SBIR Phase II: Real-time Active Image Stabilization for Microscopy

这个小企业创新研究（SBIR）二期项目将开发和商业化一个集成系统，以主动稳定光学显微镜，以满足当今尖端成像方法所要求的精度。生物科学中的显微术在几个方面正在经历根本性的进步。“超分辨率”（SR）技术绕过了曾经被认为是不可逾越的分辨率的衍射极限，并有望在分子水平上对细胞生物学的结构和过程进行成像。这将带来对细胞内部工作机制的深刻理解。然而，在广泛使用SR技术的道路上仍然存在重大的相互关联的障碍：(1)它们在技术上具有挑战性；(2)实施成本高昂；(3)他们对显微镜平台提出了物理要求，而显微镜平台的设计并没有满足这些要求。这些要求中最重要的是，SR方法需要控制生物样品的运动和显微镜系统的稳定性，具有纳米精度。这种商业化的集成系统是专门为解决这些问题和消除这些障碍而设计的。它使用一个3轴、压电驱动的纳米定位平台来控制样品运动，并以图像作为这种稳定性的参考点，积极地保持系统的稳定性。该项目更广泛的影响/商业潜力在于使SR方法对工作生物学家日常有用。这些“改变游戏规则”的工具将促进我们对疾病病理分子基础的理解，并使更精确的治疗方法成为可能。新的见解将包括分子病毒学和开发更安全、更有效的疫苗，以及神经元信号和学习与记忆的分子机制。事实上，很难想象一个细胞生物学领域不会受到这些新兴SR技术的影响。这些方法的先驱之一把它们比作哈勃望远镜：它们使人们看到以前根本看不到的东西。这个类比更进一步：由于常规使用的技术和经济障碍，目前只有一台哈勃望远镜，而且能够进行sr成像的系统非常少。虽然SR方法暴露了显微镜的物理局限性，但它们的稳定性和图像采集要求并不独特。因此，这个商业系统将有更广泛的用途：它还将为任何长期成像实验提供纳米尺度的焦稳定性和分子跟踪。

This Small Business Innovation Research (SBIR) Phase II project will develop and commercialize an integrated system to actively stabilize an optical microscope to the precision required by today's cutting-edge imaging methods. Microscopy in the biological sciences is undergoing radical advancement on several fronts. "Super-Resolution" (SR) techniques circumvent the diffraction limit on resolution once thought to be insurmountable, and promise the ability to image the structures and processes of cell biology at the molecular level. This will usher in profound advancements in the understanding of the inner-workings of the cell. However, significant interrelated barriers remain in the path towards widespread use of SR techniques: (1) they are technically challenging and (2) expensive to implement; and (3) they place physical demands on the microscope platform it was not designed to meet. Foremost of these demands is that SR methods require control over the movement of the biological sample and the stability of the microscope system with nanometer precision. This commercialized integrated system is designed specifically to address these issues and remove these barriers. It uses a 3-axis, piezo-driven nanopositioning stage to control sample motion and actively maintains the stability of the system using the image as the reference point for this stability.The broader impact/commercial potential of this project lies in making SR methods routinely useful to working biologists. These "game-changing" tools will advance our understanding of the molecular bases of disease pathologies, and enable far more exacting methods aimed at their treatments. The new insights will range from those in molecular virology and the development of safer and more effective vaccines, to the molecular mechanisms of neuronal signaling and learning and memory. In fact, it is hard to imagine an area of cell biology that will not be impacted by these emerging SR techniques. One of the pioneers of these methods has likened them to the Hubble telescope: they enable people to see things they simply could not see before. This analogy goes further: there is only one Hubble telescope, and currently very few SR-capable imaging systems, due to both the technical and economic barriers to their routine use. And while SR methods expose the physical limitations of microscopes in an acute manner, their stability and image acquisition requirements are not unique. Thus, this commercial system will be much more broadly useful: it will also enable focal-stability and molecular tracking at the nanometer-scale for any long-term imaging experiment.