适用于活体生物组织深层的高分辨率无创光学聚焦及其应用研究

Optical methods play increasingly important roles in biomedicine. The usage of light, however, suffers from an overwhelming drawback due to its strong scattering in biological tissue. At the right wavelength, light can penetrate several centimeters into tissue, but even with the best technology to date, it is not possible to noninvasively render high resolution beyond a millimeter below the skin with light alone (think about how a flashlight beam diffuses through your palm). Delivering focused light is important in nearly all disciplines of biomedical optics, but has long been one of the greatest challenges in deep tissue optics. ..To achieve this long-term goal, we propose an innovative modality, fast nonlinear photoacoustically guided wavefront shaping (PAWS), to achieve intense and tight optical-resolution focusing in deep living tissue. New schemes will be developed to generate stronger nonlinear photoacoustic (PA) signals to be used as reliable feedback for wavefront optimization. Maximizing the strength of nonlinear PA signals can focus diffuse light to a single bright speckle grain within scattering media—this feasibility has recently been demonstrated and published by the principal investigator in Nature Photonics. To improve the focusing speed and determine the optimum wavefront compensation rapidly, a high-speed digital micromirror device (DMD) will be used for shaping the wavefront of light, and a field programmable gate array (FPGA) will be used for high-speed onboard data processing, equipped with customized data transfer protocol between the DMD, the FPGA and the computer. Moreover, a stepwise drilling strategy will be developed to deepen the focal position, reaching tissue regions where no usable feedback can be generated directly. After that, we will explore deep-penetrating photoacoustic microscopy as well as its applications for the diagnosis of early stage cancer...Note that fast nonlinear PAWS is not just an imaging modality, but a universal noninvasive tool that has the potential to enable intense high-resolution optical focusing in deep living tissue. It may open an avenue for many biomedical optical applications—including imaging, sensing, therapy and manipulation—that require highly confined strong light delivery at depths in biological tissue.

光学技术在现代生物医学中发挥着越来越重要的作用，但由于光在生物组织内很容易被散射受到很多限制。在合适的波长下，光有可能穿透几厘米深的生物组织，但即使是目前最先进的光学技术，也无法在人体皮肤1毫米以下实现高分辨率的光点或者光束。如何在生物组织深处实现散射光的无创聚焦是人们期盼已久但被认为是很有挑战性的目标。本项目拟从理论方法、系统设计以及实验验证等多方面探索新型的基于非线性光声引导的快速波前整形技术，它将有望首次在活体生物组织深处实现高分辨率的无创光学聚焦。我们将开发新的方法来激发更强的非线性光声信号，改进优化算法，采用更快的空间光调制器和线上信号处理以加速整个聚焦过程。我们还提出步进式光钻方法实现光学焦点由浅入深渐进。此外，我们还将探索深穿透的光声显微技术并将之试用于癌症的早期诊断。一旦研制成功，本项目将有望为很多高分辨的生物医学光学技术在活体中的应用开辟一条新道路。

光学技术在现代生物医学中发挥着越来越重要的作用，但由于光在生物组织内很容易被散射受到很多限制。在合适的波长下，光有可能穿透几厘米深的生物组织，但即使是目前最先进的光学技术，也无法在人体皮肤1毫米以下实现高分辨率的光点或者光束。如何在生物组织深处实现散射光的无创聚焦是人们期盼已久但被认为是很有挑战性的目标。本项目从理论方法、系统设计以及实验验证等多方面探索新型的快速波前整形技术。项目执行期中，在非线性光声信号激发原理层面，我们采用单根光纤拉曼效应实现纳秒级别间隔的时间延迟，比传统的借助延迟发生器或者延时自由光路产产生的脉冲间隔（微秒或者毫秒量级）更短更精准，从而能更高效激发非线性光声信号。在系统层面，我们搭建了超快速波前整形系统，并针对该系统开发出高度匹配的光聚焦快速扫点功能，使得在散射介质（如生物组织）中的大视场探测变成可能。同时，为了克服在扫点过程中介质不稳定导致的光聚焦衰减（即增加了波前优化的错误率），本项目开发了相应的反馈式迭代算法对应该场景。我们从理论上严格推导出基于二值幅度调制波前整形的错误率与所得聚焦的关系，并根据该物理定律提出高度自适应且性能较好的迭代算法；而对于相位调制，由于其复杂度更甚于二值幅度的情况，本项目则运用人工智能算法（如深度学习）对其进行进一步的探索与优化，并展现出深度学习用于波前整形技术的可行性。这两个方面的优化都提高和维持了光聚焦在散射介质中的效率，保证了在散射介质中高分率光学聚焦的时间跨度。值得注意的是，本项目所开发的系统及算法具有高度可迁移性。由于光在多模光纤与散射介质中传播有相当程度的相似性，我们所开发的技术与理论可无缝衔接到多模光纤的复杂场景应用之中（比如内窥镜和光遗传学）。我们实现了基于单根多模光纤的单神经元精度的生物组织深层光遗传学控制。结合单模光纤的微小尺寸，为深层脑区动态、高精度的微创甚至无创神经科学研究提供了新工具。本项目及其后续的研制，将有望为很多高分辨的生物医学光学技术在深层组织中的应用开辟一条新道路。