Biomechanical microenvironment in peripheral nerve regeneration: from pathophysiological understanding to tissue engineering development

Abstract

Peripheral nerve injury (PNI) caused by trauma, chronic disease and other factors may lead to partial or complete loss of sensory, motor and autonomic functions, as well as neuropathic pain. Biological activities are always accompanied by mechanical stimulation, and biomechanical microenvironmental homeostasis plays a complicated role in tissue repair and regeneration. Recent studies have focused on the effects of biomechanical microenvironment on peripheral nervous system development and function maintenance, as well as neural regrowth following PNI. For example, biomechanical factors-induced cluster gene expression changes contribute to formation of peripheral nerve structure and maintenance of physiological function. In addition, extracellular matrix and cell responses to biomechanical microenvironment alterations after PNI directly trigger a series of cascades for the well-organized peripheral nerve regeneration (PNR) process, where cell adhesion molecules, cytoskeletons and mechanically gated ion channels serve as mechanosensitive units, mechanical effector including focal adhesion kinase (FAK) and yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) as mechanotransduction elements. With the rapid development of tissue engineering techniques, a substantial number of PNR strategies such as aligned nerve guidance conduits, three-dimensional topological designs and piezoelectric scaffolds emerge expected to improve the neural biomechanical microenvironment in case of PNI. These tissue engineering nerve grafts display optimized mechanical properties and outstanding mechanomodulatory effects, but a few bottlenecks restrict their application scenes. In this review, the current understanding in biomechanical microenvironment homeostasis associated with peripheral nerve function and PNR is integrated, where we proposed the importance of balances of mechanosensitive elements, cytoskeletal structures, mechanotransduction cascades, and extracellular matrix components; a wide variety of promising tissue engineering strategies based on biomechanical modulation are introduced with some suggestions and prospects for future directions.

A Novel Magnetic Responsive miR‐26a@SPIONs‐OECs for Spinal Cord Injury: Triggering Neural Regeneration Program and Orienting Axon Guidance in Inhibitory Astrocytic Environment

“…[25] In the context of successful CNS regeneration, transplanted OECs must cross the OEC-astrocyte boundary and form an aligned structure that guides regenerating axons to their target. Over the past few decades, several strategies, such as the use of aligned-structure biomaterials, [4a] chemotactic induction, [26] and physical cues [27] have been proposed to enhance local cell orientation. Despite these efforts, orienting cell migration and alignment in the CNS remains a significant challenge due to the formation of OEC-astrocyte borders.…”

Immune-cell-mediated tissue engineering strategies for peripheral nerve injury and regeneration

“…[3][4][5] The dynamic biochemical microenvironment homeostasis is balanced by the extracellular matrix network, blood vessels, and lymphatic vessels in connective tissues from the macroscopic level, as well as cell adhesion molecules, cytokines, chemokines secreted by Schwann cells (SCs), fibroblast cells, endothelial cells, and various immune cells at the microscopic level. [6][7][8][9] The anatomical structure of the peripheral nerve consists of bundles of longitudinal axons with or without myelinated glial cells (known as SCs) that are surrounded by three-layer membrane structures, namely, the endoneurium, perineurium, and epineurium, from the inside to the outside, respectively (Fig. 1(A)).…”

Emerging 4D fabrication of next-generation nerve guiding conduits: a critical perspective

“…Tissue-engineered nerve conduits (TENCs) can provide more sophisticated versions of scaffolding for nerve grafts that can enhance the process of regeneration by reducing neuromas, scars, and lateral germination, without any donor site morbidity and limitations in the availability of grafts. [15][16][17][18] They facilitate regeneration through alignment of the distal and proximal ends of the injured nerve and protect it from overgrowth of the surrounding fibrous tissue. For instance, cell sheet-based pre-vascularized hollow grafts can promote rapid vascularization of nerve conduits providing efficient recovery of motor functions compared to autografts.…”