Implantable MEMS Drug Delivery Device for Glaucoma Management

描述（由申请人提供）：青光眼是一种以进行性视神经损伤和视力丧失为特征的慢性疾病。青光眼无法治愈；该疾病的治疗重点是降低眼压，这对减少疾病的进展是有效的。一种治疗方法是给予噻莫洛尔以减少睫状体上皮房水的产生。不幸的是，目标结构位于遥远的眼睛内部区域。由于生理屏障、副作用和患者对药物方案的依从性差，传统的局部给药模式的疗效受到限制。副作用包括但不限于β受体阻滞剂滴剂对心脏的严重影响。本研究提出了一种利用微机电系统（MEMS）制造的微流体装置进行治疗水平青光眼药物靶向眼内输送的新方法。该装置被植入结膜下间隙，由一个可再填充的药物储存库、电解驱动泵、经巩膜插管和流量控制阀组成。储存罐内的药物由电子控制泵驱动，通过灵活的经巩膜插管进入前房，从而进入睫状体上皮——治疗部位。直接给药到眼内组织减少了药物的扩散距离，增加了每次剂量的疗效，减小了剂量的大小，并减少了未使用药物的意外全身吸收量和相关副作用。此外，该平台能够精确地控制眼部药物输送的时间和空间，这是传统方法无法做到的。具体目标1：制造用于青光眼药物靶向递送的多组分MEMS给药系统。由电解泵、储药库、止回阀和套管组成的完全集成的设备将演示可控和可重复给药。具体目标2：在离体实验中证明植入和装置可再填充性。去核的猪眼将用于开发外科手术和设备填充技术。具体目的3：在家兔青光眼模型中证明噻莫洛尔的可控和可重复给药。该装置的长期生物相容性和功能将被证明，然后该装置将在青光眼动物模型中实施。该装置在控制眼压方面的效果将与局部应用噻洛尔进行比较。为了有效地治疗青光眼，一种新型的微型药物输送装置将药物直接输送到眼睛内部。这种给药方法将使药物治疗的疗效最大化，同时通过减少副作用将患者的风险降到最低。实施该装置的广泛药物兼容性和灵活性允许其应用于治疗其他慢性疾病，特别是与视力丧失相关的疾病，需要治疗位于眼睛偏远内部区域的组织。

DESCRIPTION (provided by applicant): Glaucoma is a chronic disease characterized by progressive optic nerve damage and vision loss. There is no cure for glaucoma; management of the disease focuses on lowering intraocular pressure which has been effective in reducing the progression of the disease. One therapeutic treatment involves the administration of timolol to reduce the production of aqueous humor by the ciliary epithelium. Unfortunately, the targeted structures are located in remote inner regions of the eye. The traditional mode of topical drug delivery is limited in efficacy by physiological barriers, side effects, and poor patient compliance with the drug regimen. Side effects include but are not limited to severe cardiac effects with beta blocker drops. This proposal investigates a novel method for targeted intraocular delivery of glaucoma medication at therapeutic levels with a microelectromechanical systems (MEMS)-fabricated microfluidic device. This device is implanted in the subconjunctival space and consists of a refillable drug reservoir, electrolysis- actuated pump, transscleral cannula, and flow control valves. The medication contained within the reservoir is driven by the electronically-controlled pump through the flexible transscleral cannula which is directed into the anterior chamber and thereby to the ciliary epithelium - the site of treatment. Directed delivery to intraocular tissues reduces the diffusion distance of the drug, increases the efficacy of each dose, reduces the size of the dose, and reduces the amount of unintended systemic absorption of unused drug and the associated side effects. Furthermore, this platform enables precise temporal and spatial control of ocular drug delivery not possible with conventional methods. Specific Aim 1: Fabrication of a multi-component MEMS drug delivery system for targeted delivery of glaucoma medication. A fully integrated device consisting of an electrolysis pump, drug reservoir, check valve, and cannula will demonstrate controlled and repeatable dosing. Specific Aim 2: Demonstration of implantation and device refillability in ex vivo experiments. Enucleated porcine eyes will be used to develop surgical procedures and device refill techniques. Specific Aim 3: Demonstration of controllable and repeatable delivery of timolol in a rabbit model of glaucoma. The long term biocompatibility and function of devices will be demonstrated and then the device will be implemented in an animal model of glaucoma. Efficacy of the device in managing intraocular pressure will be compared to topically applied timolol. For the effective management of glaucoma, a novel miniaturized drug delivery device will deliver drugs directly into the interior of the eye. This method of delivery will maximize the therapeutic benefits of the drug therapy while minimizing risk to the patient by reducing side effects. The broad drug compatibility and flexibility in implementing the device allow its application to the treatment of other chronic diseases, in particular, diseases associated with vision loss requiring treatment of tissues located in remote inner regions of the eye.