CRITICAL REVIEW
org/loc | Lab on a Chip
Lab-on-a-chip devices for global health: Past studies and future
opportunities
Curtis D. Chin,a Vincent Linderb and Samuel K. Sia*a
Received 8th August 2006, Accepted 10th October 2006
First published as an Advance Article on the web 27th October 2006
DOI: 10.1039/b611455e
A rapidly emerging field in lab-on-a-chip (LOC) research is the development of devices to
improve the health of people in developing countries. In this review, we identify diseases
that are most in need of new health technologies, discuss special design criteria for LOC
devices to be deployed in a variety of resource-poor settings, and review past research into
LOC devices for global health. We focus mainly on diagnostics, the nearest-term application
in this field.
1. Introduction
Lab-on-a-chip (LOC) technologies have a tremendous but
unproven potential to improve the health of people in
developing countries. Ever since the modern inception of
LOC and microfluidic technologies around 1990, use in remote
settings has been perceived as potentially one of the most
powerful applications of the technology by taking advantage
of its small size, low volume requirement for samples, and rapid
analysis. Indeed, portable LOC devices are now beginning to
be used in remote settings, as a result of developments in
integrating fluid actuation, sample pre-treatment, sample
separation, signal amplification, and signal detection into
a single device. As they stand, these devices are not yet
appropriate for use in the extreme resource-poor settings of
developing countries; nevertheless, these advances place the
field of LOC research in a prime position to tackle the
a fulfilling these priorities by automating complex diagnostic
Department of Biomedical Engineering, Columbia University, 351
Engineering Terrace, 1210 Amsterdam Avenue, New York, NY 10027,
USA. E-mail: ss2735@columbia.edu
b
SAMLAB, Institute of Microtechnology, University of Neuchâtel, Rue
Jaquet-Droz 1, P. O. Box 526, CH-2002 Neuchâtel, Switzerland
Curtis Chin is a PhD student in the Department of Biomedical
Engineering at Columbia University. He obtained his BS in
Chemical Engineering from the Massachusetts Institute of
Technology.
Vincent Linder, PhD, is a research scientist at the University of
Neuchatel and Claros Diagnostics. He holds a MSc in
Chemistry and a PhD in Sciences from the University of
Neuchâtel (Switzerland), where he worked on microfluidic
technology for immunoassays. He completed his postdoctoral
work in the Department of Chemistry at Harvard University.
Samuel Sia, PhD, is an Assistant Professor of Biomedical
Engineering at Columbia University. He holds a BS in
Biochemistry from the University of Alberta (Canada), and a
PhD in Biophysics from Harvard University. He completed his
postdoctoral work in the Department of Chemistry at Harvard
University.
This journal is ß The Royal Society of Chemistry 2007
www.rsc.
profound issue of global health, where the challenges in device
designs are arguably the most demanding, and the need for
new health technologies the greatest.
There is an urgent need in developing countries for new
health-related technologies, and specifically, new technologies
for health diagnostics. For example, in one survey of
international scientists familiar with the public health pro-
grams of developing countries, Singer and colleagues found
that the top-ranking overall priority was ‘‘modified molecular
technologies for affordable, simple diagnosis of infectious
diseases’’.1 Similarly, in a study by the Bill and Melinda Gates
Foundation and the NIH to identify ‘Grand Challenges for
Global Health’, two of the 14 priorities involved diagnosis
and measurement of patients’ health statuses (i.e. ‘‘develop
technologies that allow assessment of individuals for multiple
conditions or pathogens at point-of-care’’, and ‘‘develop
technologies that permit quantitative assessment of population
health status’’).2 LOC research holds substantial potential for
procedures that are normally performed in a centralized
laboratory into a hand-held microfluidic chip; this capability
could empower health-care workers and patients with impor-
tant health-related information in even the most remote
settings. To this effect, funding by philanthropic foundations
(such as those from Doris Duke, Soros, and Gates) are leading
the development of microfluidics technologies for diagnostics
in developing countries. The broad aim of these scientific
initiatives is to combine new diagnostic and prevention
methods with treatment to improve public health,3 which is
in turn linked closely to the macroeconomic health of a
nation.4
In this review, we aim to aid interested scientists and
engineers by systematically reviewing the fledgling field of
LOC devices for global health. We will focus mainly on
diagnostics, the nearest-term application of LOC devices,
although we will also discuss other applications. We will first
identify the most critical health conditions and diseases that
are in need of new diagnostic methods, with an emphasis on
those in need of new LOC diagnostic devices (Section 2). In
subsequent sections, we will discuss the special design criteria
that are needed for LOC devices to be deployed in developing
Lab Chip, 2007, 7, 41–57 | 41
countries (Section 3), and provide a review of past and current
studies on LOC devices for global health, as well as examples
of LOC devices that have not been—but could be—applied to
these settings (Section 4). We will conclude with a summary
and future directions (Section 5). Throughout the review, we
will identify examples of past research, current promising
technologies, and future challenges and opportunities.
2. Current need for diagnostic devices in developing
countries
In developed and developing countries alike, early and
accurate diagnosis is important for the health of individual
patients as well as that of the general public: it permits prompt
and proper treatment of patients, limits the spread of disease in
the population, and minimizes the waste of public resources on
ineffective treatments.1 In developing countries, the value of
diagnosis for certain diseases is sometimes mitigated by the
lack of available treatment (for example, in cases of certain
neglected tropical diseases). On the whole, however, the value
of diagnosis is very high in developing countries: early
diagnosis, although not without logistical hurdles, can often
lead to some kind of treatment (either directly against the
condition or at worst palliative care), and investments in
diagnostics and prevention can be more cost-effective than
treatment.5 Moreover, point-of-care devices can improve the
epidemiological surveillance of diseases,6 which is an especially
challenging problem in developing countries.
For scientists and engineers who aim to design new
diagnostic technologies, a crucial question for achieving real-
world impact is which health conditions in developing
countries are most in need of diagnostic devices. In a study
led by Murray and Lopez, the World Health Organization
conducted an unprecedented and comprehensive initiative
to compile statistics for comparing the relative burden of
diseases, conditions, injuries, and risk factors on a global
scale.7–9 In Table 1, we list the most common diseases by
disability-adjusted life years (DALYs) in developing countries,
a metric that accounts for years of life lost due to premature
mortality as well as disability (in order to properly account for
the impact of conditions that cause significant ill health but
few direct deaths, such as neuropsychiatric conditions9,10).
As expected,10 infectious diseases constitute a large burden
of disease in developing countries (32.1%; by comparison, they
represent only 3.7% of total DALYs in developed countries).
The trifecta of HIV/AIDS, malaria, and tuberculosis (TB),
which has merited a dedicated focus from the international
community (most notably the Global Fund, which has thus far
committed $5.5 billion, www.theglobalfund.org), constitutes
an important 12% of DALYs in developing countries. The
social impact of these diseases stretches beyond the DALY
statistics, however, since HIV/AIDS (along with common
coinfections of TB) targets healthy adults, thereby leaving
behind villages of orphans which destroy the underlying
fabric of entire communities. Other infectious diseases are
also important. Most significantly, lower respiratory infections
and diarrheal diseases (such as rotavirus and cholera)
impose large burdens; these diseases are also the biggest
killers of children,10 even more so than vaccine-treatable
42 | Lab Chip, 2007, 7, 41–57
childhood-cluster diseases (such as diphtheria, measles,
pertussis, and tetanus). Another important category of infec-
tious diseases is neglected tropical diseases (which includes
lymphatic filiariasis, dengue, Chagas disease, leishmaniasis,
onchocerciasis, schistosomiasis, trypanosomiasis, trachoma,
and guinea worm), which cause 500 000 deaths annually.
Although they do not contribute as significantly as some other
infectious diseases by the measure of DALYs in the Global
Burden of Disease report, the real burden of disease is likely to
be higher than these estimates, with up to 90% of the burden
concentrated in sub-Saharan Africa (for example, there are
200 million cases of hookworm infections in Africa alone).11
Current methods for diagnosing neglected diseases are
cumbersome, invasive, and largely inadequate (e.g. for human
African typanosomiasis and visceral leishmaniasis, see ref. 12),
a consequence of the low priority given to neglected diseases
for research funding (as pointed out poignantly by studies such
as the 10/90 Report on Health Research, www.globalforum-
health.org, and ref. 13). In one analysis to define priorities for
diagnostics development, Mabey and colleagues charted the
need versus feasibility for selected diseases (including many
neglected diseases), with the conclusion that African trypano-
somiasis, visceral leishmaniasis, and TB are three of the tests
most in need of development.14 Other important diseases
include sexually-transmitted infections other than HIV/AIDS
(such as hepatitis B and C, chlamydia, gonorrhea, and
syphilis), some of which (most notably, hepatitis B and C,
and HIV) are bloodborne pathogens that can also be
transmitted by contaminated needles as well as contaminated
blood supply for transfusions.15
Like infectious diseases, the burden of non-communicable
diseases is significant (at 43.5% DALY, it even exceeds that of
infectious diseases by a large margin) (Table 1); unlike
infectious diseases, the burden of non-communicable diseases
in developing countries is often underappreciated.16 The
specific list of important non-communicable diseases is
familiar to readers from Western countries: cardiovascular
disease (such as ischaemic heart disease and stroke), cancer,
neuropsychiatric conditions (such as unipolar depressive
disorder), and respiratory diseases (such as chronic obstructive
pulmonary disorder and asthma). As the standard of living in
developing countries improves and average life span increases,
the burden of disease will gradually shift to the non-
communicable diseases; this shift is exacerbated by changes
in diet (towards saturated fats and sugars) and high tobacco
use.16 Already, obesity and diabetes are increasingly prevalent
in developing countries.17 Even for children in developing
countries, asthma, epilepsy, dental caries, diabetes, rheumatic
heart disease, and injuries are becoming increasingly promi-
nent contributors to morbidity.18 As these trends develop,
accessibility of the corresponding diagnostic technologies in
developing countries cannot be assumed from their likely
availability in Western countries, due to the special constraints
of resource-poor settings (see Section 3).
Maternal, perinatal and nutritional diseases contribute a
significant fraction of DALYs (11.8%) in developing
countries (Table 1). Two important risk factors for material
diseases include anemia and vitamin A deficiency;10 although
treatment is the most important consideration for these two
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micronutrient deficiencies, diagnosis can lead to improved
epidemiological surveillance. Overall, malnutrition is the single
most important cause of loss in global health, with the greatest
effect felt in sub-Saharan Africa.10 To combat malnutrition in
children under five years of age, a simple bracelet made by
Medicins Sans Frontieres can be used to measure the mid
upper-arm circumference in order to diagnose the stage of
malnourishment; biochemical measurements may be useful for
more specific diagnoses (e.g. serum albumin levels for protein-
energy malnutrition).
Finally, intentional and unintentional injuries (including
war) constitute a significant DALY fraction (12.5%) that rivals

