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08 December 2009 NANO Magazine - Issue 7

Squeezing the medical laboratory onto a chip

Image Credit: NANO Magazine.

Having early access to accurate and reliable diagnostic information is a crucial part of medical
treatment; it can improve the prognosis for patients by identifying diseases or conditions at a much
earlier and more treatable stage; it can provide information on the ongoing effectiveness of therapies;
and it can reduce the costs for increasingly cash-strapped healthcare systems by reducing the time
spent in expensive hospital stays. For many patients, for example those with conditions like diabetes, it
can be an important part of daily routine and essential self-testing. In-vitro diagnostic devices (IVDs) in
many ways lend themselves to the application of nanotechnology. The devices are normally remote
from the patient and any utilized nanomaterials, that otherwise might require extensive biological
safety testing, do not come into direct contact with the body. The application of nanotechnology can
come from the use of such materials, from the ability to engineer at the nanoscale and from the
combination of different nanoscale disciplines in an integrated manner.
The development of the lab-on-a-chip
Since the early 1990s the term lab-on-a-chip (LOC) has become more and more familiar, even
provoking interest in the popular press. The concept was invented, and the first LOC system
developed at Stanford University, USA, in the mid-1970s, but it was not until some 15 years later that
microfluidic engineering and sensor technologies developed sufficiently to allow new generations of
LOCs to be developed. Now, further advances mean that engineering at the nanoscale can also be
applied to add a new range of new functionalities.
The term lab-on-a-chip, sometimes also called micro-total analysis system (TAS), is usually applied
to devices that integrate a variety of functions on a single chip or slide, usually of a few square
centimetres or less, and that are capable of analysing very small fluid volumes down to picolitre levels.
LOCs comprise a convergence of micro-, or in the latest versions, nano-fluidic engineering, electronics

and small-scale fabrication, often using techniques such a photolithography, in silicon, glass, plastics,
ceramics or metal. LOCs will frequently integrate processes such as sample introduction and handling,
preprocessing (e.g. dilution, cell lysis, filtering), separation (e.g. by electrophoresis or chromatography)
and measurement/detection onto a single chip with associated electronic or optical systems. The
microfluidic elements of the chip can include pumps, mixing areas, capillary channels, valves,
heaters/coolers and, in some cases, miniaturised bioreactors.
Some of the advantages of LOCs include:
- extremely low consumption of reagents and analytes - fast heating or cooling - high surface to
volume ratios - very fast analysis times due to the very small distances substances have to move or
diffuse - a greatly improved control of analytical parameters - the possibility of carrying out large
number of analyses in parallel - extreme compactness allowing the creation of desktop standalone
modular and automated analytical systems - a reduction in fabrication costs, allowing mass production
of disposable chips - a safer platform for chemical, radioactive or biological studies because of the
integration of functions, the smaller volumes or masses of potentially hazardous materials and
biological analytes, and lower stored energies
The extreme compactness of LOC designs could have an added importance in developing highly
portable systems that could be used in some parts of the developing world that have a high prevalence
of diseases but very limited access to modern, reliable testing tools.
Lab-on-a-chip appoaches are currently being applied in a wide range of medical uses including:
- the measurement of a wide range of biomolecules in blood and other body fluids immunoassays - the
detection of bacteria, viruses and cancers DNA testing
Some new lab-on-a-chip approaches incorporating nanotechnology
During the late 1980s and 1990s, developments in microfluidics and techniques like photolithography,
driven also by initiatives such as the human genome project and the emerging need for early detection
systems for hazards such as chemical and biological warfare agents, led to features being developed
at smaller and smaller scales in lab-on-a-chip applications. In parallel with developments elsewhere,
e.g. computer chip design, nanotechnology is now also being applied to LOCs bringing new
functionalities due to the novel characteristics of materials at the nanoscale. These developments
include:
- nanopores, e.g. of 1-2 nm diameter, for electrophoretic DNA sequencing - other nanoscale surface
features or scaffolds, e.g. to faciliate the behaviour of fluids or to promote the immobilisation adhesion
and growth of cells in integrated microbioreactors (-bioreactors) or cell arrays on a cell chip for
protein studies and cell-membrane ion-channel studies.
Such -bioreactors or cell arrays will normally also include microfluidic systems designed to deliver
nutrients and remove waste products to keep such cells in optimal conditions.
One current example of a cell array under development (CEA Grenoble: ToxDrop Project) utilises a
system with a glass surface containing hydrophilic and hydrophobic areas and 800 drops per slide,

each drop containing 100 cells of different types that may be cultured for up to 5 days . Up to 50
parameters can be measured individually for each cell and the system is ultimately expected to be
used for high throughput toxicity testing.
- superhydrophobic surfaces, e.g. to facilitate the movement, separation and mixing of tiny aqueous
droplets and samples, e.g. by using magnetofluidics - nanoscale actuators, e.g. for valves, mixing or
switches - nanowire, e.g. silicon or polymer, and carbon nanotube based biosensors - other new
biosensor technologies, e.g. those based on protein nanoimprinting and nanopatterning, direct affinity
sensing, resonating beam sensing, surface plasmon sensing and ion-channel sensing - micro- or
nano-fluidic systems that can model some of the physiological conditions or stresses that cells are
subjected to in-vivo, or which can facilitate cell-to-cell signalling interactions - novel detection systems
based on field-effect sensors, electrical conductance, electrochemistry, magnetic fields, optical output
(e.g. fluorescence, quantum dots) or acoustic signals, e.g. using piezoelectrics
The large variety of parameters that can be measured using different detection systems, and the large
quantity of data that can arise from the individual assays undertaken on a LOC, also necessitate the
development and integration of powerful bioinformatics tools, including adaptive and smart software
into LOC-based systems.
While there is much progress in developing smaller, more highly integrated and more efficient LOC
systems there are still many challenges to be overcome. As one approaches the nanoscale, physical
and chemical effects change and become more complex. Some features cannot yet be scaled down
and there are size limits below which cells cannot interact effectively which means designing new
systems that can model, for example, metabolic processes in the mitochondria or other sub-cellular
organelles.
The future evolution of lab-on-a-chip technologies
The further development of LOC technology brings closer the possibility of developing systems that
can be implanted into the body and that can sample and measure physiological and metabolic
parameters in-vivo in real time, allowing doctors to continually monitor patients and track the
progression of diseases and conditions, possibly with direct feedback to drug delivery systems or other
implanted devices.
A further aim is the development of systems that are increasingly simple to use without specialist
training and which can carry out a variety of accurate analyses very quickly using tiny samples, e.g. in
emergency or field situations, or at home, e.g. smart and more patient-friendly diabetes monitoring
devices. Other integrated systems capable of detecting down to single important marker biomolecules,
individual bacteria or viral particles are also under development
The development of LOC systems based on human cells, possibly the patients own cells or even
differentiated tissues in some cases, promises to contribute to the development of higher-throughput,
more predictive and cheaper alternatives to animal test models for pharmaceutical development,
screening and testing and in toxicity studies, e.g. those required under the amended Cosmetics
Directive and the REACH Regulation of chemicals.

Richard Moore is Manager of Nanomedicine and Life Sciences at the Institute of Nanotechnology.
Source: NANO Magazine - Issue 7 /...