Development and optimization of cell based cryopreservation models

超低温保存是跨学科基础科学的一项基础性技术。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，对动植物农业中价值数十亿美元的产业至关重要，并在兽医和人类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，但低温保存后几乎没有细胞、更少的组织和任何器官能够茁壮成长。我的研究是在公认的中心假设的指导下进行的，即低温保存可以很好地理解为在非理想和非生理条件下的一系列热量和质量传输系统。在数学、工程和生物学研究的交叉中，主导的多尺度传输模型及其控制提供了一个丰富的主题。成功地在液氮中冷冻保存生物样品需要高浓度的低温保护剂(CPA)，通常包括DMSO等细胞膜可渗透的溶质、糖等不透膜的溶质或现代的阻冰化学物质。在与CPA平衡后，电池冷却到-196℃并无限期储存。当需要时，样品被加热，然后用不含CPA的介质平衡。至关重要的是，这一过程的每一步都与许多损害机制有关。因此，我的长期研究目标是开发和优化计算性低温保存损伤模型。这将使细胞、组织和器官快速冷冻保存方案设计成为可能。我的方法是综合性和跨学科的，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和质量传输组织模型，以便于对组织中细胞水平的低温保存损伤进行建模；3)开发用于优化基于细胞的低温保存和损伤模型的计算工具，以实现目标1和2的目标。

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.