Table 1 Important diseases in developing countries, burden of disease, diagnostic assays, and corresponding potential LOC devices

% %
Diseasea DALYb Type of assayc Device Disease DALY Type of assay Device
Communicable diseases 32.1 Non-communicable diseases 43.5
Respiratory infect. 6.8 IA Sec. 4.2 Neuropsychiatric conditions 11.7 Sx/Hx/PE N/A
(lower, upper, Slide agg. w/antisera Sec. 4.2 (unipol & bipol deprs, Hormone levels Sec. 4.5
ottis media) GS and cul. of CSF Sec. 4.4 others)
HIV/AIDS 6.1 IA for a-HIV Ab Sec. 4.2 Cardiovascular diseases (isc., 9.5 ELISA of CRP, BNP Sec. 4.2
(¡ vs quant) hyp., rheum., inflamm.) Cholesterol test Sec. 4.5
RT-PCR for HIV RNA Sec. 4.3 Sense order diseases (cataracts, 4.6 Sx/Hx/PE N/A
CD4+ counts Sec. 4.4 hearing loss, glaucoma)
Diarrheal diseases 4.5 EIA Sec. 4.2 Cancer 4.2 IA of biomarkers Sec. 4.2
(rotavirus, Latex agg. assay of stool Sec. 4.2 (e.g. PSA)
cholera) RT-PCR Sec. 4.3 Gene expression Sec. 4.3
Malaria 3.4 Mic. of blood smears Sec. 4.4 Respiratory diseases (COPD, 3.5 Spirometry N/A
IC test for HRP-2, Sec. 4.2 asthma, others) Sx/Hx/PE N/A
LDH, PS Digestive diseases (liver 3.0 Complete blood count Sec. 4.4
PCR for plasmodium Sec. 4.3 cirrhosis, peptic ulcer Electrolytes, creatinine Sec. 4.5
Tuberculosis 2.5 Tuberculin skin test N/A disease) Elevated liver enzymes Sec. 4.2
Mic. and sputum culture Sec. 4.4 Congenital abnormalities 1.9 Karyotype analysis N/A
Release of IFN-c Sec. 4.2 (heart dis., DS) trisomy 21
from blood RBC count Sec. 4.5
Measles 1.6 Virus isolation Sec. 4.3 Sx/Hx/PE N/A
Monitor specific IgG titers Sec. 4.2 Musculoskeletal dis. 1.8 Differential WBC Sec. 4.4
IA for virus (MV) IgM Sec. 4.2 (osteoarthritis, ELISA rheumatoid Sec. 4.2
Pertussis 0.9 PCR of nasal secretions Sec. 4.3 rheumatoid arthritis) factor
Culture Sec. 4.4 Genitourinary dis. (neph., 1.0 Sx/Hx/PE (physician) N/A
Tetanus 0.5 Culture Sec. 4.4 bphyp.)
IA Sec. 4.2 Diabetes mellitus 1.0 Plasma/glucose test Sec. 4.5
Meningitis 0.4 CSF glucose Sec. 4.5 Insulin Sec. 4.2
CSF cell count Sec. 4.4 Endocrine disorders 0.5 Hormone levels Sec. 4.5
GS & cul. of CS Sec. 4.4 X-rays, radiological N/A
Lymphatic filariasis 0.4 ELISA Sec. 4.2 exams
IC test of W. bancrofti Sec. 4.2 Oral conditions (dental caries, 0.5 Sx/Hx/PE (dentist) N/A
Mic. blood samples Sec. 4.4 edentulism, others) X-rays, radiological N/A
midnight exams
Hepatitis B & 0.3 IA HBsAg, anti-HBs, Sec. 4.2 Skin diseases 0.3 Sx/Hx/PE (physician) N/A
hepatitis C antiHBc
IA liver enzyme, AFP Sec. 4.2 Maternal, perinatal, and 11.8
HCV detection & Sec. 4.3 nutritional conditions
genotying Perinatal cond. (LW., BA., 7.0 Sx/Hx/PE (physician) N/A
Syphilis 0.3 VDRL Sec. 4.2 trauma)
RPR Sec. 4.2 Nutritional deficiencies 2.4 IA albumin Sec. 4.2
FTA-ABS of TPHA Sec. 4.2 (protein-energy, Fe-anaemia) Cell count anemia Sec. 4.4
Chlamydia 0.3 PCR from urine dipstick Sec. 4.3 Maternal cond. (hem., 2.4 Haemotology Sec. 4.4–5
ELISA of C. trachomatis Sec. 4.2 seps., hypertens.)
antigens
NAAT, hybridization test Sec. 4.3 Injuries 12.5
Gonorrhea 0.2 Mic & cul. urethral cervical Sec. 4.4 Unintentional injuries (RA, 9.2 Analytical toxicology Sec. 4.2,5
Trachoma 0.2 Culture Sec. 4.4 falls, fires, dr.)
Antigen detection Sec. 4.2 Intentional injuries (violence, 3.3 Culture (eg. C. tetani) Sec. 4.4
IC test Sec. 4.2 SII, war) IA Sec. 4.2
Leishmaniasis 0.2 Mic. & cul. spleen, bone Sec. 4.4
marrow
Trypanosomiasis & 0.2 Agg. test for IgM, PCR Sec. 4.2–3
schistosomiasis parasite
Mic. & cul. spleen, bone Sec. 4.4
marrow
Intestinal nematode 0.2 Mic. & cul. anal swab Sec. 4.4
infect.
Japanese 0.1 IA of blood and Sec. 4.2
encephalitis spinal fluid

