Regulated extravascular microenvironment via reversible thermosensitive hydrogel for inhibiting calcium influx and vasospasm

Arterial vasospasm after microsurgery can cause severe obstruction of blood flow manifested as low tissue temperature, leading to tissue necrosis. The timely discovery and synchronized treatment become pivotal. In this study, a reversible, intelligent, responsive thermosensitive hydrogel system is constructed employing both the gel–sol transition and the sol–gel transition. The “reversible thermosensitive (RTS)” hydrogel loaded with verapamil hydrochloride is designed to dynamically and continuously regulate the extravascular microenvironment by inhibiting extracellular calcium influx. After accurate implantation and following in situ gelation, the RTS hydrogel reverses to the sol state causing massive drug release to inhibit vasospasm when the tissue temperature drops to the predetermined transition temperature. Subsequent restoration of the blood supply alleviates further tissue injury. Before the temperature drops, the RTS hydrogel maintains the gel state as a sustained-release reservoir to prevent vasospasm. The inhibition of calcium influx and vasospasm in vitro and in vivo is demonstrated using vascular smooth muscle cells, mice mesenteric arterial rings, and vascular ultrasonic Doppler detection. Subsequent animal experiments demonstrate that RTS hydrogel can promote tissue survival and alleviate tissue injury responding to temperature change. Therefore, this RTS hydrogel holds therapeutic potential for diseases requiring timely detection of temperature change.