Analytica Chimica Acta 469 (2002) 63–71

Review
Electrochemical nucleic acid biosensors
Joseph Wang∗
Department of Chemistry and Biochemistry, College of Arts and Sciences, New Mexico State University,
Box 30001-Dept. 3C, Las Cruces, NM 88003, USA
Received 13 June 2001; received in revised form 5 September 2001; accepted 10 September 2001

Abstract
Electrochemical devices have received considerable attention in the development of sequence-specific DNA hybridization
biosensors. Such devices rely on the conversion of the DNA base-pair recognition event into a useful electrical signal. Electro-
chemical biosensing of DNA hybridization is not only uniquely qualified for meeting the size, cost, and power requirements
of decentralized genetic testing, but offer an elegant route for interfacing—at the molecular level—the DNA-recognition and
signal-transduction elements. This article reviews current directions in electrochemical DNA biosensors, and discusses recent
strategies and future prospects for such electrical detection.
© 2002 Elsevier Science B.V. All rights reserved.
Keywords: DNA biosensors; Electrochemistry; Voltammetry; Electrode

1. Introduction gravimetric [3] devices. The two major requirements

Wide-scale genetic testing requires the development
of easy-to-use, fast, inexpensive, miniaturized analyt-
ical devices. Traditional methods for detecting DNA
hybridization, such as gel electrophoresis or mem-
brane blots, are too slow and labor intensive. Biosen-
sors offer a promising alternative for faster, cheaper,
and simpler nucleic acid assays. DNA hybridization
biosensors commonly rely on the immobilization of
a single-stranded (ss) oligonucleotide probe onto a
transducer surface to recognize—by hybridization—
its complementary target sequence. The binding of
the surface-confined probe and its complementary tar-
get strand is translated into a useful electrical signal.
Transducing elements reported in the literature have
included optical [1], electrochemical [2], and micro-
∗ Tel.: +1-505-646-2140; fax: +1-505-646-6033.
E-mail address: joewang@nmsu.edu (J. Wang).
for a successful operation of a DNA biosensor are
high specificity (including observation of a change in
a single nucleotide) and high sensitivity. Even though
nucleic acids are relatively simple molecules, finding
the sequence that contains the desired information,
and distinguishing between perfect matches and mis-
matches, are very challenging tasks.
Electrochemical transducers have received consid-
erable recent attention in connection to the detection
of DNA hybridization [2,4,5]. The high sensitivity of
such devices, coupled to their compatibility with mod-
ern microfabrication technologies, portability, low cost
(disposability), minimal power requirements, and in-
dependence of sample turbidity or optical pathway,
make them excellent candidates for DNA diagnostics.
In addition, electrochemistry offers innovative routes
for interfacing the nucleic acid recognition system
with the signal-generating element and for amplify-
ing electrical signals. Direct electrical reading of DNA

0003-2670/02/$ – see front matter © 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 0 3 - 2 6 7 0 ( 0 1 ) 0 1 3 9 9 - X
64 J. Wang / Analytica Chimica Acta 469 (2002) 63–71

interactions thus offers great promise for developing
simple, rapid, and user-friendly DNA sensing devices
(in a manner analogous to miniaturized blood-glucose
meters). Recent efforts have led to a host of new
strategies for electrical detection of DNA hybridiza-
tion [2,4,5]. Such electrochemical avenues for gener-
ating the hybridization signal are the subject of the
present review.
2. Electrochemical biosensing
of DNA hybridization
Electrochemical detection of DNA hybridization
usually involves monitoring of a current response,
resulting from the Watson–Crick base-pair recog-
nition event, under controlled potential conditions
[2,4,5]. The probe-coated electrode is commonly
immersed into a solution of a target DNA whose
nucleotide sequence is to be tested. When the target
DNA contains a sequence which matches that of the
immobilized oligonucleotide probe DNA, a hybrid du-
plex DNA is formed at the electrode surface (Fig. 1).
Such hybridization event is commonly detected via
the increased current signal of an electroactive indi-
cator (that preferentially binds to the DNA duplex),
in connection to the use of enzyme labels or redox
labels, or from other hybridization-induced changes
in electrochemical parameters (e.g. capacitance or
conductivity).

