Cells on chips
Jamil El-Ali1, Peter K. Sorger2 & Klavs F. Jensen1
Microsystems create new opportunities for the spatial and temporal control of cell growth and stimuli by
combining surfaces that mimic complex biochemistries and geometries of the extracellular matrix with
microfluidic channels that regulate transport of fluids and soluble factors. Further integration with bioanalytic
microsystems results in multifunctional platforms for basic biological insights into cells and tissues, as well
as for cell-based sensors with biochemical, biomedical and environmental functions. Highly integrated
microdevices show great promise for basic biomedical and pharmaceutical research, and robust and portable
point-of-care devices could be used in clinical settings, in both the developed and the developing world.
In their normal environment, cells are subject to multiple cues that vary
in time and space, including gradients of cytokines and secreted proteins
from neighbouring cells, biochemical and mechanical interactions with
the extracellular matrix (ECM), and direct cell–cell contacts (Box 1).
Microfabricated systems can present cells with these cues in a control-
lable and reproducible fashion that cannot easily be achieved by standard
tissue culture, and can be used to link cell culture with integrated analy-
tical devices that can probe the biochemical processes that govern cell
behaviour. Some cell-based microsystems simply represent miniaturized
versions of conventional laboratory techniques, whereas others exploit
the advantages of small length scales and low Reynolds numbers1, such as
favourable scaling of electrical fields and the ability to create well-control-
led laminar flows. In this Review, we discuss the application of microtech-
nology to cell biology and describe methods for cell culture, regulation
of extracellular cues, cell fractionations and biochemical analysis on a
micrometre scale (Fig. 1). Emphasis is placed on microsystems aimed at
gaining biological insight, as well as on efforts to realize increasing cell-
handling integration and biochemical analysis levels on chips.
We believe these devices will become increasingly implemented in
applied and basic biomedical research, mainly because soft lithography2
has put microfluidics within the reach of biology-focused academic
laboratories. Elastomeric materials used in soft lithography, typically
1Department of Chemical Engineering, and 2Department of Biology and Biological Engineering, Center for Cell Decision Processes, Massachusetts Institute of Technology, Cambridge, Massachusetts
02139, USA.
poly(dimethylsiloxane) (PDMS), are relatively easy to fabricate, and are
compatible with most biological assays. Devices that are based on micro-
fabrication of silicon and glass require access to advanced cleanroom
facilities similar to those used for microelectronics. This typically involves
higher cost, but has unique advantages for specialized applications, such
as electrophoresis in glass devices.
Much cell-based microsystem research takes place under a ‘lab-on-
a-chip’ or ‘micro-total-analysis-system’ (µTAS) framework that seeks to
create microsystems incorporating several steps of an assay into a single
system3–5. Integrated microfluidic devices perform rapid and reproduc-
ible measurements on small sample volumes while eliminating the need
for labour-intensive and potentially error-prone laboratory manipu-
lations. Thus, microfluidics allows experiments to be carried out that
cannot be performed simply by miniaturizing and mechanizing conven-
tional laboratory procedures using robotics and microplates. For exam-
ple, in cell-based studies, the transition from 384- to 1,536-well plates
is proving challenging, largely because edge effects and uncontrolled
evaporation from very small wells result in poorly defined culture condi-
tions. Conventional handling of very small fluidic volumes is difficult,
and subject to both variability and high fixed losses. The fabrication of
many copies of an analytic device, small reagent volumes, and dimin-
ished labour associated with use of automated microfabricated devices
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Soluble signalling molecules include hormones, cytokines and growth
factors produced by local or distant cells (giving rise to paracrine and
endocrine signals, respectively), and even by the receiving cell itself
(autocrine signals). Insoluble signalling molecules include components
of the ECM and membrane-bound proteins on neighbouring cells.
Cells sense most extracellular signals (including proteins, peptides
and carbohydrates) via transmembrane receptors that activate
complex biochemical cascades of kinases, proteases, adaptor proteins,
transcription factors and so on, which together act to regulate cell
physiology. At the same time, cells alter their surrounding environment
by making or destroying ECM or soluble factors and by exerting
mechanical force99,100.
In animals, cells typically reside in environments with very specific
three-dimensional (3D) features. Cells are sensitive to the presence of
neighbouring cells of similar or different type and often make long-lasting
mechanical and biochemical connections to them. In columnar epithelia,
for example, identical cells lined up side by side assemble junctions with
neighbours to form continuous impermeable sheets. These sheets are
polarized such that cells interact with their surroundings in very different
ways on the lumenal and basolateral surfaces. In addition, epithelia
usually establish a close relationship with specific types of immune cell.
In these epithelia, both homotypic and heterotypic cell–cell interactions
are essential to maintain cell and tissue function.
Most in vitro experiments with adherent human cells are performed
in two-dimensional (2D) cultures in which cells are plated onto plastic
surfaces treated to stimulate cell binding. Depending on their type,
cells either grow directly on the plastic, secrete ECM components that
coat the plastic to facilitate cell adhesion, or require pre-coating of the
plastic with ECM. Standard 2D culture conditions are poor mimics
of the cellular environment in an animal: soluble growth factors are
present at abnormally high concentrations, 3D cues are largely absent,
oxygen tension is too high and cell–cell interactions are rarely organized.
