Development and optimization of cell based cryopreservation models

超低温保存技术是一项跨学科的基础科学技术。 它通过遗传资源库和细胞系分布促进基础研究，使动物和植物濒危物种保护成为可能，对价值数十亿美元的动物和植物农业产业至关重要，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世纪的研究，很少有细胞，更少的组织，没有器官在冷冻保存后茁壮成长。我的研究是由公认的中心假设，冷冻保存可以很好地理解为一系列的热量和质量传输系统在非理想和非生理条件下。多尺度输运模型及其控制提供了数学、工程和生物研究交叉的丰富主题。在液氮中成功地冷冻保存生物样品需要高浓度的冷冻保护剂（CPA），其通常包括细胞膜可渗透的溶质如DMSO、膜不可渗透的溶质如糖或现代的冰阻断化学品。用CPA平衡后，将细胞冷却至-196 ℃并无限期储存。需要时，加热样品，然后用不含CPA的培养基平衡。 重要的是，这个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发展和优化计算冷冻损伤模型。这将使快速的细胞，组织和器官冷冻保存方案的设计。 我的研究方法是综合性和跨学科的，在未来五年，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）建立在现有的基于细胞的热量和质量传输组织模型上，以促进组织中细胞水平的冷冻保存损伤的建模; 3）开发用于优化基于细胞的冷冻保存和目标1和2的损伤模型的计算工具。 这些目标提供了一些 在数学和生物学的交叉点的跨学科培训机会。

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.