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

虽然青光眼的发病率持续增加，但不可逆转的青光眼的主要原因是： 目前青光眼治疗的有效性有限。作为最突出的使役， 青光眼的预后危险因素，高眼压可使视神经乳头变形 (ONH)并在视网膜神经节细胞（RGC）轴突穿过ONH时损伤它们。当前青光眼 治疗集中于降低IOP，然而尽管IOP控制良好，视力丧失仍随时间持续。 大量证据表明ONH星形胶质细胞对IOP升高的反应是RGC轴突损伤的机制。 损害星形胶质细胞表达机械敏感通道，感知机械变形，并成为 反应性眼压升高，这可能导致青光眼的病理变化。但 IOP对ONH生物力学的影响尚未完全了解。值得注意的是，ONH刚度随年龄变化， 青光眼和IOP升高，并且星形胶质细胞对微环境刚度高度敏感， 机械刺激虽然广泛使用的小鼠模型是昂贵的，耗时的和设施有限的，但大多数 传统的体外ONH模型基于2-D刚性基底， 天然ONH的生理特征，导致细胞过程偏离体内事件。我们 因此，假设ONH模型非常类似于 天然ONH将允许更准确的体外青光眼研究。因此，本项目的目标是 开发ONH芯片系统，概括关键结构（星形胶质细胞和RGC的共培养）， 天然ONH的物理（径向排列的RGC和基质硬度）和机械（IOP）特征， 阐明青光眼发病的星形胶质细胞机制。一个跨学科的研究小组已经 汇集了在器官芯片技术，青光眼神经变性，生物力学和 提出了两个具体目标：（1）设计和验证病理生理学的ONH芯片， 相关性，和（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， 廉价的模型来描绘脑昏迷性神经变性。经过验证的小鼠ONH芯片将 开发人类ONH芯片以促进青光眼机制理解的基础 发病机制，并促进改善疾病的治疗方法的发展。部 生物医学工程在UNT有一个新的ABET认证的本科课程，约254 学生（117名女性，西班牙裔= 77，非洲裔= 33）在2020年。拟议的区域方案将 为本科生提供研究机会，特别是代表性不足的少数民族和女性 鼓励学生在生物医学和健康相关领域追求未来的职业生涯。

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.