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INNOVATIONS RAY ALLEN FREng

PROFESSOR OF CHEMICAL &


PROCESS ENGINEERING,
THE UNIVERSITY OF SHEFFIELD

Chemistry has caught the


microtechnology bug. Increasingly it
is becoming possible to carry out
reactions in vessels whose
dimensions are measured in
micrometres, in controlled volumes
down to picolitres. This article
examines why this is a sensible thing
to do and how the current trends in
lab-on-a-chip and high-throughput
experimentation are pointing
chemical engineering in the
direction of engineering more
precise chemistry. Will we soon be
able to manufacture only and
exactly what we want, when and
where we want it?

Figure 1: The flying helicopter manufactured by the Institute for Microtechnology


at Mainz. This, one of the most striking examples of micro engineering, is Introduction
24 mm long, 8 mm high and weighs 400 mg. It uses two 1.9 mm Ever since the classic pictures of
diameter motors capable of nearly 500,000 rpm and torques of 7.5 Nm. micron-sized gear wheels began to
It provides a spectacular showcase for the very real potential of its appear some 15 years ago,
motors which, in fact, are aimed at applications in fast-rotating systems, microtechnology has engendered
e.g. scanners, drive units in heart catheters or high-tech display systems.
intense excitement in the scientific
(Photograph courtesy of the Institute for Microtechnology, Mainz.)
community. Initially, the grounds for
such excitement were thin, often
amounting to an article of faith that it

Microchannel had to be useful for something! In


recent years, however, it has become
apparent that the initial faith was
justified. For example, microtechnology

reactors
underlies the thinking about much post-
genome work on pharmaceutical
discovery and testing, has led to a
range of micromanipulation devices
and, perhaps more spectacularly, the

Chemical
tiny flying helicopter made by the
Institute for Microtechnology at Mainz
(Figure 1).
Because of the high surface areas
involved, devices involving miniature

engineering gear races inevitably have to cope with


enhanced friction. To chemical
engineers, however, such high surface
areas represent an opportunity.

in another
Increasingly, this is being realised with
the advent of systems to perform
complete chemical procedures involving
fluid pumping, valves, chemical
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reactions, separations and analysis all

dimension?
on one chip in channels of hydraulic
diameters between tens and hundreds
of microns.
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INNOVATIONS

parallel channels or units. The extracting information about it, such as


the technology is cheapness means that any its composition, structure, the presence

already much more microreactor system can incorporate


high levels of redundancy, so that in
of antibodies and so on. From its early
beginning at Stanford in the late 1970s
than a laboratory the event of one part of the system
malfunctioning, some other part can
this technology has grown rapidly. It
has now reached the point where
curiosity take over its role. household-name companies such as
Corning, Agilent (a spin-off from Hewlett
In short, small channels allow
Packard) and Hitachi are offering a
construction of an inherently safe,
range of products for applications in the
So why does size matter? extremely well-defined chemical reactor
genomics field, including PCR and DNA
Small channels give: so that it becomes possible to think
analysis, immunoassays, sensors and
about routine engineering of precise
Small length scales, which means so on. Figure 2 shows one commercial
chemistry where all atoms are used
that the flow of the fluid, its heating chip marketed by Agilent Technologies.
efficiently and by-product wastes are
and its cooling all take place under As this first-phase commercialisation
avoided. On the downside, in the
laminar conditions (i.e. no begins to happen in earnest, the
systems which have so far been
turbulence). The movement of second wave of impact of these
studied, the throughputs are extremely
material relative to the fluid occurs in devices is emerging. This technology
small and in a traditional chemical
a predictable way by classical has teamed up with a modern
engineering context this must be a
diffusion. Thus all the processes approach to chemistry in which very
major problem. However the
relevant to reaction are calculable, large numbers of different molecules
technology is already much more than
potentially at the molecular level, so are produced by reactions (between,
a laboratory curiosity.
that it becomes possible (in principle) for example, whole homologous series
to know exactly the of precursor reagents the so-called
temperature/time and The three phases of combinatorial approach) and then
concentration/time history of exploitation screened for particular effects by a fast-
reacting mixtures in a way which is The immediate commercial driving force response analyser. This has produced
not possible with turbulent flow for these microminiaturised systems is high-throughput testing techniques that
reactors where flows are highly their exploitation for chemical and are radically changing our ability to
random. This opens the way to a far biological analysis the so-called lab discover new molecules and materials.
greater precision in the engineering on a chip. Here the emphasis is on Initial applications, currently attracting
of reactions. injecting a fluid on to the chip and a great deal of research attention,
High surface-area-to-volume ratios,
and thus vastly improved heat
transfer/catalysis and so, again,
precise control over reaction
conditions.
Small volumes, which means that
there is less material contained in the
reactor at any given instant; there is
thus less potential for toxic reagent
loss in the event of an accident. This
means a lower environmental impact
and a lowered risk of a severe
runaway reaction of any sort.
Reactors on a chip broadly similar
to an electronic chip, which means
that instrumentation can (in principle)
be integrated with the reaction
channels and so provide extremely Figure 2: A LabChip microarray marketed by Agilent Technologies:
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fast response control and analysis interconnected channels are etched into glass. The resulting chips can
systems. duplicate operations performed at the conventional laboratory bench in
The possibility of extremely cheap volumes ranging from nanolitres to picolitres. (Photograph courtesy of
replication and scale-out by use of Agilent Technologies.)
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INNOVATIONS

