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

摘要 白内障，一种自然晶状体的混浊，是世界范围内导致失明的主要原因，预计有4000万人 到2050年。代表不足的群体和医疗服务不足的人群不成比例 受白内障的影响。临床治疗仅限于手术切除白内障晶状体，以及 人工晶状体植入术不幸的是，人工晶状体对残余物的生长非常敏感。 晶状体上皮细胞(LECs)，一种称为后囊混浊(PCO)的并发症，发生在 约40%的成人人工晶状体患者。激光囊膜切开术是用来治疗后囊混浊的，但有很大的潜力 效果。这项拟议的工作将导致基于一种新的两亲性人工晶状体的开发 硅胶，减少后囊混浊的发生率和第二次手术的需要(激光囊膜切开术)。这项工作是 重要的不仅是预期的出色的LEC阻力和所需的光机械保持能力 建议的人工晶状体的性质(由初步数据支持)，但它也很容易依赖于一种战略 集成到现有人工晶状体材料、设计和制造工艺中。二苯基硅树脂用于 制备可折叠人工晶状体，其中弹性性质提供在植入时折叠人工晶状体的能力 从而可以减小切口尺寸。在这项工作中，新型两亲性表面改性剂(SMA) [由PI开发]，由聚环氧乙烷(PEO)段和硅氧烷系绳组成，将很容易 混合成IOL型二苯基硅酮。这些SMA独一无二地能够提供快速和实质性的迁移到 水/生物界面，可产生抗LEC性能，而不影响光机械性能。这个 这项工作的创新之处不仅在于PI开发的SMA的新颖性，而且在于对 试图生产抵抗LEC生长的IOL的其他策略(例如，改变为IOL 几何设计、复杂的表面处理和产生活性氧(ROS)的改性剂)。这个 完成这项工作的方法依赖于系统和可靠的方法，并将由以下团队领导 技术娴熟的专家。在目标1[由Grunlan，Pi领导]中，将用不同的SMA制备有机硅配方 二苯基硅氧烷的结构和浓度、主要材料性能评估和人工晶状体的制备 从符合成功标准的配方中提取。在目标2[由钱德勒领导，Co-I]中，精选配方将是 评估对晶状体上皮细胞生长的抵抗力，并选择在兔和人眼进行体外评估的人工晶状体 商用硅胶人工晶状体作为对照。在目标1和目标2的迭代之后，在目标3[由Scott，Co-I领导)， SMA修饰人工晶状体将在兔模型中进行评估，并对LEC生长的生物相容性和抵抗力进行评估 与商业人工晶状体相比。临床顾问，Lee博士，医学博士(综合眼科医生 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.