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Table 1 Important diseases in developing countries, burden of disease, diagnostic assays, and corresponding potential LOC devices (Continued )
a
Disease categories as grouped by Murray and Lopez,8 except maternal, perinatal, and nutritional conditions are shown as a separate
category. b The burden of disease as measured by the percentage contribution to total disability-adjusted life years (DALYs) in middle- and
low-income countries. Percentages were derived using data from WHO Global Burden of Disease 2002 revised estimates by World Bank income
groups (high, upper middle, lower middle, and low income countries)9 http://www3.who.int/whosis/
menu.cfm?path=whosis,burden,burden_estimates,burden_estimates_2002N,burden_estimates_2002N_2002Rev&language=english c Data taken
from ref. 5, 7–9, 18. Abbreviations used: immunochromatographic (IC), immunoassay (IA), enzyme-linked immunosorbent assay (ELISA),
microscopy (mic.), venereal disease research laboratory (VDRL), rapid plasma regin (RPR), fluorescent treponemal antibody-adsorption (FTA-
ABS), T. pallidum hemagglutination assay (TPHA), agglutination (agg.), culture (cul.), iodine (iod.), vitamin (vit.), gram stain (GS),
cerebrospinal (CSF), hypertension (hypertens.), iron (Fe), infections (infect.), Down syndrome (DS), disorder (dis.), ischaemic cerebrovascular
disease (isc.), rheumatory heart disease (rheum.), inflammatory heart disease (inflamm.), depression (deprs.), hepatitis B surface antigen
(HBsAg), antibody to hepatitis B surface antigen (anti-HBs), antibody to hepatitis B core antigen (anti-HBc), alpha-fetoprotein (AFP),
hepatitis C virus (HCV), C- reactive protein (CRP), prostate-specific antigen (PSA), brain naturietic peptide (BNP), hypertensive heart disease
(hyp.)., nephritis and nephrosis (neph.), benign prostatic hypertrophy (bphyp.), low weight (LW.), birth asphyxia (BA), hemorrhage (hem.),
sepsis (seps.), conditions (cond.), road accidents (RA), drownings (dr.), self-inflected injuries (SII), white blood cell (WBC), Sx/Hx/PE
(symptoms/medical history/physical exam), red blood cell (RBC).

that of other categories, and which is higher than that in
Western countries (9.1%) (Table 1). A number of behavioral
changes can be undertaken for preventing injuries in develop-
ing countries.19 From the perspective of diagnostic devices, this
burden may call for devices for detecting poisons, diagnosing
neuropsychiatric conditions (such as epilepsy) and substance
of abuse to ensure prompt treatment, and diagnosing tetanus
infections to strengthen epidemiological surveillance.
To diagnose this wide array of diseases and conditions,
assays with a variety of methodologies will be needed. The
types of assays that are currently used to diagnose them are
listed in Table 1; some assays are in great need of new
diagnostic methods, and some are not. For each diagnostic
assay, potential corresponding LOC devices are also listed.
Analysis of this table, which cross-lists diseases and techno-
logies, reveals a couple of points. (1) Similar classes of analytes
(e.g. proteins, nucleic acids) serve as useful markers for very
different diseases and conditions; hence, similar designs of
diagnostic technologies will be applicable for disparate classes
of diseases. (For example, yes/no protein markers are useful
for diagnosis of HIV/AIDS as well as indicators of coronary
heart disease). In Section 4, we will review potential LOC
technologies as grouped by analytes. (2) Multiple classes of
assay technologies are needed to produce complete diagnostic
information for groups of related diseases, and often even for
a single disease (for confirmatory testing, identification of
resistant subtypes, and/or staging of a disease). (For example,
yes/no testing for antibodies, analysis of RNA levels, and
counting of CD4+ lymphocytes are all crucial information for
diagnosing and staging HIV/AIDS.) This observation calls for
carefully considering the integration of multiple modular
technologies at the earliest design stages of LOC diagnostic
devices for developing countries.
3. Third-world design constraints
Like no other setting, the use of LOC devices in developing
countries poses a set of extremely challenging design criteria.
For maximum range of use, a LOC device would have to
perform reliably under the well-documented constraints of low
cost, absence of trained workers, lack of electricity, poorly
equipped laboratories, and transportation and storage in
unrefrigerated conditions with rough handling.14 In practice,
however, not all of these constraints apply to all settings in
developing countries. For example, in developing countries,
different design criteria apply to centralized testing in a
national laboratory, in a rural health clinic, and in a remote
setting with no infrastructure (Table 2). Similarly, there exist
subtle but important distinctions in the constraints. For ‘low
cost’, the economics of centralized testing may allow for the
purchase of a moderately priced or even expensive fixed
instrument (tens of thousands of dollars), if the cost of
disposables is kept sufficiently low. By contrast, remote point-
of-care testing requires low cost in both the fixed instrument
and the disposable (pennies). Since these considerations hold
direct pertinence to the design of the diagnostic technology, it
is beneficial to be aware of the final targeted use of the device
at the earliest design stages. For example, in the extreme points
of the landscape of resource availability in developing
countries, devices targeted for national centralized laboratories
may include currently available technologies for Western
countries (e.g. 96 well plate assays using an expensive and
bulky fluid-handling machine and detector), and devices for
point-of-care testing in rural settings will need to be designed
with all of the constraints in mind.
In the centralized laboratories of Western countries (run by
companies such as Quest Diagnostics as well as in-house
centers in hospitals) with skilled personnel, established
infrastructure, and high financial resources, sophisticated tests
such as microscopy, ELISAs, and nucleic acid amplification
tests are routinely performed (Table 2).14 Although it would be
desirable for diagnostic tests in this setting to meet criteria such
as rapid analysis to improve efficiency of operation, there exist
few constraints (compared to other settings for diagnostics)
that result from low capital or poor infrastructure.
In developing countries, there exist a small number of
privately funded centralized testing centers that have essen-
tially the same infrastructure and resources as the testing
centers in Western countries (Table 2). By contrast, in most
centralized testing centers of developing countries, cost (due to
limited budgets via public financing) and availability of skilled
workers (due to attrition of the best workers) are still limited
compared to the centers of Western countries. Thus, the cost
of the microfluidic device (which includes both the material
and the manufacturing process) must be kept low in most
settings in developing countries. Moreover, for remote point-
of-care testing in developing countries, the fixed instrument
must be portable and cheap, and the disposable must be

44 | Lab Chip, 2007, 7, 41–57 This journal is ß The Royal Society of Chemistry 2007
 Table 2 LOC design constraints in different settingsa

Low- &
Low- & middle- Low- &
High- middle- High- income middle- Low- &
income income income countries income middle-
countries countries countries national/ countries income
national centralized Extra- point-of- regional rural countries
testing lab terrestrial care testing health remote
Constraint on design criteria centerb (private)c Military sensors (POC) centerd clinice POCf

