Peripheral nerve injury repair by electrical stimulation combined with graphene-based scaffolds

Abstract

Peripheral nerve injury (PNI) is a common clinical problem, which due to poor recovery often leads to limb dysfunction and sensory abnormalities in patients. Tissue-engineered nerve guidance conduits (NGCs) that are designed and fabricated from different materials are the potential alternative to nerve autografts. However, translation of these NGCs from lab to commercial scale has not been well achieved. Complete functional recovery with the aid of NGCs in PNI becomes a topic of general interest in tissue engineering and regeneration medicine. Electrical stimulation (ES) has been widely used for many years as an effective physical method to promote nerve repair in both pre-clinical and clinical settings. Similarly, ES of conductive and electroactive materials with a broad range of electrical properties has been shown to facilitate the guidance of axons and enhance the regeneration. Graphene and its derivatives possess unique physicochemical and biological properties, which make them a promising outlook for the development of synthetic scaffolds or NGCs for PNI repair, especially in combination with ES. Considering the discussion regarding ES for the treatment of PNI must continue into further detail, herein, we focus on the role of ES in PNI repair and the molecular mechanism behind the ES therapy for PNI, providing a summary of recent advances in context of graphene-based scaffolds (GBSs) in combination with ES. Future perspectives and some challenges faced in developing GBSs are also highlighted with the aim of promoting their clinical applications.

Keywords: electrical stimulation; graphene-based scaffolds; nerve regeneration; neural tissue engineering; peripheral nerve injury.

FIGURE 1

Schematic representation of degeneration and regeneration after PNI.

FIGURE 2

Possible pathways related to biological responses to electrical stimulation. GF, growth factor; GR, growth receptor; CaM, calmodulin; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol-3 kinase; PTEN, phosphate and tensin homolog; Src, steroid receptor coactivator; YAP, yes-associated protein; TAZ, transcriptional coactivator with PDZ-binding motif; ROCK, Rho-associated protein kinase; MAP, microtubules-associated protein; mTOR, mammalian target of rapamycin; FOX1: forkhead box protein 1; GSK3β, glycogen synthase kinase-3. Adapted with permission from Ref (Liu et al., 2021). Copyright 2021, John Wiley and Sons.

FIGURE 3

(A) Schematic diagram of graphene. Adapted with permission from Ref (Bellier et al., 2022). Copyright 2022, Springer Link. (B) Manufacture of PLCL and GN films with stripe micropatterns and PDA modification and their in vitro and in vivo applicability to accelerate nerve regeneration. Adapted with permission from Ref (Lu et al., 2023). Copyright 2023, John Wiley and Sons. (C) SCs are subjected to ES on graphene/TPU composites, and a direct current of 10 mV is more suitable for the growth and proliferation of SCs. (a) SCs stained with AO/EB. (b) MTT result for SCs proliferation with different voltage. (c) LSCM for SCs with the ES of 10 and 100 mV DC. Adapted with permission from Ref (Huang et al., 2019). Copyright 2019, Royal Society of Chemistry. (D) ES accelerates the migration of rat MSCs inoculated with GCFS, and significantly enhances the regeneration and functional recovery of the sciatic nerve implanted with GCFS nerve-guided conduit. Adapted with permission from Ref (Dong et al., 2020). Copyright 2020, Elsevier.

FIGURE 4

(A) Schematic diagram of GO. Adapted with permission from Ref (Bellier et al., 2022). Copyright 2022, Springer Link. (B) SEM images of (a) PLLA fiber-film, (b) DBS-doped CCF, (c) DBS-GO-doped CCF, (d) DBS-CFGO-doped CCF. Adapted with permission from Ref (Shang et al., 2019). Copyright 2019, American Chemical Society. (C) Immunofluorescent images and SEM images of neurites from PC-12 cells on three CCFs with ES: (a,b) DBS-doped CCF, (c,d) DBS-GO-doped CCF, (e,f) DBS-CFGO-doped CCF. (g) Neurite alignment percentage. (h) Neurite length of PC-12 cells. Adapted with permission from Ref (Shang et al., 2019). Copyright 2019, American Chemical Society. (D) ES promotes the alignment of SCs along the current direction on PDA/CGO/PPy PLLA membranes. Adapted with permission from Ref (Li et al., 2020). Copyright 2020, Elsevier.

FIGURE 5

(A) Schematic diagram of rGO. Adapted with permission from Ref (Bellier et al., 2022). Copyright 2022, Springer Link. (B) Preparation of graphene IDEs and differentiation of MSC under ES. Adapted with permission from Ref (Aznar-Cervantes et al., 2017). Copyright 2017, John Wiley and Sons. (C) AP/rGO scaffold enhances the migration, proliferation, and myelin formation of SCs. PC-12 cells cultured on the conductive AP/RGO scaffold exhibit high differentiation after ES. AP/RGO neural guide conduit promotes nerve regeneration in vivo. Adapted with permission from Ref (Wang et al., 2019). Copyright 2019, Elsevier. (D) PC-12 cells cultivated with rGO-coated NF demonstrate neurogenicity upon ES. Nerve guidance conduit containing the assembly of rGO-coated NF and ADSC promote the recovery of sciatic nerve injury. Adapted with permission from Ref (Mao et al., 2023). Copyright 2023, Elsevier.