Implantable MEMS Drug Delivery Device for Glaucoma Management

描述（由申请人提供）：青光眼是一种慢性疾病，其特征是进行性视神经损伤和视力丧失。青光眼无法治愈;该疾病的管理集中在降低眼内压，这在减少疾病进展方面是有效的。一种治疗性治疗包括给予噻吗洛尔以减少睫状体上皮产生的房水。不幸的是，目标结构位于眼睛的远距离内部区域。传统的局部给药模式由于生理障碍、副作用和患者对药物方案的依从性差而在功效上受到限制。副作用包括但不限于β受体阻滞剂滴眼液的严重心脏效应。该提案研究了一种新的方法，用于用微机电系统（MEMS）制造的微流体装置在治疗水平下靶向眼内递送青光眼药物。该装置植入结膜下空间，由可再填充的药物储存器、电解驱动泵、经巩膜插管和流量控制阀组成。储存器内的药物由电子控制的泵驱动通过柔性经巩膜插管，该插管被引导到前房中，从而到达睫状体上皮-治疗部位。向眼内组织的定向递送减少了药物的扩散距离，增加了每个剂量的功效，减小了剂量的大小，并且减少了未使用的药物的非预期全身吸收的量和相关的副作用。此外，该平台能够实现常规方法不可能实现的眼部药物递送的精确时间和空间控制。具体目标1：制造用于青光眼药物靶向递送的多组分MEMS药物递送系统。由电解泵、储药器、止回阀和插管组成的完全集成的装置将证明受控和可重复的给药。具体目标2：在离体实验中证明植入和器械可再填充性。摘除的猪眼将用于开发外科手术和器械再填充技术。具体目的3：证明噻吗洛尔在兔青光眼模型中的可控和可重复给药。将证明器械的长期生物相容性和功能，然后将在青光眼动物模型中实施器械。将比较该器械在控制眼内压方面的有效性与局部应用噻吗洛尔。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。这种递送方法将使药物疗法的治疗益处最大化，同时通过减少副作用使患者的风险最小化。广泛的药物相容性和实施该装置的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需要治疗位于眼睛的远内区域的组织的疾病。

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.