Hydrogel system with growth cone-targeted hydroxyapatite nanorods: Regulating calcium signals for peripheral nerve injury repair

Calcium (Ca²⁺) regulation assumes a critical role in the repair course of peripheral nerve injury (PNI). However, effective calcium sources capable of providing sustained Ca²⁺ signals to promote growth cone extension remain limited. Herein, the coupling of biotinylated dextran amine (BDA) to amine-functionalized hydroxyapatite nanorods (nHAP-NH₂) remarkably promoted and maintained the extension of growth cones throughout nerve regeneration. Therefore, a newly developed therapeutic system for PNI was constructed based on a hydrogel (Gel) loaded with BDA-nHAP (nHAP-NH₂ with surface modification of BDA) and vascular endothelial growth factor (VEGF). The sustained-release BDA-nHAP has the potential to continuously and targetedly increase the Ca²⁺ levels within the growth cone, and further boost neurite outgrowth by modulating the PI3K-PAK and MAPK signalling pathways. Moreover, VEGF can significantly promote angiogenesis in the early stage of nerve repair, which is critical for optimizing the functional efficacy of BDA-nHAP in enhancing neurogenesis. Thus, this innovative integrated therapeutic system with neurogenesis and angiogenesis capabilities may offer a new solution for achieving high-quality functional recovery from PNI. STATEMENT OF SIGNIFICANCE: For PNI, there remains a scarcity of effective calcium sources capable of providing sustained Ca²⁺ signals within the growth cone to enhance its extension. Herein, a newly developed therapeutic system for PNI was constructed based on a Gel loaded with BDA-nHAP and VEGF. The sustained-release BDA-nHAP has the potential to continuously and targetedly increase the Ca²⁺ levels within the growth cone, and further boost neurite outgrowth throughout the whole process of nerve regeneration. Moreover, VEGF can significantly promote angiogenesis in the early stage of nerve repair, which is critical for optimizing the functional efficacy of BDA-nHAP in enhancing neurogenesis. Thus, this innovative therapeutic system may offer a new solution for achieving high-quality functional recovery from PNI.