Ultrasound-triggered disruption and self-healing of hydrogels for on-demand and repeated cargo release – UtHeal

Injectable hydrogels that allow remote, repeatable, and controlled on-off switchable drug release could have a marked impact on the treatment of a variety of medical conditions. An ideal hydrogel should safely contain a large quantity of drug, release no drug in the “off” state, be repeatedly switchable to the “on” state while maintaining its network structure, and be triggered noninvasively to release a precise dose of drug adapted to the patient needs. While several approaches have been proposed to design injectable hydrogels for on-demand and localized delivery of therapeutics, their principal limitations have been that remote activation of hydrogels frequently results in a single drug release event. The goal of the UtHeal project is to develop an injectable self-healing hydrogel that allows fast drug release where and when it is needed by applying ultrasound to disrupt the polysaccharide network crosslinked through boronate ester bonds with thermosensitive liposomes. To this end, we propose to design an original thermosensitive polymer that can be anchored in liposomes and create boronate ester crosslinks with neighboring polysaccharides (PS) so as to form a gel. We hypothesize that the dynamic bonds between the PS and the polymer-modified thermosensitive liposomes (pTSL) could be reversibly dissociated under ultrasonic stimulation due to thermal effect. The gel-to-sol transition, coupled to a sharp and fast drug release from the pTSL triggered by focused ultrasound (FUS)-induced heating, would result in localized bursts of drug release. In the absence of FUS, the pTSL would re-seal allowing the hydrogel to self-heal. Herein, we will focus on the design of these original self-healing hydrogels. We will conduct fundamental studies of their FUS-responsiveness and release processes at supramolecular level, and assess their performance in cell-based in vitro assays.