Biomaterials Combined With Physical Modulation Strategies for Spinal Cord Injury Repair: Material Design, Mechanism, and Challenges.

Spinal cord injury (SCI) causes persistent neurological deficits because primary damage initiates dynamic secondary cascades that restrict endogenous repair. Functional biomaterials can bridge lesions, provide structural and biochemical support, guide axonal growth, and remodel the inhibitory microenvironment. However, their cues are generally static or slowly evolving and cannot match the changing pathological and electrophysiological states of injured tissue. Physical modulation complements these functions by delivering electrical, magnetic, ultrasonic, optical/photothermal, or mechanical cues that regulate neural excitability, inflammation, axonal growth, remyelination, and plasticity. Nevertheless, physical modulation alone may suffer from imprecise localization, variable tissue-level dosing, and insufficient structural support. This review examines integrated biomaterial-physical modulation strategies for SCI repair, focusing on material design, mechanisms, and translational challenges. Conductive hydrogels couple lesion support with localized electrical signaling, whereas compliant electrodes improve tissue conformity and charge delivery. Piezoelectric and magnetically responsive materials convert external inputs into localized electrical or mechanical cues. Optical/photothermal systems combine localized energy conversion with on-demand release, whereas engineered matrices link structural support to mechanotransduction. Across these strategies, biomaterials act as regenerative scaffolds and active interfaces that localize, transmit, convert, and sustain physical signals. Physical inputs dynamically regulate cellular and molecular responses within this material-supported environment. This integration couples structural reconstruction and microenvironmental regulation with spatiotemporally controlled biophysical signaling, constituting the central mechanistic basis of these integrated systems. Translation requires standardized tissue-level dosing, evaluation of degradation-dependent signal stability and biocompatibility, cross-species scaling, and validation in relevant large-animal models. Stimuli-responsive materials and closed-loop systems represent important future directions. Overall, benefit depends not on simply adding stimulation to a scaffold, but on engineering coordinated material-stimulus systems. In such systems, material design controls where, when, and how physical cues are delivered during spinal cord regeneration.