Multiresponsive Hyaluronan‐p(NiPAAm) “Click”‐Linked Hydrogels

Combined reversible addition-fragmentation chain transfer (RAFT) and chemoselective “click” chemistry are used for assembling two polymeric chains into a hybrid network capable to respond simultaneously or separately to different external stimuli. An azido-derivative of hyaluronate is clicked together with a new telechelic RAFT-generated p(NiPAAm), carrying a propargyl function at both ends, suitable as macromolecular “clickable” cross-linker with controlled molecular weight. This hybrid system displays a multiresponsive behavior versus temperature, pH, and ionic strength, maintaining cumulative as well as separate sensitivities to the external stimuli. Hyaluronidase catalyzed degradation of the hydrogels, mimicking the extracellular matrix degradation process, is an additional asset for the use of this class of hydrogels as scaffold. Tumor cells, HT-29, grow on the surface of these hybrid hydrogels more than the healthy ones, as NIH3T3. This finding opens a road to micro- and nano-devices based on hyaluronic acid as a promising biopolymer to pursue localized drug delivery.