Sustainable Dual Release of Antibiotic and Growth Factor from pH-Responsive Uniform Alginate Composite Microparticles to Enhance Wound Healing

Hydrogel-based wound dressings provided a moist microenvironment and local release of bioactive molecules. Single drug loading along with fast release rates and usually in hydrogel sheets limited their performance. Hence, uniform alginate/CaCO3 composite microparticles (similar to 430 mu m) with tunable compositions for sustainable release of drug and pH-sensitivity were successfully fabricated using microfluidic technology. Due to the presence of CaCO3 and the strong interactions with alginate molecules, lyophilized composite microparticles reverted to hydrogel state after rehydration. Regardless of microparticle states (hydrogel or lyophilized) and pH values (6.4 or 7.4), in vitro release rates of model drug were inversely related with CaCO3 concentrations and much lower than that for pure alginate microparticles. The release rate at pH 6.4 (simulating wound microenvironment) was always slower than that at pH 7.4 for the same type of microparticles. Rifamycin and basic fibroblast growth factor (bFGF) were independently encapsulated into AD-5-R and AD-40-F to achieve a fast release of rifamycin and a slower, more sustained release of bFGF, respectively; CD-F-R was a mixture of AD-5-R and AD-40-F at weight ratio 1/1. For AD-5-R and CD-F-R, inhibition zones of S. aureus were observed until day 5, showing a sustained antibacterial property. On the basis of in vitro wound healing model of NIH-3T3 cell micropattern on glass coverslips with a hole array, it was found that AD-40-F and CD-F-R significantly promoted cell proliferation and migration rates. In a full-thickness skin wound model of rats, CD-F-R microparticles significantly accelerated wound healing with higher granulation tissue thickness and better bioactivity to stimulate angiogenesis than the control group. Furthermore, CD-F-R microparticles demonstrated a good biocompatibility and biodegradability in vivo. Taken together, CD-F-R composite microparticles may ideally meet the requirements for different stages during wound healing and demonstrated a good potential to be used as dressing materials.