Overcoming the Multiple Scattering Limit in Optical Coherence Tomography

扩展成像深度是光学显微镜和许多创造性方法的巨大挑战之一 正在开发中，以减轻“光学散射”现象的有害影响，并使 散射介质中更深的光学成像。光在致密组织中传播会经历散射事件 扰乱传播光波前的相位，从而破坏所需的相长干涉 将光聚焦/空间定位到衍射极限焦点。因此，显微分辨率为 通常仅适用于所谓的“单散射”（SS）或“弹道”光状态。华侨城是领先的企业之一 深度显微镜领域的模式，在散射组织中最大成像深度通常为 1-2 毫米。 然而，OCT 令人难以置信的成功在某些方面导致了与其他光学成像相比较低的动力 领域开发新方法来解决多重散射（MS）问题。这也是一个伟大的 机会——通过以其已经深厚的成像能力为基础，OCT 有机会再次成为 处于突破光学显微镜成像深度极限的研究前沿。我们提出一个综合的 方法结合了 (1) 长波长 OCT（1700 nm 窗口，较低的散射系数支持 更深入的成像），（2）共轭成像配置中的谱域 OCT（SD-OCT），以增强 深度 OCT 信号相对于标准成像配置提高 2-3 个数量级，(3) 硬件 自适应光学 (HAO) 可以纠正组织引起的像差，从而增强内部深处的弹道信号 (4) 用于抑制 MS 的像差多样化 OCT (AD-OCT)。我们最近开发的 AD-OCT 该方法结合了基于光纤的 OCT 系统的优点和极具前景的原理 单次散射相干累积（CASS）方法。 CASS 方法连贯地累积 SS 多个照明角度（全场成像几何中的平面波照明），而 AD-OCT 相干 累积由于用不同的已知像差状态照射样品而产生的 SS，并利用 计算自适应光学 (CAO)，以避免通常与这些相关的分辨率损失 像差。目标1将开发一种克服像差分集饱和极限的方法，实现高 加速基于 GPU 的处理，解决 AD-OCT 中的大数据问题，并实现实时反馈 成像时间。目标 2 将定量比较高斯光束 OCT 的性能（有和没有 组织像差的 HAO 校正）与 AD-OCT（组织像差的 HAO 校正）。这将包括 深度相关 3D 点扩散函数的测量，这也将填补重要的知识空白 从事 OCT 中 MS 的基础研究。目标 3 将展示 AD-OCT 超越当前 OCT 倍数 人体皮肤和小鼠大脑体内的散射极限（我们将“解锁”2-5毫米深度范围）。如果成功的话， 该提案将展示有史以来在人类皮肤和小鼠大脑中进行的最深的 OCT 成像，以及 从基础成像科学和 OCT 生物医学应用的角度来看，这具有重要意义。

Extending imaging depth is one of the grand challenges in optical microscopy, and many creative approaches are under development to mitigate the detrimental impact of the phenomenon of ‘optical scattering’ and enable deeper optical imaging in scattering media. Light propagating in dense tissue undergoes scattering events that scramble the phase of the propagating optical wavefront, and thus disrupts the constructive interference needed to focus/spatially localize the light to a diffraction-limited focal spot. Consequently, microscopic resolution is typically only available in the so-called ‘single-scattering’ (SS) or ‘ballistic’ light regime. OCT is one of the leading modalities in the field of deep microscopy, with maximum imaging depths typically 1–2 mm in scattering tissues. However, the incredible success of OCT has in some ways led to lower motivation than in other optical imaging fields to develop new approaches to address the problem of multiple scattering (MS). This is also a great opportunity – by building upon its already deep imaging capabilities, OCT has the opportunity to once again be at the forefront of research on pushing the imaging depth limits of optical microscopy. We propose an integrated approach that combines (1) long-wavelength OCT (1700 nm window, lower scattering coefficient supporting deeper imaging), (2) spectral-domain OCT (SD-OCT) in the conjugate imaging configuration to enhance the deep OCT signal by 2-3 orders of magnitude relative to the standard imaging configuration, (3) hardware adaptive optics (HAO) to correct tissue-induced aberrations and thereby boost the ballistic signal deep within tissue, and (4) aberration-diverse OCT (AD-OCT) for suppressing MS. Our recently-developed AD-OCT approach combines the advantages of a fiber-based OCT system with the principle behind the highly promising coherent accumulation of single scattering (CASS) method. The CASS method coherently accumulates SS from multiple illumination angles (plane wave illumination in full-field imaging geometry), whereas AD-OCT coherently accumulates SS arising from illuminating the sample with different known aberration states, and leveraging computational adaptive optics (CAO) to circumvent the resolution penalty normally associated with these aberrations. Aim 1 will develop a method to overcome the aberration-diversity saturation limit, implement high- speed GPU-based processing to address the Big Data problem in AD-OCT, and enable real-time feedback at the time of imaging. Aim 2 will quantitatively compare the performance of Gaussian-beam OCT (with and without HAO correction of tissue aberrations) vs. AD-OCT (with HAO correction of tissue aberrations). This will include measurements of the depth-dependent 3D point-spread-function, which will also fill an important knowledge gap in fundamental research on MS in OCT. Aim 3 will demonstrate AD-OCT beyond the current OCT multiple scattering limit in human skin and mouse brain in vivo (we will ‘unlock’ the 2-5 mm depth range). If successful, this proposal will demonstrate the deepest OCT imaging ever performed in human skin and mouse brain, and so is significant from the perspective of fundamental imaging science and the biomedical applications of OCT.