Biocompatibility of thermo-responsive hydrogel ocular drug delivery system

热响应水凝胶眼部给药系统的生物相容性

• 批准号: 7940224
• 负责人: JENNIFER J Kang-Mieler
• 金额: $ 36.09万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7940224
• 关键词: Age related macular degeneration; Area; Biocompatible Materials; Blindness; Blood Vessels; Body Temperature; Bolus Infusion; Characteristics; Choroidal Neovascularization; Clinical; Clinical Data; Diabetic Retinopathy; Diagnosis; Disease; Drug Delivery Systems; Electroretinography; Encapsulated; Gel; Goals; Hemorrhage; Histology; Hydrogels; Image; Implant; In Vitro; Inflammation; Injection of therapeutic agent; Laboratories; Lasers; Liquid substance; Methods; Needles; Ophthalmoscopes; Optical Coherence Tomography; Patients; Posterior eyeball segment structure; Property; Proteins; Regimen; Research; Retina; Retinal; Rodent Model; Scanning; Site; Solid; Solutions; System; Testing; Time; Toxic effect; Treatment Protocols; Vascular Diseases; Vascular Endothelial Growth Factors; Venous; angiogenesis; biomaterial compatibility; blood flow measurement; drug efficacy; implantation; improved; in vivo; innovation; novel; response

DESCRIPTION (provided by applicant): Recently employed anti-vascular endothelial growth factor (VEGF) therapy is a very promising treatment for the wet form of age-related macular degeneration and diabetic retinopathy. To be effective, multiple intravitreal injections are needed every four to six weeks. This is not a desirable method as it is associated with several inherent complications. Currently, there is no alternative method; hence, there is a great need to develop a relatively non-invasive delivery method that is more effective than the current clinical regimen. The proposed drug delivery system uses thermo-responsive hydrogel that would optimize the anti-angiogenic effects but minimize the potential for ectopic effects of a large bolus delivery. Due to its novel thermo-responsive characteristic, the hydrogel can be injected as a liquid form to the juxtascleral region or vitreous cavity via a small gauge needle. Once exposed to the body temperature, the solution will become a solid gel that will release the anti-VEGF agents. In vitro studies have demonstrated that thermo-responsive hydrogels can encapsulate and release active protein. The goal of this proposal is to investigate the feasibility and biocompatibility of thermo-responsive hydrogel as an ocular drug delivery system in vivo. Specific Aim 1 will investigate the biocompatibility of the thermo-responsive implant in either the vitreous cavity or juxtascleral region in an in vivo rodent model. To evaluate biocompatibility, electroretinogram (ERG) responses, scanning laser ophthalmoscope (SLO)-imaging blood flow measurements, spectral domain optical coherence tomography (SD-OCT) imaging and histological examination of retinal toxicity and inflammation will be performed at various time points after the implantation. Specific Aim 2 will determine the efficacy of released anti-VEGF from the hydrogels to suppress angiogenic responses in a laser-induced choroidal neovascularization rodent model. ERG responses, SLO-imaging blood flow measurements, OCT imaging and histology will be used to evaluate the efficacy. Widespread clinical use of anti-VEGF necessitates a practical and effective delivery method to the posterior segment. The innovation of this project is that a novel biomaterial will be used to minimize the need for repeated intravitreal injections and improve the efficacy of the drug. The proposed drug delivery system will have a great impact on the current treatment regimen. PUBLIC HEALTH RELEVANCE: Widespread clinical use of anti-vascular endothelial growth factor (VEGF) therapy necessitates a practical and effective delivery method to the posterior segment of the eye. Recently developed biodegradable thermo- responsive hydrogel system has demonstrated to encapsulate and release active protein. The overall goal of this proposal is to investigate the feasibility and biocompatibility of thermo-responsive hydrogel as an ocular drug delivery system which can have a significant impact on the current treatment of age-related macular degeneration and diabetic retinopathy.

描述（由申请人提供）：最近采用的抗血管内皮生长因子（VEGF）治疗是一种非常有前途的治疗湿型老年性黄斑变性和糖尿病视网膜病变的方法。为了有效，每四到六周需要多次玻璃体内注射。这不是一种理想的方法，因为它与几个固有的并发症有关。目前，没有替代方法；因此，非常需要开发一种相对非侵入性的递送方法，这种方法比目前的临床方案更有效。所提出的给药系统使用热反应性水凝胶，可优化抗血管生成作用，但最大限度地减少大剂量给药的异位效应。由于其新颖的热响应特性，水凝胶可以通过小规格针以液体形式注射到巩膜旁区域或玻璃体腔。一旦暴露在体温下，溶液就会变成固体凝胶，释放出抗vegf药物。体外研究表明，热反应性水凝胶可以包封并释放活性蛋白。本研究的目的是研究热反应性水凝胶作为眼内给药系统的可行性和生物相容性。特异性目的1将在体内啮齿动物模型中研究热响应性植入物在玻璃体腔或巩膜旁区的生物相容性。为了评估生物相容性，将在植入后的各个时间点进行视网膜电图（ERG）反应、扫描激光检眼镜（SLO）成像血流测量、光谱域光学相干断层扫描（SD-OCT）成像以及视网膜毒性和炎症的组织学检查。特异性目的2将确定从水凝胶中释放的抗vegf抑制激光诱导脉络膜新生血管啮齿动物模型血管生成反应的功效。ERG反应、慢速成像血流测量、OCT成像和组织学将用于评估疗效。抗vegf在临床的广泛应用需要一种实用有效的后段给药方法。该项目的创新之处在于，将使用一种新型生物材料，以尽量减少玻璃体内重复注射的需要，并提高药物的疗效。提出的给药系统将对目前的治疗方案产生重大影响。