Optic-nerve-head (ONH) Chips for Glaucomatous Neurodegeneration

虽然青光眼的发病率在不断增加，但青光眼是不可逆转的主要原因 在全世界失明的情况下，目前的青光眼治疗方法显示疗效有限。作为最突出的致因和 青光眼的预后危险因素，高眼压可使视神经头变形 (ONH)并在穿过ONH时损害视网膜神经节细胞(RGC)轴突。当前青光眼 治疗的重点是降低眼压，然而，尽管眼压得到了很好的控制，但随着时间的推移，视力下降仍在继续。 大量证据表明ONH星形胶质细胞对高眼压的反应是RGC轴突形成的一种机制 损坏。星形胶质细胞表达机械敏感通道，感受机械变形，并成为 对眼压升高的反应性反应，可能导致青光眼的病理改变。然而， 眼压对ONH生物力学的影响尚不完全清楚。值得注意的是，ONH的刚度随着年龄的变化而变化， 青光眼和眼压升高，星形胶质细胞对微环境僵硬和 机械刺激。虽然广泛使用的鼠标型号昂贵、耗时且设备有限，但大多数 传统的体外ONH模型是基于2-D刚性底物，没有结合关键的解剖学和 天然ONH的生理特征，导致细胞过程偏离体内事件。我们 从而假设，与ONH模型的物理和力学特性非常相似 国产ONH将允许更准确的体外青光眼研究。因此，这个项目的目标是 开发芯片上系统，概括关键结构(星形胶质细胞和视网膜节细胞的共培养)， 自然ONH的物理(径向排列的RGC和基质刚度)和机械(IOP)特性 阐明青光眼发病的星形细胞机制。一个跨学科的研究团队已经 在芯片器官技术、青光眼神经退行性变、生物力学和 提出了两个具体目标：(1)设计和验证ONH病理生理学芯片 相关性，以及(2)在芯片上描绘青光眼发病机制的机械传感机制。 该项目的成功完成将提供新颖的仿生ONH芯片，以提供可靠、快速和 描述青光眼神经变性的廉价模型。经过验证的鼠标ONH芯片将放置 开发人类ONH芯片促进青光眼发病机制认识的基础 这是一种新的致病机制，并有助于开发治疗疾病的方法。美国商务部 北卡罗来纳大学生物医学工程专业新开设了一个经教唆认可的本科课程，约有254名学生。 2020年的学生(117名女性，西班牙裔=77名，非裔美国人=33名)。拟议的区域方案将 为本科生提供研究机会，特别是为代表不足的少数族裔和女性提供研究机会 并激励他们在生物医学和健康相关领域追求自己未来的职业生涯。

While there is a continuous increase in the incidence of glaucoma, the leading cause of irreversible blindness worldwide, current glaucoma therapies show limited efficacy. As the most prominent causative and prognostic risk factor of glaucoma, elevated intraocular pressure (IOP) could deform the optic nerve head (ONH) and damage the retinal ganglion cell (RGC) axons as they pass through the ONH. Current glaucoma therapies focus on lowering IOP, yet the vision loss continues over time despite a well-controlled IOP. Extensive evidence suggests the ONH astrocyte response to elevated IOP as a mechanism for RGC axonal damage. The astrocytes express mechanosensitive channels, sense the mechanical deformation, and become reactive in response to IOP elevation, which may lead to pathological changes of glaucoma. However, the effects of IOP on ONH biomechanics are not fully understood. Of note, the ONH stiffness changes with age, glaucoma and IOP elevation, and the astrocytes are highly sensitive to microenvironment stiffness and mechanical stimuli. While widely used mouse models are costly, time-consuming and facility limited, most of conventional in vitro ONH models are based on 2-D stiff substrates without incorporating key anatomical and physiological characteristics of native ONH, leading to cellular processes deviated from the in vivo events. We thus hypothesized that the ONH model that closely resembles the physical and mechanical characteristics of native ONH will allow more accurate in vitro glaucoma study. Therefore, the objective of this project is to develop ONH-on-a-chip systems that recapitulate the key structural (co-culture of astrocytes and RGCs), physical (radial aligned RGCs and matrix stiffness), and mechanical (IOP) characteristics of native ONH to delineate the astrocytic mechanisms of glaucoma pathogenesis. An interdisciplinary research team has been assembled to have expertise in organ-on-a-chip technology, glaucoma neurodegeneration, biomechanics and biomaterials, and two Specific Aims are proposed: (1) engineer and validate ONH chips of pathophysiological relevance, and (2) delineate mechanosensing mechanisms underlying glaucoma pathogenesis on the chips. Successful completion of this project will deliver novel, biomimetic ONH chips to provide a reliable, rapid, and inexpensive model to delineate the glaucomatous neurodegeneration. The validated mouse ONH chips will lay the foundation for developing human ONH chip to advance the mechanistic understanding of glaucoma pathogenesis and facilitate the development of disease-modifying therapeutic approaches. The Department of Biomedical Engineering at UNT has a newly ABET-accredited undergraduate program with approximately 254 students (117 women, Hispanic = 77, African American = 33) in 2020. The proposed AREA program will provide research opportunity to undergraduate students, particularly for underrepresented minority and female students and motivate them to pursue their future career in biomedical and health-related areas.