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.

中文翻译：

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声响应支架：揭示持续、稳定药物输送的释放动力学和机制


水凝胶可以作为局部药物递送库，保护不稳定疗法的生物活性。然而，传统水凝胶的药物释放通常很快，这对于许多治疗剂来说并不理想。我们开发了一种复合水凝胶，能够响应超声波持续释放药物。这种复合材料被称为声响应支架（ARS），由纤维蛋白水凝胶和相移乳液组成。暴露于超声波后，乳剂汽化成气泡，导致乳剂中所含药物的释放。此前，ARS 已用于再生应用以刺激血管生长。在这里，我们描述了 ARS 的释放动力学和机制。释放表现出三相模式，在超声暴露之前有一个慢相；超声暴露后立即出现瞬态快速阶段，遵循 S 形曲线；以及一个持续、稳定的阶段。在每个阶段，我们演示了 ARS 成分（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）如何影响导出的动力学参数。使用共聚焦显微镜、蛋白质测定和 B 型超声成像，我们证明 ARS 中的药物释放与纤维蛋白降解无关，并且依赖于气泡生长。这些结果对于优化 ARS 递送治疗剂至关重要。