QK@CM-CTS/OCS-DA hydrogel repairs rat sciatic nerve injury by reprogramming inflammation and promoting regeneration

Effective repair of peripheral nerve injury (PNI) is severely hampered by a dysregulated inflammatory microenvironment and a lack of sufficient bioactive components to support regeneration. Current hydrogel-based strategies often fall short, failing to concurrently offer dynamic responsiveness, neural biomimicry, and robust inflammation regulation. This gap limits their ability to create an optimal microenvironment for nerve healing. Understanding how to modulate the immune response, particularly macrophage polarization, and provide sustained trophic support is crucial for advancing PNI therapies.

Researchers engineered a biomimetic supramolecular hydrogel, QK@CM-CTS/OCS-DA, through the reversible self-assembly of carboxymethyl chitosan (CM-CTS) and oxidized chondroitin sulfate (OCS). This innovative design enabled the sequential release of a vascular endothelial growth factor mimetic peptide (QK) and dopamine (DA). The hydrogel was characterized for its injectability, rapid self-healing, structural stability, appropriate mechanical strength, and favorable cytocompatibility. For in vivo evaluation, the QK@CM-CTS/OCS-DA hydrogel was implanted into injured rat sciatic nerves. The study assessed its ability to modulate the immune microenvironment, promote cellular processes like Schwann cell migration and axonal extension, and ultimately restore nerve function. Degradation was monitored over 6 weeks.

The QK@CM-CTS/OCS-DA hydrogel demonstrated significant therapeutic effects in a rat model of sciatic nerve injury. Crucially, in vivo implantation elicited no discernible inflammatory response, and the hydrogel achieved near-complete degradation within 6 weeks. The dual-agent release mechanism proved effective: the initial burst release of the QK peptide potently modulated macrophage polarization toward an anti-inflammatory M2 phenotype and drove early angiogenesis. Subsequently, the sustained release of dopamine synergized with the CM-CTS/OCS matrix to significantly promote Schwann cell migration, axonal extension, and myelination. This orchestrated action led to comprehensive functional recovery. > The QK@CM-CTS/OCS-DA hydrogel successfully repaired the injured rat sciatic nerve, significantly attenuated gastrocnemius atrophy, promoted remyelination, and restored both conduction function and motor function. Beyond modulating inflammation and immune responses, the hydrogel also effectively enhanced energy supply, creating a highly favorable microenvironment for peripheral nerve regeneration.