Trends in Cell Biology
Volume 21, Issue 12, December 2011, Pages 745-754
Journal home page for Trends in Cell Biology

Review
Special Issue – 3D Cell Biology
From 3D cell culture to organs-on-chips

https://doi.org/10.1016/j.tcb.2011.09.005Get rights and content

3D cell-culture models have recently garnered great attention because they often promote levels of cell differentiation and tissue organization not possible in conventional 2D culture systems. We review new advances in 3D culture that leverage microfabrication technologies from the microchip industry and microfluidics approaches to create cell-culture microenvironments that both support tissue differentiation and recapitulate the tissue–tissue interfaces, spatiotemporal chemical gradients, and mechanical microenvironments of living organs. These ‘organs-on-chips’ permit the study of human physiology in an organ-specific context, enable development of novel in vitro disease models, and could potentially serve as replacements for animals used in drug development and toxin testing.

Section snippets

3D cell culture

To understand fully how tissues form and function, as well as their pathophysiology, it is crucial to study how cells and tissues behave as parts of whole living organs that are composed of multiple, tightly opposed tissue types that are highly dynamic and variable in terms of their 3D structure, mechanical properties and biochemical microenvironment. Unfortunately, most studies on cell and tissue regulation have relied on analysis of cells grown in 2D cell-culture models that fail to

Microengineering meets cell biology

Microfabrication techniques, such as photolithography (Figure 1a), replica molding, and microcontact printing (Figure 1b), are well-suited to create structures with defined shapes and positions on the micrometer scale that can be used to position cells and tissues, control cell shape and function, and create highly structured 3D culture microenvironments 2, 3, 4. Microfluidics – the science of manipulating small amounts (10–9 to 10–18 L) of fluids in microfabricated hollow channels (Figure 1) –

Microengineering cells into tissues on biochips

Recently, more complex microfluidic devices have been created to develop controlled microenvironments for manipulation and long-term differentiation of various types of cultured cells. For example, a microfluidic device containing a cross-flow bioreactor composed of two parallel arrays of silicon and stainless steel microchannels separated by a thin permeable membrane was developed to study the high metabolic demands of cultured primary rat hepatocytes 29, 30. Efficient delivery of oxygen and

Recreating tissue–tissue interfaces to mimic organ microarchitecture

Development of these microengineering approaches has opened entirely new possibilities to create in vitro models that reconstitute more complex 3D organ-level structures and to integrate crucial dynamic mechanical cues as well as chemical signals. To study polarized functions of various epithelial cells (e.g. intestine 47, 48, lung [49], kidney 50, 51, cornea [52]), for example, two PDMS cell-culture chambers were stacked and separated by a permeable synthetic membrane or ECM (Figure 2a). A

Potential applications and future prospects

These studies have revealed that although 3D cell cultures represent a great improvement over planar 2D models, and altering the ECM mechanical compliance can further control cell differentiation and fate switching in 3D systems, the reality is that we can do even better to achieve our goal of recapitulating organ-level functionality by combining microengineering with cell biology. The key to meeting this challenge has been to recognize the importance of reconstituting the appropriate tissue

Concluding remarks

Although bioengineered 3D microsystems and organ-on-chip technologies are relatively new and still require further validation and characterization, their potential to predict clinical responses in humans could have profound effects on drug discovery and environmental toxicology testing. The scale-up of these complex technologies, together with systems integration of the engineering (e.g. fluidics handling, pumps) into easy to use, scalable, reproducible and user-friendly systems will be the key

Acknowledgments

This study was supported by the Wyss Institute for Biologically Inspired Engineering at Harvard University, and by National Institutes of Health grant R01-ES65.

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