Abstract
Currently, on-demand treatment of pain (both chronic and acute) is primarily achieved using opioids that are delivered systemically. Unfortunately, these drugs are highly addictive; over 5 people per hour die from opioid abuse in the US alone. A safer, nonsystemic mechanism for pain relief is therefore needed. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been explored for this purpose; they are nonaddictive, provide excellent pain relief, and can be delivered locally to minimize dosage and systemic side effects. However, an on-demand release method is needed to make local delivery of these drugs a viable, convenient replacement for opioids; external stimulus-triggered release from an implantable depot is one approach. Stimuli such as heat, light, ultrasound, and RF electromagnetic radiation have been used to trigger release of various drugs from implantable drug depots; however, these require energy input and complex apparatus and are thus not comparable to the ease of oral administration. We propose localized cooling as a safe, convenient stimulus. As icepacks are already widely applied to temporarily ease local pain, introducing a drug delivery mechanism switched "ON" by cooling could enable long duration, enhanced pain relief triggered by a method with which patients are already familiar. Herein, we demonstrate that cooling-triggered release of NSAIDs can be achieved by leveraging the gel-to-sol transition exhibited by physically cross-linked thermoresponsive polymer hydrogels upon cooling below their lower critical solution temperature (LCST). We demonstrate and characterize cooling-triggered release in simulated body fluid, in cell culture, in explanted tissue, and in a live animal wound model. We show that hydrogels loaded with an NSAID (Celecoxib) can be combined with a nonthermoresponsive membrane material to create implantable devices that demonstrate up to a ∼40× increase in drug release rate upon mild cooling (29 °C) and that support multiple cycles of triggered release. These results demonstrate that cooling-triggered release of therapeutics is a promising concept that could allow patients to use a familiar method (applying an icepack to pain points) to achieve enhanced pain relief.