Development of Nanoneedle Array for Painless and Long-Term Sustained Intraocular Drug Delivery

项目摘要/摘要 角膜新生血管(CNV)，或新血管侵入无血管角膜 世界范围内导致失明的主要原因之一。局部滴眼液疗法是最容易获得的 和非侵入性治疗CNV，但其治疗效果有限，因为角膜屏障和 鼻泪引流，可在几分钟内迅速排出眼药水。可生物降解材料的研究进展 微针已经导致了许多通过角膜输送眼内药物的策略的发展 障碍，这增加了治疗效果。然而，这些微针在中国的临床应用 人眼由于其相对较大的人眼角膜和快速溶解的自然界而经常受到阻碍 (通常在15分钟-2小时内)，分别会引起疼痛和有限的治疗效果。这个 该项目的研究工作将集中在开发一种新型的眼内给药系统。 平台由完全微型化(即纳米级)和缓慢生物降解的硅纳米针制成，这些纳米针 与目前的生物可降解材料相比，&gt；小30倍，降解速度慢10倍 微针。硅纳米针将建立在一种可溶于水的隐形眼镜上，这种隐形眼镜提供了极好的 生物相容性、柔软性、在泪液中的快速降解性(不超过30秒)和最佳 曲率以适应各种角膜形状(8.3-9.0 mm的基本曲线半径)。这些方面对于允许 用于微创、无痛和长期(持续数天)的眼科药物输送 角膜屏障。在本项目中，我们将揭示硅的结构-性能-性能关系 不同大小、形状、长径比和表面孔隙率的纳米针在体外和体外。我们还将 评估硅纳米针的生物安全性、治疗效果和副作用 体内兔CNV模型与常规抗血管内皮细胞生长因子治疗(抗血管内皮生长因子治疗)的比较 血管内皮生长因子)和激光治疗。因为用于纳米针头和水溶隐形眼镜的材料 已经在临床上使用，这种眼内给药平台可以迅速转化为临床实践 用于治疗人眼的CNV。此外，已建立的眼内给药平台将是 也可用于治疗其他慢性眼病，包括角膜、视网膜和脉络膜 新生血管。

PROJECT SUMMARY/ABSTRACT Corneal neovascularization (CNV), or the invasion of new blood vessels into the avascular cornea, remains one of the major causes of blindness worldwide. Topical eye drop therapy serves as the most easily accessible and noninvasive treatment of CNV, but its therapeutic efficacy is limited due to the corneal barriers and nasolacrimal drainage that quickly eliminates eye drops within a few minutes. Recent advances of biodegradable microneedles have led to the development of many strategies for intraocular drug delivery through the corneal barriers, which increases therapeutic efficacy. However, the clinical implementation of these microneedles in human eyes is often impeded due to their relatively large size for the human cornea and rapidly dissolving nature (typically, within 15 minutes-2 hours), which causes pain and limited therapeutic efficacy, respectively. The research endeavors of this project will focus on the development of a new class of intraocular drug delivery platform made from fully-miniaturized (i.e., at nanoscale) and slowly-biodegradable silicon nanoneedles that are > 30-fold smaller and provide > 10-fold slower degradation rate compared to current biodegradable microneedles. The silicon nanoneedles will be built upon a water-soluble contact lens that offers excellent biocompatibility, softness, rapid degradability in tear fluid (within no more than 30 seconds), and optimal curvature to fit a variety of corneal shapes (8.3-9.0 mm base curve radii). These aspects are essential to allow for the minimally-invasive, painless, and long-term (over days) sustained delivery of ocular drugs through the corneal barriers. In this project, we will reveal the structure-property-performance relationship of the silicon nanoneedles with various size, shape, aspect ratio, and surface porosity in vitro and ex vivo. We will also evaluate the biosafety, therapeutic efficacy, and side-effects of the silicon nanoneedles in a well-established rabbit CNV model in vivo, as compared to conventional anti-vascular endothelial growth factor therapy (anti- VEGF) and laser therapy. Because the materials used for both the nanoneedles and water-soluble contact lens are already in clinical use, this intraocular drug delivery platform can be rapidly translated into clinical practice for the treatment of CNV in human eyes. Furthermore, the established intraocular drug delivery platform will be also useful for the treatment of other chronic ocular diseases, including corneal, retinal, and choroidal neovascularization.