CRII: OAC: A Hybrid Finite Element and Molecular Dynamics Simulation Approach for Modeling Nanoparticle Transport in Human Vasculature

通过纳米医学，正在出现直接将药物分子输送到疾病区域用于癌症治疗的重要方法。靶向给药是最有前景的方法之一，它依赖于携带和释放药物的纳米颗粒(NPs)。基于NP的药物载体的治疗效果取决于病变部位药物分子的适当浓度。NPS需要直接输送到患病组织，同时最大限度地减少其他组织对NPS的摄取，从而减少对健康组织的潜在伤害。因此，通过了解纳米粒携带的药物是如何在人体内运输和分散的，这些纳米粒的设计和靶向药物传递的效果可以得到显著的改进。该项目提出了一套计算工具来模拟和研究NPs在人类血管系统中的传输和扩散。这反过来可以提供更好的成像敏感性，治疗效果和较低的毒性NP为基础的药物载体。该项目的多学科性质还将生物学、工程学和计算机科学的概念结合在一起，以培养下一代计算生物学家、科学家和工程师。因此，这项研究符合美国国家科学基金会的使命，即促进科学进步，促进国民健康、繁荣和福利。该项目的技术目标是创建一种混合的有限元和分子动力学计算方法来模拟NP在人体血管中的运输和黏附。通过有限元模型准确地捕捉到了血管网络的真实几何形状和血液流动的流体动力学。通过分子动力学模拟，解决了血液流动中纳米粒子与红细胞的微观相互作用以及纳米粒子与血管壁的黏附问题。建立了一个健壮而高效的耦合接口来耦合有限元和分子动力学求解器。具体地说，这个项目的目标是1)建立一个多尺度和多物理的计算模型，用于预测受人体血管真实几何和物理化学特征影响的NPs的血管动力学；2)开发一种界面耦合技术，通过耦合有限元和分子动力学解算器来提高计算精度和可预测性；3)为耦合解的误差和收敛分析建立多尺度和多物理模拟测试套件；以及4)推进现有的网络基础设施，以加快材料设计进程，并丰富网络使能的材料设计社区。这种计算方法可以用来探索纳米颗粒的大小、形状、表面和硬度特性以及人体血管的复杂几何形状对血管动力学的影响。模拟结果可以进一步指导实验者设计NP介导的药物传递平台，该平台以最佳方式在病变组织内蓄积，以提供更好的成像灵敏度、治疗效果和较低的毒性。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Through nanomedicine significant methods are emerging to deliver drug molecules directly to diseased areas for cancer treatment. Targeted drug delivery is one of the most promising approaches which relies on nanoparticles (NPs) that carry and release drugs. The therapeutic efficacy of NP-based drug carriers is determined by the proper concentration of drug molecules at the lesion site. NPs need to be delivered directly to the diseased tissues while minimizing their uptake by other tissues, thereby reducing the potential harm to healthy tissue. Therefore, the design of these NPs and hence the efficacy of the targeted drug delivery could be significantly improved by understanding how the drugs carried by NPs are transported and dispersed in human body. This project proposes a set of computational tools to model and investigate the transport and dispersion of NPs in human vasculature. This, in turn, can provide better imaging sensitivity, therapeutic efficacy and lower toxicity of NP-based drug carriers. The multidisciplinary nature of the project also brings together concepts from biology, engineering and computer science to educate the next generation of computational biologists, scientists and engineers. This research, thus, aligns with the NSF mission to promote the progress of science and to advance the national health, prosperity and welfare. The technical objective of this project is to create a hybrid finite element and molecular dynamics computational approach for modeling NP transport and adhesion in human vasculature. The realistic geometry of vascular network and fluid dynamics of blood flow are accurately captured through the finite element model. The microscopic interactions between NPs and red blood cells within blood flow and adhesion of NPs to vessel wall are resolved through the molecular dynamics simulation. A robust and efficient coupling interface is built to couple the finite element and molecular dynamics solvers. Specifically, this project aims to 1) create a multiscale and multiphysics computational model for predicting the vascular dynamics of NPs under the influence of realistic geometrical and physiochemical features of human vasculature; 2) craft an interface coupling technique that enhances computational accuracy and predictability by coupling the finite element and molecular dynamics solvers; 3) build testsuits for multiscale and multiphysics simulations for coupled solution error and convergence analysis; and 4) advance the current cyberinfrastructure to accelerate the material design process and enrich the cyber-enabled materials design community. Such a computational method can be used to explore how the vascular dynamics of NPs will be affected by their size, shape, surface and stiffness properties, as well as complex geometry of human vasculature. The simulation results can further guide experimentalists to design NP-mediated drug delivery platforms that optimally accumulate within diseased tissue to provide better imaging sensitivity, therapeutic efficacy and lower toxicity.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.