HA-Alginate Hydrogels with RGD and IKVAV Peptides Enhance V2a Interneuron Maturation for CNS Repair

Injury to the central nervous system (CNS) often leads to severe consequences, including chronic inflammation, extensive cell death, and the formation of a glial scar, all of which actively inhibit tissue repair and functional recovery. Current therapeutic strategies struggle to overcome these barriers, highlighting an urgent need for novel approaches. Injectable hydrogels, especially those modified with extracellular matrix (ECM)-derived peptides, represent a promising solution by providing essential biochemical cues to promote neural tissue repair and serving as a minimally invasive vehicle for targeted therapeutic delivery across the blood-spinal/blood-brain barrier. This study investigates such a platform to support neuronal regeneration.

Researchers developed an injectable hydrazone crosslinked hyaluronic acid-alginate (HA-Alg) hydrogel platform. They fabricated hydrogels across a range of polymer concentrations to identify formulations that precisely mimic the stiffness and viscoelastic properties of native CNS tissue. Hyaluronic acid was further modified with ECM-derived, cell-adhesive peptides (RGD and IKVAV) to enhance neuronal adhesion and viability. To assess therapeutic potential, mouse embryonic stem cell aggregates were embedded within the hydrogels and differentiated toward mature V2a interneurons. The primary endpoint was the successful enrichment and maturation, specifically evaluating neurite length in interneuron-enriched cultures, comparing peptide-modified hydrogels to those without peptides.

The study successfully demonstrated the generation and enrichment of V2a interneurons within the HA-Alg hydrogels containing ECM-derived peptides. Physicochemical characterization confirmed the ability to tune hydrogel properties to match native CNS tissue. Critically, the addition of specific peptides significantly impacted neuronal development. > Both the newly described HA-Alg hydrogels and established crosslinked HA-HA hydrogels containing IKVAV peptides demonstrated significantly increased neurite length in interneuron-enriched cultures compared to hydrogels without peptides. This finding underscores the essential role of ECM-derived peptides in supporting the neuronal adhesion and viability necessary for functional CNS tissue repair. The successful enrichment for V2a interneurons within the peptide-modified HA-Alg hydrogels highlights their potential as a supportive scaffold for specific neuronal populations.