Development and optimization of cell based cryopreservation models

低温保存是一门跨学科基础科学的基础技术。它通过遗传资源库和细胞系分布促进基础研究，使动植物濒危物种得以保护，对数十亿美元的动植物农业产业至关重要，并在兽医和人体移植和输血医学中发挥关键作用。然而，尽管有这些无数的应用和近一个世纪的研究，只有很少的细胞，更少的组织，没有器官在冷冻保存后能茁壮成长。******我的研究以公认的中心假设为指导，即低温保存可以很好地理解为一系列非理想和非生理条件下的热量和质量传输系统。控制多尺度输运模型及其控制为数学、工程和生物学交叉研究提供了丰富的主题。******在液氮中成功低温保存生物样品需要高浓度的冷冻保护剂（cpa），这些保护剂通常包括细胞膜渗透性溶质，如DMSO，膜渗透性溶质，如糖，或现代阻冰化学物质。用CPAs平衡后，细胞被冷却到-196℃并无限期储存。需要时，将样品加热，然后用不含cpa的介质进行平衡。关键的是，这一过程的每一步都与许多损伤机制有关。因此，我的长期研究目标是开发和优化计算低温保存损伤模型。这将使快速的细胞、组织和器官冷冻保存方案设计成为可能。我的方法是综合和跨学科的，在接下来的五年里，我将专注于以下三个目标：1)使用创新的迭代优化和机器学习方法以及新颖的反馈控制来建立细胞水平的损伤模型，以分离体积效应和浓度效应；2)建立现有的基于细胞的热量和质量传递组织模型，以促进组织中细胞水平低温保存损伤的建模；3)开发基于目标1和目标2的细胞低温保存和损伤模型优化的计算工具。这些目标在数学和生物学的交叉领域提供了许多跨学科的培训机会。

Cryopreservation is a foundational technology based in interdisciplinary fundamental science. It facilitates basic research through genetic resource repositories and cell-line distribution, enables animal and plant endangered species conservation, is crucial to billion dollar industries in animal and plant agriculture, and plays a critical role in veterinary and human transplantation and transfusion medicine. However, in spite of these myriad applications and nearly a century of research, few cells, fewer tissues, and no organs thrive after cryopreservation.******My research is guided by the accepted central hypothesis that cryopreservation can be well understood as a series of heat and mass transport systems in non-ideal and non-physiologic conditions. The governing multiscale transport models and their controls provide a rich subject at the intersection of mathematical, engineering, and biological research.******Successful cryopreservation of biological samples in liquid nitrogen requires high concentrations of cryoprotective agents (CPAs) that typically include cell-membrane-permeable solutes such as DMSO, membrane-impermeable solutes like sugars, or modern ice-blocking chemicals. After equilibration with CPAs, cells are cooled to -196\degC and stored indefinitely. When needed, samples are warmed and then equilibrated with CPA-free media. Critically, each step of this process is associated with a number of mechanisms of damage. Consequently, my long term research goal is to develop and optimize computational cryopreservation damage models. This will enable rapid cell, tissue, and organ cryopreservation protocol design. My approach is integrative and interdisciplinary, and in the next five years, I will focus on the following three objectives: 1) build cell-level damage models using innovative iterative optimization and machine learning approaches as well as novel feedback control to separate volume effects from concentration effects; 2) build upon existing cell-based heat and mass transport tissue models to facilitate modeling of cell-level cryopreservation damage in tissues; 3) develop computational tools for optimization of cell based cryopreservation and damage models from Objectives 1 and 2. These objectives provide a number of interdisciplinary training opportunities at the intersection of mathematics and biology.