Implantable MEMS Drug Delivery Device for Glaucoma Management

描述(申请人提供)：青光眼是一种慢性疾病，以进行性视神经损害和视力丧失为特征。青光眼没有治愈的方法；治疗青光眼的重点是降低眼压，这在减少疾病的进展方面是有效的。一种治疗方法包括服用噻吗洛尔，以减少睫状体上皮产生房水。不幸的是，目标结构位于眼睛的偏远内侧区域。传统的局部给药模式受到生理障碍、副作用和患者对药物方案依从性差等因素的限制。副作用包括但不限于β受体阻滞剂滴注造成的严重心脏影响。这项建议研究了一种新的方法，利用微电子机械系统(MEMS)制造的微流体装置，在治疗水平上靶向地给药青光眼。该装置植入结膜下间隙，由可再充填的药盒、电解泵、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，通过灵活的跨巩膜插管直接进入前房，从而到达睫状上皮--治疗的部位。眼内定向给药缩短了药物的扩散距离，提高了每个剂量的疗效，减小了剂量的大小，减少了未使用药物的意外全身吸收和相关副作用。此外，该平台能够对眼部药物输送进行精确的时间和空间控制，这是传统方法无法实现的。具体目标1：构建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、储药罐、止回阀和插管组成的全集成装置将演示可控和可重复的剂量。具体目标2：在体外实验中演示植入和装置的再充注性。摘除的猪眼将被用来开发外科手术程序和设备再填充技术。具体目标3：在兔青光眼模型上演示噻吗洛尔的可控性和可重复性。该装置的长期生物兼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。该设备在控制眼压方面的效果将与局部应用的噻吗洛尔进行比较。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疗法的治疗效益最大化，同时通过减少副作用将对患者的风险降至最低。广泛的药物兼容性和实施该设备的灵活性使其能够应用于其他慢性疾病的治疗，特别是与视力丧失有关的疾病，需要治疗位于眼内偏远区域的组织。

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.