Dual-responsive injectable hydrogels encapsulating drug-loaded micelles for on-demand antimicrobial activity and accelerated wound healing

Disease microenvironment stimuli-responsive hydrogels are of special interests in enhancing the drug delivery specificity for biomedical applications. In order to achieve specific drug release characteristic at the inflammation region, a smart pH-and reactive oxygen species (ROS)-responsive injectable hydrogel with self healing and remodeling capability was designed in our present work. By grafting phenylboronic acid to the side chain of the alginate polymer, a highly specific dual-responsive hydrogel with low pH and high ROS was obtained. Moreover, the hydrogel was endowed with antibacterial and anti-inflammatory properties respectively via the effective assembly of antibiotic amikacin (AM), and anti-inflammatory drug naproxen (Nap) which were preloaded into the micelles. Such hydrogel formulation not only preserved the structural integrity and excellent rheological properties of the hydrogel but also allowed for a controllable drug release rate at inflammation sites. The antibacterial experiment results in vitro demonstrated that the hydrogel could effectively kill bacteria by amikacin release, with the inhibitive rate reached to 90% for S. aureus and 98% for P.aeruginosa. Furthermore, the anti-inflammatory drug naproxen was also controllably released from the ROS-responsive micelles within 24 h under pH 5.0, and 10 mM H2O2 in vitro. Most importantly, the smart hydrogels showed good biocompatibility, and greatly promoted the healing of infected wounds in vitro by cell scratch assay. In addition, it efficiently reduced the levels of TNF-alpha (the pro-inflammatory cytokine) by 2.80 times, and increased IL-10 (antiinflammatory cytokine) by 2.41 times than the hydrogel control without antibiotic and anti-inflammatory drug. Within the dual-responsiveness of pH and ROS, the hydrogel reduced the inflammation response of the surrounding tissues significantly and accelerated the healing process of the infected area. Collectively, this smart hydrogel formula containing antibiotic and drug-loaded micelles is very promising to be applied topically against various microbial infections. We believe that this strategy can also be applied to various disease treatments.