Sustained Local Delivery of Sodium Butyrate To Support Muscle Recovery in a Murine Model of Hindlimb Ischemia

Chronic limb threatening ischemia (CLTI) is a debilitating disease in which chronic ischemia causes skeletal muscle degeneration, fat infiltration, and metabolic dysregulation. This study aims to develop a biomaterials-based strategy for the localized, sustained delivery of sodium butyrate, a gut-derived short-chain fatty acid, using poly(lactic- co -glycolic acid) (PLGA) microspheres. In vitro ischemic culture models demonstrated that butyrate improves cell viability and preserves mitochondrial membrane polarization in both myoblasts and myotubes. Butyrate was successfully encapsulated using a double emulsion method, achieving sustained release over 4 weeks. In a murine hindlimb ischemia model, treatment with butyrate-loaded microspheres improved muscle fiber architecture and reduced fat infiltration, despite no significant changes in limb perfusion. These findings highlight butyrate as a perfusion-independent therapeutic that preserves muscle quality under ischemic conditions and supports its potential as a regenerative strategy for CLTI. This research will serve as the basis for biomaterial-focused therapies for regeneration and provide another therapeutic target to study in CLTI.