Joel Voldman and colleagues at Massachusetts Institute of Technology discuss how microtechnology can improve precision and throughput of stem cell research. 

Much of the excitement over embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) arises from the great promise these cells hold for basic science and medicine. 

These pluripotent cells can self-renew indefinitely in culture and have the ability to generate all tissues in the body. So, they are poised for applications in regenerative medicine (to replace diseased or damaged tissues), as tissue models for drug screening, and for understanding the biology of embryogenesis. 

Despite these advances, stem cell researchers are still striving to improve the efficiency of deriving and identifying stem cell populations, the ability to both expand the cells and control their fate in culture and the accuracy in assessing the state of these cells. These steps are all critical for eventual translation to the clinic while avoiding side effects, illustrated by the case where a glio-neuronal brain tumor of stem cell origin was found 4 years after a patient was injected with human fetal neural stem cells. 

The plasticity of stem cells and number of possible endpoint states pose significant control and measurement challenges, and hence there is a need to increase experimental throughput (i.e., acquiring more or better data to map out complex regulatory networks) and precision of presenting environmental cues to the stem cells (to "coax" stem cells to adopt a desired fate). Shrinking the scale at which we conduct stem cell research is one way to increase both experimental throughput and precision, thus providing many (although certainly not all) solutions to the challenges faced by the field. 

For the past decade, bioengineers have been applying microfabrication technologies, traditionally used to fabricate electronic chips, to create engineered features whose size matches the length scales of cells. These micrometer-scale technologies, or microtechnologies, provide opportunities to more precisely manipulate different facets of the environment around a stem cell - such as neighboring cells, soluble signaling molecules, matrix and mechanical forces - than conventional macroscale culture systems such as Petri dishes. The idea behind creating a precision-engineered stem cell environment is that what fate a stem cell decides to adopt is (at least partially) determined by the collective environmental cues being presented to the cell. Hence, the more precisely we can engineer the environment, the better we can control the stem cell fate. This principle has been demonstrated to some extent, for instance, one can micro-pattern stem cells into different shapes to fine tune the mechanical forces experienced by the cells and guide their decision to become either bone or fat. 

Additionally, the small scale of microtechnologies can reduce consumption of reagents, reducing the cost of experiments and making it practical to perform high throughput multiplex experimentation on stem cells. A surge in experimental data can in turn be connected to computational models to provide understanding of how stem cell fates are regulated. The desire to tap into the versatility of stem cells to create any functional cells and tissues to treat or study diseases obligates technologists to acknowledge that stem cells behave differently from other terminally differentiated cells in the body. 

This presents challenges when applying existing microtechnologies, designed for other cellular systems, to stem cell research, therefore the challenge is adapting the technology to guide and refine the design of future generations of biological microtechnologies. 

Read more in the review 'Advancing research with microtechnologies: opportunities and challenges' in Integrative Biology