Organs-on-Chips

How microsystems technology

can transform the drug
development process.

By Jeffrey T. Borenstein

T
he drug development pipeline, once one of
the most successful and lucrative commercial
sectors in the United States, is now strained
by a combination of factors: increased devel-
opment costs, lengthy time lines, and the poor
predictive power of preclinical studies, among oth-
ers. These factors, in combination with the need to
respond to newly evolving demands—including the
trend toward personalized or precision medicine,
rising rates for many chronic diseases, and contin-
ued threats from emerging infectious diseases—are
placing extraordinary pressure on an already strained
development process.
In response to this situation, there is a grow-
ing recognition that new science and new tools will
be needed to reduce the costs of drug development
and to improve the predictive power of preclini-
cal studies in assessing the safety and efficacy of
compounds in the pipeline. Currently, preclini-
cal studies rely most heavily on a combination of
image licensed by ingram publishing

experiments in animals (in vivo studies) and mea-

surements using cultured animal or human cells in
various formats (in vitro studies), all of which are

Digital Object Identifier 10.1109/MPUL.2015.2513722

Date of publication: 14 March 2016

22  ieee pulse  ▼  march/april 2016 2154-2287/16©2016IEEE

aimed at assessing the fate of the drug (absorption, metabolism,
and interactions) and the drug’s potential toxicity.
The in vivo process is very costly, suffers from inaccuracies
due to differences in how drugs affect humans versus various
animal models, and raises ethical concerns regarding heavy reli-
ance on animals for this testing. A further drawback of animal
models is that mechanistic studies involving precisely controlled
experiments and measurements are extremely difficult in living
organisms. The in vitro process typically involves drug testing
using transformed cell lines arranged in two-dimensional con-
figurations in multiwell plates. This approach suffers from the
relatively poor correlation between human responses and those
obtained in the artificial environment of a cell culture system, in
which neither the cells nor the microenvironments are particu-
larly representative of human physiology.
These deficiencies exhibited by current preclinical models
have spurred the development of the field known as organs-on-
chips, in which human primary cells are cultured in microfluidic
devices designed to mimic key features of the microenviron-
ment of human organs [1]. This article addresses the applica-
tion of microsystems technology—up to now used primarily for
producing microelectronic and microelectromechanical systems
(MEMS) devices such as the memory chips and sensors found
in mobile phones—to fabricate microscale models of human
organs, pump fluids around those organ models much as the
heart pumps blood through the body, and sense and measure
critical parameters so as to ensure that these organ models oper-
ate properly for periods of days or weeks during experiments
testing the efficacy and safety of drug compounds.
then be replicated in polymer devices. Lithographic patterning is
employed to generate a relief pattern on silicon wafers, and these
patterned wafers are then used as masters in a process known as
replica molding, where a soft and elastic polymer such as silicone
or poly(dimethylsiloxane) (PDMS) is cast and peeled from the
master and then used to form a transparent polymer structure
for cell culture. Multiple layers of these PDMS structures can be
cast from various patterned masters and then bonded together
and connected to plastic tubing, at which point cells are intro-
duced into various chambers in the structures and fluid. For
example, cell culture media can be introduced into the devices
to create an artificial tissue or organ construct.
As shown in Figure 1, where a pattern represents a branch-
ing network of blood vessels, these patterns can be designed at
the microscale or nanoscale to replicate structures in human
organs, such as capillary networks. Another example of such a
device is shown in the cross-sectional scanning electron micro-
graph in Figure 2. Here, a membrane bilayer device designed
and built using PDMS replica molding from silicon photolitho-
graphic masters is assembled to form a dual-compartment sys-
tem with an intervening semipermeable membrane dividing
the two chambers. This fundamental construct has been applied
to numerous barrier tissue and organ models, including the kid-
ney, lung, liver, vascular system, and blood–brain barrier. In
another example, a lung-on-a-chip comprising an engineered
blood vessel network and “breathing” chambers that contain