Absence of ground electricity U U I I U U S I

This journal is ß The Royal Society of Chemistry 2007

Low cost of fixed instrument U U U U U S I I
Low cost of disposables U U U U S I I I
Absence of trained end-users U U S N/A I S S I
Absence of equipped end-use U U I I I S I I
facilities
Rapid Analysis U U I S I U I I
High sensitivity & specificity I I I I I I I I
Large fluctuations in U S I I I S I I
temperature
Portability U U I I I S I I
Rough handling U S I I S S I I
a
I = important, S = somewhat important, U = unimportant. b In a typical in-house hospital laboratory in Western countries, for example, costs of reagents are $5 for immunoassays, and $5–$30
for nucleic acid tests.138 Reimbursement rates are typically $20–$50 per test for immunoassays, and $50–$300 for nucleic acid tests. Fixed instruments (such as liquid handling robots and detectors)
can cost hundreds of thousands of dollars, although they can be leased or borrowed using reagent-rental agreements. Typically, turnaround times for most tests of between 0.5 and 2 days (from
the time it is ordered to the time the result is provided to the physician). Excluding sample transportation to the lab, turnaround time for emergency testing is about 1 h. Most reagents are stored
in the fridge until time of use. c This heading describes centralized testing centers that are funded by private organizations (e.g. philanthropies, NGO). These testing centers are typically located in
urban locations, and can be as well-equipped as testing centers in Western countries. An example is the MTCT-Plus Initiative that funded two clinical laboratories in Maputo and Nampula to
provide diagnostics services for supporting HIV programs in Mozambique. d Centralized testing centers in national or regional health centers are typically funded by the government, and are
responsible for many of the tests in the country. The quality of these health centers vary substantially, depending on the investment of the government into public health infrastructure.4 For
example, a cell-counting instrument (about $20 000) would be among the most expensive instruments, with typical equipment including a spectrophotometer, a microscope and a centrifuge costing
$1000 to $2000 each. e Rural towns often have a local health clinic or a hospital, with a wide range of conditions. Often, their clinical laboratories are run by poorly trained workers, are poorly
equipped, and have intermittent or no ground electricity. One such laboratory would be equipped, for instance with a centrifuge (manual or electric), a microscope (for counts of cells like platelets
or total WBC, the diagnosis of TB using colorations and the direct observation of stool), semi-quantitative strip tests for clinical chemistry applications (i.e., pH and sugar in urines), agglutination
tests for HIV, and the reagents for basic tests like blood type compatibility on glass slides. f These tests can be administered anywhere in developing countries. Currently used non-LOC tests in this
category include yes/no immunochromatographic tests for malaria (i.e., a Paracheck Pf, which at a price of $1 can be limited to an emergency case for ruling out infection of Plasmodium
falciparum) or semi-quantitative strip tests for clinical chemistry. An external instrument must be light, portable, rugged, and cheap (tens of dollars or cheaper, for widespread use), with very cheap
disposable microfluidic chips (pennies). For example, optical microscopes in such settings can be only equipped with a mirror as a light source to facilitate maintenance.

Lab Chip, 2007, 7, 41–57 | 45

Fig. 1 Pictures of current LOC devices for use in remote settings. (A) A handheld device, iSTAT, for measuring electrolyte levels. Taken from
www.istat.com with permission of i-STAT Corporation. (B) A portable device and a fixed instrument for analyzing DNA from the company
Cepheid. Taken from www.cepheid.com with permission of Cepheid Inc. (C) Mars Organic Analyzer, an extraterrestrial LOC device. Reprinted
from ref. 24. Copyright 2005 by the National Academy of Sciences of the United States of America, all rights reserved.

extremely cheap. All components of the device (including
the instrument and disposable) must be robust and rugged
under a variety of environmental conditions. Overall, remote
point-of-care testing in developing countries imposes perhaps
the severest constraints on the design of LOC devices, with
extremely low cost a distinguishing feature from most
applications in the Western world.
Although interest in designing LOC devices for developing
countries is only beginning, it will be beneficial to exploit the
commonalities in the settings of developing countries with
other resource-poor settings in Western countries (Table 2).
For example, one can leverage the large body of existing
research on LOC designs for point-of-care testing for
physicians’ and home use,20,21 devices for military applica-
tions22 and first responders, and extraterrestrial sensors23–25 in
designing LOC devices for developing countries (Fig. 1). In all
these settings, integration, portability, low power consump-
tion, automation, and ruggedness are important qualities.
These general design constraints suggest some LOC com-
ponents and procedures to be more appropriate than others
in resource-poor settings. In Fig. 2, we outline a sample of
appropriate LOC technologies for use in developing countries.
In general, the differences in appropriate LOC technologies are
pronounced between centralized testing versus point of care,
with cost being the distinguishing feature between technologies
for use in high-income versus low-income countries.
Material and manufacturing
To minimize the cost of the microfluidic device, it is important
to reduce the footprint of expensive components such as glass
($500–4000 m22),26 quartz, and silicon (a number of challen-
ging issues exist in the scale-up of silicon micromachining for
biological devices27). An alternative is to use plastics, which
are inexpensive (the manufacturing cost of an injection-
moulded device is generally less than $0.3028), available in an
abundant choice of materials, and appropriate for single-use
disposal to avoid cross-contamination. Challenges in plastic
include minimization of batch-to-batch variation, improve-
ment in chemical resistance, improvement in control over
surface chemistry, and compatibility with fluorescence.26,29,30
Additional steps for processing the microfluidic chip (such as

Fig. 2 A range of appropriate LOC procedures for different settings.

