Collaborative Research: Multiscale Modeling and Experimental Study of Blood Cell Interactions with Application to Functionalized Leukocytes Killing Cancer Cells

超过90%的癌症相关死亡是由癌症转移引起的，即癌症的扩散。在许多情况下，癌细胞从原发肿瘤逃逸，进入血管系统形成循环肿瘤细胞(CTCs)。血管内的CTCs能够附着在血管壁上，然后迁移到组织中，最终形成微转移。最近，研究发现，当表面包裹着某种配体和受体的纳米颗粒被注入血液中时，这些颗粒可以与CTCs结合，从而引发血液中CTCs的死亡。该项目涉及使用集成的数学/计算建模和实验来定量地了解这种结合过程是如何发生的，并确定配体-受体结合和细胞-细胞相互作用在这一过程中所起的作用。该项目的结果将有助于设计治疗癌症转移的新的纳米粒子医疗过程，并广泛扩展血细胞动力学的知识。这些结果在生物工程和医学领域的许多应用中都具有重要的实际意义。这项研究还将为学生提供跨学科的培训。通过建模、模拟和实验相结合，该项目解决了一个关键的生物学问题，该问题对于了解癌症转移具有重要意义。哪些关键因素有助于提高涂层纳米粒子在血管系统内触发循环癌细胞死亡的效率？将为这项研究开发新的三维多尺度模型。在此背景下，将发展和耦合描述细胞膜力学的新的子模型、流-结构相互作用模拟方法和随机配体-受体结合/解结子模型。原子力显微镜和微流体实验将在三个空间尺度上设计，用于模型验证和验证模拟预测。将校准的多尺度模拟与实验相结合的变革性策略将使测试某些脂质体涂层杀死流动的肿瘤细胞的新假设机制成为可能。这些目标将通过使用迭代程序来实现，该程序涉及开发子模型，运行实验来确认子模型，然后运行预测性模拟并设计新的实验来验证这些预测。

More than 90% of cancer-related deaths are caused by cancer metastasis, the spread of a cancer. In many cases, cancer cells escape from the primary tumor and enter vasculature to form circulating tumor cells (CTCs). CTCs inside blood vessels are able to adhere to vessel walls, and then migrate into tissues, eventually forming micro-metastases. Recently, it was found that when nano-particles coated with certain types of ligands and receptors on their surfaces were injected into the blood, these particles can bind to CTCs and subsequently trigger death of CTCs in the blood. The project concerns using integrated mathematical/computational modeling and experiments to understand quantitatively how this binding process occurs and to identify the roles that ligand-receptor binding and cell-cell interactions play during this process. Results from the project will shed light on designing new nano-particle medical processes for the treatment of cancer metastasis and broadly extend the knowledge of blood cell dynamics. The results are of practical importance in many applications in both bio-engineering and medical communities. The research will also provide interdisciplinary training for students.By combining modeling, simulation and experiments, this project addresses a key biological question of importance to understanding cancer metastasis. What are the key factors that contribute to improving the efficiency of coated nano particles for triggering the death of circulating cancer cells within the vascular system? New three-dimensional multi-scale models will be developed for this study. In this context, a novel sub-model representing cell membrane mechanics, a fluid-structure interaction simulation method and a stochastic ligand-receptor bond bind/unbinding sub-model will be developed and coupled. Atomic force microscopy and micro-fluidic experiments at three spatial scales will be designed for model validation and verifying simulation predictions. The transformative strategy of coupling calibrated multi-scale simulations with experiments will enable testing of novel hypothesized mechanisms by which certain coatings of liposomes kill flowing tumor cells. These goals will be achieved by using an iterative procedure involving development of sub-models, running experiments to validate the sub-models, and then running predictive simulations and designing new experiments for verification of these predictions.