Improving Outcomes in Cataract Surgery: Intraocular Lenses (IOLs) Resistant to Cell Growth

摘要 白内障是一种使自然透镜混浊的疾病，是全世界失明的主要原因， 到2050年。代表性不足的群体和医疗服务不足的人群不成比例地 受白内障影响临床治疗仅限于手术摘除白内障透镜， 植入眼内透镜（IOL）。不幸的是，IOL非常容易从残留的 透镜上皮细胞（LEC），一种称为后囊膜混浊（PCO）的并发症， 约40%的成人IOL患者。激光后囊膜切开术是治疗后囊混浊的有效方法，但有明显的潜在副作用 方面的影响.拟议的工作将导致开发基于新的两亲性 硅胶，减少PCO的发生率和第二次手术（激光囊切开术）的需要。这项工作是 不仅考虑到预期的特殊LEC抗性和所需光机械性能的保持， 建议的IOL的特性（由初步数据支持），但也依赖于一种策略， 集成到现有IOL材料、设计和制造过程中。二苯基有机硅用于 制备可折叠IOL，其中弹性体性质提供在植入时折叠IOL的能力 从而可以减小切口尺寸。在这项工作中，新的两亲性表面改性添加剂（SMA） [由PI开发]，由聚（环氧乙烷）（PEO）链段和硅氧烷系链组成， 混合到IOL型二苯基硅树脂中。这些SMA独特地提供了快速和大量迁移到 水/生物界面，以产生LEC抗性，而不影响光机械性能。的 这项工作的创新不仅在于PI开发的SMA的新奇， 试图生产具有LEC生长抗性的IOL的其它策略（例如，变更为IOL 几何设计、复杂的表面处理和产生活性氧（ROS）的改性剂）。的 完成这项工作的方法依赖于系统和强大的方法，并将由一个团队领导， 熟练的专家。在目标1 [由Grunlan，PI领导]中，将使用不同SMA制备硅胶制剂， 二苯基硅橡胶的结构和浓度、评估的关键材料特性和制备的IOL 符合成功标准的配方。在目标2 [由钱德勒，Co-I领导]中，将选择配方 评价了对LEC生长的抗性，并在兔眼和人眼中对选择的IOL进行了离体评估， 商业硅胶IOL用作对照。在目标1和目标2的迭代之后，在目标3中（由Scott，Co-I领导）， 将在兔模型中评价SMA改良IOL，并评价其生物相容性和对LEC生长的抵抗力。 与市售IOL相比。临床顾问，李医生，医学博士。（综合眼科专家 和眼科病理学家）将为这些研究提供指导。

ABSTRACT Cataracts, a clouding of the natural lens, is the leading cause of blindness worldwide, with a projected 40M cases by 2050. Underrepresented groups and medically underserved populations are disproportionately impacted by cataracts. Clinical treatment is limited to surgical removal of the cataractous lens, and implantation of an intraocular lens (IOL). Unfortunately, the IOL is highly susceptible to growth from residual lens epithelial cells (LECs), a complication known as posterior capsule opacification (PCO) that occurs in ~40% of adult IOL patients. Laser capsulotomy surgery is used to treat PCO, but has significant potential side effects. The proposed work will lead to the development of “LEC-resistant IOLs” based on a new amphiphilic silicone, reducing the incidence of PCO and the need for a 2nd surgery (laser capsulotomy). This work is significant given not only the expected exceptional LEC-resistance and retention of desired opto-mechanical properties of the proposed IOLs (supported by preliminary data), but also that it relies on a strategy readily integrated into existing IOL materials, designs, and manufacturing processes. Diphenyl silicones are used to prepare foldable IOLs, wherein the elastomeric nature provides the ability to fold the IOL upon implantation such that the incision size may be reduced. In this work, new amphiphilic surface-modifying additives (SMAs) [developed by the PI], comprised of a poly(ethylene oxide) (PEO) segment and siloxane tether, will be readily blended into an IOL-type diphenyl silicone. These SMAs uniquely afford rapid and substantial migration to the aqueous/biological interface to produce LEC-resistance, without impacting opto-mechanical properties. The innovation of this work rests not only in the novelty of the PI-developed SMAs, but in the departure from other strategies that have attempted to produce IOLs with resistance to LEC growth (e.g., change to IOL geometric design, complex surface treatment, and reactive oxygen species (ROS)-producing modifiers). The approach to accomplish this work relies on a systematic and robust methods, and will be led by a team of skilled experts. In Aim 1 [led by Grunlan, PI], silicone formulations will be prepared with SMAs of varying structure and concentration in the diphenyl silicone, key material properties assessed, and IOLs prepared from formulations meeting success criteria. In Aim 2 [led by Chandler, Co-I] select formulations will be evaluated for resistance to LEC growth, and select IOLs assessed ex vivo in rabbit and human eyes with a commercial silicone IOL used as a control. Following iterations of Aim 1 and 2, in Aim 3 [led by Scott, Co-I), a SMA-modified IOL will be evaluated in a rabbit model, and biocompatibility and resistance to LEC growth compared to the commercial IOL. The clinical consultant, Dr. Lee, M.D. (a comprehensive ophthalmologist and ocular pathologist) will provide guidance to these studies.