Biosensors and Bioelectronics 20 (2005) 2512–2516

Review

Biosensors—a 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. Electrochemicalbiosensors are the oldest of the breed, yet sensors for only one analyte (glucose) have achieved widespread commercial success at the retaillevel. This perspective provides some cautions related to expectations for biosensors, the funding of science, and the wide gap betweenacademic and commercial achievements for sensor research. The goal of this commentary is not to arrive at any particular truth, but rather tostimulate lively discussion.© 2004 Elsevier B.V. All rights reserved.

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eywords:Biosensors; History; Electrochemistry; Commercial development; Economics

ontents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2512

2. Classification of amperometric and other sensors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25132.1. Single use sensors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25132.2. Intermittent use sensors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25142.3. Continuous use sensors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2514

3. Getting good numbers economically. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25143.1. Money and politics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2514

4. What should we publish?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2515

5. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2515

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2515

. Introduction

I would like to thank Prof. Turner for this opportunity to

sors. The purpose of this commentary is to provide somespective to stimulate discussion. It is likely that some reawill put me in the same class as terrorists. My co-worand I have spent 30 years developing, using, and cons

omment on the state of electrochemical (and other) biosen-

∗ Tel.: +1 765 497 8801; fax: +1 765 497 1102.E-mail address:pete@bioanalytical.com.

on sensors for biological purposes. Our motivation has beento help develop commercial sensors that are useful to the bio-logical/clinical community. I should make the important ad-mission that much of what we have tried has not (yet) worked

956-5663/$ – see front matter © 2004 Elsevier B.V. All rights reserved.oi:10.1016/j.bios.2004.10.004

P.T. Kissinger / Biosensors and Bioelectronics 20 (2005) 2512–2516 2513

adequately, but some research in this field has resulted in verysuccessful products. There is no better way to measure thissuccess than to note the value of electrochemical biosensorcompanies 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 and1970s), a sensor seemed to always be a probe of some sort,perhaps due to a vision inextricably linked to pH, ion selec-tive or oxygen electrodes. If you follow the old literature, youwill find biosensors that were called bioelectrodes or enzymeelectrodes or biocatalytic membrane electrodes (Arnold andMeyerhoff, 1984). More recently, we have seen the defini-tion broadened to include sensors buried within large auto-mated instruments (Aldridge, 2004). There are some who seemass spectrometry, chromatography or electrophoresis as aviable sensor component (Huynh et al., 2004). This trendclearly reflects progress in miniaturization, whereby with allthree of these technologies, size and performance can betraded down to briefcase size and below. The compromisesbetween size, performance, power consumption and cost de-fine the profession of instrumentation engineer. Redefininga subject to fit the fashion of the day is not new. The roomsized mass spectrometers of 1950 can be reduced to a few cu-bic centimeters (Ouyang et al., 2004). For some, chemistryhas become nanotechnology. For others, nanotechnology ist e of“ en-s or asa lt in( lec-t sesa ture,p dt onr2 int bles or theQn wasa herea urnaln news on tof

greatpt logyb e avA rld”bcJ BG)a ges

(Winter, 2004). In May,Genetic Engineering NewscoveredSPR biosensors from a number of companies for screeningbiomolecular interactions (Aldridge, 2004). Contrary edito-rial views appeared inAnalytical Chemistry,noting “littlereal progress. . . by this over-focusing of attention on glu-cose” (Murray, 2004) and the cover ofThe Scientistasks“Are biosensors still science fiction?” with reference to field-able sensors to rapidly report a bioterror event (May, 2004).The summer issue ofInterface from The ElectrochemicalSociety is devoted to sensors with reviews on microsen-sors (Liu et al., 2004), sensors for energy and transportation(Mukundan and Garzon, 2004), and biosensors for homelandsecurity (Bruckner-Lea, 2004). TheEighth World Congresson Biosensors (2004)demonstrated that there is no paucity ofideas on applying new transducers and new biological recog-nition elements to sensors. It is clear from all of this thatmany solid-state engineers quite often do not appreciate thechemical challenges of sensing analytes larger than CO or O2in a complex biological soup. They show striking photos ofnanostructures, but many can only imagine that there mustbe a rugged, perfectly selective enzyme or antibody to makethis work.

