Biosensors and Bioelectronics 20 (2005) 25122516

Review

Biosensorsa perspective
Peter T. Kissinger
Bioanalytical Systems and Purdue University, 2701 Kent Avenue, West Lafayette, IN 47906-1382, USA
Received 9 August 2004; accepted 6 October 2004

Abstract
Biosensors have been under development for over 35 years and research in this field has become very popular for 15 years. Electrochemical
biosensors are the oldest of the breed, yet sensors for only one analyte (glucose) have achieved widespread commercial success at the retail
level. This perspective provides some cautions related to expectations for biosensors, the funding of science, and the wide gap between
academic and commercial achievements for sensor research. The goal of this commentary is not to arrive at any particular truth, but rather to
stimulate lively discussion.
2004 Elsevier B.V. All rights reserved.
Keywords: Biosensors; History; Electrochemistry; Commercial development; Economics

Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2512

2. Classification of amperometric and other sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.1. Single use sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Intermittent use sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Continuous use sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2513
2513
2514
2514

3. Getting good numbers economically. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.1. Money and politics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2514
2514

4. What should we publish? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2515

5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2515

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2515

1. Introduction
I would like to thank Prof. Turner for this opportunity to
comment on the state of electrochemical (and other) biosen

Tel.: +1 765 497 8801; fax: +1 765 497 1102.

E-mail address: pete@bioanalytical.com.

0956-5663/$ see front matter 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.bios.2004.10.004

sors. The purpose of this commentary is to provide some perspective to stimulate discussion. It is likely that some readers
will put me in the same class as terrorists. My co-workers
and I have spent 30 years developing, using, and consulting
on sensors for biological purposes. Our motivation has been
to help develop commercial sensors that are useful to the biological/clinical community. I should make the important admission that much of what we have tried has not (yet) worked

P.T. Kissinger / Biosensors and Bioelectronics 20 (2005) 25122516

adequately, but some research in this field has resulted in very

successful products. There is no better way to measure this
success than to note the value of electrochemical biosensor
companies that have been acquired by large diagnostic firms,
the latest being the acquisition of Therasense by Abbott for
$1.2 billion.
What is a biosensor? In the early days (the 1960s and
1970s), a sensor seemed to always be a probe of some sort,
perhaps due to a vision inextricably linked to pH, ion selective or oxygen electrodes. If you follow the old literature, you
will find biosensors that were called bioelectrodes or enzyme
electrodes or biocatalytic membrane electrodes (Arnold and
Meyerhoff, 1984). More recently, we have seen the definition broadened to include sensors buried within large automated instruments (Aldridge, 2004). There are some who see
mass spectrometry, chromatography or electrophoresis as a
viable sensor component (Huynh et al., 2004). This trend
clearly reflects progress in miniaturization, whereby with all
three of these technologies, size and performance can be
traded down to briefcase size and below. The compromises
between size, performance, power consumption and cost define the profession of instrumentation engineer. Redefining
a subject to fit the fashion of the day is not new. The room
sized mass spectrometers of 1950 can be reduced to a few cubic centimeters (Ouyang et al., 2004). For some, chemistry
has become nanotechnology. For others, nanotechnology is
then adopted by Luddites as the fear du jour. The value of
buzz is clear. It is surprising to not yet hear of nanosensoromics. For purposes here, I will consider a biosensor as
a device where a biological recognition element is built in
(physically attached or confined) and is the primary selectivity element. Many sensors used for biological purposes
are therefore not biosensors, including those for temperature,
pressure, electrocardiograms, pH, Ca2+ , catecholamines and
the like. By contrast, it is fair to consider surface plasmon
resonance (SPR) devices as utilizing biosensors (Aldridge,
2004; Hitt, 2004). Even labeled nanoparticles imbedded in
the cytosol of individual cells that report optically are viable
sensors. Useful references are reported at the website for the
Quantum Dot Corporation (2004), www.qdots.com. Originally the biological recognition element of a biosensor was
assumed to be isolated from a living system, but now there
are prospects of synthesizing this component. The journal
now includes a synthetic receptors section to reflect this new
science. As science advances, it is common for the jargon to
fall behind.
There is no doubt that biosensors remain a subject of great
popular interest. In the July 2004 issue of Fast Company,
there is mention of an ingestible, one-use nanotechnology
biosensor. This wireless device would be swallowed like a
vitamin (Conley, 2004). The June 2004 issue of Scientic
American describes smart sensors to network the world
based on nodes called motes (Culler and Mulder, 2004). One
can imagine biomotes. The Clinical Chemistry editorial for
June addresses self-monitoring of blood glucose (SMBG)
and current thinking on its clinical relevance and challenges