include drug discovery, advanced processes. Given a demand for a electro-osmotic flows, which are the
solvent selection, materials discovery particular product, this will require a result of an applied voltage along the
and catalyst development. The small green chemistry approach in which length of the channel.
amounts of material used, the ease of solvents are not used (or at least not
The latter approach is potentially the
integration with automatic analysis consumed) and where whole
most exciting since it provides
systems together with the rapid processes, including the reaction step,
instantaneous electrical control and a
response, make chip-based systems are atom efficient. A radical new
velocity profile across the channel that
ideally suited for such applications and approach is, therefore, required to
is precise and flat. However, it can only
the two technologies are merging engineering chemistry and the
be used in channels with appropriate
rapidly. When linked with databases and excitement surrounding the early work
surface properties.
suitable searching techniques such as on microchannel reactors is based on
In either case, we need to obtain
genetic algorithms, then a powerful the fact that it is pointing the way to
flow conditions which allow reagents to
platform can be created on which the achieving some of these benefits.
mix in such a way that the temperature
rate of discovery can be enhanced by
and composition variations with time
many orders of magnitude.
Microfluidics are known and controlled as precisely
In terms of commercialisation, the
as possible. For gases, the molecules
most distant but also the most far At the small channel sizes we are
mix very rapidly by diffusion at the
reaching in its potential impact on considering, the flow is laminar such
length scales being considered. Most
chemical engineering is the idea of a that packets of fluid follow smooth
interest, however, centres on liquid
plant on a chip, which involves putting streamlines. Historically chemical
systems and here the situation is more
one set of materials on to a chip and engineers, whose primary interests
complex. Diffusion is generally smaller
taking different materials off. The centre on mixing reagents and
than for gases, so that mixing across
Chemical Process Industries (CPI) in the stimulating heat and mass transfer at a
the channel is weak. The extent of
UK, as elsewhere in Europe, are forced large scale, have ignored the potential of
mixing along the length of the channel
to compete through enhanced, value- laminar flow regimes and opted instead
depends upon how the flow is induced.
adding technology. The trend is, to harness the randomness inherent in
In pressure-driven flows, the variation of
therefore, towards greater differentiation turbulent flow structures to achieve their
velocity across the channel follows a
of products (based on the effects that ends. In molecular terms, however, the
profile resembling a parabola. Thus fluid
can be achieved) and away from bulk mixing structures thus created are of a
at the walls of the channel is flowing
chemicals sold on as a commodity on very large scale and this inevitably has
much slower than fluid in the centre of
the basis solely of their molecular an impact on the precision with which
the channel and this causes substantial
structure. a reaction can be controlled. In
mixing in the axial direction.
For this reason, electro-osmotic
the most distant but also the most far systems tend to be favoured for precise
control. Outside of the very thin (of
reaching idea is that of a plant on a chip nanometre order) electrical double layer
at the wall, the velocity profile is
uniform. If this is considered in
conjunction with the extremely high
Increasingly the effect that will be microchannels, by contrast, the flows
levels of heat transfer that can in
sold will be achieved through some are predictable in a deterministic way.
principle occur in microchannel
precise formulation involving an exact This has stimulated a renewed interest
systems, then it creates a very exciting
supra-molecular structure produced, for in this flow regime for fluid flow and
opportunity completely to control the
example, by a self-assembling gel. reactor design a field now commonly
concentration/temperature/time history
Differentiation, particularly in terms of referred to as microfluidics.
of a reacting system. Properly
reliability, will drive the chemical Whilst there have been many
engineered, this can provide a more
engineering of the future so that mass suggestions made for on-chip fluid
direct link between reactions at the
commercialisation, agile manufacturing pumps, the majority of research
molecular level and bulk flow systems
and dispersed, point-of-sale attention is being paid to just two
than has previously been realisable.
manufacture are thought to be key techniques for creating flows through
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trends. microchannels:
In addition societal forces are Reactions in microchannels
pressure differences, which can
demanding more and more that the CPI Some reactions are so fast that the
move both gases and liquids;
look to the sustainability of their system is mass-transfer limited; in other
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INNOVATIONS