There are so many ways biosensors may be used (Newmanet al., 2002). Sensors can be qualitative (pregnant or not?SNP or not?), semi-quantitative (drunk or not?), or can covera wider dynamic range with either trend information or ac-c evenr 79u lity ist The( icalc

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hen adopted by Luddites as the fear du jour. The valubuzz” is clear. It is surprising to not yet hear of nanosoromics. For purposes here, I will consider a biosensdevice where a biological recognition element is bui

physically attached or confined) and is the primary seivity element. Many sensors used for biological purpore therefore not biosensors, including those for temperaressure, electrocardiograms, pH, Ca2+, catecholamines an

he like. By contrast, it is fair to consider surface plasmesonance (SPR) devices as utilizing biosensors (Aldridge,004; Hitt, 2004). Even labeled nanoparticles imbedded

he cytosol of individual cells that report optically are viaensors. Useful references are reported at the website fuantum Dot Corporation (2004), www.qdots.com. Origi-ally the biological recognition element of a biosensorssumed to be isolated from a living system, but now tre prospects of synthesizing this component. The joow includes a synthetic receptors section to reflect thiscience. As science advances, it is common for the jargall behind.

There is no doubt that biosensors remain a subject ofopular interest. In the July 2004 issue ofFast Company,

here is mention of “an ingestible, one-use nanotechnoiosensor.” This wireless device would be swallowed likitamin (Conley, 2004). The June 2004 issue ofScientificmericandescribes “smart sensors to network the woased on nodes called motes (Culler and Mulder, 2004). Onean imagine biomotes. TheClinical Chemistryeditorial forune addresses self-monitoring of blood glucose (SMnd current thinking on its clinical relevance and challen

urate numbers on which decisions can be based. I haveeviewed a paper where the sensor determined 72.38�gsing a standard reported to be only 97% pure. The rea

hat 70± 5�g would have been a more impressive truth.in)significance of digits continues to plague bioanalythemistry (Kissinger, 2002).

. Classification of amperometric and other sensors

Previously I prepared a brief article classifying the thajor configurations for amperometric biosensors asle use (disposable), intermittent use, and continuousKissinger, 1997). Several years later, this classification sem seems even more appropriate than before and I wicribe it very briefly again. There are direct parallels forors based on an optical response, whether they invoolor change or something more sophisticated, whethere disposable or reusable.

.1. Single use sensors

These contain the selectivity elements and the transdlements in a complete electrochemical (or optical)hich is typically not activated until the sample is appl

n all cases that I am familiar with, the measurementurs by chronoamperometry some seconds after thele solution initiates a reaction. The entire process is

n less than 60 s. Such biosensors are characterized btively poor precision, relatively poor accuracy, extrem

2514 P.T. Kissinger / Biosensors and Bioelectronics 20 (2005) 2512–2516

poor concentration detection limits, and a very high total costper data point (ca. $1). They cannot be calibrated in use. Nev-ertheless, the performance of such devices is adequate for themost important analyte in modern amperometry: glucose inblood (Winter, 2004). Instruments and accessories based onthis 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 ex-hibit excellent precision, excellent accuracy, and concentra-tion sensitivity even in the nanomolar range. The cost perdata point is very modest because such sensors are used formonths (not minutes). Their advantages derive from the factthat background current and calibration are very easily estab-lished for both electrochemical and optical devices. Hydrody-namics also provides a great improvement in detection limitversus stationary solution sensors (Kissinger and Heineman,1996). The improvement for amperometry can be better than106. Naturally, the apparatus is laboratory based, not portable.Sensors used in this manner require the sample to be trans-ported 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 limitsr

