Label-Free, Longitudinal, Multi-Metric Viability Imaging of 3D Tissue Spheroid Array

3D 组织球体阵列的无标记、纵向、多指标活力成像

基本信息

批准号：
10295612
负责人：
Jonghwan Lee
金额：
$ 35.03万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-09 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10295612
关键词：
3-Dimensional Address Adopted Biological Assay Biopsy Cancer Patient Cell Adhesion Cell Culture Techniques Cell Nucleus Cell Survival Cells Chemicals Chemosensitivity Assay Clinical Trials Combined Modality Therapy Cultured Cells Data Data Set Development Diffusion Dimensions Dose Drug Combinations Drug usage End Point Assay Ethanol Fractals Future Genomics Guidelines Hour Image Imaging technology In Vitro Individual Investigation Label Lung Malignant Neoplasms Malignant neoplasm of liver Measurement Measures Medicine Membrane Metabolism Methods Microscopy Oligomycins Oncology Optical Coherence Tomography Optics Outcome Paclitaxel Pancreas Patient Monitoring Patients Pharmaceutical Preparations Physicians Pilot Projects Population Precision Medicine Initiative Process Research Sampling Sensitivity and Specificity Series Signal Transduction Specificity Surface Techniques Technology Testing Time Tissue Engineering Tissues Toxicity Tests Tumor Cell Line Validation Variant attenuation base cancer therapy cancer type cell type chemotherapy clinical application design drug discovery drug testing image processing imaging study in vivo individual patient individualized medicine innovation longitudinal dataset malignant breast neoplasm neoplastic cell novel strategies optimal treatments patient population personalized medicine precision medicine precision oncology prevent response statistics three dimensional cell culture tumor tumor microenvironment

项目摘要

SUMMARY When selecting cancer therapy, physicians generally begin with first-line treatment options and monitor patient progress on a watch-and-wait basis, following a set of guidelines based on clinical trials from a large patient population. But this traditional method has been questioned on whether it provides individual patients with the optimal treatment. To better find a matching treatment individually, a concept called precision cancer medicine or personalized cancer medicine has been studied. Among other approaches, functional precision medicine directly tests chemotherapy options on tumor cells biopsied from a patient to find the best matching treatment for the specific patient. This promising approach, however, has not been widely adopted by clinicians because the tumor microenvironment in a lab differed from the one within the patient’s body, leading to inconsistent drug responses between the sample and patient, and the quantity of biopsied cells is generally insufficient for a reliable number of options to be tested. The first problem is being addressed by recent advances in three- dimensional (3D) cell culture techniques, which better mimic the body’s microenvironment in a lab. But the second problem, the limited number of testable options, is mainly due to limitations in the current assay techniques that assess chemosensitivity in 3D culture. With most current assays, a sample can only be tested once, and multiple drugs with different mechanisms of action cannot be simultaneously tested by a single assay. Combined, these limitations exponentially reduce the number of testable options when involving multiple assessment time points to design a sequential therapy or when increasing the number of drugs to test a combination therapy. Here, we will develop a new technique for the assessment of chemosensitivity in 3D culture, by maximizing the potential of a label-free 3D microscopy technology, called optical coherence tomography (OCT). The majority of prior OCT research measured only one or two types of signals and showed the signals corresponding to only a single type of cell viability disruption process in each study. But this approach has led to a concern about specificity (i.e., other types of processes than the one tested in the study can generate similar OCT signals). This low specificity, along with unclear mechanisms of viability assessment, have prevented OCT methods from being adopted for the promising concept of functional precision medicine. Therefore, we will develop at least 18 different types of OCT signals and establish their sensitivity and specificity to four major types of viability disruption processes. The feasibility of this approach has been strongly supported by a pilot study where we imaged and analyzed more than 6,000 3D-cultured cell spheroids. This R01 project will image and analyze up to 100,000+ spheroids for an unprecedentedly systemic investigation of the comprehensive range of OCT signal types.

概括在选择癌症治疗时，医生通常从一线治疗方案开始并监测患者遵循一系列基于大患者临床试验的指南，在观察和等待的基础上取得进展但这种传统方法是否能够为个体患者提供治疗受到质疑。为了更好地找到个体匹配的治疗方法，这个概念被称为精准癌症医学。或个性化癌症医学已被研究，其中包括功能性精准医学。直接对患者活检的肿瘤细胞进行化疗方案测试，以找到最佳匹配的治疗方案针对特定患者。然而，这种有希望的方法尚未被殖民者广泛采用，因为肿瘤实验室的微环境与患者体内的微环境不同，导致药物不一致样本和患者之间的反应，并且活检细胞的数量通常不足以进行需要测试的可靠数量的选项正在通过三个方面的最新进展得到解决。三维（3D）细胞培养技术，可以更好地模拟实验室中的人体微环境。第二个问题，可测试选项的数量有限，主要是由于当前测定的限制评估 3D 培养中化学敏感性的技术在大多数当前检测中只能测试样品。一次不能同时测试多种不同作用机制的药物综合限制，这些在涉及时会成倍地减少可测试选项的数量。设计序贯疗法或增加要测试的药物数量时的多个评估时间点联合疗法。在这里，我们将开发一种新技术，通过最大化 3D 培养中的化学敏感性评估无标记 3D 显微技术（称为光学相干断层扫描 (OCT)）的潜力。之前的 OCT 研究仅测量了一种或两种类型的信号，并显示了对应于每项研究中只有一种类型的细胞活力破坏过程，但这种方法引起了人们的担忧。关于特异性（即，除研究中测试的过程之外的其他类型的过程可以生成类似的 OCT 这种低特异性以及不明确的活力评估机制阻碍了 OCT。功能性精准医学这一有前途的概念被采用的方法。因此，我们将开发至少 18 种不同类型的 OCT 信号并建立它们的灵敏度和四种主要类型的可行性破坏过程的特异性。得到一项试点研究的大力支持，我们对 6,000 多个 3D 培养细胞进行了成像和分析该 R01 项目将对多达 100,000 多个球体进行成像和分析，以实现前所未有的系统性。对 OCT 信号类型的综合范围进行研究。