46 | Lab Chip, 2007, 7, 41–57 This journal is ß The Royal Society of Chemistry 2007
pre-treatment of surfaces with capture reagents) should be
simple and scalable to minimize the cost of the manufacturing
process.
Storage and transportation
Unlike controlled research environments, the LOC device
will be subjected to a variety of environmental conditions.
Reagents, including those stored inside the microfluidic chip,
must be stable to fluctuations in temperature as well as
physical shocks. Methods for stabilizing dry reagents (such as
trehalose,31 a chemical that has been used to stabilizing dried
proteins in conventional 96 well ELISA assays) and wet
reagents32,33 will be needed.
Sample pre-treatment
A number of sources of physiological fluids are available.
Although whole blood (from venipuncture or finger prick)
and its derivatives (plasma and serum) are most common,
the use of non-invasive samples such as saliva34 and urine35 are
gaining prominence. For real-world samples, sample pre-
treatment before the analysis step is needed. Pre-treatment
steps include sampling, extraction, filtration, pre-concentra-
tion, and dilution;36 a centrifugation or filtration step is
necessary, for example, to obtain plasma or serum from whole
blood. In a centralized laboratory, these steps can be
performed by a technician or a liquid handling robot before
injection into the microfluidic chip. In remote settings,
however, automation and integration of these steps in the
LOC device is ideal.37–43 To minimize cost and power
consumption, passive methods may be most appropriate.
Fluid actuation
An ideal LOC device for developing countries should be
capable of actuating the flow of fluids with reliable flow rates
using inexpensive and compact instrumentation. Electrokinetic
actuation of fluids is popular in research laboratories, but it
requires a charged surface for electroosmotic flow (which
limits the type of material that can be used) and a high voltage
supply. Pneumatic actuation may be most practical for
portable applications, with battery- or hand-powered vacuum
sources.44 Capillary force is a simple method for pumping
fluids in portable LOC devices.45
Fluid control
For complex assays, a series of different reagents need to be
delivered into the microfluidic chip. In centralized testing
facilities, these procedures can be performed manually by a
technician, an external liquid handling robot, or on-chip valves
that are controlled by an external instrument. For portable
automated devices, passive delivery of a series of reagents is an
attractive option.32,45–47
Mixing
Some assays will require mixing of samples with different
reagents. In such cases, active micromixers can be used if a
power supply is available.48 Passive mixers, which rely on the
This journal is ß The Royal Society of Chemistry 2007
geometry and topography of the microchannels, can also be
used to mix and dilute samples.49 In general, however,
heterogeneous assays (which include many immunoassays)
do not require mixing since the analyte is captured on the
surface.
Signal detection
An intrinsic challenge in microfluidics is detection of a signal
emanating from a small physical region; in developing
countries, this detection must be inexpensive, and ideally, use
compact instrumentation that consumes little power.
Fluorescence is a sensitive and popular detection method,
but typically requires expensive and complicated optics and
consumes significant power, whereas absorbance can be low-
cost.44,50 With simple electronic modulation, the background
in optical detection can be shielded from ambient light.44
Electrical measurements such as conductance are also poten-
tially appropriate low-cost and portable detection methods for
use in developing countries.51
Disposal
In point-of-care settings in both Western and developing
countries, it is ideal to contain the chemical reagents and
blood samples in the LOC device for disposal. Also, because
incineration is often not accessible, environmentally friendly
chemicals are preferred.
Overall strategy for development of LOC devices
More broadly, in developing a LOC device for a new setting,
scientists and engineers can take two different approaches:
adapt existing methods or design new technologies. Both
approaches have been undertaken in the past for developing
countries. Adaptation of Western-world technologies for use
in developing countries has a number of precedents in
technology-transfer projects; to be successful, these projects
must carefully take into account the local needs, culture, and
constraints.52 It is arguably more challenging (but perhaps
more scientifically rewarding) to develop new technologies
with consideration of local factors from the earliest stages of
design. Collaboration with local partners could produce a
device that best suits the health needs of the local people
(rather than a device driven by the convenience of available
technology); with the right initial testing group, this route can
succeed extremely well as a disruptive technology.53
4. Review of current work on LOC devices for global
health
4.1 Overview
Examination of diagnostic tests that are currently used in the
field in developing countries can bring insights for designing
LOC devices. Most of the current diagnostic tests used in
developing countries are simple to use and provide rapid
results.54 The most prevalent example is immunochromato-
graphic tests (also known as dipstick or lateral-flow tests),
which provide yes/no results in minutes in the form of a visible
band (these tests typically use gold colloids or latex beads
Lab Chip, 2007, 7, 41–57 | 47
conjugated to antibodies).55–57 Moreover, immunochromato-
graphic strips are cheap to produce. These strip tests, however,
are not quantitative, and are not sufficiently sensitive for the
detection of all important markers. As such, development of
strip tests for diseases in developing countries (such as
chlamydia and trachoma from Lee’s group)58 is ongoing.
LOC devices bring exciting capabilities of high analytical
performance, but they must be made cost-effective, among
other important requirements (Table 2). Also, LOC devices
can also potentially be used for multiplexed and parallel
analysis of many relevant markers at once; this capability,
however, is challenging since different analytes typically call
for the designs of different LOC methods. Below, we review
LOC studies that have been applied (or have the potential to
be applied) for use in developing countries, as grouped by the
class of analytes.
4.2 Proteins
A wide range of diseases is characterized by changes in protein
concentrations in a patient’s physiological fluids. These
diseases span viral infections (e.g. anti-HIV antibodies as a
marker for HIV/AIDS), bacterial infections (e.g. enterotoxin B
as a marker for Staphylococcus aureus), parasitic infections
(e.g. histidine-rich protein 2 as a marker for malaria), and
non-communicable diseases (e.g. PSA as a marker for prostate
cancer) (Table 1). Immunoassays are routinely used, with
high sensitivity and specificity, to detect and quantitate
protein markers. The most commonly used samples from
the patient are whole blood, serum, and plasma, with less
common samples being saliva, urine, feces, sperm, tears and
sweat. In developing countries, the use of fluids that can be
sampled non-invasively can encourage adoption of tests and
decrease the incidence of infection due to contaminated
needles. For example, saliva and urine offer a simple and safe
alternative to blood sampling, but they typically contain
lower concentrations of protein makers than in blood;
successful detection will necessitate an improved sensitivity in
the LOC device. As an example, a LOC immunoassay
developed by McDevitt and colleagues to measure levels of
C-reactive protein in saliva required a 1000-fold improvement
in sensitivity over ELISA in microtiter plates (by using porous
beads to increase the surface density of capture probe on the
solid phase).59 Microfluidic chips to detect enteric antigens
from human stool, a complex sample matrix, are being
developed.60
Enzyme immunoassays, which comprise most protein tests,
typically require the established infrastructure of centralized
testing facilities to accomplish complex reagent handling and
optical detection. LOC devices have the potential to transpose
antigen–antibody assays into assay formats that are much less
demanding in infrastructure. At least two important hurdles
exist in the processes of miniaturization and automation:
storage of multiple reagents and fluid handling capability to
carry out the complex protein assay, and detection of the
signal in the microfluidic system. Below, we review approaches
that have addressed these challenges using inexpensive and
portable solutions that are, or have the potential to be,
compatible with use in resource-poor settings.
48 | Lab Chip, 2007, 7, 41–57
(1) Fluid actuation. Capillary force is a simple method for
pumping fluids in a LOC device, because the liquid flows
spontaneously with no external power or moving parts.
Delamarche and co-workers demonstrated autonomous
capillary flow in an array of microchannels to carry out an
immunoassay for C-reactive protein.45 The sensitivity was
increased by integrating Pelletier elements underneath the
LOC device to tune the rate of evaporation and hence capillary
flow.47 As an alternative to capillary force, pressure or vacuum
can be generated by applying a finger on the surface of a LOC
device, as illustrated by an assay for botulinum toxin
developed by Beebe and co-workers,33 or the commercially
available ABO Card from the company Micronics. A hand-
operated vacuum pump can also be used to actuate fluid flow
in the field.32,44
(2) Mixing and fluid control. Besides pumping, fluid mixing
is often required in protein assays. In resource poor-setting,
passive mixers offer the advantages of intrinsic automation
(no user intervention) and the absence of power requirements.
Planar mixers based on chaotic mixing with staggered
herringbones,61 creation of bubbles,62 in situ photopoly-
merized porous material,42 three-dimensional microchannels,41
design of curved channel geometries,63 and other methods48
have demonstrated efficient mixing capabilities. Whitesides
and colleagues created a device based on splitting and re-
mixing to dilute a sample over a range of 210 (or y1000-fold),
thus circumventing off-chip pipetting steps.49 Also,
Delamarche and colleagues developed a micromosaic immuno-
assay that significantly reduced the number of pipetting steps
required for a multiplexed assay;64 this method was used to
develop a panel test for cardiac markers (C-reactive protein,
myoglobin, and cardiac troponin I).65
We and Whitesides reported a simple and reliable technique
for storing and delivering a sequence of reagents to a
microfluidic device to carry out automated immunoassays32
(Fig. 3A). In this method, cartridges made of commercially
available tubing were filled by sequentially injecting plugs
of reagents separated by air spacers (which prevented the
reagents from mixing with each other); in this form, the
reagents were stable to shocks, and antibody solutions could
be stored for months without loss in activity. By applying
negative pressure at the outlet, all reagents were dispensed
sequentially, and a solid-phase immunoassay could be
completed in 2 minutes with low nM sensitivity. Another
attractive method for passive fluid control and delivery is
the autonomous capillary system,45,47 although this
method currently requires a multi-step fabrication process.
In contrast to passive delivery, active valves can also be
used to deliver a complex series of pre-stored reagents.
The groups of Beebe33 and Whitesides66 have developed
inexpensive, hand-operated valving systems for point-of-care
immunoassays. For long-term storage at high temperatures,
storage of the reagents in a dry form may be more stable than
as wet liquids. Yager and colleagues demonstrated that
enzymes could be stored dry in LOC devices in mixtures of
dextran and trehalose.67
All common fluid handling steps required for protein assays,
including actuation and control of fluid flow, have been
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Fig. 3 Simple and low-cost LOC methods for detecting proteins in developing countries. (A) Optical detection of proteins and reagent storage and
delivery. (i) Schematic representation of the POCKET immunoassay powered by a 9 V battery. (ii) Actual device. (iii) Apparent silver absorbance
values of anti-HIV-1 antibodies from HIV-positive patients and control patients. (iv) Schematic representation of reagent-loaded cartridges. (v)
Overlay of fluorescence and brightfield images of the immunoreaction area, with fluorescent signal corresponding to presence of labeled detection
antibodies on antigen stripes. The concentrations indicated above the picture refer to the concentration of sample tested in each microchannel.
Reprinted from ref. 32 with permission from ACS Publications. (B) Immunomagnetic separation and detection of proteins with CMOS Hall
sensors. (i) Schematic representation with inset showing actual chip. (ii) Comparison of the outputs of CMOS chip and ELISA. Reprinted from
ref. 78 with permission from Elsevier.

demonstrated on centrifugal microfluidic devices.68,69 For
example, the Bioaffy chip from the company Gyros can
quantify clinical markers such as a-fetoprotein, interleukin-6
and carcinoembryonic antigen down to low pM concentra-
tions.70 Also, Bernard and colleagues used a common
compact-disc player as a digital detector of silver-based signals
of C-reactive protein in immunoassays;71 the simplicity of this
overall format makes it attractive for use in resource-poor
settings.72
(3) Signal detection. Silver dots produced by autometallo-
graphic precipitation are also directly detectable by optical
density measurements, as illustrated by the microfluidic
POCKET assay as developed by ourselves and Whitesides
and co-workers,44 as well as by Mirkin and colleagues using a
scanometric reader.50 Since amplification resulted in a signal
that was immobilized on a surface, the POCKET assay
avoided washing away optically active and freely diffusible
products that would be generated in a continuous-flow format
for ELISA (Fig. 3A). Importantly for use in developing
countries, since the silver signal developed over an area of
2 6 2 mm2, an inexpensive custom-built detector (for less than
$45 in components, including a laser diode and a photo-
detector) can be used to detect the signal, thereby circumvent-
ing the need for expensive optical instrumentation for
detecting signals confined to small microchannels.
For high-sensitivity assays, Mirkin and co-workers have
reported an assay based on DNA-coated nanoparticles,
magnetic separation, and PCR to detect protein markers at
up to 6 orders of magnitude in improvement in the limit of
detection compared to conventional assays.73 This format
can in principle be adapted to a low-cost LOC device. High-
sensitivity and quantitative assays can greatly benefit certain
applications, including the measurement of levels of HIV-1
p24, a viral protein antigen which has been advocated as a
potential simpler alternative to viral load or CD4 counting for