2513

(Winter, 2004). In May, Genetic Engineering News covered

SPR biosensors from a number of companies for screening
biomolecular interactions (Aldridge, 2004). Contrary editorial views appeared in Analytical Chemistry, noting little
real progress . . . by this over-focusing of attention on glucose (Murray, 2004) and the cover of The Scientist asks
Are biosensors still science fiction? with reference to fieldable sensors to rapidly report a bioterror event (May, 2004).
The summer issue of Interface from The Electrochemical
Society is devoted to sensors with reviews on microsensors (Liu et al., 2004), sensors for energy and transportation
(Mukundan and Garzon, 2004), and biosensors for homeland
security (Bruckner-Lea, 2004). The Eighth World Congress
on Biosensors (2004) demonstrated that there is no paucity of
ideas on applying new transducers and new biological recognition elements to sensors. It is clear from all of this that
many solid-state engineers quite often do not appreciate the
chemical challenges of sensing analytes larger than CO or O2
in a complex biological soup. They show striking photos of
nanostructures, but many can only imagine that there must
be a rugged, perfectly selective enzyme or antibody to make
this work.
There are so many ways biosensors may be used (Newman
et al., 2002). Sensors can be qualitative (pregnant or not?
SNP or not?), semi-quantitative (drunk or not?), or can cover
a wider dynamic range with either trend information or accurate numbers on which decisions can be based. I have even
reviewed a paper where the sensor determined 72.3879 g
using a standard reported to be only 97% pure. The reality is
that 70 5g would have been a more impressive truth. The
(in)significance of digits continues to plague bioanalytical
chemistry (Kissinger, 2002).

2. Classication of amperometric and other sensors

Previously I prepared a brief article classifying the three
major configurations for amperometric biosensors as single use (disposable), intermittent use, and continuous use
(Kissinger, 1997). Several years later, this classification system seems even more appropriate than before and I will describe it very briefly again. There are direct parallels for sensors based on an optical response, whether they involve a
color change or something more sophisticated, whether they
be disposable or reusable.
2.1. Single use sensors
These contain the selectivity elements and the transducer
elements in a complete electrochemical (or optical) cell,
which is typically not activated until the sample is applied.
In all cases that I am familiar with, the measurement occurs by chronoamperometry some seconds after the sample solution initiates a reaction. The entire process is over
in less than 60 s. Such biosensors are characterized by relatively poor precision, relatively poor accuracy, extremely

2514

P.T. Kissinger / Biosensors and Bioelectronics 20 (2005) 25122516

poor concentration detection limits, and a very high total cost

per data point (ca. $1). They cannot be calibrated in use. Nevertheless, the performance of such devices is adequate for the
most important analyte in modern amperometry: glucose in
blood (Winter, 2004). Instruments and accessories based on
this idea now sell at perhaps $4.5 B/year (Newman et al.,
2002).
2.2. Intermittent use sensors
These are commonly used in a flow stream (FIA or LC).
Sensors (including biosensors) used in this way often exhibit excellent precision, excellent accuracy, and concentration sensitivity even in the nanomolar range. The cost per
data point is very modest because such sensors are used for
months (not minutes). Their advantages derive from the fact
that background current and calibration are very easily established for both electrochemical and optical devices. Hydrodynamics also provides a great improvement in detection limit
versus stationary solution sensors (Kissinger and Heineman,
1996). The improvement for amperometry can be better than
106 . Naturally, the apparatus is laboratory based, not portable.
Sensors used in this manner require the sample to be transported to the sensor. There has been some progress toward
lab on a chip systems based on this concept (Lacher et al.,
2004); however, to date, the concentration detection limits
remain very poor.
2.3. Continuous use sensors
These are the most talked about, but least attractive sensors, especially in an in vivo form. Detection limits are often
very poor, precision and accuracy are for the most part uncontrolled, and background response cannot be determined
in the system under study. Such devices are characterized by
uncontrolled drift in response, but have the advantage of requiring extremely simple and inexpensive instrumentation.
The desire here is to find a biosensor technology as reliable as an amperometric oxygen electrode or as good as a
pH electrode. Thus far, there is very little practical success
(i.e., sales) in this area even though perhaps several hundred million dollars have been invested. When commercial
success comes, it will likely come for the unique analyte
glucose due to its exceptionally high concentration in biological situations (in vivo and in fermentations and cell cultures). There have been many clever approaches, but success
to date can be defined only in academic terms and not in
commercial terms. The cynic in me notes that the primary
economic success has come from raising capital or stock
price from hyping the investment community. This use of
glucose sensors is well proven. I would like to see this situation change soon. The likelihood of an implanted sensor
that would be viable (hold calibration) for more than a few
days still seems extremely remote. Thus, the market is not
nearly as large as it might first appear in a company press
release.

