Conduits harnessing spatially controlled cell-secreted neurotrophic factors improve peripheral nerve regeneration

Aaron X Sun; Travis A Prest; John R Fowler; Rachel M Brick; Kelsey M Gloss; Xinyu Li; Michael DeHart; He Shen; Guang Yang; Bryan N Brown; Peter G Alexander; Rocky S Tuan

doi:10.1016/j.biomaterials.2019.01.038

Conduits harnessing spatially controlled cell-secreted neurotrophic factors improve peripheral nerve regeneration

Biomaterials. 2019 May:203:86-95. doi: 10.1016/j.biomaterials.2019.01.038. Epub 2019 Feb 19.

Authors

Aaron X Sun¹, Travis A Prest², John R Fowler³, Rachel M Brick⁴, Kelsey M Gloss⁴, Xinyu Li², Michael DeHart⁵, He Shen⁶, Guang Yang⁷, Bryan N Brown⁸, Peter G Alexander⁹, Rocky S Tuan¹⁰

Affiliations

¹ Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA.
² Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA.
³ Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴ Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁵ Department of Biology, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, China.
⁷ Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tissue Engineering & Biomaterials Lab, Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
⁸ Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁹ Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: pea9@pitt.edu.
¹⁰ Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA; Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: rst13@pitt.edu.

PMID: 30857644
DOI: 10.1016/j.biomaterials.2019.01.038

Abstract

An essential structure in nerve regeneration within engineered conduits is the "nerve bridge" initiated by centrally migrating Schwann cells in response to chemokine gradients. Introducing exogenous cells secreting neurotrophic factors aims to augment this repair process, but conventional cell-seeding methods fail to produce a directional chemokine gradient. We report a versatile method to encapsulate cells within conduit walls, allowing for reproducible control of spatial distribution along the conduit. Conduits with stem cells encapsulated within the central third possessed markedly different cell distribution and retention over 6 weeks in vivo, compared to standard cell lumen injection. Such a construct promoted Schwann cell migration centrally, and at 16 weeks rats presented with significantly enhanced function and axonal myelination. The method of utilizing a spatially restricted cell secretome departs from traditional homogeneous cell loading, and presents new approaches for studying and maximizing the potential of cell application in peripheral nerve repair.

Keywords: Mesenchymal stem cells; Nerve conduit; Peripheral nerve repair; Schwann cell distribution; Wall encapsulation.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cytoskeleton / metabolism
Guided Tissue Regeneration / methods
Hydrogels / chemistry
Immunohistochemistry
Mesenchymal Stem Cells / cytology
Mesenchymal Stem Cells / metabolism
Nerve Growth Factors / metabolism*
Nerve Regeneration / physiology*
Rats
Schwann Cells / cytology
Schwann Cells / metabolism
Sciatic Nerve / cytology
Sciatic Nerve / physiology
Tissue Engineering / methods
Tissue Scaffolds / chemistry

Substances

Hydrogels
Nerve Growth Factors

Grants and funding

T32 EB001026/EB/NIBIB NIH HHS/United States