Abstract
In peripheral nerve (PN) injuries requiring surgical repair, as in PN transection, cellular and ECM remodeling at PN epineurial repair sites is hypothesized to reduce PN functional outcomes by slowing, misdirecting, or preventing axons from regrowing appropriately across the repair site. Herein this study reports on deriving and analyzing fetal porcine urinary bladder extracellular matrix (fUB-ECM) by vacuum assisted decellularization, fabricating fUBM-ECM nerve wraps, and testing fUB-ECM nerve wrap biocompatibility and bioactivity in a trigeminal, infraorbital nerve (ION) branch transection and direct end-to-end repair model in rat. FUB-ECM nerve wraps significantly improved epi- and endoneurial organization and increased both neovascularization and growth associated protein-43 (GAP-43) expression at PN repair sites, 28-days post surgery. However, the number of neurofilament positive axons, remyelination, and whisker-evoked response properties of ION axons were unaltered, indicating improved tissue remodeling per se does not predict axon regrowth, remyelination, and the return of mechanoreceptor cortical signaling. This study shows fUB-ECM nerve wraps are biocompatible, bioactive, and good experimental and potentially clinical devices for treating epineurial repairs. Moreover, this study highlights the value provided by precise, analytic models, like the ION repair model, in understanding how PN tissue remodeling relates to axonal regrowth, remyelination, and axonal response properties.
Highlights
Peripheral nerve (PN) injury can lead to permanently lost sensation, motor control, and neuropathic pain
To determine how tissue remodeling influences functional axonal regrowth, we developed a nerve wrap from fetal porcine urinary bladder extracellular matrix
After vacuum assisted decellularization (VAD), hematoxylin positive nuclei were absent from fetal porcine urinary bladder extracellular matrix (fUB-extracellular matrix (ECM)) but eosin positive acidophilic nuclear-associated protein staining remained (Fig. 1b)
Summary
Peripheral nerve (PN) injury can lead to permanently lost sensation, motor control, and neuropathic pain. By wrapping PN epineurial repairs, nerve wraps protect the repair site during the initial healing phase These wraps are hypothesized to improve outcomes by providing a positive microenvironment that can reduce scarring[9], scar-based ischemic adhesions[10], neuroma formation[11], and, in some cases, increase functional axonal reinnervation[8,12]. Whether nerve wrap associated functional improvements are due to improved tissue remodeling at epineurial repair sites that in turn increase appropriate functional axon regrowth across the repairs or due to reduced comorbidities remains unclear. To determine how tissue remodeling influences functional axonal regrowth, we developed a nerve wrap from fetal porcine urinary bladder extracellular matrix (fUB-ECM). Axon regrowth across repair sites, remyelination, and whisker-evoked response properties were unchanged, indicating positive tissue remodeling at PN repair sites is insufficient to predict axonal regrowth, remyelination, and functional reinnervation
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