Aberrant mechanosensing in injured intervertebral discs as a result of boundary-constraint disruption and residual-strain loss

In fibrous tissues, pre-stressed boundary constraints at bone interfaces instil residual strain throughout the tissue, even when unloaded. For example, internal swelling pressures in the central nucleus pulposus of the intervertebral disc generate pre-strain in the outer annulus fibrosus. With injury and depressurization, these residual strains are lost. Here, we show that the loss of residual strains in the intervertebral disc alters the microenvironment and instigates aberrant tissue remodelling and the adoption of atypical cellular phenotypes. By using puncture surgery of the annulus fibrosus in rabbits, ex vivo puncture experiments, and electrospun nanofibrous scaffolds recapitulating evolving boundary constraints, we show that the loss of residual strain promotes short-term apoptosis and the emergence of a fibrotic phenotype, that local fibre organization and cellular contractility mediate this process, and that the aberrant cellular changes could be abrogated by targeting the cell-mechanosensing machinery with small molecules. Our findings indicate that injury to dense connective tissues under pre-strain alters boundary constraints and residual strain, leading to aberrant mechanosensing, which in turn promotes disease progression.