A Novel Treatment for Retinal Ischemia

描述(申请人提供)：糖尿病视网膜病变(DR)和视网膜静脉阻塞(RVO)是导致低视力和失明的主要原因。虽然DR和RVO有不同的病理生理基础，但继发于缺血的视网膜内缺氧是这些疾病的核心。现有的治疗方法，如药物注射、全视网膜光凝、焦点激光和手术，要么无法解决视网膜缺氧问题，要么以损害视网膜组织为代价。此外，即使在玻璃体内注射抗血管内皮生长因子或激光，在大约50%的患者中，视力也没有改善。我们由来自七个机构的生物学家、物理学家、工程师和医生组成的跨学科团队已经采取了一种新的方法来治疗缺血性视网膜疾病。在这项建议中，利用复杂的生物学实验、生物信息学、生物物理学和先进的生物微电子机械系统(BioMEMS)工程，我们提出了一个氧合器系统，以提供高度受控的氧气水平，精确地针对缺血的视网膜(即，治疗窗口内的局部氧合)。我们在设计一种无线生物电子植入物(氧合器)方面取得了重大进展，这种植入物可以以受控的方式将安全数量的氧气输送到视网膜。氧合器由两个单元组成；一个可穿戴，另一个可植入。眼外可穿戴组件(单一符合人体工程学的灵活低调设计，可在白天和夜间使用)提供感应(RF)链接 为了电力和数据。可植入的组件包括接收电力和数据的电子设备、连接到用于电解的透氧膜袋内的微机械系统电极的电子电路、以及用于补充透氧性内的盐水的可再充填的盐水池 袋子。当外部组件在定制的软件控制下将电力和数据传输到植入的电子设备时，氧合器就会发挥作用(注：软件可以根据每个患者的需要进行个性化)。植入的电子设备接收、解码并将受控电脉冲传送到MEMS电极，以导致电解透氧膜袋内的盐水。然后氧气以受控和定向的方式从袋子扩散到视网膜，同时保护眼睛的前部结构，如晶状体。尽管在几个月的电解过程中只使用了纳升的盐水，但已经设计了一个可再填充的盐水池来补充渗透袋中的盐水，以将氧合器的寿命延长到5年以上。在这份提案中，我们分享了我们迄今为止在这一新方法上的成果，并概述了我们的研究计划，具体有三个目标。在临床前研究中成功完成这三个目标将使我们能够吸引后续的产业资金，以加强临床研究。第一个目标是使用短期和长期测试来量化细胞和组织水平上的视网膜氧合需求。第二个目标是设计氧合器，以证明长期疗效并最大限度地提高效率。第三个目标是研究眼内受控电解产生和扩散氧气的时空动力学。

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) and retinal vein occlusions (RVO) are major causes of low vision and blindness. Although DR and RVO have different underlying pathophysiology, inner retinal hypoxia secondary to ischemia is central to these diseases. Existing therapeutic approaches like pharmacological injections, pan-retinal photocoagulation, focal laser, and surgery either do not address retinal hypoxia or do so at the cost of damaging retinal tissue. Moreover, even with intravitreal injections of anti-Vascular Endothelial Growth Factors, or laser, in approximately 50% of patients, vision does not improve. Our interdisciplinary team of biologists, physicists, engineers, and physicians from seven institutions has taken a novel approach towards treating ischemic retinal disease. In this proposal, using sophisticated biological experiments, bioinformatics, biophysics and advanced bio-microelectromechanical systems (bioMEMS) engineering, we propose an OXYGENATOR system to deliver highly controlled levels of oxygen that are precisely targeted to the ischemic retina (i.e., local oxygenation within a therapeutic window). We have made significant advances towards engineering of a wireless bioelectronic implant (OXYGENATOR) that can deliver safe amounts of oxygen to the retina in a controlled manner. The OXYGENATOR consists of two units; one wearable and the other implantable. The extraocular wearable components (single ergonomic, flexible, low profile design for day and night time use) provide the inductive (RF) link for power and data. The implantable components consist of electronics to receive power and data, electronic circuitry attached to MEMS electrodes inside oxygen permeable membrane bag for electrolysis, and a refillable saline reservoir to replenish the saline inside oxygen permeable bag. The OXYGENATOR functions when the external component transmits power and data under customized software control to the implanted electronics (note software can be personalized for each patient need). The implanted electronics receive, decode and deliver controlled electrical pulses to the MEMS electrodes to result in electrolysis of the saline inside the oxygen permeable membrane bag. The oxygen then diffuses in a controlled and directional manner out the bag to the retina while shielding the anterior eye structures such as the lens. Although only nanoliters of saline are used over months of electrolysis, a refillable saline reservoir to replenish the saline inside the permeable bag has been designed to lengthen the life of the OXYGENATOR to 5+ years. In this proposal, we share our results to date on this novel approach and outline our research program in 3 specific aims. Successful completion of these 3 aims in preclinical studies will enable us to attract follow-on industrial funding to embar on clinical studies. The first aim is to use short and long term tests to quantify the retinal oxyen requirements at the cellular and tissue level. The second aim is to engineer the OXYGENATOR to demonstrate long-term efficacy and maximize efficiency. The third aim is to study the spatiotemporal dynamics of oxygen production and diffusion by controlled electrolysis in the eye.