Abstract：
This study employed superficial ultrasound exposure of good ocular safety and a drug-loaded hydrogel of long residence time to enable transscleral delivery. First, we designed an acoustic adaptor to limit the ultrasound exposure depth to 1.59 mm to protect the posterior eye segments. Then, we optimized the alginate/polyacrylamide ratio (3:7) of a dual-crosslinked hydrogel to enable ultrasound-triggered release of model drug (70-kDa fluorescein isothiocyanate-conjugated dextran). Using fluorescence imaging to quantify the drug release, we showed that the developed method resulted in enhanced transscleral delivery in both ex vivo porcine scleras (2.6-fold) and in vivo rabbit scleras (2.2-fold). We also demonstrated that the method increased the drug penetration depth to the whole thickness of the sclera. In particular, the drug release efficiency increased with increasing ultrasound exposure time (1 and 3 min) and intensity (8, 19, 36, and 61 mW/cm2). Using scanning electron microscopy, we revealed that ultrasound exposure resulted in rougher surfaces and microscale rupture of the hydrogel. Moreover, Masson staining of scleral slices showed that the integrity of the top scleral fibers was disturbed by ultrasound exposure, and this disturbance recovered 3 days later. Our work demonstrates that the developed method holds great potential for mediating ocular drug delivery.
摘要：
这项研究采用了具有良好眼部安全性的表面超声暴露和长停留时间的载药水凝胶，以实现经巩膜递送。首先,我们设计了一种声学适配器，将超声暴露深度限制在1.59mm，以保护眼睛后部。然后，我们优化了双交联水凝胶的藻酸盐/聚丙烯酰胺比例(3:7),使超声触发释放模型药物(70kDa异硫氰酸荧光素缀合的葡聚糖).使用荧光成像来量化药物释放，我们表明，开发的方法导致增强的经巩膜递送在离体猪巩膜（2.6倍）和体内兔巩膜（2.2倍）。我们还证明了该方法将药物穿透深度增加到巩膜的整个厚度。特别是,药物释放效率随着超声暴露时间（1和3分钟）和强度（8、19、36和61mW/cm2）的增加而增加。使用扫描电子显微镜，我们发现，超声暴露导致粗糙的表面和微尺度的水凝胶破裂。此外，巩膜切片的Masson染色显示顶部巩膜纤维的完整性受到超声照射的干扰,这种干扰在3天后恢复。我们的工作表明，所开发的方法具有介导眼部药物递送的巨大潜力。
