Overcoming the Multiple Scattering Limit in Optical Coherence Tomography

扩展成像深度是光学显微镜的重大挑战之一，许多创造性的方法 正在开发中，以减轻“光散射”现象的有害影响， 散射介质中的更深光学成像。在致密组织中传播的光经历散射事件， 扰乱传播的光学波前的相位，从而破坏所需的相长干涉 以将光聚焦/空间定位到衍射受限的焦斑。因此，显微镜分辨率是 通常仅在所谓的“单散射”（SS）或“弹道”光状态下可用。华侨城是一个领先的 这是深度显微镜领域中的最佳模式，在散射组织中最大成像深度通常为1-2 mm。 然而，OCT令人难以置信的成功在某些方面导致了比其他光学成像更低的动力 领域开发新的方法来解决多重散射（MS）的问题。这也是一个伟大 机会-通过建立其已经深入的成像能力，OCT有机会再次成为 在推动光学显微镜成像深度极限的研究前沿。我们提出了一个综合 结合（1）长波长OCT（1700 nm窗口，较低散射系数支持 更深的成像），（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增加2-3个数量级，（3）硬件 自适应光学（HAO），用于校正组织诱导的像差，从而增强内部深处的弹道信号 组织，和（4）用于抑制MS的像差多样化OCT（AD-OCT）。 这种方法结合了基于光纤的OCT系统的优点和非常有前途的 单次散射相干积累（卡斯）方法。卡斯方法相干地累积SS， 多个照明角度（全视场成像几何结构中的平面波照明），而AD-OCT相干 累积由用不同的已知像差状态照射样品而产生的SS， 计算自适应光学（CAO），以规避通常与这些相关的分辨率惩罚 畸变目标1将开发一种方法来克服像差多样性饱和限制，实现高性能， 加速基于GPU的处理，以解决AD-OCT中的大数据问题，并在 成像的时间。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，这也将填补一个重要的知识空白 在OCT的MS基础研究中，Aim 3将证明AD-OCT超出当前OCT倍数 在人体皮肤和小鼠大脑中的体内散射极限（我们将“解锁"2-5 mm的深度范围）。如果成功， 该提案将展示在人类皮肤和小鼠大脑中进行的最深OCT成像， 因此，从基础成像科学和OCT的生物医学应用的角度来看，这是有意义的。

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.