Microsystems for the Design of Organ Models

One critical deficiency of existing cell culture models used to predict
drug behavior in humans is the use of transformed cell lines or cells
that are derived from a single source, rather than human primary
cells taken from living human organs or tissues. This aspect of cell
culture model optimization and development is being addressed
through the emergence of systems that utilize human primary cells
from a variety of commercial sources, as well as stem-cell-based
approaches that can be engineered to represent a broader range of FIGURE 1  A photograph of a membrane bilayer device mimick-
genetic heterogeneity in human populations [2]. ing an engineered microvascular network.
These advances on the biological side of organ-model devel-
opment are being made in parallel with significant progress in
the development of microscale organ models that are designed to
simulate critical aspects of human tissues and organs. It is here
that microfabrication technology plays a key role in the ability
to recapitulate the chemical and mechanical microenvironment
within human organs, but at a size scale hundreds or thousands
of times smaller than the organs these devices are designed to
mimic. The reasons for this size reduction are numerous and
generally relate to practical limitations in the number of cells,
the volume of drug and other reagents required for testing, and
the need for multiple high-throughput experiments that drive
the economics of the preclinical drug evaluation process.
Microfabrication technologies take many forms, but a com-
mon approach uses the same photolithographic patterning tech-
FIGURE 2  A scanning electron micrograph showing two micro-
niques that form the basis of microelectronic and MEMS device fluidic channels, above and below a semipermeable membrane,
fabrication to create a template for microstructures that can used to simulate barrier tissue function.

march/april 2016  ▼  ieee pulse  23

 In response to
the limitations of
existing systems,
an electromagnetic
actuator pumping
technology has
been developed
that provides wide
dynamic range,
precision control, and
high reliability and
that can be embedded
directly into
the well plate.

lung-specific human cells is operated by applying alternating
vacuum and room-pressure levels to recapitulate the respiration
cycle. Studies have shown that effects such as the toxicity of
certain types of nanoparticles can be demonstrated using this
breathing lung-on-a-chip [3], whereas conventional cell culture
models that lack this system’s structural and dynamic aspects
do not exhibit such toxicities and so do not correlate as well to
human responses.
Microdevices for Controlling Flow
A common feature of virtually all organs-on-chips technologies—and
one that distinguishes them from conventional cell culture model
systems—is the presence of controlled levels of media flow within
and between the organ models. This requirement for flow stems
from the rate of oxygen consumption of highly metabolic tissues
(such as liver and heart), the importance of fluid mechanical shear
stress in governing cell behavior in tissue structures that are
exposed to flow (such as vascular and kidney), and the need
to replenish and refresh culture media in organ models so
as to maintain a healthy physiological state where nutrients
and waste products do not reach unacceptably low or high
levels, respectively. In addition, the emerging trend toward
multiorgan systems in which models of different organs are
FIGURE 3  The placement of a modular organ model into a recon-
figurable multiwell plate.
arranged in an interacting circuit on a platform necessitates
fluid exchange to mimic the organ crosstalk that occurs in
the body, presenting a significant engineering challenge for
fluid circuits that must operate precisely for periods of days or
weeks while maintaining fluid levels in each individual well.
Figure 3 shows a multiorgan platform in which various organ
and tissue models may be placed in a modular or reconfigu-
rable fashion.
Several approaches have been pursued toward the goal of
establishing precision fluid flow on organ model platforms for
the purposes of perfusing oxygen and nutrients; controlling
drug, nutrient, and metabolite concentrations and gradients; and
applying fluid shear to cultured cell populations [4]. Early efforts
focused on gravity-based effects, largely by rocking the well plate
in a manner to realize flow across an organ model and to move
fluid from one chamber to another. While this is a convenient
and relatively simple method, it lacks precision and cannot pro-
vide a wide dynamic range of flow conditions across a highly
multiplexed plate of organ models.
Rocking-plate systems have been supplanted to a degree by
technologies that leverage capillary-driven flow, where surface
tension in small channels is used to provide controlled flow
within an organ model and to enable interactions between
neighboring wells. Again, while the technique is attractive due
to its simplicity, there are limitations in the ability of capillary-
driven systems to provide a wide range of flow rates, shear forces,
and exchange capabilities due to the strong dependence of the
flow on the local geometry.
The limitations of gravity-driven systems have propelled efforts
in developing active pumping systems, typically based on pneu-
matically actuated valves in which a membrane in a pump cham-
ber is deflected due to actuation from an air-pressure line. These
pneumatic systems have enjoyed wide use and form the basis of
many commercial microfluidic systems—not just in organ model
research but in much broader applications for lab-on-a-chip appli-
cations. However, while they provide wide dynamic range and
precision flow, they involve separate air lines for control of each