3. Getting good numbers economically

The purpose of a concentration sensor is to obtain a number that can be relied on to make a decision. Why are so many
people working on developing sensors for analytes where no
sensor is needed or desired? Quite often there are alternative
methodologies that are much cheaper per data point, much
more reliable, much more specific, and already commercially
available in stable form at very low prices relative to the high
data rate, automation and analyte flexibility available. Examples include chromatography, mass spectrometry, and immunoassays. Some have even gone to Mars, but would not
come back. As a cynic, I think it fair to conclude that much
biosensor work is done because it can be done and not
because it needs to be done.
We have a large differentiation between the nonprofit academic world and the tax paying commercial world in attitude about labor versus equipment. In academics, we view
labor as cheap and equipment as expensive. In the commercial world, we view labor as expensive and equipment as
cheap. The widely mistaken view is that this has something
to do with relative salaries in these different worlds. This
is not the case except to a very small degree. This perception primarily comes from the fact that labor and physical
overhead (buildings, electricity, vacations, medical expense,
retirement plans, etc.) in academia are frequently paid for by
taxpayers, students, endowments, and grants, whereas labor
in industry must pay taxes. It also derives from the concept of
depreciation expense, which chemistry Professors and government scientists do not always worry about. They view an
instrument as costing say $120,000 in one month, whereas
a business person sees it as less that $1000 per month spent
over 10 years or so. An enormous amount of talented human
capital is perhaps wasted by the way grants are awarded, unless we consider academic research only as a means to train
students. This leads to a focus on what looks like exceptionally low cost science, such as biosensors, which in reality can
be very high cost science because much of it is not needed
at all. This is slowly being corrected as we move more in
the direction of academic center grants, collaborations and
general cost sharing of major instruments.
3.1. Money and politics
It is, of course, human nature to follow the money to
some extent. There is, after all, profit in nonprofit institutions
for the indivuals involved. Biosensors are very attractive for
academic research. They do, in fact, require relatively little
investment in equipment. They are an excellent way for students to become familiar with enzymes, antibodies, polymer
films, kinetics, electrochemistry, fiber optics, biological selectivity, data acquisition, and materials science.
Academic research involves the three-cornered stool of
peer review of science, funding agencies, and politics. This
is an admixture that is inefficient and characterized by various conflicts of interest. While I make observations about it,

P.T. Kissinger / Biosensors and Bioelectronics 20 (2005) 25122516

I do not know a better system and this one has resulted in

enormous scientific advances over the last 50 years. Nevertheless, it is often committees of academics who determine
the priorities of funding agencies. They mix with politicians
who seek dramatic justification for the funding they approve.
The most recent rationale is the war on terror, chemical and
biological. If a subject can be made to appear flashy and
trendy, it has a better chance for success. Biosensors have a
certain cachet. They have been skillfully sold as a priority
(most notably in Europe and Japan). This could be viewed as
a situation where something is made a priority without careful consideration of the commercial realities. In my view, this
is a mistake. Sensors are intended to be practical devices to be
used. They employ basic science, but can hardly be justified
as curiosity driven research.
I suspect that the prefix bio is the blessing and the curse.
It sells well to politicians who think it will do something for
human health or the environment (and it might). A global
problem is the ignorance of the general public for scientific
subjects. There is little recognition that funding solid-state
physics has aided brain surgery or that funding mathematics
has aided medical imaging. That MRI is good and NMR is bad
provides a nice example of bowing to public ignorance rather
than working to correct it. Scientific progress is very inefficient and opportunities from basic science are largely unforeseen. We are now asked to rationalize our work in practical
terms. This has merit, but too often it is overdone. Biosensor
research is a clear example. There have been great successes
(glucose, SPR) (Newman et al., 2002) among a much larger
number of attempts.
I fully recognize the restraints that faculty must deal with
to obtain funding and publish results quickly. We must deal
with the reality of the system as it exists today. At the same
time, let us recognize the deficiencies and explore ways the
process of funding science can be improved.

4. What should we publish?

A few years ago, an editor from a prestigious analytical
chemistry journal asked how we could distinguish the best
biosensor papers from the others. I offered the following criteria.
1. Do enough people want or need to have a sensor for the
analyte of interest?
2. Are there existing sensors for the same analyte? Does the
new sensor present clearly defined advantages over the
older technology, or is it simply a small variation on a wellestablished theme? Unless this new sensor is so innovative
that it is interesting for its conception alone, the following
five issues should be addressed.
3. Has the chemical stability of each component used to prepare the sensor been considered?
4. Has the stability of the sensor itself been thoroughly tested
both in use and in storage? At what temperatures? Six

2515

months stability of a prepared sensor is perhaps the absolute minimum for any practical commercial application.
5. If the sensor is intended for biological samples, has it
actually been tested with biological samples and not just
aqueous buffers?
6. If a sensor is intended to be used in tissue, have biocompatible components been chosen? Has tissue reaction to the
foreign implant been considered both for its effect on the
sensor and on the organism? Has a means of sterlization
and sterile packaging been considered?
7. Has the dynamic range of the sensor been tested appropriate to the anticipated analyte concentration in real
samples?
These seven criteria for a really good biosensor manuscript
still seem reasonable to me. The task is difficult. Standards
should be very high. The reaction to a paper should be, Wow!
Fantastic! and not, So what?

