Tuning stimuli-responsive properties of alginate hydrogels through layer-by-layer functionalization for dual-responsive dual drug release

This study aimed to understand the effect of layer-by-layer (LbL) modification on the stimuli-responsive prop-erties of physical alginate (ALG) hydrogels and examine the potential of LbL-coated hydrogels as dual responsive, dual drug releasing platforms for antibacterial applications. ALG hydrogels were functionalized through LbL self-assembly using temperature-responsive poly(2-isopropyl-2-oxazoline) (PiPOX) and pH-responsive tannic acid (TA). Ciprofloxacin (CIP) and Curcumin (CUR) were used as model hydrophilic and hydrophobic drugs, respectively. CIP was included in the hydrogel during LbL process, whereas CUR was incorporated into the hydrogel through gelation in the presence of CUR-loaded CaCO3 microparticles. The effect of LbL modification on the stimuli-responsive swelling, stability and drug release properties of hydrogels was examined in com-parison with bare hydrogels. We have shown that LbL modification resulted in a partial loss of solid content from the hydrogel, leading to a greater swelling. In addition, LbL modification imparted temperature-responsiveness to ALG hydrogel and provided enhanced CIP release upon increasing the temperature at pH 7.4. On the other hand, LbL-coated hydrogels displayed minimal CIP release at pH 5.5 regardless of the temperature. The anti-bacterial activity of LbL-coated hydrogels was greater at pH 7.4 than pH 5.5 against both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) bacteria. The combination of CIP and CUR provided enhanced antibacterial effect on the inhibition of E.coli growth at both pH 7.4 and pH 5.5. This effect became more remarkable as the CIP concentration was decreased at a constant CUR concentration in the hydrogels. However, the combinatorial effect of CIP and CUR was not observed with S. aureus. Overall, these results may be promising for wound healing applications where drug release is triggered when the pH becomes alkaline in the presence of bacterial colonization.