Scaffold design considerations for peripheral nerve regeneration

Abstract

Peripheral nerve injury (PNI) represents a serious clinical and public health problem due to its high incurrence and poor spontaneous recovery. Compared to autograft, which is still the best current practice for long-gap peripheral nerve defects in clinics, the use of polymer-based biodegradable nerve guidance conduits (NGCs) has been gaining momentum as an alternative to guide the repair of severe PNI without the need of secondary surgery and donor nerve tissue. However, simple hollow cylindrical tubes can barely outperform autograft in terms of the regenerative efficiency especially in critical sized PNI. With the rapid development of tissue engineering technology and materials science, various functionalized NGCs have emerged to enhance nerve regeneration over the past decades. From the aspect of scaffold design considerations, with a specific focus on biodegradable polymers, this review aims to summarize the recent advances in NGCs by addressing the onerous demands of biomaterial selections, structural designs, and manufacturing techniques that contributes to the biocompatibility, degradation rate, mechanical properties, drug encapsulation and release efficiency, immunomodulation, angiogenesis, and the overall nerve regeneration potential of NGCs. In addition, several commercially available NGCs along with their regulation pathways and clinical applications are compared and discussed. Lastly, we discuss the current challenges and future directions attempting to provide inspiration for the future design of ideal NGCs that can completely cure long-gap peripheral nerve defects.

Keywords: nerve guidance conduits; peripheral nerve regeneration; scaffold design; tissue engineering.

Figure 1.

Illustration of peripheral nerve degeneration and regeneration after injury. Peripheral nerves possess self-repairing ability due to actions of immune cells and SCs. Axons regrow in the defect area with the guide of ‘bands of Büngner’, which was formed by highly ordered SCs. In the scenario while the ‘bands of Büngner’ failed to form, new axons cannot cross the whole defect area and functional recovery is unsuccessful. NGCs are therefore required to better guide the regrowth of axons from the proximal end to the distal end of the never tissue. Created with BioRender.com.

Figure 2.

Illustration of cross-sectional anatomy of a peripheral nerve trunk. The entire nerve trunk mainly consists of three different layers of connective tissues and signal-transmission fascicles, which were formed by bundles of myelinated or unmyelinated axons. Created with BioRender.com.

Figure 3.

Different scaffold designs of NGCs. (A) and (B), single channel solid and porous hollow NGCs. Reproduced from [102]. © IOP Publishing Ltd All rights reserved. (C), single channel hollow NGCs with inner pattern (grooves). [212] John Wiley & Sons. © 2023 Wiley-VCH GmbH (D), single channel porous NGC with luminal filler. [213] John Wiley & Sons. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (E) multilayered porous single channel hollow NGCs. Reproduced from [214]. CC BY 4.0. Reprinted from [8], Copyright (2020), with permission from Elsevier. (F): multichannel NGCs with several (F-a). [109] John Wiley & Sons. © 2013 Wiley Periodicals, Inc. or hundreds of (F-b) Reproduced from [106]. CC BY 4.0 microchannels. (G): 3D printed customized NGCs with (a) single channel, (b) multichannel, (c) bifurcated, and (d), (e), human life-size NGC mimicking the human facial nerve system. Reprinted from [101], Copyright (2018), with permission from Elsevier.

Figure 4.

Different Fabrication techniques of NGCs. (A), Solvent casting. Reprinted from [219], Copyright (2021), with permission from © 2021 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd (B), Dip-coating. Reproduced from [220]. CC BY 3.0. Copyright © 2010 Shanfeng Wang and Lei Cai. (C), Unidirectional lyophilization. Reprinted from [219], Copyright (2021), with permission from © 2021 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd (D), Electrospinning. Reprinted with permission from [221]. Copyright (2020) American Chemical Society. (E), 3D printing. Reprinted from [101], Copyright (2018), with permission from Elsevier. (F). Biomimetic. Reproduced from [174]. © The Author(s). Published by IOP Publishing Ltd CC BY 4.0. (G). Wrapping/rolling. Reproduced from [106]. CC BY 4.0