5. Conclusion
In summary, biosensor research has suffered from a crisis
of expectations that has gone on too long. It is unfortunate
that so many people working in this area do not present a
balanced view of alternatives for making the same measurements, often more reliably and less expensively with proven,
readily available tools. Glucose is a fine example and a great
success commercially. This degree of success is unlikely to
translate to analytes where the concentration is 1010,000
times lower and the market is 1010,000 times smaller. In
research applications, the economics of the sensor itself are
less important than the ultimate use of the data. For example, if SPR helps us develop a drug that will treat millions of
people annually, the cost of the sensor will be very small versus the benefit achieved. There are many such examples, but
we should be cautious. Sensors are extraordinarily expensive
when the cost of developing them greatly exceeds the annual
size of the market for the analyte to be served. Chromatography, mass spectrometry, and immunoassay methods are much
faster to develop and give better precision at lower limits of
quantitation for a wide variety of analytes. Likewise, the advantages of miniaturization and portable instrumentation are
often overstated. Biosensors are by definition not versatile.
This is their strength, but also their substantial weakness. As
evidenced by this journal, the biosensor art is rich with exciting new ideas deserving support.
Note: Some of the thoughts presented here are elaborated
from earlier publications (Kissinger, 1997; Kissinger, 2000).

References
Aldridge, S., 2004. Biosensors offer advantages for screening. Genet. Eng.
News 24, 25.
Arnold, M.A., Meyerhoff, M.E., 1984. Ion-selective electrodes. Anal.
Chem. 56, 20R48R.

2516

P.T. Kissinger / Biosensors and Bioelectronics 20 (2005) 25122516

Bruckner-Lea, C.J., 2004. Biosensor systems for homeland security. Interface 13 (2), 3641.
Conley, L., 2004. A pill with brains. Fast Company. July, 34.
Culler, D.E., Mulder, H., 2004. Smart sensors to network the world. Sci.
Am. 290 (6), 8591.
Hitt, E., 2004. Label-free methods are not problem free. Drug Discov.
Devel. 7 (9), 3442.
Huynh, B.H., Fogarty, B.A., Lunte, S.M., Martin, R.S., in press. On-line
coupling of microdialysis sampling with microchip-based capillary
electrophoresis. Anal. Chem. 76.
Kissinger, P.T., Heineman, W.R., 1996. Laboratory Techniques in Electroanalytical Chemistry, second ed. Marcel Dekker, New York.
Kissinger, P.T., 1997. Introduction to amperometric biosensor configurations. Curr. Separations 16, 101103.
Kissinger, P.T., 2000. Electrochemical biosensorspromise vs. reality.
Quim. Analitica 19 (Suppl. 1), 57.
Kissinger, P.T., 2002. A primer on bad laboratory practices (BLPs) for
bioanalytical chemistry. Curr. Separations 20 (2), 4143.
Lacher, N.A., Lunte, S.M., Martin, R.S., 2004. Development of a microfabricated palladium decoupler/electrochemical detector for microchip

capillary electrophoresis using a hybrid glass/poly(dimethylsiloxane)

device. Anal. Chem. 76, 24822491.
Liu, C.C., Hesketh, P.J., Hunter, G.W., 2004. Chemical microsensors.
Interface 13 (2), 2227.
May, M., 2004. Building a better biosensor. Scientist 18 (10), 3638.
Mukundan, R., Garzon, F., 2004. Electrochemical sensors for energy and
transportation. Interface 13 (2), 3035.
Murray, R.W., 2004. Cadmium horses and glucose. Anal. Chem. 76, 149.
Newman, J.D., Tigwell, L.J., Turner, A.P.F., Warner, P.J., 2002. Biosensors: an inside view. Institute of Bioscience and Technology, Bedfordshire 45 4DT, UK.
Ouyang, Z., Wu, G., Song, Y., Li, H., Plass, W.R., Cooks, R.G., 2004.
Rectilinear ion trap: concepts, calculations, and analytical performance
of a new mass analyzer. Anal. Chem. 76, 45954605.
Quantum Dot Corporation, 2004. Retrieved 21 September 2004 from The
World Wide Web: http://www.qdots.com.
The Eighth World Congress on Biosensors, 2004. 2426 May 2004.
Granada, Spain, Elsevier, Oxford, UK.
Winter, W.E., 2004. A rosetta stone for insulin treatment: self-monitoring
of blood glucose. Clin. Chem. 50 (6), 985987.