2

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3. Getting good numbers economically

The purpose of a concentration sensor is to obtain a num-ber that can be relied on to make a decision. Why are so manypeople working on developing sensors for analytes where nosensor is needed or desired? Quite often there are alternativemethodologies that are much cheaper per data point, muchmore reliable, much more specific, and already commerciallyavailable in stable form at very low prices relative to the highdata rate, automation and analyte flexibility available. Ex-amples include chromatography, mass spectrometry, and im-munoassays. Some have even gone to Mars, but would notcome back. As a cynic, I think it fair to conclude that muchbiosensor work is done because “it can be done” and notbecause “it needs to be done.”

We have a large differentiation between the nonprofit aca-demic world and the tax paying commercial world in atti-tude about labor versus equipment. In academics, we viewlabor as cheap and equipment as expensive. In the commer-cial world, we view labor as expensive and equipment ascheap. The widely mistaken view is that this has somethingto do with relative salaries in these different worlds. Thisis not the case except to a very small degree. This percep-tion primarily comes from the fact that labor and physicaloverhead (buildings, electricity, vacations, medical expense,retirement plans, etc.) in academia are frequently paid for byt labori pt ofd gov-e ani ereasa spento manc d, un-l o trains tion-a canb ededa e int andg

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emain very poor.

.3. Continuous use sensors

These are the most talked about, but least attractiveors, especially in an in vivo form. Detection limits are ofery poor, precision and accuracy are for the most parontrolled, and background response cannot be determn the system under study. Such devices are characterizncontrolled drift in response, but have the advantage ouiring extremely simple and inexpensive instrumentahe desire here is to find a biosensor technology asble as an amperometric oxygen electrode or as goodH electrode. Thus far, there is very little practical suci.e., sales) in this area even though perhaps severalred million dollars have been invested. When commeuccess comes, it will likely come for the unique analucose due to its exceptionally high concentration in

ogical situations (in vivo and in fermentations and cellures). There have been many clever approaches, but so date can be defined only in academic terms and nommercial terms. The cynic in me notes that the primconomic success has come from raising capital or srice from hyping the investment community. This uselucose sensors is well proven. I would like to see thisation change soon. The likelihood of an implanted se

hat would be viable (hold calibration) for more than aays still seems extremely remote. Thus, the market iearly as large as it might first appear in a company pelease.

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axpayers, students, endowments, and grants, whereasn industry must pay taxes. It also derives from the conceepreciation expense, which chemistry Professors andrnment scientists do not always worry about. They view

nstrument as costing say $120,000 in one month, whbusiness person sees it as less that $1000 per month

ver 10 years or so. An enormous amount of talented huapital is perhaps wasted by the way grants are awardeess we consider academic research only as a means ttudents. This leads to a focus on what looks like exceplly low cost science, such as biosensors, which in realitye very high cost science because much of it is not net all. This is slowly being corrected as we move mor

he direction of academic center grants, collaborationseneral cost sharing of major instruments.

.1. Money and politics

It is, of course, human nature to “follow the money”ome extent. There is, after all, profit in nonprofit institutior the indivuals involved. Biosensors are very attractivecademic research. They do, in fact, require relatively

nvestment in equipment. They are an excellent way forents to become familiar with enzymes, antibodies, polylms, kinetics, electrochemistry, fiber optics, biologicalectivity, data acquisition, and materials science.

