Engineering spatially-confined conduits to tune nerve self-organization and allodynic responses via YAP-mediated mechanotransduction

Chronic allodynia stemming from peripheral stump neuromas can persist for extended periods, significantly compromising patients' quality of life. Conventional managements for nerve stumps have demonstrated limited effectiveness in ensuring their orderly termination. In this study, we present a spatially confined conduit strategy, designed to enhance the self-organization of regenerating nerves after truncation. This innovative approach elegantly enables the autonomous slowing of axonal outgrowth in response to the gradually constricting space, concurrently suppressing neuroinflammation through YAP-mediated mechanotransduction activation. Meanwhile, the decelerating axons exhibit excellent alignment and remyelination, thereby helping to prevent failure modes in nerve self-organization, such as axonal twisting in congested regions and overgrowth beyond the conduit's capacity. Overall design: To investigate the genetic mechanism of CC for pain relief, mRNA sequencing was performed on nerve stumps. These include control samples (CON), different gradients of truncated cone shaped conduits CC 4:2, 4:4 (labeled as EXP 42, EXP 44). Furthermore, to verify the effect of YAP, vertaporfin loaded groups (VP42) were also done.