24  ieee pulse  ▼  march/april 2016

 Pneumatic systems
often contain
elastomeric
membranes that can
become damaged over
time or adsorb drugs
and other compounds
in unpredictable and image licensed by ingram publishing

uncontrolled ways.

pump, and this becomes an unwieldy requirement when scaling power and control signals to tether the plate to a computer. Ele-
up to larger numbers of wells in multiplex systems. ments of individual microactuators are shown in Figure 4, placed
In addition, pneumatic systems often contain elastomeric against the backdrop of an actuator plate that houses the actuators
membranes that can become damaged over time or adsorb drugs in various valving and pumping configurations.
and other compounds in unpredictable and uncontrolled ways. Reliability is achieved through careful design and processing
Another active pumping approach uses robotic dispensing sys- of the stacked microfluidic layers and the materials choices in this
tems that can be easily multiplexed in a manner similar to cur- micropump architecture, as well as by housing the critical compo-
rent instrumentation in many pharmaceutical research labs. nents in a hermetically sealed manner. Ultimately, these systems
These systems essentially enable fluid transfer between wells by can be rendered completely untethered by integrating the power
withdrawing fluid into a chamber and then dispensing the bolus and electronic control into the plate itself, making these instru-
into a neighboring chamber. While the system is highly scalable, mented well plates essentially dynamic, “smart” versions of cur-
it involves complex instrumentation and does not provide for a rent conventional plastic well plates for cell culture applications.
full range of continuous or semicontinuous flow rates.
In response to the limitations of these systems, efforts have Microsensors for Measurement and Control
been aimed at developing a micropumping technology that pro- Microsensors based on MEMS technology are having an enor-
vides for wide dynamic range and high-precision control over mous impact in a wide range of industries and applications,
flow rates, eliminates the need in actuation for bulky and unreli-
able air lines that become unwieldy as systems scale, provides
high reliability in a harsh environment, and can be embedded
directly into the well plate rather than requiring extensive exter-
nal instrumentation that raises cost and system complexity. Such
a micropump technology has been developed for implantable
drug delivery systems [5], which, by definition, require extreme
miniaturization and power efficiency while maintaining high
reliability during extended operation under harsh temperature
and humidity conditions.
The micropump comprises a miniaturized electromagnetic
actuator designed to operate in a normally closed condition to min-
imize power consumption when the pump is not being actuated.
The actuator addresses a membrane atop a displacement cham-
ber, and valves situated at the entrance and exit positions enable
precise flow control across a range of stroke volumes that can be
tuned by changes to the displacement chamber and membrane
geometries. The electromagnetic actuator-driven micropumps can
be situated across a multiwell plate at high densities; current sys-
FIGURE 4  Microactuator components for micropumps and
tems comprise as many as 62 actuators on a single plate roughly microvalves atop a flow control plate for a dynamic multiwell
the size of a 96-well plate, with only a ribbon cable to provide platform.

