Engineering Topographical Cues to Enhance Neural Regeneration in Spinal Cord Injury: Overcoming Challenges and Advancing Therapies

Abstract Spinal cord injury (SCI) poses significant challenges for regeneration due to a series of secondary injury mechanisms, including ischemia, oxidative stress, and neuroinflammation. These pathological processes lead to neuronal apoptosis and create a microenvironment that hinders neural regeneration. Recent advancements in tissue engineering have introduced biomaterials that feature precisely engineered micro‐ and nanoscale topographical cues, representing a novel class of therapeutic interventions. These biomimetic scaffolds are designed to modulate the mechanotransduction pathways of neural stem cells (NSCs), thereby enhancing neurogenesis and guiding neuronal differentiation. They also influence essential cellular processes such as adhesion, cytoskeletal alignment, morphological polarization, and gene regulation. This review systematically evaluates current strategies for optimizing topographical designs, emphasizing their role in promoting neurite outgrowth, axonal guidance, and synaptic reformation. The mechanisms are elucidated by which scaffold topographies regulate NSC fate decisions through mechanobiological signaling and interactions with the extracellular matrix. Additionally, critical barriers are analyzed for clinical translation, including the precision fabrication of tunable architectures, the scalability of novel materials, and strategies to mitigate glial scar formation. By synthesizing interdisciplinary insights from biomaterial science, neurobiology, and translational medicine, this work aims to provide a roadmap for developing next‐generation topographical scaffolds that address the pressing clinical need for effective SCI repair.