Integrated, miniaturized fluorescence microscopes for biology research and general science education

摘要技术描述：本提案涉及一种新型荧光显微镜的开发，旨在使科学研究人员和学生更容易获得高性能光学成像。传统上，高性能光学显微镜需要精心设计的物镜，其复杂性和费用限制了可用性。即使在最好的研究实验室里，也很难找到几台高性能显微镜和物镜。在高中和社区大学，很难在教学实验室找到高质量的显微镜。显微镜的台式尺寸也排除了许多潜在的用途，例如在其他仪器中或需要便携性。然而，由于可批量生产的微型透镜和用于其他用途的光电元件（如手机相机）的兴起，光学显微镜范式转变的技术种子最近已经播下。发光二极管（LED）和互补金属氧化物半导体（CMOS）图像传感器现在提供了高质量的光源和高分辨率的相机，每个只需要几美元。因此，我们工作的基本前提是现有的技术可以实现高性能显微镜，同时将所有光学元件-光源，镜头，滤光片和相机-集成到一个大约一角硬币大小的包装中，并且成本远低于今天的显微镜。为了实现这一目标，这项研究将是斯坦福大学两个具有互补专业知识的实验室之间的密切合作，他们已经密切合作了2年。生物物理学家Mark Schnitzer在设计、建造和使用荧光显微镜进行活体脑成像方面经验丰富。Abbas El Gamal工程师是mos相机行业的创始人之一，也是数字成像的先驱。为了证明显微镜最终可以变得更容易使用，这两个小组将设计、制造、测试和改进20台集成的微型荧光显微镜，其设计原则上可以大规模制造。更广泛的意义和重要性：生物学研究将集中在Schnitzer实验室对运动神经生物学的兴趣上，但这项工作将通过帮助将光学显微镜从一种相对稀缺的资源转变为更多的商品来广泛影响研究和教育。与任何颠覆性技术一样，在受影响的社区重新思考当前的技术角色之前，最好的应用可能不会出现。然而，这些显微镜或类似设备的关键未来用途可能包括：(1)模式生物的大规模遗传或化学筛选；(2)其他仪器（如培养箱）内生物样品的延时成像；(3)人体细胞功能成像；(4)野外生态样本监测；(5)偏远地区、欠发达国家或家庭的蜂窝诊断；（六）土壤、农产品、空气、水等病原体监测；(7)给每个学生一台显微镜，在课堂内外使用。虽然解决这些不同用途的大规模生产显然还有很长的路要走，但该项目将更快地影响当地社区的教育，通过与附近一所大学的合作，为历史上服务不足的人口提供中学和副学士学位教育。这将为我们的设备在高中课堂上的可用性提供有价值的反馈。该设备的另一个子集将用于斯坦福大学的教学实验室，也将允许多个生物学研究实验室在他们自己的项目中尝试显微镜。

ABSTRACTTECHNICAL DESCRIPTION: This proposal concerns the development of a new type offluorescence microscope intended to make high-performance optical imaging vastly more accessible to science researchers and students. Traditionally, high-performance light microscopy requires exquisitely engineered objective lenses, whose complexity and expense limit availability. Even in the best research labs it is not common to find more than a handful of high-performance microscopes and objective lenses. In high schools and community colleges it is truly rare to find fine quality microscopes in teaching labs. Microscopes' bench-top size also precludes many potential uses, such as those inside other instrumentation or requiring portability.However, the technological seeds of a paradigm shift in light microscopy have recently been sown, due to the rise of mass-producible miniature lenses and opto-electronic components made for other purposes, such as in cell phone cameras. Light-emitting diodes (LED) and complementary metal-oxide semiconductor (CMOS) image sensors now provide quality light sources and high-resolution cameras available for a few dollars apiece. Thus, our work's basic premise is available technology enables high-performance microscopy while integrating all optical components - light source, lenses, filters, and camera - into one package about the sizeof a dime and costing far less than microscopes do today. To pursue this goal, this research will be an intimate collaboration between two Stanford labs of complementary expertise who have worked closely together for 2 years. Biophysicist Mark Schnitzer is deeply experienced in the design, construction, and use of fluorescence microscopes for in vivo brain imaging. Engineer Abbas El Gamal is one of the founders of theCMOS camera industry and a pioneer in digital imaging. To prove microscopy could ultimately become vastly more accessible, the two groups will design, build, test, and refine 20 integrated, miniature fluorescence microscopes with a design that could in principle be mass-fabricated. BROADER SIGNIFICANCE AND IMPORTANCE: The biological studies will focus on the Schnitzer lab's interests in motor neurobiology, but the work is poised to broadly impact research and education by helping to transform light microscopy from a relatively scarce resource into more of a commodity. As with any disruptive technology, the best applications might not emerge until after the affected communities re-think current technological roles.However, key future usages of these microscopes--or devices like them--may include: (1) Large-scale genetic or chemical screens of model organisms; (2) Time-lapse imaging of biological samples inside other instrumentation, such as incubators; (3) Imaging cellular functions of the human body; (4) In the field monitoring of ecological samples; (5) Cellular diagnostics in remote locations, underdeveloped nations, or the home; (6) Pathogen surveillance, such as in soil, agricultural products, air or water; (7) Giving each student a microscope for use in and outside the classroom. Although any mass production to address these diverse usages clearly remains a long way in the future, this project will more quickly impact education in the local community, via a partnership with a nearby university that offers secondary and associate's degree education to an historically underserved population. This will provide valuable feedback on the usability of our devices in the high school classroom. Another subset of the devices will be used in Stanford's teaching labs and will also permit multiple biology research labs to try the microscopes in their own projects.