Advanced Engineering Development of a Chronic Retinal Implant

我们建议开发和改进一种新的微创视网膜假体设计。其目标是恢复有限的，但有用的视力水平的患者失明视网膜色素变性或黄斑变性。植入物将被无线驱动，几乎整个植入物都附着在眼睛的外壁（巩膜）上。只有一个薄的微电极阵列将穿透巩膜，从下面电刺激视网膜。这种微创设计避免了侵入性玻璃体手术、用于附着到视网膜的钉或胶的需要、通过眼内电子设备对视网膜的加热以及来自植入物的运动诱导的视网膜应力。如果需要的话，它也可以在没有太大困难的情况下被移除。我们将在以下三个主要方面发展我们现有的设计和原型 最终供人类用途： 1)我们将开发一种高馈通密封微封装，以保护植入电子设备免受体液的影响。它将是薄的，轮廓符合眼睛的曲率，便于手术植入和生物相容性。这是唯一的方法，将保护电子产品的10年最低要求的FDA。最初的设计将允许200个导电针穿过外壳，以刺激近200个电极，是目前任何其他密封设计的3倍多。我们还将进一步开发外科植入技术。 2)对于穿透巩膜的薄微电极阵列，我们将开发具有生物相容性聚合物涂层的防水碳化硅封装，以防止可能阻碍电刺激的密集细胞过度生长。在防止细胞过度生长方面，聚合物涂层还使得能够在植入后数月或数年内手术移除装置。涂层将共价连接以牢固粘附，足够致密以防止蛋白质或细胞接近阵列表面，并且能够保持和释放抗炎剂和其他药物。 3)我们将使植入的电子设备能够抵抗电噪声和干扰，增加一个系统来控制来自外部的电力传输，以增加电池寿命，并增加电极驱动电路的电压摆幅，以便能够用更大，更短的电流脉冲刺激视网膜。 我们将在尤卡坦小型猪的眼睛中进行许多植入实验，以测试该设计的正确轮廓、手术便利性和长期生物相容性。外部供应商实验室将对器械材料、植入物原型和候选聚合物涂层进行生物相容性细胞毒性试验。 请注意：在这次修订中，NIH根据2009年《美国复苏和再投资法案》（ARRA）的要求，我们被要求将提案缩短为两年。我们要求增加的研究助理和研究科学家将使我们能够在两年内完成上述订正项目摘要中概述的所有工作。从最初的三年提案中减少的数额是：（i）在领域1）下，我们将无法进行密封包装的第三年手术试验，在领域2）下，我们将能够开始但无法完成多层电极阵列加速体外试验的拟议工作，并且我们将不能合成基于三嵌段聚合物的涂层或比较共价键合的胶束与物理粘附的胶束的药物释放动力学，和（iii）动物植入实验将限于两年和16只尤卡坦小型猪，而不是最初提议的三年和24只小型猪。

We propose to develop and improve a novel minimally-invasive retinal prosthesis design. The goal is to restore a limited but useful level of vision to patients blind with retinitis pigmentosa or macular degeneration. The implant will be driven wirelessly, with almost the entire bulk of the implant attached to the outer wall (sclera) of the eye. Only a thin microelectrode array will penetrate the sclera to electrically stimulate the retina from beneath. This minimally invasive design avoids intrusive vitreal surgery, the need for tacks or glue for attachment to the retina, heating of the retina by intraocular electronics, and motion-induced retinal stress from the implant. It can also be removed without major difficulty if needed. We will develop our existing design and prototype in the following three major areas for eventual human use: 1) We will develop a high-feedthrough hermetic micropackage to protect the implant electronics from bodily fluids. It will be thin, contoured to the curvature of the eye, surgically convenient to implant and biocompatible. This is the only method that will protect the electronics for the ten year minimum required by the FDA. The initial design will allow for 200 electrically conducting pins to pass through the case to stimulate almost 200 electrodes, over 3 times as many as any other hermetically sealed design currently available. We will also further develop techniques for surgical implantation. 2) For the thin microelectrode array that penetrates the sclera, we will develop a waterproof silicon carbide encapsulation with a biocompatible polymer coating to prevent dense cellular overgrowth that can hinder electrical stimulation. In preventing cellular overgrowth, the polymer coating also enables surgical removal of the device, if that were to become necessary months or years after implantation. The coating will be covalently attached for firm adhesion, sufficiently dense to prevent proteins or cells from approaching the surface of the array, and capable of holding and releasing anti-inflammatory agents and other drugs. 3) We will make the implanted electronics resistant to electrical noise and interference, add a system to control power transmission from outside to increase battery life, and increase the voltage swing of the electrode driver circuits to enable stimulation of the retina with larger, shorter current pulses. We will carry out a number of implantation experiments in the eye of the Yucatan minipig to test the design for correct contour, surgical convenience and long-term biocompatibility. An outside vendor laboratory will conduct cytotoxicity tests on device materials, implant prototypes and candidate polymer coatings for biocompatibility. Please Note: In this revision, which NIH requested under the American Recovery and Reinvestment Act (ARRA) of 2009, we have been asked to reduce the proposal to a two-year duration. The additional research assistant and research scientist we have requested will make it possible to complete all the work outlined in the revised project summary above in two years. The reductions from the original three-year proposal are: (i) under Area 1), we will not be able to perform the third year's surgical trials of the hermetic package, under Area 2) we will be able to begin but not complete the proposed work on accelerated in-vitro testing of the multilayered electrode arrays, and we will not be able to synthesize coatings based on triblock polymers or compare the drug-release kinetics of covalently-bonded vs physically adhered micelles, and (iii) the animal implantation experiments will be limited to two years and16 Yucatan mini-pigs rather than the three years and 24 mini-pigs originally proposed.