CAREER: Photoacoustic-Brillouin microscopy for multimodal mechanical imaging of tumor growth

肿瘤组织通常比周围的健康组织更坚硬，导致癌细胞内部的微环境不同。由于细胞的行为和功能受到来自微环境的物理信号的调节，新的研究表明，肿瘤组织机制的改变在转移性癌症的进展中起着至关重要的作用。为了了解微环境特性与肿瘤生长之间的关系，有必要在三维空间上以高空间分辨率量化这些力学特性。然而，现有的机械测试工具大多是基于接触和侵入性的，这使得这种测量非常具有挑战性。这个教师早期职业发展（Career）项目旨在通过开发一种名为光声布里渊显微镜（PABM）的光学技术来解决当前的技术挑战，该技术可以以非接触、非侵入性和高分辨率的方式测量癌细胞及其微环境的机械特性。与研究目标相一致，该项目将开发教育模块，以促进创新布里渊技术的传播，并激发高中、本科生和研究生对生物光子学的持久兴趣。共聚焦布里渊显微镜最近被证明是一种很有前途的非接触机械测试工具。然而，由于缺乏对被测样品折射率和密度的了解，现有的布里渊显微镜大多用于估计相对力学变化，而不是提供力学模量的绝对测量，因此不适用于异质肿瘤微环境，对标和跨研究比较。本课题将基于散射布里渊光和时间分辨光声信号的共定域激发，开发一种新的光学技术——PABM。除了直接量化力学模量外，PABM还可以提供互补的对比机制，包括刚度、光吸收和声速。这种能力将使我们能够全面了解肿瘤生长的异质过程。总而言之，PABM解决了当前癌症研究方法中的一个重大差距。从这项技术中获得的新数据和见解具有独特的潜力，可以推进生物光子学和癌症疾病的广泛研究。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Tumor tissues are usually harder than surrounding healthy tissues, leading to a different microenvironment for cancer cells inside. Since the behaviors and functions of cells are regulated by physical cues from their microenvironment, emerging research has suggested that the altered mechanics of tumor tissue plays a crucial role in the progression of metastatic cancers. To understand the relationship between the properties of the microenvironment and tumor growth, it is essential to quantify these mechanical properties with high spatial resolution in three dimensions. However, existing mechanical testing tools are mostly contact-based and invasive, making such measurement highly challenging. This Faculty Early Career Development (CAREER) project aims to address the current technical challenge by developing an optical technology named photoacoustic-Brillouin microscopy (PABM), which can measure the mechanical properties of cancer cells and their microenvironment in a non-contact, non-invasive, and high-resolution manner. In concert with the research goal, this project will develop educational modules to promote the dissemination of the innovative Brillouin technology and to stimulate a lasting interest in biophotonics for high school, undergraduate, and graduate students.Confocal Brillouin microscopy has been recently demonstrated as a promising non-contact mechanical testing tool. However, due to the lack of knowledge on refractive index and density of the sample under test, existing Brillouin microscopy is mostly used to estimate the relative mechanical change, rather than to provide an absolute measurement of mechanical modulus, making it inapplicable for heterogeneous tumor microenvironment, benchmarking, and comparison across studies. In this project, a novel optical technique named PABM will be developed based on the colocalized excitation of scattered Brillouin light and time-resolved photoacoustic signals. In addition to directly quantifying mechanical modulus, the PABM can provide complementary contrast mechanisms, including stiffness, optical absorption, and acoustic speed. This capability will enable a comprehensive understanding of heterogeneous processes in tumor growth. Taken together, the PABM addresses a significant gap in current cancer research methodologies. The new data and insights gained from this technology holds a unique potential to advance a wide range of research in both biophotonics and cancer diseases.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.