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

ABSTRACT: Rationale: 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. Methods: 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 in vivo (SCI rat model). Moreover, microtubule dynamic and energy transportation, which regulated axonal regeneration was evaluated by Lap/Hep@FGF4 gel in vitro (primary neuron). Results: 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. Conclusion: 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.

SUBMITTER: Wang C

PROVIDER: S-EPMC6815951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Immediately following spinal cord injury, further injury can occur through several secondary injury cascades. As a consequence of cell lysis, an increase in extracellular Ca(2+) results in additional neuronal loss by inducing apoptosis. Thus, hydrogels that reduce extracellular Ca(2+) concentration may reduce secondary injury severity. The goal of this study was to develop composite hydrogels consisting of alginate, chitosan, and genipin that interact with extracellular Ca(2+) to enable in situ gelation while maintaining an elastic modulus similar to native spinal cord (∼1000 Pa). It was hypothesized that incorporation of genipin and chitosan would regulate hydrogel electrostatic characteristics and influence hydrogel porosity, degradation, and astrocyte behavior. Hydrogel composition was varied to create hydrogels with statistically similar mechanical properties (∼1000 Pa) that demonstrated tunable charge characteristics (6-fold range in free amine concentration) and degradation rate (complete degradation between 7 and 28 days; some blends persist after 28 days). Hydrogels demonstrate high sensitivity to Ca(2+) concentration, as a 1 mM change during fabrication induced a significant change in elastic modulus. Additionally, hydrogels incubated in a Ca(2+)-containing solution exhibited an increased linear viscoelastic limit (LVE) and an increased elastic modulus above the LVE limit in a time dependent manner. An extension of the LVE limit implies a change in hydrogel cross-linking structure. Attachment assays demonstrated that addition of chitosan/genipin to alginate hydrogels induced up to a 4-fold increase in the number of attached astrocytes and facilitated astrocyte clustering on the hydrogel surface in a composition dependent manner. Furthermore, Western blots demonstrated tunable glial fibrillary acid protein (GFAP) expression in astrocytes cultured on hydrogel blends, with some hydrogel compositions demonstrating no significant increase in GFAP expression compared to astrocytes cultured on glass. Thus, alginate/chitosan/genipin hydrogel composites show promise as scaffolds that regulate astrocyte behavior and for the prevention of Ca(2+)-related secondary neuron damage during acute SCI.

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

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