Advances in microengineering technologies have enabled a variety of insights into biomedical sciences that would not have been possible with conventional techniques. Engineering microenvironments that simulate in vivo organ systems may provide critical insight into the cellular basis for pathophysiologies, development, and homeostasis in various organs, while curtailing the high experimental costs and complexities associated with in vivo studies. In this article, we aim to survey recent attempts to extend tissue-engineered platforms toward simulating organ structure and function, and discuss the various approaches and technologies utilized in these systems. We specifically focus on microtechnologies that exploit phenomena associated with compartmentalization to create model culture systems that better represent the in vivo organ microenvironment.

Mechanical forces play an important role in regulating cellular function and have been shown to modulate cellular response to other factors in the cellular microenvironment. Presently, no technique exists to rapidly screen for the effects of a range of uniform mechanical forces on cellular function. In this work, we developed and characterized a novel microfabricated array capable of simultaneously applying cyclic equibiaxial substrate strains ranging in magnitude from 2 to 15% to small populations of adherent cells. The array is versatile, and capable of simultaneously generating a range of substrate strain fields and magnitudes. The design can be extended to combinatorially manipulate other mechanobiological culture parameters in the cellular microenvironment. As a first demonstration of this technology, the array was used to determine the effects of equibiaxial mechanical strain on activation of the canonical Wnt/beta-catenin signaling pathway in cardiac valve mesenchymal progenitor cells. This high-throughput approach to mechanobiological screening enabled the identification of a novel co-dependence between strain magnitude and duration of stimulation in controlling beta-catenin nuclear accumulation. More generally, this versatile platform has broad applicability in the fields of mechanobiology, tissue engineering and pathobiology.

Understanding how forces orchestrate tissue formation requires technologies to map internal tissue stress at cellular length scales. Here, we develop ultrasoft mechanosensors that visibly deform under less than 10 Pascals of cell-generated stress. By incorporating these mechanosensors into multicellular spheroids, we capture the patterns of internal stress that arise during spheroid formation. We experimentally demonstrate the spontaneous generation of a tensional ‘skin’, only a few cell layers thick, at the spheroid surface, which correlates with activation of mechanobiological signalling pathways, and balances a compressive stress profile within the tissue. These stresses develop through cell-driven mechanical compaction at the tissue periphery, and suggest that the tissue formation process plays a critically important role in specifying mechanobiological function. The broad applicability of this technique should ultimately provide a quantitative basis to design tissues that leverage the mechanical activity of constituent cells to evolve towards a desired form and function.