Academic research involves the three-cornered stoeer review of science, funding agencies, and politics.

s an admixture that is inefficient and characterized byus conflicts of interest. While I make observations abo

P.T. Kissinger / Biosensors and Bioelectronics 20 (2005) 2512–2516 2515

I do not know a better system and this one has resulted inenormous scientific advances over the last 50 years. Never-theless, it is often committees of academics who determinethe priorities of funding agencies. They mix with politicianswho seek dramatic justification for the funding they approve.The most recent rationale is the war on terror, chemical andbiological. If a subject can be made to appear flashy andtrendy, it has a better chance for success. Biosensors have acertain cachet. They have been skillfully sold as a priority(most notably in Europe and Japan). This could be viewed asa situation where something is made a priority without care-ful consideration of the commercial realities. In my view, thisis a mistake. Sensors are intended to be practical devices to beused. They employ basic science, but can hardly be justifiedas “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 forhuman health or the environment (and it might). A globalproblem is the ignorance of the general public for scientificsubjects. There is little recognition that funding solid-statephysics has aided brain surgery or that funding mathematicshas aided medical imaging. That MRI is good and NMR is badprovides a nice example of bowing to public ignorance ratherthan working to correct it. Scientific progress is very ineffi-cient and opportunities from basic science are largely unfore-seen. We are now asked to rationalize our work in practicalt nsorr cesse( rn

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months stability of a prepared sensor is perhaps the abso-lute minimum for any practical commercial application.

5. If the sensor is intended for biological samples, has itactually been tested with biological samples and not justaqueous buffers?

6. If a sensor is intended to be used in tissue, have biocompat-ible components been chosen? Has tissue reaction to theforeign implant been considered both for its effect on thesensor and on the organism? Has a means of sterlizationand sterile packaging been considered?

7. Has the dynamic range of the sensor been tested appro-priate to the anticipated analyte concentration in “real”samples?

These seven criteria for a really good biosensor manuscriptstill seem reasonable to me. The task is difficult. Standardsshould 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 crisisof expectations that has gone on too long. It is unfortunatethat so many people working in this area do not present abalanced view of alternatives for making the same measure-m ven,r greats ly tot ,000t r. Inr lf arel xam-p s ofp ver-s s, butw nsivew nnuals ogra-p muchf s ofq ad-v areo atile.T s. Ase ex-c

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erms. This has merit, but too often it is overdone. Bioseesearch is a clear example. There have been great sucglucose, SPR) (Newman et al., 2002) among a much largeumber of attempts.

I fully recognize the restraints that faculty must deal wo obtain funding and publish results quickly. We must dith the reality of the “system” as it exists today. At the sa

ime, let us recognize the deficiencies and explore wayrocess of funding science can be improved.

. What should we publish?

A few years ago, an editor from a prestigious analyhemistry journal asked how we could distinguish theiosensor papers from the others. I offered the following

eria.

. Do enough people want or need to have a sensor foanalyte of interest?

. Are there existing sensors for the same analyte? Doenew sensor present clearly defined advantages oveolder technology, or is it simply a small variation on a westablished theme? Unless this new sensor is so innothat it is interesting for its conception alone, the followfive issues should be addressed.

. Has the chemical stability of each component used topare the sensor been considered?

. Has the stability of the sensor itself been thoroughly teboth in use and in storage? At what temperatures?

s

ents, often more reliably and less expensively with proeadily available tools. Glucose is a fine example and auccess commercially. This degree of success is unlikeranslate to analytes where the concentration is 10–10imes lower and the market is 10–10,000 times smalleesearch applications, the economics of the sensor itseess important than the ultimate use of the data. For ele, if SPR helps us develop a drug that will treat millioneople annually, the cost of the sensor will be very smallus the benefit achieved. There are many such examplee should be cautious. Sensors are extraordinarily expehen the cost of developing them greatly exceeds the aize of the market for the analyte to be served. Chromathy, mass spectrometry, and immunoassay methods are

aster to develop and give better precision at lower limituantitation for a wide variety of analytes. Likewise, theantages of miniaturization and portable instrumentationften overstated. Biosensors are by definition not vershis is their strength, but also their substantial weaknesvidenced by this journal, the biosensor art is rich withiting new ideas deserving support.

Note: Some of the thoughts presented here are elaborom earlier publications (Kissinger, 1997; Kissinger, 2000).

eferences

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