Leveraging the Gel-to-Sol Transition of Physically Crosslinked Thermoresponsive Polymers to Enable Cooling-Triggered Stimulus-Responsive Applications

Abstract

Physically crosslinked thermoresponsive polymer hydrogels are known to exhibit a LCST (lower critical solution temperature) wherein they transition reversibly from gel to solution upon cooling, and vice versa. Thus far, this simple but useful property has been used in stimulus-responsive applications like on-skin temperature sensors and in-situ gelling drug delivery depots. However, the ability of these hydrogels to selectively sequester payloads based on temperature has not yet been fully explored. To demonstrate this concept, we first establish a platform for cooling-triggered initiation of colorimetric reactions. Next, we explore the use of cooling triggered release of sequestered payload molecules in a drug delivery context, using Soluplus (a poly vinylcaprolactam- poly vinylacetate- poly ethyleneglycol graft copolymer) for cooling-triggered release of the NSAID (nonsteroidal anti-inflammatory drug) Celecoxib and subsequently using poly-n-isopropylacrylamide (PNIPAM) for cooling-triggered release of Bupivacaine, a local anesthetic. Controlled release of these and similar drugs has previously been shown using numerous stimuli like heat, ultrasound, magnetic fields, and even RF signals. However, as cooling is already familiar to patients as a means of achieving transient pain relief, it is a particularly appealing external stimulus for release of pain relief therapeutics. These studies illustrate how the hydrogels mentioned above can be combined with other materials to create implantable cooling-triggered drug depots and demonstrate cooling-triggered release both in vitro (with cell culture assays) and in vivo (using a rodent full-depth skin wound model for NSAIDs and neurobehavioral testing for Bupivacaine).