'MacuSIM': A microfluidic, in vitro model of the outer retina as an experimental platform for macular disease and therapeutic trials.

“MacuSIM”：外视网膜的微流体体外模型，作为黄斑疾病和治疗试验的实验平台。

• 批准号: NC/T002336/1
• 负责人: Savannah Amy Lynn
• 金额: $ 15.7万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FT002336%2F1
• 关键词: MacuSIM; microfluidic; vitro; model; outer

Age-related Macular Degeneration (AMD) is a common blinding condition that results in the gradual loss of central vision. This is often associated with difficulties in performing simple daily activities such as reading, driving and recognising faces and is a particular concern for the elderly who are at a greater risk of developing the disease. In fact, one in three people will exhibit some form of AMD by the age of 70. AMD currently affects around 600,000 people in the UK alone and costs the economy £1.6 billion annually. This is predicted to increase as our population ages, where outpatient appointments have risen by 30% over the past 4 years and approximately 200 new AMD cases are reported daily. Although treatments exist for some forms of AMD, these are only applicable to 50% of cases and remain ineffective long-term. Thus, there is no cure for AMD at present, which is largely due to our limited understanding of how the disease develops. This constantly remains under investigation by scientists in order to develop new treatments.A number of animals are used by AMD researchers to investigate the underlying causes of disease and in the development of new drugs. Of these, rodents are the most commonly used species which have provided important insights into detrimental changes associated with AMD. However, the structure of the rodent eye is markedly different to that of humans and therefore they have been questioned as a relevant model for the study of AMD. In fact, rodents do not have a macula, the specialised part of the eye affected in AMD. Monkeys (non-human primates) offer the closest similarity to the human eye but come with considerable ethical concerns and must be aged for long periods in order to exhibit disease symptoms. There has therefore been a longstanding requirement for a system that is capable of modelling the full disease spectrum of AMD, but that also exhibits fast turnaround times as well as economic viability. One method of avoiding this difficulty is using cells cultured in a dish, which scientists have used effectively to make discoveries. However, whilst current cell culture models have allowed researchers to investigate individual components of the outer retina and how these are affected in AMD, none have succeeded in modelling the complex relationships and how they may collectively lead to disease. Similarly, no current system models the blood supply to the human retina and how it differs within the macula, the specific region of the eye affected.In this proposal, we aim to validate and demonstrate the applicability of MacuSIM to AMD research, a novel cell culture model of the outer retina developed by the applicants that is capable of recapitulating the key cell types affected in AMD as well as their reliance on the retinal blood supply. This allows the region of the eye most susceptible to AMD to be investigated outside of animal models for the first time, thus reducing their requirement in AMD research. We will employ cutting edge techniques at the forefront of engineering and physics to manufacture this transformative model and will validate the system for use with various biological applications. Our experiments will then involve demonstrating its relevance to AMD research and benefits over existing methods, to promote its uptake within both the academic and pharmaceutical sectors. Here, we will model increased environmental stresses to the macula and test the ability of compounds to alleviate disease symptoms.Through this research we hope to provide a more economic and high throughput model that will lead to the faster development of treatments for AMD patients and reduce associated costs to the NHS. In fact, this work will also benefit research into other eye diseases including Best disease, Stargardt disease and retinitis pigmentosa, highlighting the far reaching impacts and benefits of MacuSIM to society.

视网膜相关性黄斑变性（AMD）是一种常见的致盲疾病，导致中心视力逐渐丧失。这通常与进行简单的日常活动（如阅读、驾驶和识别面孔）的困难有关，对于老年人来说，这是一个特别值得关注的问题，因为他们患上这种疾病的风险更大。事实上，三分之一的人在70岁时会表现出某种形式的AMD。AMD目前仅在英国就影响了约60万人，每年给经济造成16亿英镑的损失。预计随着人口老龄化，这一数字将增加，在过去4年中，门诊预约增加了30%，每天报告约200例新的AMD病例。尽管存在针对某些形式的AMD的治疗，但这些治疗仅适用于50%的病例，并且长期无效。因此，目前还没有治愈AMD的方法，这在很大程度上是由于我们对疾病如何发展的了解有限。科学家们一直在研究这一点，以开发新的治疗方法。AMD研究人员使用许多动物来研究疾病的根本原因和新药的开发。其中，啮齿类动物是最常用的物种，它们为与AMD相关的有害变化提供了重要的见解。然而，啮齿类动物眼睛的结构与人类眼睛的结构明显不同，因此它们作为AMD研究的相关模型受到质疑。事实上，啮齿动物没有黄斑，黄斑是眼睛受AMD影响的专门部分。猴子（非人类灵长类动物）与人类的眼睛最相似，但有相当多的伦理问题，必须长时间老化才能表现出疾病症状。因此，长期以来一直需要一种能够对AMD的全部疾病谱进行建模的系统，但该系统也表现出快速的周转时间以及经济可行性。避免这种困难的一种方法是使用培养皿中培养的细胞，科学家们已经有效地利用这种方法进行了发现。然而，虽然目前的细胞培养模型允许研究人员研究外视网膜的各个组成部分以及这些组成部分如何在AMD中受到影响，但没有人成功地模拟了复杂的关系以及它们如何共同导致疾病。同样，目前还没有一个系统能够模拟人类视网膜的血液供应，以及它在黄斑（眼睛受影响的特定区域）内的差异。在本提案中，我们的目标是验证和证明MacuSIM对AMD研究的适用性，由申请人开发的外视网膜的新细胞培养模型，其能够重现AMD中受影响的关键细胞类型以及它们对视网膜细胞的依赖，血液供应这使得眼睛最易受AMD影响的区域首次在动物模型之外进行研究，从而降低了AMD研究的要求。我们将采用工程和物理前沿的尖端技术来制造这种变革性的模型，并将验证该系统是否可用于各种生物应用。然后，我们的实验将涉及证明其与AMD研究的相关性以及优于现有方法的益处，以促进其在学术和制药领域的应用。在这里，我们将模拟黄斑增加的环境压力，并测试化合物减轻疾病症状的能力。通过这项研究，我们希望提供一个更经济和高通量的模型，这将导致更快地开发AMD患者的治疗方法，并降低NHS的相关成本。事实上，这项工作也将有利于其他眼科疾病的研究，包括Best病，Stargardt病和视网膜色素变性，突出了MacuSIM对社会的深远影响和益处。