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。其目标是为患有视网膜色素变性或黄斑变性的盲人恢复有限但有用的视力水平。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。只有薄薄的微电极阵列才能穿透巩膜，从下方对视网膜进行电刺激。这种微创设计避免了侵入性玻璃体手术，避免了连接到视网膜需要大头针或胶水，避免了眼内电子设备对视网膜的加热，以及植入物引起的运动诱导的视网膜压力。如果需要，也可以毫不费力地取出它。我们将在以下三个主要方面开发我们现有的设计和原型 最终供人类使用的区域： 1)我们将开发一种高通量密封式微封装，以保护植入电子设备免受体液的影响。它将是薄的，轮廓到眼睛的弯曲度，手术上便于植入，生物相容性好。这是唯一一种可以在FDA要求的至少10年内保护电子产品的方法。最初的设计将允许200个导电针穿过外壳，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，我们将开发一种防水碳化硅胶囊，并涂覆一层生物相容的聚合物涂层，以防止密集的细胞过度生长，从而阻碍电刺激。在防止细胞过度生长的过程中，如果植入后几个月或几年有必要的话，聚合物涂层还可以实现手术移除设备。涂层将以共价方式附着，以实现牢固的粘合，足够致密以防止蛋白质或细胞接近阵列表面，并能够容纳和释放抗炎剂和其他药物。 3)我们将使植入的电子设备耐受电气噪声和干扰，增加一个控制外部电力传输的系统以延长电池寿命，并增加电极驱动电路的电压摆幅，以实现以更大、更短的电流脉冲刺激视网膜。 我们将在尤卡坦小型猪的眼部进行一些植入实验，以测试设计的轮廓正确、手术方便和长期生物相容性。一个外部供应商实验室将对设备材料、植入原型和候选聚合物涂层进行细胞毒性测试，以实现生物兼容性。 请注意：在NIH根据2009年《美国复苏和再投资法案》(ARRA)要求的这次修订中，我们被要求将提案的期限减少到两年。我们要求增加的研究助理和研究科学家将使我们有可能在两年内完成上文订正项目摘要中概述的所有工作。与最初的三年提案相比，减少的内容如下：(I)在第1区)，我们将无法进行密封包的第三年外科试验，在第2区)我们将能够开始但不能完成关于加速多层电极阵列体外测试的拟议工作，我们将无法合成基于三嵌段聚合物的涂层，也无法比较共价键合胶束与物理附着胶束的药物释放动力学，以及(Iii)动物植入实验将限于两年和16头尤卡坦小型猪，而不是最初提议的三年和24头迷你猪。

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.