The spatiotemporal co-delivery of hydrogen and magnesium via microneedle patches demonstrates significant therapeutic potential for spinal cord injury treatment by addressing the triple barrier through dual mechanisms: acute-phase hydrogen gas rapidly reduces reactive oxygen species by 55% while subsequent magnesium release promotes microglia polarization and axonal regeneration, resulting in substantial locomotor recovery improvements. This innovative penetration-confinement-dual-engine approach represents a paradigm shift from symptomatic management to targeted neural microenvironment reconstruction, with the elucidated ROS-MAPK/AP-1 regulatory axis providing mechanistic support for clinical translation.
Plain-Language Summary
Researchers developed a special patch containing magnesium microparticles that can penetrate the protective membrane surrounding the spinal cord. When implanted after spinal cord injury in rats, the patch releases hydrogen gas first (which reduces harmful molecules called reactive oxygen species by 55%), followed by magnesium (which helps immune cells switch to a repair mode and promotes nerve fiber growth). This two-stage approach improved movement recovery in injured rats compared to untreated controls.
Abstract
Spinal cord injury (SCI) treatment is hindered by a "triple barrier:" the physical dura, a chemical storm of reactive oxygen species (ROS), and an immune barrier mediated by pro-inflammatory microglia. To address these, we developed a "Hydrogen/Magnesium dual-engine microneedle" (MN-Mg) system by embedding magnesium (Mg) microparticles within a methacrylated hyaluronic acid (HAMA) hydrogel matrix via micromolding. Possessing high mechanical strength, Mg-MNs penetrate the dura mater. Upon implantation, the system triggers a controllable magnesium-water reaction, initiating a spatiotemporally synergistic dual-engine therapeutic mode. The "hydrogen engine" rapidly releases high-concentration hydrogen gas (H2) during the acute SCI phase. It efficiently scavenges ROS storm (reducing levels by 55%) by inhibiting the MAPK pathway and downregulating AP-1 transcription, creating an antioxidant window for neural repair. Subsequently, the "magnesium engine" provides sustained Mg2 + release during the subacute phase, exerting a dual restorative effect: induces microglia polarization toward the pro-reparative M2 phenotype (4.8-fold increase) and promotes axonal regeneration (2.9-fold increase). This synergy leads to locomotor recovery in a rat SCI model, with scores improving from 5.5 ± 1.05 (Controls) to 14.8 ± 1.17 at 8 weeks. This "Penetration-Confinement-Dual-Engine Modulation" paradigm enables spatiotemporal synergistic H2/Mg therapy supported by an elucidated ROS-MAPK/AP-1 regulatory axis, advancing SCI treatment from symptomatic relief to targeted neural microenvironment reconstruction.
