosslinked urethane-doped polyester (CUPE) [1] that locally deliver folic acid at the injury site for the repair of critical-sized peripheral nerve gaps (>20 mm) in Wistar rats [2]. A folic acid-incorporated nerve guidance conduit is considered to create a chemical gradient in the surrounding tissue as a guide for Schwann cells to migrate into the device, and then serve as a suitable microenvironment that provides both chemical and mechanical cues to facilitate 1) Schwann cell proliferation, 2) the release of neurotrophins from the Schwann cells, and 3) axonal regeneration.