Non-linear Optical Collagen Cross-linking (NLO CXL) for Treatment of Keratoconus.

用于治疗圆锥角膜的非线性光学胶原交联 (NLO CXL)。

• 批准号: 9303387
• 负责人: James V Jester
• 金额: $ 37.64万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303387
• 关键词: Acoustics; Affect; Anterior; Area; Bullous Keratopathy; Caliber; Cataract; Cells; Collagen; Complication; Cone; Cornea; Corneal Diseases; Corneal Endothelium; Corneal Stroma; Corneal Ulcer; Crystallins; Devices; Elasticity; Endothelium; Exposure to; Eye; Fluorescence; Free Radicals; Frequencies; Generations; Hydrogels; Infection; Keratoconus; Laser In Situ Keratomileusis; Laser Scanning Confocal Microscopy; Lasers; Lateral; Lead; Light; Long-Term Effects; Measures; Mechanics; Microbubbles; Microscopic; Microscopy; Modification; Modulus; Monitor; Optics; Oryctolagus cuniculus; Pathological Dilatation; Patients; Photons; Photosensitization; Photosensitizing Agents; Phototoxicity; Positioning Attribute; Process; Radiation; Retina; Riboflavin; Safety; Scanning; Speed; Surface; System; Testing; Therapeutic; Thick; Time; Ultrasonography; Ultraviolet A radiation; Ultraviolet B Radiation; Visible Radiation; cell injury; computerized; crosslink; immunocytochemistry; improved; in vivo; lens; microbial; novel; novel strategies; photoactivation; public health relevance; repaired; two-photon; ultraviolet

DESCRIPTION (provided by applicant): The major objective of this proposal is to test the hypothesis that photoactivation of riboflavin by non- linear optical (NLO), two photon processes (TP) using femtosecond laser (FS) light induces spatially resolved (X-Y-Z) collagen cross-linking (CXL) and mechanical stiffening of intact, live rabbit eyes. Recent studies have established that photoactivation of riboflavin by 370 nm light (UVA) leads to the generation of free radical-induced collagen CXL and corneal stiffening that shows significant therapeutic benefits for patients suffering from Keratoconus. While UVA and riboflavin are themselves non-toxic, the generation of free radicals within the UVA collimated light path can lead to cellular damage affecting the corneal endothelium and crystallin lens, resulting in bullous keratopathy and potentially cataract. To avoid this complication, therapeutic administration of UVA CXL has been titrated to limit free radical generation to the anterior cornea, thus reducing the efficacy o CXL and limiting the therapeutic range to patients with affected corneas thicker than 400 um. We propose that replacement of collimated UVA light with near-infrared FS laser light to induce NLO CXL within a spatially resolved focal volume determined by the focusing lenses would greatly improve the safety and efficacy of CXL. Major benefits of NLO CXL compared to conventional UVA CXL would included: 1) expanded application of corneal CXL to the treatment of thinner ectatic corneas (<400 um) including post LASIK ectasia patients and other corneal disorders currently proposed for conventional UVA CXL including, bullous keratopathy, corneal ulceration and microbial infection; 2) additional treatment areas beyond that of the anterior stroma, including middle, posterior and full thickness corneal stroma; and 3) expanded use of alternative photosensitizers activated by low ultraviolet (UVB and UVC) and visible light (400 to 780 nm) that would be phototoxic to the retina using a single photon approach. To test this hypothesis we propose the following Specific Aims: 1) Adapt the current FS delivery system for live rabbit corneal NLO CXL, 2) Determine the effect of varying TP focal volume, FS laser power and scanning speed on NLO CXL corneal stiffening, 3) Determine the short-term affect (1 and 3 days) of NLO CXL on corneal CAF, 3D corneal elastic modulus, and cell damage compared to UVA CXL, 4) Determine the long-term affects (1 and 6 months) of NLO CXL on corneal CAF, 3D corneal elastic modulus, and cell repair compared to UVA CXL.

描述（由申请人提供）：该提案的主要目的是测试以下假设：核黄素通过非线性光学（NLO）的光活化，使用flemtosecond laser（fs）光（fs）光诱导空间分辨（X-y-Z）交叉链接（cxl）和机械强度的强度，使用空间分辨率（X-y-Z）诱导了两个光子过程（TP）。 最近的研究表明，370 nm光（UVA）将核黄素的光活化导致产生自由基诱导的胶原蛋白CXL和角膜僵硬，从而显示出对患有角膜核的患者的显着治疗益处。 虽然UVA和核黄素本身是无毒的，但UVA准直的光路中的自由基产生会导致细胞损伤影响角膜内皮和结晶蛋白透镜，从而导致乳突性角质疾病和潜在的白内障。 为了避免这种并发症，已对UVA CXL的治疗施用已滴定，以将自由基产生限制为前角膜，从而降低了疗效O CXL，并将治疗范围限制在受影响厚400 UM的角膜较厚的患者中。 我们建议，用近红外FS激光灯代替准直的UVA光，以在通过聚焦镜头确定的空间分辨焦点内诱导NLO CXL，这将大大提高CXL的安全性和功效。 与传统的UVA CXL相比，NLO CXL的主要好处包括：1）角膜CXL扩大应用于治疗较薄的骨骼角膜（<400 um），包括Lasik后的患者和其他目前提议的角膜疾病，目前建议用于传统的UVA CXL，包括常规的UVA CXL，包括牛角膜细胞病和微角膜微生物，微生物静脉曲张和微生物静脉曲张； 2）超出前基质的其他治疗区域，包括中部，后和全厚的角膜基质； 3）扩大使用低紫外线（UVB和UVC）和可见光（400至780 nm）激活的替代光敏剂，使用单个光子方法对视网膜具有光毒性。 To test this hypothesis we propose the following Specific Aims: 1) Adapt the current FS delivery system for live rabbit corneal NLO CXL, 2) Determine the effect of varying TP focal volume, FS laser power and scanning speed on NLO CXL corneal stiffening, 3) Determine the short-term affect (1 and 3 days) of NLO CXL on corneal CAF, 3D corneal elastic modulus, and cell damage compared to UVA CXL，4）确定与UVA CXL相比，在角膜CAF，3D角膜弹性模量和细胞修复上的NLO CXL的长期影响（1和6个月）。