Implications of tensile loading for the tissue engineering of nerves

Nerves and neurons undergo tensile loading, or stretch, in many scenarios, including development and growth, normal joint movement, nerve injury and disease, and orthopedic surgery. The response of the nervous system to such loading is modulated by the conditions of loading. Within an empirically determined range of strains and strain rates, tensile loading holds the potential to accelerate axonal growth. On the other hand, exceeding these limits can damage the nerve, resulting in the dysfunction of sensory and motor systems. Understanding and pushing the limits of nerve stretch holds tremendous potential for tissue engineering efforts to prevent nervous system injury and facilitate nerve repair. This review aims to elucidate the phenomenon of nerve stretch in the peripheral nervous system and in the spinal cord. At the tissue level, we summarize the biomechanical, structural, and functional responses of nerves to tensile loading, in vitro, in situ, and in vivo. Further, we identify a range of strains and strain rates at which the nervous response transits from a regime of growth to injury. At the cell level, we assess the structural and functional plasticity of the neuron under tensile loading conditions that promote growth. We also review extrinsic factors that modulate cellular processes underlying neuronal growth. We propose that these pathways may be exploited during tensile loading to promote axonal growth. Finally, we review recent efforts that examine the tensile loading of nerves in the context of clinical problems such as limb lengthening surgeries and nerve regeneration.