SCIENTIFIC RepoRTs | (2018) 8:4474 | DOI:10.1038/s41598-018-22628-8
Fetal extracellular matrix nerve
wraps locally improve peripheral
nerve remodeling after complete
transection and direct repair in rat
, Anne Faust
, Yolandi van der Merwe
, Bo Xiao
, Scott Johnson
, Vijay S. Gorantla
, Stephen F. Badylak
, Kia M. Washington
Michael B. Steketee
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 signicantly 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 neurolament 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.
Peripheral nerve (PN) injury can lead to permanently lost sensation, motor control, and neuropathic pain.
ough PN axons can regrow to restore function, the severity, location, and repair method inuences local tissue
remodeling and axon regrowth across the repaired injury site. PN injuries requiring surgical epineurial repair
are the most challenging, as in anastomosis or coaptation to reconnect severed nerve trunks, and functional
outcomes are generally poor despite advances in microsurgical nerve reconstruction techniques
repairs can locally increase the pro-inammatory innate immune response and tissue remodeling that forms scar
tissue. Increased scarring is hypothesized to slow and misdirect axon regrowth and increase decits in tactile and
, neuroma formation and persistent pain
, and neuronal death
. However, whether improving
tissue remodeling at epineurial repair sites is sucient to increase functional axon regrowth is unclear.
Nerve wraps have been used to treat epineurial repairs since the early 1900s
and several nerve wraps made
from puried collagen
or amniotic membrane
are FDA approved, commercially available, and used clinically
to treat both direct and indirect PN repairs, including neurolysis, direct end-to-end anastomosis, and coaptation
Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Center for Neuroscience,
University of Pittsburgh, Pittsburgh, PA, USA.
Swanson School of Engineering, Department of Bioengineering,
Pittsburgh, PA, USA.
Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Plastic Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Healthcare System Pittsburgh, Pittsburgh, PA, USA.
Plastic Surgery, Xijing Hospital, The Fourth Military Medical
University, Xi’an, China. Correspondence and requests for materials should be addressed to M.B.S. (email:
Received: 20 September 2017
Accepted: 27 February 2018
Published: xx xx xxxx