Bisphosphonate-Based Hydrogel with pH-Responsive Minocycline Release Inhibits Microglia/Macrophages of M1 Polarization for Spinal Cord Injury Therapy

After spinal cord injury (SCI), the persistent presence of pro-inflammatory microglia/macrophages (M1 phenotype) in injury lesion is one of the major reasons for inducing neuron damage and preventing neurological function recovery. Inhibition of microglia/macrophages of M1 polarization using minocycline-based biomaterials efficiently reduces SCI of pro-inflammatory microenvironment. However, previously reported minocycline-loading biomaterials lack precise injured-microenvironment-responsive drug release behavior. Here the bisphosphonate (BP)–metal coordination method together with polymeric networks is used to deliver minocycline locally in SCI lesions, where the slight acid in the injured site triggers minocycline release. The data from in vitro cellular experiments and in vivo rat SCI model demonstrated that minocycline-loaded BP-based hydrogel (MH@BP Gel) availably inhibits microglia/macrophage polarization toward the M1 phenotype. Moreover, MH@BP Gel promotes animal motor functional recovery, inhibits glial scar formation, and promotes neurofilament- and class III β-tubulin-positive neuron survival and regeneration in vivo. Therefore, our presented MH@BP Gel provides a facile strategy for localized minocycline delivery and a promising solution for SCI therapy.