Injectable pH-responsive Bletilla striata polysaccharide-sodium alginate hydrogel promoting peripheral nerve regeneration.

Within the clinical realm, the complex process of nerve regeneration following traumatic peripheral nerve injury (TPNI) remains a formidable challenge. Injectable multifunctional hydrogels that align with the highly orchestrated cascades of nerve regeneration have emerged as promising biomaterial strategies for the TPNI treatment. Here, we develop an injectable pH-responsive composite hydrogel (BSP-SA) based on physical interactions between Bletilla striata polysaccharide (BSP) and sodium alginate (SA). This system responds to the mildly acidic microenvironment of the injured nerve, enabling controlled release of BSP to promote peripheral nerve regeneration. The hydrogel exhibits shear-thinning injectability, high swelling ratio, excellent biocompatibility, and compatibility with soft tissue environments, supporting sustained BSP release. In a rat model of TPNI, treatment with the hydrogel significantly enhanced the axonal regrowth and myelination, ultimately facilitating functional recovery across sensory, motor, and sensorimotor coordination assessments. Transcriptomic analyses further implicate the Interleukin-1 beta/Matrix metalloprotease 13 (IL-1β/MMP-13) signaling pathway in Schwann cell-mediated regeneration, a mechanism validated through in vivo and in vitro experiments. Collectively, these findings present a pH-responsive hydrogel capable of spatiotemporal BSP delivery, offering a novel and translatable therapeutic platform for the treatment of TPNI.