Caring for cells in microsystems: principles and practices of cell-safe device design and operation

Microfluidic device designers and users continually question whether cells are 'happy' in a given microsystem or whether they are perturbed by micro-scale technologies. This issue is normally brought up by engineers building platforms, or by external reviewers (academic or commercial) comparing multiple technological approaches to a problem. Microsystems can apply combinations of biophysical and biochemical stimuli that, although essential to device operation, may damage cells in complex ways. However, assays to assess the impact of microsystems upon cells have been challenging to conduct and have led to subjective interpretation and evaluation of cell stressors, hampering development and adoption of microsystems. To this end, we introduce a framework that defines cell health, describes how device stimuli may stress cells, and contrasts approaches to measure cell stress. Importantly, we provide practical guidelines regarding device design and operation to minimize cell stress, and recommend a minimal set of quantitative assays that will enable standardization in the assessment of cell health in diverse devices. We anticipate that as microsystem designers, reviewers, and end-users enforce such guidelines, we as a community can create a set of essential principles that will further the adoption of such technologies in clinical, translational and commercial applications.