march/april 2016  ▼  ieee pulse  25

including inertial sensors in automotives, mobile phone devices,
and gaming systems; pressure sensors in several biomedical appli-
cations; and chemical sensors for industrial and security purposes.
One of the most powerful opportunities for microsystems technol-
ogy in the drug development process is the ability of microsensors
to monitor and control organ models in a real-time manner.
Currently, automation technologies capable of monitoring
cell culture conditions in multiwell plates focus on assessment
of morphology, cell growth, and protein expression, using a
variety of markers and stains that provide basic feedback on
cell viability and other parameters. However, with the advent
of organ model systems in which environmental conditions
and cues such as flow, gradients of oxygen and other nutrients,
and matrix composition and mechanics can be varied and pre-
cisely controlled, techniques for monitoring these parameters
in real time are urgently needed. In response to these emerging
needs, several types of microsensors for real-time monitoring
of conditions in a higher throughput or multiplex manner are
being developed.
One class of microsensor technology that is finding wide use
in organ models and systems provides measurement of basic
cell culture parameters such as oxygen, temperature, pH, and
molecular measurements, including glucose and lactate. A key
aspect of these sensors is miniaturization and simplification of
the sensor architecture and the routing of signals in multiwell
plates to improve the reliability and robustness of the system and
to reduce the impact of the sensor network architecture on other
properties of the system, including the ability to retain high-reso-
lution optical access. Many of these sensor architectures leverage
patterning techniques from MEMS fabrication processes, such as
the formation of interdigitated electrode geometries and various
chemistries using photolithographic techniques and sputter- and
chemical-vapor-deposited films.
As described previously, one of the most critical aspects of
organ model systems is the ability to provide controlled levels
of flow for perfusion and to impart fluid shear stress on cul-
tured cell populations. Flow sensor technologies based on the
calorimetric principle can be deployed on multiwell plates to
monitor pump rates over periods of weeks as needed during
extended operation of these organ model systems. Progress in
flow sensor technologies for applications in biomedical devices
such as insulin delivery systems and ventilators can be lever-
aged toward multiplex configurations where flow sensors are
integrated in line with the micropumps to ensure stable opera-
tion and to detect any problems during experiments that other-
wise might be misinterpreted as biological issues with the cells
or drug responses.
More specialized sensor measurements in organ model sys-
tems can be very useful in assessing tissue responses to drugs
and other stimuli in various preclinical studies. An example with
wide application is the measurement of trans-epithelial electrical
resistance (TEER) to monitor the health of barrier tissues in organ
models and systems. These measurements are highly useful in
assessing the properties of models of the lung, intestine, skin, and
other tissues, as well as to monitor changes in TEER over time
(during operation of organ model systems) and across responses
26  ieee pulse  ▼  march/april 2016
to inflammatory insults and drug dosing in these experiments.
Conventional monitoring of TEER is manual, and requires inter-
ruption of operation of the cell culture, removal from the incu-
bator (and the resulting disturbance of the cell culture), and the
potential for contamination. Therefore, an automated measure-
ment of TEER in a multiplex organ model system would increase
reliability and provide critical information on the status of the
model and the response to drug dosing. Recent efforts point out
that TEER measurements in microfluidic systems present specific
challenges [6] and are highly sensitive to small changes in the
confluence of cells cultured on barrier membranes. These mea-
surements thus present a powerful opportunity for real-time
monitoring using microfabrication and microsensing technology.
Summary
This article described a range of opportunities for microsys-
tems technology to address and positively impact the challeng-
ing environment of the drug development process. Deficiencies
in the ability of animal studies and currently existing simpli-
fied cell culture systems to accurately predict the safety and
efficacy of compounds in the drug development pipeline can
be addressed by a combination of advances in cell biology and
in the domain of microengineered systems. Toward this lat-
ter end, a combination of emerging capabilities in microfluidic
design and fabrication techniques, microactuator and pump
technologies, and microsensors and integration methods,
presents a powerful opportunity to create a new generation
of physiologically relevant, precisely controlled, and scalable
engineered systems for use in the drug development process.
Jeffrey T. Borenstein (jborenstein@draper.com) is with Draper
Laboratory, Cambridge, Massachusetts.
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