Accelerating repair of infected bone defects through post-reinforced injectable hydrogel mediated antibacterial/immunoregulatory microenvironment at bone-hydrogel interface

Abstract

Functional injectable hydrogel (IH) is promising for infected bone defects (IBDs) repair, but how to endow it with desired antibacterial/immunoregulatory functions as well as avoid mechanical failures during its manipulation has posed as main challenges. Herein, rosmarinic acid (RosA), a natural product with antibacterial/immunoregulatory activities, was utilized to develop a FCR IH through forming phenylboronic acid ester bonds with 4-formylphenyl phenylboronic acid (4-FPBA) grafted chitosan (CS) (FC). After being applied to the IBD site, the FCR IH was then injected with tobramycin (Tob) solution, another alkaline antibacterial drug, to induce in situ crystallization of the FC, endowing the resultant FCRT hydrogel with adaptively enhanced mechanical strength and structural stability. Owing to the specific structural composition, the FCRT hydrogel could sustainedly release Tob and RosA molecules at the IBD interface, effectively eliminating in situ bacterial infection. In addition, the released RosA molecules also induced the M₂ polarization of in situ macrophages (M_φ), which was identified to be related to the NF-κB and PI3K-AKT pathways, therefore promoting the osteogenic differentiation of in situ bone marrow stromal cells (BMSCs). Due to the simultaneous antibacterial/osteo-immunoregulatory microenvironment at the IBD interface, the repair of IBDs was proved to be greatly accelerated by the FCRT hydrogel.