Abstract
Researchers are investigating the use of biomaterials with aligned guidance cues, like those provided by aligned electrospun fibers, to facilitate axonal growth across critical-length peripheral nerve defects. To enhance the regenerative outcomes further, these aligned fibers can be designed to provide local, sustained release of therapeutics. The drug fingolimod improved peripheral nerve regeneration in preclinical rodent models by stimulating a pro-regenerative Schwann cell phenotype and axonal growth. However, the systemic delivery of fingolimod for nerve repair can lead to adverse effects, so it is necessary to develop a means of providing sustained delivery of fingolimod local to the injury. Here we created aligned fingolimod-releasing electrospun fibers that provide directional guidance cues in combination with the local, sustained release of fingolimod to enhance neurite outgrowth and stimulate a pro-regenerative Schwann cell phenotype. Electrospun fiber scaffolds were created by blending fingolimod into poly(lactic-co-glycolic acid) (PLGA) at a w/w% (drug/polymer) of 0.0004, 0.02, or 0.04%. We examined the effectiveness of these scaffolds to stimulate neurite extension in vitro by measuring neurite outgrowth from whole and dissociated dorsal root ganglia (DRG). Subsequently, we characterized Schwann cell migration and gene expression in vitro. The results show that drug-loaded PLGA fibers released fingolimod for 28 days, which is the longest reported release of fingolimod from electrospun fibers. Furthermore, the 0.02% fingolimod-loaded fibers enhanced neurite outgrowth from whole and dissociated DRG neurons, increased Schwann cell migration, and reduced the Schwann cell expression of promyelinating factors. The in vitro findings show the potential of the aligned fingolimod-releasing electrospun fibers to enhance peripheral nerve regeneration and serve as a basis for future in vivo studies.
Highlights
Peripheral nervous system (PNS) injury due to disease or trauma leads to sensory and/or motor dysfunction, which significantly reduces the patient’s quality of life
Using scanning electron microscopy (SEM), we investigated the degree of fiber alignment, fiber diameter, and percent fiber coverage on the coverslip of each electrospun fiber group (Figures 2A–D)
Note that we studied 0.0004, 0.02, and 0.04% fingolimod-loaded fibers because, in pilot studies, we found that increasing the loading concentration to 0.4% fingolimod resulted in poor fiber formation, inconsistent fiber diameter, and decreased fiber alignment (Supplementary Figure S1)
Summary
Peripheral nervous system (PNS) injury due to disease or trauma leads to sensory and/or motor dysfunction, which significantly reduces the patient’s quality of life. The transected peripheral nerves regenerate readily over short distances, but gaps between the proximal and the distal nerve stumps greater than 1–2 cm in length typically require surgical intervention where a construct is placed to bridge the gap and facilitate axonal regeneration. An autograft is the current gold standard for peripheral nerve reconstruction, but with larger injury gaps, the availability of an autograft with appropriate length and diameter is limited and has the potential to cause donor site morbidity (Deumens et al, 2010). Allografts are comprised of native extracellular matrix that supports and directs axonal regeneration, but the availability of cadaveric tissues is limited and the decellularization and the sterilization processes are labor-intensive (Fishman et al, 2012; Safa et al, 2019)
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