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Fig. 4 LOC methods for detecting nucleic acids that can be adapted for use in developing countries. (A) Integrated nanolitre DNA analysis
device. (i) Schematic representation with two liquid samples and electrophoresis gel present. (ii) Optical micrograph of device. Reprinted with
permission from ref. 90. Copyright 1998 AAAS. (B) Schematic representation of oligonucleotide-conjugated nanoparticles for probing DNA
sequence arrays. Reprinted with permission from ref. 50. Copyright 2000 AAAS.
monitoring AIDS progression in HIV patients and diagnosing
HIV/AIDS in newborns.74
With appropriate amplification schemes, surface plasmon
resonance (SPR), which detects at the surface minute changes
in the index of refraction induced by the binding of molecule,
can approach the sensitivity of ELISA.75 The company Texas
Instruments Sensors & Controls (now renamed Sensata
Technologies) has developed a portable SPR sensor (named
Spreeta) for heterogeneous antibody-antigen binding and
solid-phase DNA hybridization; this disposable device is
designed to be manufacturable in very large quantities.76 The
device can be integrated with a temperature-controlled
instrument that runs on a 12 V battery to detect enterotoxin
B in urine, milk, and sea water, with a sensitivity in the fM
range.77 Currently, a Spreeta evaluation module is available
at $200 per sensor (http://aigproducts.com/surface_plasmon_
resonance/spr_evaluation_module.htm). Since the gold-coated
chip could be regenerated up to 80 times before disposal, each
assay can potentially be priced below $1 in the future.77
Boser, Harris, and colleagues developed on a 2.5 6 2.5 mm2
CMOS chip an array of Hall sensors to quantify the number of
magnetic beads associated to immunocomplexes at the surface
of the sensor (Fig. 3B).78 The use of magnetic beads facilitated
removal of unbound antibodies conjugated to magnetic beads,
and produced signals at the surface that were recorded by the
Hall sensors. The average reading from 120 sensors was
sufficient to quantify dengue fever antibodies in clinical serum
samples with a good correlation compared to ELISA assays.
When combined with proper fluidic control, this method can
potentially be developed into an integrated simple and low-
cost LOC device for immunoassays.
50 | Lab Chip, 2007, 7, 41–57
4.3 Nucleic acids
Analysis of nucleic acids offers powerful diagnostic informa-
tion that complement protein analysis of antigens and
antibodies. For example, by analyzing conserved DNA or
viral RNA sequences, PCR and RT-PCR can be used to
specifically detect infectious diseases important in developing
countries (such as HIV/AIDS, hepatitis B and C, and TB).79,80
For HIV/AIDS, quantitative measurements of RNA levels
(based on amplification of the 59-long terminal repeat) provide
information on the stage of diseases; as such, low-cost methods
for PCR have been studied for use in developing countries.81–83
As a technology, nucleic acid detection can be very sensitive
due to amplification, and specific due to the intrinsic com-
plementarity of the base-pairing interactions. Nevertheless, the
building of an integrated LOC device for detecting nucleic
acids is typically more challenging than for proteins. Overall,
there are at least three LOC design issues for nucleic acid
detection.
(1) Sample pre-treatment. A general challenge in nucleic acid
detection is the requirement of processes (such as cell sorting,
concentration, and lysis, as well as DNA extraction) to isolate
the DNA or RNA of interest from desired cells,84–86 in
contrast to protein detection in which the analyte is typically
free-floating in the blood, saliva, or urine sample. These steps
of sample pre-treatment can take place off the chip, but for use
in remote settings with untrained users, it is ideal to integrate
these steps seamlessly with the rest of the microfluidic
processing steps.87 The challenge in developing countries is
even greater since these procedures must be performed at
low cost.
This journal is ß The Royal Society of Chemistry 2007
 A number of groups have successfully integrated sample
pre-treatment with analysis.84,87 For example, Quake’s group
used valves to automate cell isolation, cell lysis, nucleic acid
purification, and analysis on the same microchip.86 Integration
of sample pre-treatment with analysis is important to achieve
ease of use, as well as to improve sensitivity by reducing
sample losses in between steps. For example, integration of
cell capture, cell lysis, mRNA purification, cDNA synthesis,
and cDNA purification has been demonstrated for a RT-PCR
microfluidic chip.88 Grodzinski and co-workers have
developed a self-contained device in plastic that integrates
sample preparation, cell capture, cell preconcentration
and purification, cell lysis, PCR, DNA hybridization, and
electrochemical detection to analyze DNA from pathogenic
bacteria.89 In addition, metering samples is important to
automate sample preparation,90 an important consideration in
remote settings.
(2) Method of signal amplification. PCR/RT-PCR.
Miniaturizing PCR on LOC devices has the potential to
reduce the cost of reagents, speed up analysis, and automate
the procedure for use in remote settings by integrating multiple
functionalities such as cell concentration and lysis, DNA
extraction, removal of PCR inhibitors, amplification of DNA,
and separation and detection of the amplified products of
interest.84 In the most straightforward adaptation of conven-
tional PCR into LOC devices, a microchamber or microwell
can be created in which the sample and PCR reaction mixture
are thermally cycled (Fig. 4A). In one of the first studies by
Burns and colleagues (which featured microfluidic channels,
mixers, heaters, temperature sensors, and fluorescence detec-
tors90), the low voltages and power suggested that hand-held
battery operation is feasible; this technology is now being
commercialized by the company HandyLab. Although
directed more for biodefense than global health, the company
Cepheid has developed a miniature analytical thermal cycling
instrument (MATCI) that consists of silicon-micromachined
reaction chambers with integrated heaters, optical windows,
and diode-based fluorescence detection.22,91 Although the
current size of these instruments may be too large for use in
remote testing, they may be appropriate for centralized testing
centers in developing countries. Similarly, since most LOC
devices that use well-based PCR require bulky instruments as
well as expensive and complex manufacturing, they may be
most appropriate for use in centralized testing centers.92–94 The
design of disposable micro-PCR devices on polycarbonate
plastic95 may ultimately be suitable for use in resource-poor
settings, although it currently lacks extensive integration.
In contrast to well-based LOC PCR, continuous-flow
PCR systems operate by passing a sample continuously over
regions of different temperatures. Continuous-flow systems
offer flexible design geometry (for changing the number of
amplification cycles), and fast transition times for heating and
cooling (which depend on the flow rate and kinetics for
reaching thermal equilibrium).84,96 Another design that is
potentially simple to manufacture and simple to use include
passive reactors in closed-loop designs that operate without
valves.97 An interesting novel scheme for PCR amplification
takes advantage of convective flow inside a Rayleigh–Bénard
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cavity to yield comparable performance to conventional
PCR;98 because this system requires only a single heating
element held at a fixed temperature, it can potentially be made
low cost, although design challenges exist in adapting the
system to a LOC device.84
Isothermal. The need for temperature cycling in PCR has
made it challenging to build low-cost and simple devices
suitable for point-of-care testing. An exciting development that
bypasses thermocycling is isothermal DNA amplification,
which includes techniques such as single-strand displacement
amplification, rolling circle amplification, and ligase chain
reaction.84 Harrison and co-workers have integrated isother-
mal amplification in an electrokinetic LOC device that used
cycling probe technology to amplify a DNA sequence from
S. aureus.99 More recently, Zhang and co-workers demon-
strated loop-mediated isothermal amplification (LAMP) in a
cross-shaped microfluidic system in PMMA.100 Also,
Gulliksen and colleagues used an isothermal amplification
method in a microfluidic device made of cyclic olefin
copolymer for multiplexed detection of human papilloma
virus at-the-point-of-care application.101 In the future, other
schemes (such as helicase-dependent DNA amplification102)
may be integrated into LOC devices.
(3) Detection. The most popular method for analyzing DNA
after amplification is gel electrophoresis of fluorescently
labeled DNA. In LOC devices, DNA analysis by capillary
electrophoresis may be suitable for centralized testing centers
in which power supplies and external fluorescence detectors
are available. For remote testing, molecular beacons, which
are single-stranded oligonucleotides whose fluorescence is
dequenched upon hybridization to a target probe, are a
promising technology for use in developing countries due to
their high sensitivity and specificity.103,104 For example, they
have been used to detect pathogenic retroviruses,79 and in
LOC devices to screen for the breast cancer gene
(BRCA1).105,106 The use of molecular beacons, however, still
requires an external fluorescence detector.
A potentially low-cost and sensitive detection system for
nucleic acids that may be appropriate for resource-poor
settings is oligonucleotide-conjugated nanoparticle probes, as
demonstrated by Mirkin and others (and now commercialized
by the company Nanosphere) (Fig. 4B). Coupled with silver
reduction amplification, they can be quantitated by an
inexpensive scanometric reader,50 and potentially by a low-
cost and portable reader.44 These nanoparticles, when reduced
to form a micron-sized metallic bridge across an electrode gap,
can also result in quantifiable changes in conductivity,73 which
can in principle be measured by a low-cost and portable
conductivity meter. Other electrochemistry-based methods for
detecting DNA have been reported.107 Simple detection of
