Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates

• Published in: Science translational medicine Vol. 12; no. 527
• Main Authors: Fadia, Neil B, Bliley, Jacqueline M, DiBernardo, Gabriella A, Crammond, Donald J, Schilling, Benjamin K, Sivak, Wesley N, Spiess, Alexander M, Washington, Kia M, Waldner, Matthias, Liao, Han-Tsung, James, Isaac B, Minteer, Danielle M, Tompkins-Rhoades, Casey, Cottrill, Adam R, Kim, Deok-Yeol, Schweizer, Riccardo, Bourne, Debra A, Panagis, George E, Asher Schusterman, 2nd, M, Egro, Francesco M, Campwala, Insiyah K, Simpson, Tyler, Weber, Douglas J, Gause, 2nd, Trent, Brooker, Jack E, Josyula, Tvisha, Guevara, Astrid A, Repko, Alexander J, Mahoney, Christopher M, Marra, Kacey G
• Format: Journal Article
• Language: English
• Published: United States 22.01.2020
• Subjects: Animals; Axons - drug effects; Axons - metabolism; Delayed-Action Preparations; Glial Cell Line-Derived Neurotrophic Factor - administration & dosage; Glial Cell Line-Derived Neurotrophic Factor - chemistry; Glial Cell Line-Derived Neurotrophic Factor - pharmacology; Macaca; Nerve Regeneration - drug effects; Nerve Regeneration - physiology; Schwann Cells - drug effects; Schwann Cells - metabolism
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aav7753

Severe injuries to peripheral nerves are challenging to repair. Standard-of-care treatment for nerve gaps >2 to 3 centimeters is autografting; however, autografting can result in neuroma formation, loss of sensory function at the donor site, and increased operative time. To address the need for a synthetic nerve conduit to treat large nerve gaps, we investigated a biodegradable poly(caprolactone) (PCL) conduit with embedded double-walled polymeric microspheres encapsulating glial cell line-derived neurotrophic factor (GDNF) capable of providing a sustained release of GDNF for >50 days in a 5-centimeter nerve defect in a rhesus macaque model. The GDNF-eluting conduit (PCL/GDNF) was compared to a median nerve autograft and a PCL conduit containing empty microspheres (PCL/Empty). Functional testing demonstrated similar functional recovery between the PCL/GDNF-treated group (75.64 ± 10.28%) and the autograft-treated group (77.49 ± 19.28%); both groups were statistically improved compared to PCL/Empty-treated group (44.95 ± 26.94%). Nerve conduction velocity 1 year after surgery was increased in the PCL/GDNF-treated macaques (31.41 ± 15.34 meters/second) compared to autograft (25.45 ± 3.96 meters/second) and PCL/Empty (12.60 ± 3.89 meters/second) treatment. Histological analyses included assessment of Schwann cell presence, myelination of axons, nerve fiber density, and -ratio. PCL/GDNF group exhibited a statistically greater average area occupied by individual Schwann cells at the distal nerve (11.60 ± 33.01 μm ) compared to autograft (4.62 ± 3.99 μm ) and PCL/Empty (4.52 ± 5.16 μm ) treatment groups. This study demonstrates the efficacious bridging of a long peripheral nerve gap in a nonhuman primate model using an acellular, biodegradable nerve conduit.