words it is the movement of the


Consider a reaction: A+BC
reagents that controls the rate at which
the product is made, rather than the where the reactants A and B are in the reservoirs and the fluids are moved
speed of the actual reaction itself. electro-osmotically.
Conversely, some reactions are slower
and are limited by the kinetics. For
reactions between gases,
microchannels show the greatest
promise for mass-transfer controlled
reactions. Assuming that the high
surface areas allow the energy
associated with reactions to be
transferred appropriately, then a halving
of channel diameter will quadruple the
reactor intensity in terms of the reaction
that can be accomplished within a given
volume of reactor. This has significant By alternately pulsing the voltages at points A and B we can get slugs of B
implications for advanced energy- (coloured blue) in A. These can be in the nanolitre to picolitre range. The
generation systems, including fuel cells. distribution of material along the length of the channel would look like this:
Prototype palm sized compact
heating, cooling and power-generation
systems have been constructed that
are capable of delivering as much as a
The reaction to C will occur at the edges of the slugs under precisely
kilowatt of thermal power. Because of calculable conditions. Graphically, the distribution of material along the length
the large surface area created by the of the channel looks likes this as the reaction begins:
microchannels, heat flows per unit area
greater than 25 W/cm2 have been
obtained. Because of the small size of
these units, they heat up quickly and
can be carried easily so that they can
be used for distributed and man-
portable applications including room-
by-room home heating, air conditioning
for a soldier, or power generation for a
backpacker.
In the liquid phase, it is possible to
use microfluidic techniques to provide
even greater opportunities for control. After a certain length of time, there will be substantial quantities of C formed.
As well as subdividing the flow streams However, A, B, and C all have different electrophoretic velocities and respond
in parallel, it has been suggested that at different rates to the applied voltage gradient. Separation thus occurs as
the flow should be compartmentalised the mixture flows along the channel:
into very small (nanolitre and smaller)
reacting volumes down the channel.
The idea is to create, at the beginning
of the channel, a continuous flow of
reactant A containing discrete slugs of
reactant B. The reaction can then
proceed at the boundary of the slugs
under precisely known conditions. The
situation is summarised in Figure 3.
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Figure 3: Further subdivision of a


reaction by means of a Z
Correct design means that reaction and separation can occur in a single channel.
chip.
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INNOVATIONS

It has been suggested that a Z Figure 4: A microfluidic oscillator used for mixing two fluid streams.
chip, of the geometry shown, could be
used to subdivide the reactants into the
slugs in series. The idea is attractive
because as the product C is formed, it
will also respond to the voltage
gradient. In real systems, A, B and C
will all respond differently so that
separation will occur as the fluid moves
along the channel. If the device is
designed correctly, precise reaction and
separation can be made to occur in a
single chip.
In fact the flows are more complex
than this simple picture suggests. The
fluids inertia causes its flow path to
distort close to changes of curvature,
such as the junctions in the channel. As
a result, clean interfaces are more
difficult to achieve than expected and
new designs of chip are being evolved
to allow the required degree of Schematic of oscillator geometry
precision.
A microfluidic approach allows The oscillatormixer made from
convention to be defied in other ways. through-etched stainless steel and
Figure 4, for example, shows an etched sandwiched between two
oscillatormixer that uses two opposing transparent plates. In operation, a
stream of colourless liquid is being
fluid streams. At a small scale the
interleaved with a stream of blue
oscillation frequency, and hence the
liquid. The oscillation frequency
thickness of the layers in which the two depends upon feedback from the
materials are interleaved, depends upon interaction of the jet with the cavity
feedback from the interaction of the wall. By miniaturising the device, controlled oscillations have been achieved
streams with the wall of the cavity. By more easily than previously thought possible. The resulting interleaving of the
miniaturising the device, it becomes two fluid streams allows mixing by diffusion to occur more quickly. (Courtesy
possible to generate oscillatory flows of the Institute of Applied Catalysis.)
more easily and create very small length
scales over which diffusion has to take
place.