amplified nucleic acid products with a dipstick method for
resource-poor settings has been demonstrated.60,108
4.4 Cells
Analysis and counting of cells are important for diseases such
as anaemia and hematology (via erythrocyte and complete
Lab Chip, 2007, 7, 41–57 | 51
blood counts), as well as for monitoring the progression of
AIDS. Flow cytometry, the current standard for cell analysis
and counting, can measure up to 10 or more cell properties
and separate and isolate cells at rates up to 10 000 cells per
second without loss of viability.109 Since conventional flow
cytometers are bulky, expensive, and mechanically complex,
they are currently limited to well-financed centralized testing
centers.
Due mainly to the importance of counting CD4+ lympho-
cytes for monitoring the progression of AIDS, a number of
initiatives have started to support the development of an
inexpensive and compact device for cell counting for global
health. In one non-LOC method, Mwaba and colleagues used
filter papers to store dried blood samples, which were
transported to a centralized facility for ELISA testing using
anti-CD4 antibodies.110 The results of this simple technology
were encouraging but exhibited limitations in accuracy. With
support from the Gates Foundation, Imperial College London
is supporting the development of a simple, low-cost, and semi-
quantitative CD4+ lymphocyte-counting device (http://
www1.imperial.ac.uk/medicine/about/divisions/medicine/infec-
tious_diseases/cd4_initiative/) that exhibits cut-offs at 200, 350,
500 cells mm23 with 10% coefficient of variation. Perhaps
more so than simple membrane-based tests, LOC devices have
the potential to meet these targets due to their increased
versatility in design and enhanced analytical performance.
Fluid control for design of mechanism of cell sorting. There
are different methods for designing a LOC device for cell
counting, all of which require different methods for fluid
control. For example, conventional flow cytometers use a
sheath fluid to enclose a stream of cells such that the cells pass
by the detector one by one in a single file for analysis. In a
LOC device, microfluidic mechanisms such as hydrodynamic
flow switching, electrokinetic flow switching, dielectro-
phoresis, and electrowetting-assisted flow switching can be
used to focus the cells into a stream.109 Valves can
Fig. 5 A low-cost LOC device for counting CD4+ lymphocytes. (A) Schematic representation of pyramidal wells in Si. (B) Scanning electron
micrograph of single well with microbead. Reprinted from ref. 112 with permission from ACS publications. (C) Schematic representation of the
device system. (D) (Left) Transmission image of membrane flow cell showing selective capture of lymphocytes. Holes are 3 mm in diameter. (Right)
Fluorescent antibody staining of lymphocytes. (E) Results of cell counting from microchip versus flow cytometry. Reprinted from ref. 113.
52 | Lab Chip, 2007, 7, 41–57
subsequently be used to sort the cells.111 These devices,
however, have yet to be made portable and inexpensive.
A different approach to count cells takes advantage of the
relatively large size of cells (compared to the scale of
microfabrication techniques) by capturing them for analysis.
For example, in an initial study based on the capture of
microbeads, McDevitt and colleagues micromachined arrays
of pyramidal cavities on silicon wafers; these cavities housed
microspheres that produced optical changes in the presence of
analytes.112 Subsequently, Rodriguez, Walker, and colleagues
adapted this device (by adding a polycarbonate, track-etch
filter that selectively trapped lymphocytes and not red blood
cells) to capture and measure the levels of CD4+ lymphocytes
from blood samples in Botswana (Fig. 5).113 The results were
in good agreement with those obtained with a conventional
flow cytometer. This device (now being commercialized by the
company LabNow) is potentially cheaper than other available
systems for single-purpose flow cytometry114 and microbead
separation; because of the cost, bulkiness, and power
requirements of an epifluorescence microscope and a camera,
however, the current system is likely most suitable for
centralized testing centers rather than remote point-of-care
testing. Other inexpensive flow cytometric methods have been
developed, including capabilities for multiplexing.115
A third approach for capturing and counting cells is
immunomagnetic separation, which typically uses antibody-
conjugated superparamagnetic beads to isolate the cells of
interest. Tibbe and co-workers used antibody-labeled ferro-
magnetic nanoparticles to perform a differential white blood
cell count (with analysis of neutrophils, lymphocytes, mono-
cytes, and eosinophils).116 In a magnetic field, immuno-
magnetic cells are aligned in a capillary along the magnetic
field lines for fluorescent analysis. This design functions with
potentially simple fluidic control, but still requires a conven-
tional fluorescence imaging system.
Cell counting has important applications beyond the
monitoring of HIV/AIDS progression. For example,
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Fig. 6 Integrated LOC devices with potential for use in developing countries. (A) Schematic representation of LOC for detecting enteric diseases.
Reprinted from ref. 60 with permission from the International Society for Optical Engineering. (B) Picture of a plastic LOC device for point-of-care
clinical diagnostics. Reprinted from ref. 139 with permission from the Proceedings of the IEEE.
McDevitt and colleagues adapted their microbead system to
build a multifunctional LOC device for performing leukocyte
counts and measuring C-reactive protein levels, two important
indicators of coronary heart disease.117 Like the CD4+-
lymphocyte counting device, this device may be useful in
centralized testing centers in developing countries (in this case,
to address the increasing incidences of cardiovascular disease,
which constitutes 9.5% of total DALYs in developing
countries). In a different application, Chiu and colleagues
used a microfluidic device to show decreased deformability in
erythrocytes when infected with P. falciparum.118 Although
this study did not focus on a diagnostic application, it suggests
a potential route for diagnosing and monitoring malaria
infection using a LOC device. For example, in a study by
Gascoyne and colleagues in Thailand using dielectrophoresis
and field-flow fractionation, parasitized erythrocytes eluted
more quickly than normal erythrocytes.119
Another promising cell-based application of LOC devices
for global health is the miniaturization of microbiological
culture assays. Currently, conventional microbiological
techniques are used to identify drug-resistant bacterial strains;
this identification is critical for administering efficacious
therapy for TB patients. Techniques in culturing bacteria
in microfluidic chips120–122 can potentially automate this
laborious process (and other microbiological assays involving
differential cultures) even in remote settings. Devices that
culture and analyze pathogens and cells in microfluidic devices
could moreover be adapted to perform diagnostic procedures
that are conventionally microscope-based (such as blood
smears for diagnosis of malaria). Low-cost microscopy
using optofluidics, if it can be made robust, may be an
attractive technique in resource-poor settings.123 The power of
LOC technologies can potentially be augmented with genetic
and molecular biological approaches, such as Jacobs’ clever
luminometric technology for low-cost TB diagnosis using
luciferase-reporter phage124 (now commercialized by the
company Sequella).
4.5 Clinical chemistry
Currently, the most popular LOC technologies for analyzing
electrolytes are based on electrochemical detection. An active
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area of research in this field is potentiometric sensing using
ion-selective field-effect transistors (ISFET); ISFETs, however
often require a large reference electrode.27 Nevertheless,
integration of electrochemical detection and semiconductor
technologies have resulted in commercial products, such as the
iSTAT from Abbott Diagnostics.20 This device is a portable
blood analyzer that uses microfabricated thin-film electrodes
to measure levels of electrolytes (Na+, K+, Cl2, Ca2+), general
chemistries (pH, urea, glucose), blood gases (pCO2, pO2),
and hematology (hematocrit). The electrochemical detection
system includes amperometry, voltammetry, and conductance,
depending on the analyte.
Despite this important achievement, there are limitations of
MEMS devices that feature electrochemical detection. The
lack of suitable manufacturing facilities makes it expensive
and, for some devices, impractical to scale up the manufactur-
ing of the sensor. Although it is in principle possible to
leverage existing microelectronics fabrication facilities for the
manufacturing of biological and chemical sensors, there exist a
number of challenging issues, such as differences in dimensions
(below 1 mm for microelectronics and above 5 mm for sensors),
in thickness and type of gate insulator, in materials (e.g. for
conductors, Al, polysilicon, and Cu for electronics, versus
Au and Pt in sensors), and in the passivation layer (e.g. high-
density silicon nitride for sensors that are exposed to
solutions).27,125,126 Although their current design still relied
on a bulky instrument for fluid actuation and detection,
Madou, Bachas and colleagues developed a LOC device that
measured electrolyte levels optically using optodes;127 in the
future, it may be possible to design a low-cost, integrated,
optical device for electrolyte measurements.128
4.6 Non-diagnostics applications of LOC devices in developing
countries
Although health diagnostics is the nearest-term application of
LOC devices in developing countries, other important areas of
global health can benefit in the future from this technology.
For example, LOC diagnostic devices can be used for
environmental sensing and monitoring.60 Sandia Labs, for
example, is developing a portable device to monitor water
quality by detecting pathogenic bacteria and toxins.129
Lab Chip, 2007, 7, 41–57 | 53
Table 3 Sample list of current commercial ventures that have the potential to develop LOC devices for developing countries
Company Website Focus Funding source

