Excellence in Research: Novel Label-free Optical Imaging Approaches for Early Breast Cancer Detection

乳腺癌是美国女性癌症死亡的第二大原因。大多数死亡是由于疾病扩散到身体其他部位（转移）和重要身体功能受损。尽管乳房X线摄影术被广泛使用，但由于灵敏度和特异性有限，转移性乳腺癌的早期检测和准确诊断仍然是一个挑战。该研究建议开发一种集成系统，采用两种新型筛查技术，在疾病的早期阶段在细胞群中识别癌细胞。第一种技术使用两束相同的激光束来捕获和拉伸细胞，而没有任何机械接触，以表征它们在癌症存在时发生变化的弹性。第二种技术是利用细胞或组织样本的光散射原理，即所谓的拉曼效应，来识别癌症相关的生物标志物。该技术旨在及早预测癌症的发作，以便进行有效的预防性治疗，并可靠地区分致命与非致命，或局部与转移性乳腺癌。在教育影响方面，该研究为高中教师提供了以实验为中心的教学方法，这可能有助于吸引高素质的学生进入STEM学科。创新的高年级本科生设计项目将开发旨在留住学生和招聘研究生课程。该项目将为少数民族学生提供宝贵的经验和接触现代研究实践的机会，并为他们成功的STEM职业生涯做好准备。拟议的研究设想了一种新的策略，将两种光学筛查技术整合在微流体平台上，以在乳腺癌疾病的早期阶段识别细胞群中的癌细胞。研究人员假设，通过进行两个独立但互补的细胞表征，甚至在结构性疾病表现开始出现之前，就有可能在细胞中识别乳腺癌的存在。提出了以下两种筛选方法：a）使用光镊（OT）细胞拉伸器的细胞骨架弹性的生物力学表征作为恶性肿瘤的指标，和B）使用表面增强拉曼光谱（SERS）的细胞生物标志物的生物光子表征。该项目有两个具体目标：1）OT/SERS分析装置开发以产生便携式微流体平台，该平台能够使用激光镊子微拉伸组件基于SERS成像和机械敏感表征来执行细胞的生物电表征，以及和人表皮生长因子受体2阳性模型，以测试OT/SERS谱分析装置区分癌症进展中发生的早期细胞变化的能力。研究人员提出了一种创新的方法，通过量化细胞的细胞骨架弹性和生物光子特征来筛选它们的组合表型，而不是单独筛选乳腺癌的许多形态学和生化标志物。该技术可适用于临床环境中使用血液、唾液和其他含有活细胞的身体分泌物样本进行早期癌症检测。该研究有可能对癌症诊断领域产生重大影响。该奖项反映了NSF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。

Breast cancer is the second leading cause of cancer deaths among women in the United States. Majority of the deaths is due to disease spreading to other parts of the body (metastasis) and impairment of vital body functions. Early detection and accurate diagnosis of metastatic breast cancer remains a challenge despite the widespread use of mammography, due to limited sensitivity and specificity. The study proposes to develop an integrated system with two novel screening technologies to identify cancer cells among a cell population at very early stages of the disease. The first technology uses two identical laser beams to trap and stretch cells without any mechanical contact to characterize their elasticity which changes in presence of cancer. The second technology is to identify cancer-related biomarkers by using the principles of light scattering from the cell or tissue samples, called Raman effect. The proposed technology aims to predict the onset of cancer early enough to allow effective preventive treatment and reliably differentiate between deadly vs. non-deadly, or localized vs. metastatic breast cancers. In terms of educational impact, the study offers experiment-centric teaching methodologies for high school teachers which may help in attracting high caliber students to STEM disciplines. Innovative senior undergraduate design projects will be developed aiming at student retention and recruitment to graduate programs. The project will provide minority students an invaluable experience and exposure to modern research practices and will prepare them for successful STEM careers.The proposed study envisions a novel strategy to integrate two optical screening technologies on a microfluidic platform to identify cancer cells among a cell population at very early stages of the breast cancer disease. The investigators hypothesize that by performing two independent but complementary cell characterizations, it is possible to identify the presence of breast cancer in cells even before the structural disease manifestation begins to show up. The following two screening methods are proposed: a) biomechanical characterization of cytoskeletal elasticity as an indicator for malignancy using optical tweezer (OT) cell-stretcher, and b) biophotonic characterization of cell biomarkers using Surface Enhanced Raman Spectrometry (SERS). The project has two specific aims: 1) OT/SERS profiling device development to produce a portable microfluidic platform capable of performing bioelectric characterization of cells based on SERS imaging and mechanosensitive characterization using a laser tweezer microstretch assembly, and 2) Identification of non-invasive, pre-invasive, and invasive breast cells from triple-negative, hormone receptor positive, and human epidermal growth factor receptor 2 positive models to test the ability of the OT/SERS profiling device to distinguish early cellular changes that occur in cancer progression. Instead of individually screening for numerous morphological and biochemical markers of breast cancer, the investigators propose an innovative approach to screen their combined phenotype by quantifying cell's cytoskeletal elasticity and biophotonic signatures. The technology can be adapted for early cancer detection in clinical setting using blood, saliva, and other bodily secretions samples containing live cells. The study has potential to significantly impact the field of cancer diagnostics.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.