An injectable heparin-Laponite hydrogel bridge FGF4 for spinal cord injury by stabilizing microtubule and improving mitochondrial function

Abstract

<b>Rationale:</b> Spinal cord injury (SCI) remains a critical clinical challenge. The controlled release of FGF4, a novel neuroprotective factor, from a versatile Laponite hydrogel to the injured site was a promising strategy to promote axon regeneration and motor functional recovery after SCI. <b>Methods:</b> Characterization of Laponite, Laponite/Heparin (Lap/Hep) and Laponite/Heparin loaded with FGF4 (Lap/Hep@FGF4) hydrogels were measured by rheometer. Multiple comprehensive evaluations were used to detect motor functional recovery and the axonal rehabilitation after Lap/Hep@FGF4 treatment <i>in vivo</i> (SCI rat model). Moreover, microtubule dynamic and energy transportation, which regulated axonal regeneration was evaluated by Lap/Hep@FGF4 gel <i>in vitro</i> (primary neuron). <b>Results:</b> FGF4 released from Lap/Hep gel locally achieves strong protection and regeneration after SCI. The Lap/Hep@FGF4 group revealed remarkable motor functional recovery and axonal regrowth after SCI through suppressing inflammatory reaction, increasing remyelination and reducing glial/fibrotic scars. Furthermore, the underlying mechanism of axonal rehabilitation were demonstrated via enhancing microtubule stability and regulating mitochondrial localization after Lap/Hep@FGF4 treatment. <b>Conclusion:</b> This promising sustained release system provides a synergistic effective approach to enhance recovery after SCI underlying a novel mechanism of axonal rehabilitation, and shows a translational prospect for the clinical treatment of SCI.