Attempts have been made to overcome these problems using organ
culture and various laboratory-scale bioreactors, but microsystems
provide a much more effective means of controlling cell environment
in vitro. Particularly promising are various artificial organ systems in
which multiple cell types are grown together under conditions that mimic
normal 3D environmental and circulatory cues.
Box 1 | Cell physiology, phenotype and fate are regulated by cell-autonomous processes and extracellular signalling molecules
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should make them highly cost effective. Moreover, the small footprint
and low power consumption of integrated systems creates opportunities
for portable, point-of-care devices that can perform analyses hitherto
possible only in the research or clinical laboratory. Devices such as these
with sophisticated diagnostic capabilities are likely to become important
in the personalization of medical care.
Many of the promises of µTAS have yet to be realized: integration
and packaging of several functionalities into a single system is proving
to be a complex task (Fig. 1), and many cell-based microsystems avail-
able today are still in the proof-of-concept phase. Typical unit opera-
tions (for example, growth, treatment, selection, lysis, separation and
analysis) have been demonstrated (Fig. 2), but robust approaches to
fabrication, integration and packaging (such as communication with
the macroenvironment) remain major areas of research.
Microfabricated cell cultures
Culturing cells in vitro is one of the cornerstones of modern biology.
Nevertheless, even for intensively studied tissues, many of the factors
that induce or stabilize differentiated phenotypes are poorly under-
stood and difficult to mimic in vitro6. One approach to increase control
over cell–cell and soluble cues typical of in vivo cell environments is
to combine microfabrication of 3D ECM structures and microfluidic
networks that transport soluble factors such as nutrients and oxygen.
Microfluidics has the additional advantage of being capable of creating
mechanical strain, through shear, in the physiological range.
Cells and the extracellular matrix
Microfabrication integrating micropatterning techniques with advanced
surface chemistry makes it possible to reproducibly engineer cell micro-
environment at cellular resolution. A large variety of surface-patterning
techniques are available, including standard photolithography liftoff
techniques, photoreactive chemistry and, increasingly, techniques based
on soft lithography (microcontact printing and fluidic patterning)7.
Surface patterning of micrometre-sized features allows micrometre-
scale control over cell–ECM interactions and can be used to generate
ensembles of cells with defined geometry. Lamination, moulding and
photo-polymerization techniques all allow fabrication of 3D scaffolds
with feature sizes in the lower micrometre range, including microstruc-
tured scaffolds made of biodegradable materials8.
The precise control of the cellular environment that has been made pos-
sible by microtechnology provides new opportunities for understanding
biochemical and mechanical processes responsible for changes in behav-
iour such as the effects of cell shape on the anchorage-dependence of cell
growth9,10. For example, by altering the spacing of a grid of cell-adhesive
islands it is possible to control the extent of cell spreading, while keeping
the cell–ECM contact area constant10 (Fig. 3a). Human capillary endothe-
lial cells confined to closely spaced islands undergo apoptosis, whereas
cells that can spread freely survive and proliferate normally10. Adhesive
ECM patches can also be designed so that the locations of focal adhesions
(integrin-mediated links between the ECM and actin cytoskeleton) result
in the same overall cell shape, but with a different underlying cytoskeletal
organization (Fig. 3b). By allowing cells to spread and proliferate on these
adhesive patches the orientation of the cell division axis can be controlled11.
Similar regulation of the division axis by the ECM is likely to be important
for tissue morphogenesis and other developmental processes.
The force exerted on the ECM by cells can be measured in several
ways. A particularly powerful method involves measuring the deflec-
tion of arrays of micrometre-sized vertical elastomer posts (Fig. 3c).
When tested with smooth muscle cells, forces acting in the plane of
the substrate are in the range of 100 nN, and appear to scale with the
area covered by focal adhesions12. Compared with conventional meth-
ods that rely on substrate distortion, the elastomer-post technique has
Growth media
Stimulation Cell lysis
Tissue organization Cell selection
Cell imaging
Biochemical analysis
Figure 1 | Tissue organization, culture and analysis in microsystems. Advanced tissue organization and culture can be performed in microsystems by
integrating homogeneous and heterogeneous cell ensembles, 3D scaffolds to guide cell growth, and microfluidic systems for transport of nutrients
and other soluble factors. Soluble factors — for example, cytokines for cell stimulation — can be presented to the cells in precisely defined spatial and
temporal patterns using integrated microfluidic systems. Microsystems technology can also fractionate heterogeneous cell populations into homogeneous
populations, including single-cell selection, so different cell types can be analysed separately. Microsystems can incorporate numerous techniques for
the analysis of the biochemical reactions in cells, including image-based analysis and techniques for gene and protein analysis of cell lysates. This makes
microtechnology an excellent tool in cell-based applications and in the fundamental study of cell biology. As indicated by the yellow arrows, the different
microfluidic components can be connected with each other to form an integrated system, realizing multiple functionalities on a single chip. However,
this integration is challenging with respect to fluidic and sample matching between the different components, not least because of the difficulty in
simultaneously packaging fluidic, optical, electronic and biological components into a single system.
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