Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
Department of Radiology, University of Michigan, Ann Arbor, MI, USA; Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, USA.
J Control Release. 2024 Oct;374:205-218. doi: 10.1016/j.jconrel.2024.08.001. Epub 2024 Aug 16.
Hydrogels can serve as local drug delivery depots that protect the biological activity of labile therapeutics. However, drug release from conventional hydrogels is typically rapid, which is not ideal for many therapeutic agents. We developed a composite hydrogel that enables sustained drug release in response to ultrasound. The composite, termed an acoustically responsive scaffold (ARS), consists of a fibrin hydrogel and a phase-shift emulsion. Upon exposure to ultrasound, the emulsion is vaporized into bubbles, which leads to release of drugs contained within the emulsion. Previously, ARSs have been used in regenerative applications to stimulate blood vessel growth. Here, we characterize the release kinetics and mechanisms of ARSs. Release exhibits a triphasic pattern compromising a slow phase prior to ultrasound exposure; a transient, fast phase immediately after ultrasound exposure that follows a sigmoidal profile; and a sustained, steady phase. In each phase, we demonstrate how derived kinetics parameters are impacted by the ARS composition (e.g., fibrin and emulsion concentrations) and ultrasound properties (e.g., acoustic pressure, pulse duration). Using confocal microscopy, protein assays, and B-mode ultrasound imaging, we demonstrate that drug release from an ARS is independent of fibrin degradation and dependent on bubble growth. These results are critical in optimizing ARSs for delivery of therapeutic agents.
水凝胶可用作局部药物输送库，以保护不稳定治疗剂的生物活性。然而，传统水凝胶的药物释放通常很快，这对许多治疗剂来说并不理想。我们开发了一种复合水凝胶，可通过超声响应来实现持续的药物释放。这种复合材料称为声响应支架（ARS），由纤维蛋白水凝胶和相移乳液组成。在超声暴露下，乳液会蒸发成气泡，从而导致乳液中包含的药物释放。以前，ARS 已用于再生应用中以刺激血管生长。在这里，我们对 ARS 的释放动力学和机制进行了表征。释放表现出三相模式，包括超声暴露前的缓慢相；超声暴露后立即出现的短暂、快速相，遵循 S 形曲线；以及持续、稳定的相。在每个阶段，我们都证明了如何通过 ARS 组成（例如纤维蛋白和乳液浓度）和超声特性（例如声压、脉冲持续时间）来影响衍生的动力学参数。通过共聚焦显微镜、蛋白质分析和 B 型超声成像，我们证明了 ARS 中的药物释放与纤维蛋白降解无关，而与气泡生长有关。这些结果对于优化 ARS 以输送治疗剂至关重要。
