Aligned microchannel polymer-nanotube composites for peripheral nerve regeneration: Small molecule drug delivery.
4-Aminopyridine
/ administration & dosage
Animals
Cell Survival
/ drug effects
Cells, Cultured
Chitosan
/ administration & dosage
Clay
Drug Delivery Systems
Drug Liberation
Elastic Modulus
Female
Humans
Nanotubes
/ chemistry
Nerve Regeneration
/ drug effects
Potassium Channel Blockers
/ administration & dosage
Rats, Wistar
Schwann Cells
/ drug effects
Sciatic Nerve
/ drug effects
Tensile Strength
Halloysite nanotube
Nerve guidance conduit
Peripheral nerve regeneration
Polymer composite
Sciatic nerve defect
Small molecule drug delivery
Sustained release
Journal
Journal of controlled release : official journal of the Controlled Release Society
ISSN: 1873-4995
Titre abrégé: J Control Release
Pays: Netherlands
ID NLM: 8607908
Informations de publication
Date de publication:
28 02 2019
28 02 2019
Historique:
received:
06
09
2018
revised:
03
01
2019
accepted:
14
01
2019
pubmed:
19
1
2019
medline:
23
5
2020
entrez:
19
1
2019
Statut:
ppublish
Résumé
Peripheral nerve injury accounts for roughly 2.8% of all trauma patients with an annual cost of 7 billion USD in the U.S. alone. Current treatment options rely on surgical intervention with the use of an autograft, despite associated shortcomings. Engineered nerve guidance conduits, stem cell therapies, and transient electrical stimulation have reported to increase speeds of functional recovery. As an alternative to the conduction effects of electrical stimulation, we have designed and optimized a nerve guidance conduit with aligned microchannels for the sustained release of a small molecule drug that promotes nerve impulse conduction. A biodegradable chitosan structure reinforced with drug-loaded halloysite nanotubes (HNT) was formed into a foam-like conduit with interconnected, longitudinally-aligned pores with an average pore size of 59.3 ± 14.2 μm. The aligned composite with HNTs produced anisotropic mechanical behavior with a Young's modulus of 0.33 ± 0.1 MPa, very similar to that of native peripheral nerve. This manuscript reports on the sustained delivery of 4-Aminopyridine (4AP, molecular weight 94.1146 g/mol), a potassium-channel blocker as a growth factor alternative to enhance the rate of nerve regeneration. The conduit formulation released a total of 30 ± 2% of the encapsulated 4AP in the first 7 days. Human Schwann cells showed elevated expression of key proteins such as nerve growth factor, myelin protein zero, and brain derived neurotrophic factor in a 4AP dose dependent manner. Preliminary in vivo studies in a critical-sized sciatic nerve defect in Wistar rats confirmed conduit suturability and strength to withstand ambulatory forces over 4 weeks of their implantation. Histological evaluations suggest conduit biocompatibility and Schwann cell infiltration and organization within the conduit and lumen. These nerve guidance conduits and 4AP sustained delivery may serve as an attractive strategy for nerve repair and regeneration.
Identifiants
pubmed: 30658124
pii: S0168-3659(19)30031-8
doi: 10.1016/j.jconrel.2019.01.013
pmc: PMC6379151
mid: NIHMS1519270
pii:
doi:
Substances chimiques
Potassium Channel Blockers
0
Chitosan
9012-76-4
4-Aminopyridine
BH3B64OKL9
Clay
T1FAD4SS2M
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
54-67Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR055607
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB020640
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
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