Electroceuticals for peripheral nerve regeneration

Abstract

Electroceuticals provide promising opportunities for peripheral nerve regeneration, in terms of modulating the extensive endogenous tissue repair mechanisms between neural cell body, axons and target muscles. However, great challenges remain to deliver effective and controllable electroceuticals via bioelectronic implantable device. In this review, the modern fabrication methods of bioelectronic conduit for bridging critical nerve gaps after nerve injury are summarized, with regard to conductive materials and core manufacturing process. In addition, to deliver versatile electrical stimulation, the integration of implantable bioelectronic device is discussed, including wireless energy harvesters, actuators and sensors. Moreover, a comprehensive insight of beneficial mechanisms is presented, including up-to-datein vitro, in vivoand clinical evidence. By integrating conductive biomaterials, 3D engineering manufacturing process and bioelectronic platform to deliver versatile electroceuticals, the modern biofabrication enables comprehensive biomimetic therapies for neural tissue engineering and regeneration in the new era.

Keywords: conductive conduit; electrical stimulation; electroceuticals; nerve conduit; peripheral nerve regeneration.

Figure 1.

Current treatment options for promoting PNR. The state-of-art of multi-modality approaches to repair or reconstruct PNI include surgical, non-surgical and physical stimulation. Surgical intervention includes all kinds of microsurgical repair, nerve graft, nerve/muscle transfer. Non-surgical approach includes pharmaceuticals, various synthetic growth factors and cell-based therapies. Physical stimulation consists of optogenetics, ultrasound, microwave, radiofrequency and electroceuticals. Biomaterial approaches include synthetic NGCs, hydrogel and controlled release drug-containing vehicles.

Figure 2.

Current evidence of electroceuticals for PNR. (a) Therapeutic stimulation parameters and application of brief ES. (b) Proposed mechanism of peripheral nerve ES. (c) Current established in vivo evidence for transection/crush injuries at sciatic/femoral nerves of rodent and rabbits. (d) Current human evidence among median nerve [64], digital nerve [34], spinal accessory nerve [75] and ulnar nerve [76]. (e) Choice of NGC with electroceuticals.

Figure 3.

The in vitro and in vivo beneficial effects of neural regeneration with combined conductive conduit and ES. (a) Neural cell response on the electrical field; in vitro. Illustration of various cell activity by ES on the conductive substrate. Reprinted from [107], Copyright (2019) with permission from Elsevier. (b) Electroceuticals to accelerate nerve repair; in vivo. Illustration of phenomena by ES in sciatic nerve repair. From [112] Reprinted with permission from AAAS. Reprinted from [107], Copyright (2019) with permission from Elsevier.

Figure 4.

Various methods of constructing a nerve guidance conduit (NGC) with a cylindrical structure comprising single or multi-channel. (a) Mold casting; (i) representative illustration of the injection molding process and microstructure image of the manufactured conduit. Reprinted with permission from [140]. Copyright (2017) American Chemical Society. (ii) NGCs tube manufactured in various shapes according to the size and number of cores and location. Reprinted with permission from [141]. Copyright (2017) American Chemical Society. (b) Roll-up sheet; (i) schematic diagram of the rolled-up process using sheet and rod spacer (above) and manufactured conduit (below). [142] John Wiley & Sons. [original copyright notice]. (ii) Approach using electrospun shape memory nanofibers. The sheet keeps temporarily plane and then triggered by a physical temperature at 37 ° C to form a cylindrical conduit. Reprinted with permission from [143]. Copyright (2020) American Chemical Society. (c) Electrospinning; (i) illustration of dual electrospinning method. [142] John Wiley & Sons. [Original copyright notice]. Nano network conduits can be produced by jetting a polymer solution through a capillary nozzle with high voltage and depositing nanofibers in the collector. (ii) Photograph and microstructure of the electrospun NGCs. Reprinted from [144], Copyright (2019), with permission from Elsevier. (d) Co-axial extrusion; (i) schematic diagram of co-axial extrusion using a dual nozzle composed of inner and outer nozzles. Reproduced from [145], with permission from Springer Nature. (ii) The tube structure is produced by removing the core part of the extruded cylindrical filament. [146] Taylor & Francis Ltd. http://tandfonline.com. (e) Additive manufacturing (3D printing); (i) nozzle extrusion-based 3D plotting technique according to designed toolpath. [147] John Wiley & Sons. [Original copyright notice]. Reprinted with permission from [148]. Copyright (2015) American Chemical Society. (ii) Schematic diagram of the stereolithography based additive manufacturing using photocurable solution. Reprinted from [149], Copyright (2019), with permission from Elsevier. Stereolithography can provide customized therapy options for complex-shaped nerves defect. [150] John Wiley & Sons. [Original copyright notice]. Optical image of 3D printed NGCs, which has high flexibility. Reprinted from [151], Copyright (2018), with permission from Elsevier.

Figure 5.

Integration between bioelectronics conduit and wireless platforms to efficient energy transmittance for improving neural regeneration. (a) Energy harvester with wireless control; (i) ultrasound-based wireless platform. © 2018 IEEE. Reprinted, with permission, from [158]. (ii) The induced current by radiofrequency (RF) signal from an external coil. Reproduced from [159], with permission from Springer Nature. (iii) Optogenetic wirelessly powered device by near-infrared (NIR) light. Reprinted from [160], Copyright (2021), with permission from Elsevier. (b) Actuator; (i) ultrasound-driven piezoelectric thin film nanogenerator. Reprinted from [161], Copyright (2021), with permission from Elsevier. (ii) Stretchable, bioresorbable electronic stimulator worked by induced current. Reproduced from [162], with permission from Springer Nature. (iii) Compact optical nerve cuff electrode for neural stimulation and monitoring. Reproduced from [163], with permission from Springer Nature. (c) Sensor; (i) nervous recording system with ultrasonic neural dust. Reprinted from [164], Copyright (2016), with permission from Elsevier. (ii) Long-term nerve impedance monitoring microsystem. © 2013 IEEE. Reprinted, with permission, from [165]. (iii) Multi-sites long-term recording electrodes. Reproduced from [166]. © IOP Publishing Ltd. All rights reserved.