Mechano-adaptive regenerative niches for orchestrating functional reinnervation of peripheral nerve defects

Abstract Transcending the paradigm of passive structural support, contemporary peripheral nerve repair pivots decisively toward the deliberate spatiotemporal programming of instructive microenvironments. Integrative evidence, synthesized from bibliometric landscapes and high-resolution single-cell transcriptomic atlases, has firmly established mechanotransduction as a preeminent regulatory hub, while concurrently resolving the injury-elicited mechanosensitive phenotypic landscapes. This evidence informs a mechano-adaptive niche-engineering framework that systematically deciphers how biophysical cues govern Schwann cell plasticity, directed axonal navigation, macrophage phenotypic re-polarization, vascular integration, and global tissue homeostasis. In this context, advanced additive manufacturing platforms, notably three- and four-dimensional biofabrication, serve as foundational cornerstones for constructing biomimetic niches endowed with spatiotemporally programmable and dynamically interactive features. Collectively, these mechanistic insights are rigorously codified into rational design blueprints, wherein stiffness gradients, topographical anisotropy, and dynamic mechanical actuation converge to define next-generation neural guidance conduits. In their clinical translation, adaptive, patient-conformal, and context-responsive biofabrication ecosystems constitute transformative modalities, propelling mechano-regenerative biomaterials toward a new vanguard in neural reinnervation.