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

项目总结/摘要 角膜新生血管（CNV），或新血管侵入无血管角膜， 这是世界范围内导致失明的主要原因之一。局部滴眼液治疗是最容易获得的 和CNV的非侵入性治疗，但由于角膜屏障， 鼻泪管引流，在几分钟内迅速消除眼药水。生物可降解材料的研究进展 微针导致了许多通过角膜的眼内药物递送策略的发展 屏障，从而提高治疗效果。然而，这些微针的临床应用在临床上并不理想。 由于人眼角膜相对较大的尺寸和快速溶解的性质 （典型地，在15分钟-2小时内），这分别引起疼痛和有限的治疗功效。的 本项目的研究工作将集中于开发一类新型眼内给药系统 由全小型化（即，在纳米级）和缓慢生物降解的硅纳米针， 比目前的生物可降解材料小> 30倍，降解速率慢> 10倍 微型针。硅纳米针将建立在一个水溶性接触透镜上， 生物相容性、柔软性、在泪液中的快速降解性（不超过30秒），以及最佳的 曲率以适应各种角膜形状（8.3-9.0 mm基弧半径）。这些方面是必不可少的， 用于微创、无痛和长期（超过数天）持续递送眼部药物， 角膜屏障在本项目中，我们将揭示硅的结构-性质-性能关系 纳米针具有各种尺寸、形状、纵横比和体外和离体的表面孔隙率。我们还将 评估生物安全性，治疗效果，以及硅纳米针的副作用， 兔CNV模型，与常规的抗血管内皮生长因子治疗（抗 VEGF）和激光治疗。因为用于纳米针和水溶性接触透镜的材料 已经在临床使用，这种眼内药物输送平台可以迅速转化为临床实践， 用于治疗人眼的CNV。此外，已建立的眼内药物递送平台将是 也可用于治疗其它慢性眼部疾病，包括角膜、视网膜和脉络膜疾病 新生血管形成

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.