Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates
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...
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Published in | Science translational medicine Vol. 12; no. 527 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
22.01.2020
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Abstract | 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. |
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AbstractList | 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. |
Author | Waldner, Matthias DiBernardo, Gabriella A Sivak, Wesley N Fadia, Neil B Bliley, Jacqueline M Spiess, Alexander M Washington, Kia M Mahoney, Christopher M Liao, Han-Tsung Guevara, Astrid A Brooker, Jack E Cottrill, Adam R Repko, Alexander J Tompkins-Rhoades, Casey Bourne, Debra A Gause, 2nd, Trent Marra, Kacey G Josyula, Tvisha Schweizer, Riccardo Schilling, Benjamin K James, Isaac B Campwala, Insiyah K Simpson, Tyler Panagis, George E Weber, Douglas J Minteer, Danielle M Asher Schusterman, 2nd, M Crammond, Donald J Egro, Francesco M Kim, Deok-Yeol |
Author_xml | – sequence: 1 givenname: Neil B orcidid: 0000-0002-9328-9215 surname: Fadia fullname: Fadia, Neil B organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 2 givenname: Jacqueline M orcidid: 0000-0002-6605-9916 surname: Bliley fullname: Bliley, Jacqueline M organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 3 givenname: Gabriella A orcidid: 0000-0001-8022-7288 surname: DiBernardo fullname: DiBernardo, Gabriella A organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 4 givenname: Donald J surname: Crammond fullname: Crammond, Donald J organization: Department of Neurosurgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 5 givenname: Benjamin K orcidid: 0000-0002-5509-0803 surname: Schilling fullname: Schilling, Benjamin K organization: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 6 givenname: Wesley N surname: Sivak fullname: Sivak, Wesley N organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 7 givenname: Alexander M orcidid: 0000-0001-8677-6181 surname: Spiess fullname: Spiess, Alexander M organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 8 givenname: Kia M surname: Washington fullname: Washington, Kia M organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 9 givenname: Matthias orcidid: 0000-0002-7123-4205 surname: Waldner fullname: Waldner, Matthias organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 10 givenname: Han-Tsung surname: Liao fullname: Liao, Han-Tsung organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 11 givenname: Isaac B surname: James fullname: James, Isaac B organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 12 givenname: Danielle M orcidid: 0000-0002-4853-9385 surname: Minteer fullname: Minteer, Danielle M organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 13 givenname: Casey surname: Tompkins-Rhoades fullname: Tompkins-Rhoades, Casey organization: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 14 givenname: Adam R orcidid: 0000-0001-6800-3038 surname: Cottrill fullname: Cottrill, Adam R organization: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 15 givenname: Deok-Yeol orcidid: 0000-0001-6288-6597 surname: Kim fullname: Kim, Deok-Yeol organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 16 givenname: Riccardo surname: Schweizer fullname: Schweizer, Riccardo organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 17 givenname: Debra A surname: Bourne fullname: Bourne, Debra A organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 18 givenname: George E orcidid: 0000-0002-9752-2942 surname: Panagis fullname: Panagis, George E organization: Department of Biology, University of Pittsburgh, Greensburg, PA 15601, USA – sequence: 19 givenname: M orcidid: 0000-0002-7960-5613 surname: Asher Schusterman, 2nd fullname: Asher Schusterman, 2nd, M organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 20 givenname: Francesco M orcidid: 0000-0003-1536-7713 surname: Egro fullname: Egro, Francesco M organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 21 givenname: Insiyah K orcidid: 0000-0002-7999-8197 surname: Campwala fullname: Campwala, Insiyah K organization: Department of Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 22 givenname: Tyler surname: Simpson fullname: Simpson, Tyler organization: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 23 givenname: Douglas J orcidid: 0000-0002-9782-3497 surname: Weber fullname: Weber, Douglas J organization: McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA – sequence: 24 givenname: Trent surname: Gause, 2nd fullname: Gause, 2nd, Trent organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 25 givenname: Jack E surname: Brooker fullname: Brooker, Jack E organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 26 givenname: Tvisha orcidid: 0000-0002-4345-5318 surname: Josyula fullname: Josyula, Tvisha organization: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 27 givenname: Astrid A surname: Guevara fullname: Guevara, Astrid A organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 28 givenname: Alexander J surname: Repko fullname: Repko, Alexander J organization: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 29 givenname: Christopher M orcidid: 0000-0003-3617-1218 surname: Mahoney fullname: Mahoney, Christopher M organization: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA – sequence: 30 givenname: Kacey G orcidid: 0000-0002-8437-4864 surname: Marra fullname: Marra, Kacey G email: marrak@upmc.edu organization: McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA |
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ContentType | Journal Article |
Copyright | Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. |
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Snippet | Severe injuries to peripheral nerves are challenging to repair. Standard-of-care treatment for nerve gaps >2 to 3 centimeters is autografting; however,... |
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SubjectTerms | 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 |
Title | Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates |
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