Microenvironmentally enhanced supramolecular hydrogels reverse multiple dilemmas in bone infection

Abstract

The increasing incidence of osteomyelitis and the emergence of drug-resistant bacteria due to antibiotic misuse pose significant challenges to traditional treatments. The formation of biofilms through bacterial proliferation and intracellular infections perpetuates recurrent and prolonged infections. Concurrently, the immune response triggered by bacterial infection disrupts the intrinsic bone metabolism balance, leading to inflammatory osteolysis. Herein, a cerium-alendronate supramolecular hydrogel (CAG) with multiple antimicrobial capabilities and bone metabolism regulation ability was developed to address the multifaceted challenges of osteomyelitis. Injectable and self-healing CAG demonstrated heightened antibacterial efficacy against Staphylococcus aureus (S.A) and Escherichia coli (EcN) in response to the ROS microenvironment, effectively disrupting biofilms and eradicating intracellular infection. Ce ions within CAG destroyed bacterial membrane and disrupted the bacterial membrane potential, thereby impeding bacterial energy production. Moreover, CAG successfully reversed endotoxin-induced apoptosis and aberrant osteogenic differentiation of osteoblasts. RNA sequencing revealed that CAG promoted osteogenic differentiation by facilitating calcium influx, upregulating the calcium signaling pathway and TGFβ pathway, and enhancing the expression of Bmp2/Smad5 pathway-related proteins. In vivo experiments demonstrated the efficacy of CAG in treating S.A-induced osteomyelitis and improving bone tissue generation in both 7-day and 28-day osteomyelitis mice. Overall, this study proposed a comprehensive therapy targeting whole-stage bacterial infections and restoring the balance of bone metabolism, highlighting a novel approach to the treatment of infectious bone injuries.