Lobban Romario, Carroll Michael, Vest Victoria, McCune Josh T, Hall Sarah, Yu Fang, Uddin Md Jashim, Marnett Lawrence J, Duvall Craig L, Bellan Leon M
Department of Mechanical Engineering, Vanderbilt University, 2201 West End Avenue, Nashville, Tennessee 37235, United States.
Division of General Engineering, Vanderbilt University, 2201 West End Avenue, Nashville, Tennessee 37235, United States.
ACS Biomater Sci Eng. 2025 Sep 8;11(9):5413-5425. doi: 10.1021/acsbiomaterials.5c00867. Epub 2025 Aug 25.
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.
目前，对疼痛（包括慢性和急性疼痛）的按需治疗主要通过全身给药的阿片类药物来实现。不幸的是，这些药物极易成瘾；仅在美国，每小时就有超过5人死于阿片类药物滥用。因此，需要一种更安全的非全身作用的疼痛缓解机制。为此人们探索了非甾体抗炎药（NSAIDs）；它们不会成瘾，能有效缓解疼痛，并且可以局部给药以减少剂量和全身副作用。然而，需要一种按需释放方法，以使这些药物的局部给药成为阿片类药物可行、便捷的替代品；从可植入储库进行外部刺激触发释放是一种方法。诸如热、光、超声和射频电磁辐射等刺激已被用于触发各种药物从可植入药物储库中释放；然而，这些方法需要能量输入和复杂的设备，因此与口服给药的简便性不可相提并论。我们提出局部冷却作为一种安全、便捷的刺激方式。由于冰袋已被广泛应用于临时缓解局部疼痛，引入一种通过冷却开启的药物递送机制可以实现由患者已经熟悉的方法触发的长时间、增强的疼痛缓解。在此，我们证明通过利用物理交联的热响应性聚合物水凝胶在冷却至其下临界溶液温度（LCST）以下时表现出的凝胶 - 溶胶转变，可以实现NSAIDs的冷却触发释放。我们在模拟体液、细胞培养、离体组织和活体动物伤口模型中证明并表征了冷却触发释放。我们表明，负载有NSAID（塞来昔布）的水凝胶可以与非热响应性膜材料结合，制成可植入装置，该装置在轻度冷却（29°C）时药物释放速率提高约40倍，并支持多个触发释放循环。这些结果表明，治疗药物的冷却触发释放是一个有前景的概念，它可以让患者使用熟悉的方法（在疼痛部位敷冰袋）来实现增强的疼痛缓解。
