Succinic acid-based biodegradable hydrogels drive Bv2 microglial polarization by ATP metabolism

Abstract

Effective regenerative strategies for spinal cord injury (SCI) depend on promoting neuronal regeneration and suppressing inflammation, both requiring substantial energy. Succinic acid-based materials have attracted attention for enhancing cellular energy through the tricarboxylic acid (TCA) cycle and mitochondrial electron transport. However, succinic potential to exacerbate inflammation complicates therapeutic use, making it crucial to understand how these materials regulate microglial polarization. Here, we presented a degradable bioenergy hydrogel system by integrating succinic acid (SA) into chitosan (CS), yielding an energy-active unit. Upon implantation, degradation of chitosan released energy-active units, which were transported into Bv2 microglial cells via SLC13A3, thereby engaging mitochondrial electron transport chain and the TCA cycle. At optimized concentrations, these energy-active units facilitated M2 polarization of Bv2 cells, augmenting adenosine triphosphate (ATP) levels and driving anti-inflammatory factor expression to support tissue repair. Conversely, excess concentrations triggered mitochondrial reverse electron transport, elevating reactive oxygen species (ROS) production, impairing ATP synthase, and enhancing pro-inflammatory factor release via SLC25A10-mediated succinate export. This concentration-dependent effect underscores the nuanced role of succinic acid in modulating microglial polarization states. Furthermore, degradation of CSSA fragments activated the AMPK-mTOR and cAMP signaling pathways, significantly boosting ATP synthesis and fostering M2 microglial polarization. Our findings offer a novel avenue to enhance SCI repair by modulating cellular energy balance and refining the inflammatory milieu, while establishing critical concentration parameters for the deployment of succinic acid-based biomaterials in tissue regeneration contexts.