the interface between the micro and


techniques including laser cutting,
Engineering challenges macro environments;
moulding and electrochemical
scaleout or parallelisation to achieve
The first work on microchannel reactors deposition. Geometries tend still to be
significant throughputs.
sprang from silicon chip manufacturing two-dimensional with overall units being
techniques. As a result, early work constructed from layers of material The term scaleout is used since one
tended to be performed on silicon bonded together to form a single layer of the strongly perceived advantages of
substrates and in a two-dimensional of channels. In fact the vast majority of microchannel reactors is that, because
geometry. Manufacturing techniques the reported research still concentrates replicate manufacturing costs of the
involved photochemical etching, on single channels. Very few centres chips are low, higher throughputs will
reactive ion etching, LIGA and so on. are attempting to create many parallel be achieved by placing many duplicate
In the last few years, it has been reaction streams to allow scale-up to chips in parallel. This will create the
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demonstrated that suitable channels useful throughputs. Thus two main advantage of allowing systems with
can be made from a very broad range challenges to the widespread high levels of built-in redundancy to
of materials including stainless steel, exploitation of microchannel reactors make failure-tolerant plant as well as
glass and several polymers via may be identified as: the very real prospect of disposable
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INNOVATIONS

chemical plant. Although these


possibilities were identified many years
Microchannel devices have the capacity
ago, the engineering challenges
underlying them have only recently
radically to change the way that major
begun to be tackled.
Reactors can simply be built with
companies do business
multiple channels in parallel on a single
layer and also with layers in parallel in a this technology will change their distributed manufacture. It almost
stack. Reactions involve energy business but when it will. Examples of certainly will be the opportunity to
changes and this requires control over what they thought would be done using exploit completely novel chemistry. In
the heat transfer in every layer. As a this technology included: fact, if microchemical engineering were
result, the stacks that have been to turn out to be just miniaturisation for
massively high-throughput
proposed tend to be of alternating its own sake, it probably wouldnt be
experimentation for drug discovery;
layers, either by using a heat-transfer worth the bother.
enabling highly personal diagnosis of
fluid to provide the necessary control
illness at the proteomic level;
over the temperature profile in the
high-throughput studies of gene Web sites
reacting layers or by matching energy-
expression to develop optimal plants
releasing and energy-consuming MEMS Precision Instruments site
and healthier foods;
reactions on either side of a thermally (micromanipulation devices):
understanding an individuals skin
conductive plate. Either way, extra http://www.memspi.com
care requirements at the cellular
challenges associated with sealing
level; The Institute for Microtechnology, Mainz:
between internal channels arise.
self-assessment and health http://www.immmainz.de/english/
It is probable that, for the
monitoring. developm/products
commercial application of this type of
technology, highly flexible modules will Agilent Technologies:
be necessary which can easily be Conclusions http://www.chem.agilent.com
connected and disconnected to The challenge for chemical reaction
Micro-Cats (Micro Chemical and
achieve particular aims and a required engineering is to develop ever more
Thermal Systems):
throughput. This building-block detailed understanding to give fault-free
http://www.pnl.gov/microcats/fullmenu/
approach to the constructing of products from zero-emission
microchannel.html
chemical plant will require radical processes. In short, to manufacture
developments in packaging technology. only and exactly:
This must involve standardisation of
what we want,
connectors and seals. It will also involve
when we want it, Ray Allen was the inaugural Head of
common standards for electrical
where we want it. the new Chemical
connections, heat-transfer fluids,
Engineering
reagents, control signals and so on. This will require a different approach to
Department at the
Some work is already well advanced in reactor design that involves radical
University of
the production of such modules. changes to the way we control,
Sheffield from
Microchannel devices have the inter alia,
19952000. He
capacity radically to change the way
mixing and continues there as
that major companies do business and
heat transfer. a research professor with a
to change the landscape in terms of
specialist interest in the modelling
human health and happiness. This was It is these features of microchannel
and visualisation of reacting flows to
a conclusion from a recent DTI seminar reactors that suggest that they do have
enable the engineering of reactors to
(Microsystems The Big Future, the potential to take chemical
give precise chemistry. Prior to
London, 4 April 2001) at which top- engineering into another dimension.
joining the University of Sheffield,
level technical managers from both They provide the means to use a
Ray worked for AEA Technology at
Unilever and Glaxo SmithKline gave an reactor configuration, in conjunction
the Harwell Laboratory where,
insight into how the technology is seen with clever microfluidics, more directly
amongst other things, he managed
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as core enabler in their forward to influence the reaction and


SPS and then became Business
business planning. Both speakers (Dr formulation processes. Accordingly, the
Development Director.
Peter Goodfellow and Dr Kurt Schilling) driving force for their use will not be
agreed that it is not a matter of whether miniaturisation for it own sake, nor yet Email: r.w.k.allen@sheffield.ac.uk
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