IDBR: TYPE A: Directly Integratable Photoacoustic Microscopy with Established Optical Microscopy for Comprehensive Sub-cellular Biological Imaging

西北大学获得了一项奖项，用于开发与商用光学显微镜兼容的光声显微镜（PAM）技术平台。PAM与其他已建立的光学显微技术的不同之处在于，它直接感知组织中生理特异性的光学吸收特性，而不是光散射或荧光特性。因此，它有望通过提供一种新型的成像对比，大大提高当前生物学研究的成像能力。然而，尽管前景广阔，由于缺乏商用系统，PAM只能在美国由非常有限的研究小组进行，这主要是因为现有的PAM系统与商用光学显微镜不兼容。因此，研究人员必须构建自己的PAM系统，这显然超出了生物学研究人员的能力，而且在经济上可能不可行。为了解决这一障碍，该项目旨在使绝大多数已经在日常研究中使用先进光学显微镜的生物学研究人员更容易使用PAM。该项目将有利于需要定量成像的生物研究，例如，组织血流动力学、细胞及其微环境的相互作用、细胞/组织再生和药物评估。PAM系统既可以独立用于无标签体积成像，也可以与共聚焦/双光子显微镜集成用于多模态成像。这个项目的主要智力优点来自于它的新颖设计，通过使PAM与现有的光学显微镜兼容，使PAM能够广泛地访问。两个不兼容性问题阻碍了现有的PAM与现代光学显微镜的无缝集成：(1)PAM缓慢而笨重的机械扫描机制无法匹配现代光学显微镜中使用的高速光学扫描；(2)PAM的不透明且较大的超声波探测器无法轻松安装到与高功率物镜相关的极其有限的工作空间中。本项目为解决这两个问题提供了有效的解决方案。这项研究的关键影响在于，它将首次为PAM的广泛应用奠定坚实的基础，使绝大多数生物学研究人员而不仅仅是少数光学研究小组能够广泛使用PAM。生物学研究的突破往往伴随着技术的进步；然而，开发一种适用于生物学研究的新技术仅仅是个开始。带来社会效益的关键一步是使新开发的技术为用户所接近。由于PAM在提供高分辨率的组织和细胞三维无染色功能成像方面的巨大优势，该集成系统具有扩大广泛生物学研究领域的潜力。这个项目需要本科生和研究生的积极参与。这个项目的独特之处在于，学生将获得从物理、光学、化学、工程到医学等各个领域的跨学科专业知识。此外，先进分子成像中心庞大的生物研究用户基础，以及生命过程化学研究所吸引广泛公众关注的能力，将保证本项目开发的技术得到最大程度的传播。该奖项是由两个项目联合颁发的，(1)生物基础设施部（生物科学理事会）的生物研究仪器开发，(2)化学、生物工程、环境和运输系统部（工程理事会）的生物光子学。

An award is made to Northwestern University to develop a photoacoustic microscopy (PAM) technology platform that is compatible with commercial optical microscopes. PAM differs from other established optical microscopic technologies by directly sensing the physiologically-specific optical absorption properties in tissue rather than optical scattering or fluorescence properties. Hence, it holds promise to greatly enhance the imaging capability of current biological research by offering a new type of imaging contrast. Despite this great promise, however, PAM can be performed only by a very limited number of research groups in the US due to the lack of a commercially available system, which is mainly because the existing PAM systems are incompatible with commercial optical microscopes. Thus, researchers have to construct their own PAM systems, which is clearly beyond the capability of biological researchers and may not be economically feasible. To address this barrier, this project aims to make PAM more accessible to the vast majority of biological researchers who are already using advanced optical microscopy in their daily research. This project will benefit biological investigations that require quantitative imaging of, for example, tissue hemodynamics, interactions of a cell and its microenvironment, cell/tissue regeneration, and drug evaluation. The PAM system can either be used independently for label-free volumetric imaging or be integrated with confocal/two-photon microscopes for multimodal imaging. The key intellectual merit of this project comes from its novel designs that enable PAM to be broadly accessible by making PAM compatible with existing optical microscopy. Two incompatibility issues prevent existing PAM from being seamlessly integrated with modern optical microscopes: (1) PAM's slow and bulky mechanical scanning mechanism cannot match the high-speed optical scanning used in modern optical microscopy and (2) PAM's opaque and sizeable ultrasonic detectors cannot be easily fit into the extremely limited working space associated with high-power objective lenses. This project provides effective solutions to address these two issues.The key broader impact of this research is that it will, for the first time, lay a solid foundation for PAM to be broadly accessible by the vast majority of biological researchers rather than just a few optics research groups. Breakthroughs in biological research often follow technology advancement; however, developing a novel technology applicable to biological research is only the beginning. The key step to bringing a societal benefit is to make newly developed technologies approachable by users. Owing to the great strengths of PAM to offer unstained functional imaging in tissues and cells at high resolution in three dimensions, the integrated system has the potential to augment a wide range of biological research fields. This project requires active involvement of students at both the undergraduate and graduate levels. A unique aspect of this project is that students will gain interdisciplinary expertise across fields from physics, optics, chemistry, and engineering to medical sciences. Moreover, the large biological research user base of the Center for Advanced Molecular Imaging and the ability to draw wide-spread public attention by the Chemistry of Life Processes Institute will warrant the maximum dissemination of the technology being developed in this project.This award is being made jointly by two Programs- (1) Instrument Development for Biological Research, in the Division of Biological Infrastructure (Biological Sciences Directorate), and (2) Biophotonics, in the Division of Chemical, Bioengineering, Environmental and Transport Systems (Engineering Directorate).