Dual-Responsive Chitosan-Grafted PNIPAAm Hydrogel Eye Drop Incorporating Insulin-Imprinted Microgels for Dry Eye Syndrome Treatment.

Dry eye syndrome (DES) happens as a result of inadequate tear secretion or excessive evaporation, which leads to ocular surface irritation and damage. A major therapeutic challenge is maintaining effective drug concentrations, as topical formulations are rapidly cleared by blinking and tear turnover. To address this limitation, we developed a dual pH- and temperature-responsive composite hydrogel composed of chitosan (Cs)-grafted poly-N-isopropylacrylamide (PNIPAAm)- CPN integrated with alginate-based insulin-imprinted microgels (IMIP). Incorporation of IMIP particles allowed tuning of rheology, swelling behavior, wettability, and biodegradation while preserving proper topical administration. Microgel addition increased viscosity from 3.1 mPa·s (CPN-IMIP10) to 37.3 mPa·s (CPN-IMIP35), and the sol-gel transition between 25 and 37°C enabled flowability at room temperature followed by rapid gelation on the ocular surface. All CPN-IMIP hydrogels exhibited elastic-dominant behavior (G' > G″), confirming formation of a stable, shear-resistant network. Insulin release was tunable: at pH 6.4 and 25°C, diffusion governed delivery (29.8 ± 3.6% at 48 h), whereas at pH 7.4 and 37°C, swelling-controlled release predominated (54.4 ± 4.8%). The composite hydrogels supported human corneal epithelial cell viability and enhanced tear secretion, preserved corneal integrity, and reduced inflammation in a rat DES model. This system provides a minimally invasive, long-acting therapeutic platform for DES.