Brennan Martin D, Rexius-Hall Megan L, Elgass Laura Jane, Eddington David T
UIC Bioengineering (MC 563), 820 S Wood St W103 CSN, Chicago, IL 60612, USA.
Lab Chip. 2014 Nov 21;14(22):4305-18. doi: 10.1039/c4lc00853g.
Cellular function and behavior are affected by the partial pressure of O2, or oxygen tension, in the microenvironment. The level of oxygenation is important, as it is a balance of oxygen availability and oxygen consumption that is necessary to maintain normoxia. Changes in oxygen tension, from above physiological oxygen tension (hyperoxia) to below physiological levels (hypoxia) or even complete absence of oxygen (anoxia), trigger potent biological responses. For instance, hypoxia has been shown to support the maintenance and promote proliferation of regenerative stem and progenitor cells. Paradoxically, hypoxia also contributes to the development of pathological conditions including systemic inflammatory response, tumorigenesis, and cardiovascular disease, such as ischemic heart disease and pulmonary hypertension. Current methods to study cellular behavior in low levels of oxygen tension include hypoxia workstations and hypoxia chambers. These culture systems do not provide oxygen gradients that are found in vivo or precise control at the microscale. Microfluidic platforms have been developed to overcome the inherent limits of these current methods, including lack of spatial control, slow equilibration, and unachievable or difficult coupling to live-cell microscopy. The various applications made possible by microfluidic systems are the topic of this review. In order to understand how the microscale can be leveraged for oxygen control of cells and tissues within microfluidic systems, some background understanding of diffusion, solubility, and transport at the microscale will be presented in addition to a discussion on the methods for measuring the oxygen tension in microfluidic channels. Finally the various methods for oxygen control within microfluidic platforms will be discussed including devices that rely on diffusion from liquid or gas, utilizing on-or-off-chip mixers, leveraging cellular oxygen uptake to deplete the oxygen, relying on chemical reactions in channels to generate oxygen gradients in a device, and electrolytic reactions to produce oxygen directly on chip.
细胞功能和行为受微环境中O2的分压（即氧张力）影响。氧合水平很重要，因为维持正常氧合需要氧气供应与消耗之间的平衡。氧张力的变化，从高于生理氧张力（高氧）到低于生理水平（低氧）甚至完全无氧（缺氧），都会引发强烈的生物学反应。例如，低氧已被证明有助于维持和促进再生干细胞及祖细胞的增殖。矛盾的是，低氧也会导致包括全身炎症反应、肿瘤发生和心血管疾病（如缺血性心脏病和肺动脉高压）等病理状况的发展。目前研究低氧张力下细胞行为的方法包括低氧工作站和低氧培养箱。这些培养系统无法提供体内存在的氧梯度，也无法在微观尺度上进行精确控制。微流控平台的开发是为了克服这些现有方法的固有局限性，包括缺乏空间控制、平衡缓慢以及难以与活细胞显微镜实现耦合或耦合困难。微流控系统实现的各种应用是本综述的主题。为了理解如何在微流控系统中利用微观尺度对细胞和组织进行氧控制，除了讨论微流控通道中氧张力的测量方法外，还将介绍一些关于微观尺度下扩散、溶解度和传输的背景知识。最后将讨论微流控平台内氧控制的各种方法，包括依赖于从液体或气体扩散的装置、利用片上或片外混合器、利用细胞对氧的摄取来耗尽氧气、依赖通道中的化学反应在装置中产生氧梯度以及通过电解反应直接在芯片上产生氧气的装置。