Cepheid http://www.cepheid.com/ DNA (TB) FIND, US gov.

Claros Diagnostics http://www.clarosdx.com/ Proteins Private
HandyLab http://www.handylab.com/ DNA, proteins NIST, private
iStat http://www.istat.com/ Clinical chemistry markers Private
LabNow http://www.labnow.com/ CD4 for HIV/AIDS George Soros, private
Micronics http://www.micronics.net/ Enteric disease pathogens PATH, University of Washington,
NIH, Gates Foundation
Nanogen http://www.nanogen.com/ Cardiac biomarkers, DNA/RNA Private
Nanosphere http://www.nanosphere-inc.com/ DNA, proteins NIAID, NIH, private
Sensata http://www.sensata.com/ Proteins, viruses, bacteria Private
Sequella http://www.sequella.com/ Proteins (TB) Private

In addition to diagnostics and sensors, LOC technologies
can be used to promote the development of therapeutic
compounds. The use of LOC technologies (through high-
throughput drug screening, genomics, and proteomics) for
drug discovery has been reviewed in detail elsewhere;130 as
research into drug discovery for neglected diseases increases
(in universities and industrial companies such as the Novartis
Institute for Tropical Diseases), LOC technologies can play
an increasingly important role. More broadly, Singer and
colleagues have investigated the potential contribution of
biotechnology, genomics, and nanotechnology to address
issues in global health and development;1,131,132 LOC techno-
logy has a clear potential to address these issues through its
close association with all these research fields.
Even when drugs (and vaccines) are available, simple
needle-free delivery into the patient is an important challenge
in developing countries.2 Current approaches for improving
drug delivery in developing countries include inhalation and
oral delivery, and are a focus of a non-profit organization
(Medicine in Need) based on the work of Edwards et al.133
Langer and colleagues have developed LOC devices for
programmed time-release of drugs.134,135 In the long term,
these technologies can conceivably be combined with other
miniaturized medical devices (such as wireless capsule endo-
scope) for use in health centers without large infrastructure.
5 Conclusion
There is a pressing need for new health technologies for
diagnosing and treating communicable and non-communic-
able diseases in developing countries. The LOC field is well-
positioned to contribute to this challenge by leveraging recent
advances in integrated devices for use in settings with low or
moderate resources (such as point-of-care health testing,
military sensors, and extraterrestrial devices), and through
advances in the young but growing field of LOC devices for
developing countries.
What will be the roadmap in the near future for designing
and deploying LOC devices in developing countries? First and
foremost, new devices will be needed (Fig. 6); the design
criteria of these devices are vast, demanding, and context-
dependent, and they will need to be considered carefully
from the early stages of development. Beyond the scientific
challenges, successful deployment of the device in developing
countries will involve a complex interplay of political and
socioeconomic considerations.136 Scientists will therefore need
to work closely with members from NGOs and local
governments as early as possible (and well before a field-
testable device is ready) to ensure proper distribution channels
(Table 4 and Table 5). Since much of the work in engineering
and development will best take place in the industrial rather
than academic setting, the private sector has a significant role
to play as well (Table 3). As an example of the importance of
such multidisciplinary efforts, the Bill and Melinda Gates
Foundation is supporting a consortium of academic
researchers (Yager and co-workers), industry (Micronics,
Nanogen, and Invetech), and an NGO (PATH) to develop a
multifunctional LOC device for infectious diseases137 (Fig. 6A),
and another consortium of academic researchers (Kelso and
co-workers) and industry (Abbott and Inverness Medical
Innovations) to develop a low-cost diagnostic device.
Finally, potential obstacles can be anticipated from studies
on the introduction and dissemination of LOC devices in
developed countries; these obstacles include cost per test
and reliability (see the market study FlowMap, available at
http://www.microfluidics-roadmap.com/).

Table 4 Sample list of NGOs focusing on the development of new diagnostics for global health
NGOs Website Focus Year Founded

FIND http://www.finddiagnostics.org/ TB 2003

PATH http://www.path.org/ Diarrheal diseases, malaria, STIs, 1977
AIDS, and cervical cancer
Tuberculosis Diagnostics Initiative http://www.who.int/tdr/diseases/tb/tbdi.htm TB 1996
WHO Malaria Rapid Diagnostics Tests http://www.wpro.who.int/sites/rdt Malaria 2005
WHO Sexually Transmitted Diseases http://www.who.int/std_diagnostics/ Chlamydia, gonorrhea, syphilis 2001
Diagnostic Initiative
WHO/TDR http://www.who.int/tdr/ TB, AIDS, malaria, STIsa 1975
a
Abbreviation: sexually transmitted infections (STIs).

54 | Lab Chip, 2007, 7, 41–57 This journal is ß The Royal Society of Chemistry 2007
Table 5 Sample list of organizations that sell or provide low-cost diagnostic instruments to developing countries
Organization Website
Binax, Inc. http://www.binax.com/
Gede Foundation http://www.gedefoundation.org/
Human GmbH http://www.human.de/
Partec http://www.partec.de/
Sustainable Sciences http://www.ssilink.org/
Initiative
a
Abbreviation: immunochromatographic tests (ICTs).
In the long term, miniaturization of medical technologies
has the potential to improve public health, and perhaps even
change the basic methods by which patients are diagnosed and
treated, in developing countries. This pathway has a well-
known precedent in information and communication tech-
nologies. Over the last 10 years in developing countries,
adoption of cell phones and wireless internet has resulted in
‘leapfrogging’ over conventional communication technologies
(such as landlines) that require significant infrastructure.52 In
the next 10 years, will LOC methods follow a similar path, by
promoting in developing countries a leapfrog over conven-
tional medical technologies (such as radiology, microbiological
culture, and centralized testing centers)?
Acknowledgements
We acknowledge Roberto Delatour from Medecins Sans
Frontieres and George Whitesides for helpful discussions,
Benjamin Wang for help on the figures, and Andreas Martinez
for help in compiling Table 1. This work was supported by an
Early Career Award from the Wallace H. Coulter Foundation.
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