Fig. 1. Major processes involved in electrochemical DNA biosensors based on the use of redox indicators (Ox).
 J. Wang / Analytica Chimica Acta 469 (2002) 63–71
In the following sections, we will focus on the
major steps involved in electrochemical biosensing of
DNA hybridization, namely the formation of the nu-
cleic acid recognition layer, the actual hybridization
event, and the transformation of this recognition event
into an electrical signal (Fig. 1). As will be illustrated,
the success of such devices requires a proper com-
bination of synthetic-organic and surface chemistries,
DNA-recognition, and electrical detection protocols.
2.1. Interfacial confinement
The probe immobilization step plays a major role
in the overall performance of electrochemical DNA
biosensors. The achievement of high sensitivity and
selectivity requires maximization of the hybridization
efficiency and minimization of non-specific adsorp-
tion events, respectively. The probes are typically
short oligonucleotides (25–40-mer) that are capable
of hybridizing with specific and unique regions of
the target nucleotide sequence. Control of the sur-
face chemistry and coverage is essential for assuring
high reactivity, orientation/accessibility, and stability
of the surface-bound probe, as well as for avoiding
non-specific binding/adsorption events. For example,
it was demonstrated recently that the density of im-
mobilized ss-DNA can influence the thermodynamics
of hybridization, and hence, the selectivity of DNA
biosensors [6]. Greater understanding of the relation-
ship between the surface environment of biosensors
and the resulting analytical performance is desired.
This is particularly important as the physical environ-
ment of hybrids at solid/solution interface can differ
greatly from that of hybrids formed in the bulk solu-
tion [6]. Several useful schemes for attaching nucleic
acid probes onto electrode surfaces have thus been
developed. The exact immobilization protocol often
depends on the electrode material used for signal
transduction.
Common probe immobilization schemes in-
clude attachment of biotin-functionalized probes to
avidin-coated surfaces [7], self-assembly of organized
monolayers of thiol-functionalized probes onto gold
transducers [8,9], carbodiimide covalent binding to
an activated surface [10], as well as adsorptive ac-
cumulation onto carbon-paste or thick-film carbon
electrodes [11]. The use of alkanethiol self-assembly
methods has been particularly attractive for fabricating
65
Fig. 2. Schematic of the preparation of a mixed thiol-derivatized
single-stranded oligonucleotide/6-mercapto-1-hexanol monolayer
in a solution containing the target DNA: (A) adsorption of the
ss-DNA (HS-ss-DNA); (B) formation of the mixed layer after
the addition and adsorption of mercaptohexanol (from [9] with
permission).
reproducible probe-modified surfaces with high
hybridization activity [8,9]. For this purpose, the
DNA is commonly immobilized on gold by forming
mixed monolayers of thiol-derivatized single-stranded
oligonucloetide and 6-mercapto-1-hexanol (Fig. 2).
The thiolated probe is ‘put upright’ as a result of
such coassembly with a short-chain alkanethiol. The
latter, along with a hydrophilic linker (between the
thiol group and DNA), is often used for minimizing
non-specific adsorption effects (of unwanted non-
hybridized DNA adsorbates). Such monolayer-based
structures can also provide a general route for linking
to the surface relevant (enzyme or redox) labels.
Despite of this considerable progress, there are
many fundamental questions concerning the surface
orientation and accessibility, and the nature of the
interfacial molecular interactions. Surface characteri-
zation techniques (e.g. XPS, reflectance IR ellipsome-
try) can shed useful insights into the surface coverage
and organization [8,9].
2.2. The hybridization event
The development of electrochemical DNA biosen-
sors (as well as other DNA biosensors), requires proper
66 J. Wang / Analytica Chimica Acta 469 (2002) 63–71
attention to experimental variables affecting the hy-
bridization event at the transducer-solution interface.
These include the salt concentration, temperature, vis-
cosity, the presence of accelerating agents, contacting
time, base composition (G + C, %), and length of
probe sequence. Careful control of the hybridization
event is thus required. The stability of hybrids formed
between strands with mismatched bases is decreased
according to the number and location of the mis-
matches. Many DNA biosensors are not capable of
selectively detecting a point mutation, as desired in
numerous practical situations. Controlling the strin-
gency of hybridization, particularly using elevated
temperatures, can thus be used for discriminating
among oligonucleotide hybrids (including mismatch
discrimination). Control of the hybridization time can
be used for tuning the linear dynamic range, with
shorter time offering an extended range at the cost of
lower sensitivity [12]. Detection limits ranging from
the nanomolar to the picomolar concentration range
can thus be achieved in connection to 5 and 60 min
hybridization times. Even lower detection limits can
be attained in connection to advanced amplification
protocols (described in the following sections).
We have demonstrated that significantly enhanced
selectivity can be achieved by the use of peptide nu-
cleic acid (PNA) probes [13]. Such DNA analogues,
possess an uncharged pseudopeptide backbone (in-
stead of the charged phosphate-sugar one of natu-
ral DNA). Because of their neutral backbone, PNA
probes offer greater affinity in binding to comple-
mentary DNA, and improved distinction between
closely related sequences (including the detection of
single-base imperfections). This is attributed to the fact
that mismatch in PNA/DNA duplexes is much more
destabilizing than in a DNA/DNA duplexes (with a
lowering of the Tm by 15 versus 11 ◦ C, respectively).
Such mismatch discrimination is of particular impor-
tance in the detection of disease-related mutations.
Proper attention should be given also to the
reusability of the DNA biosensors, namely to the
regeneration of the surface-bound single-stranded
probe after each assay. Both thermal and chemical
(sodium hydroxide, urea) regeneration schemes have
been shown useful for ‘removing’ the bound target
in connection with different DNA biosensor formats.
Even more elegant is the use of controlled electric
fields for facilitating the denaturation of the duplex
[14]. Such electronic control has been used also for
differentiating among oligonucleotide hybrids. Me-
chanically renewed electrodes, including polishable
biocomposites and graphite pencils, have also been
used for regenerating a ‘fresh’ probe layer [15,16].
Alternately, one can use “one-shot” screen-printed
electrodes, similar to those used for self-testing of
blood glucose, and hence obviate the need for regen-
eration [11]. Such disposable DNA sensor strips also
meet the needs of many decentralized genetic testing.
2.3. Electrochemical transduction
of DNA hybridization
The hybridization event is commonly detected via
the increased current signal of a redox indicator (that
associates with the newly formed surface hybrid), or
from changes in electrochemical parameters (such as
capacitance or conductivity) or in the redox activity of
the nucleic acid resulting from the duplex formation.
2.3.1. Indicator-based detection
Earlier devices have relied primarily on the use
of electroactive hybridization indicators [4]. Such
indicators are small electroactive DNA-intercalating
or groove-binding substances, that posses a much
higher affinity for the resulting hybrid compared
to the single-stranded probe. Accordingly, the con-
centration of the indicator at the electrode surface
increases when hybridization occurs, resulting in in-
creased electrochemical response. Besides effective
differentiation between ss- and ds-DNA, the indicator
should possess a well-defined, low-potential, voltam-
metric response. Such properties of redox indicators
are essential for attaining high sensitivity and selec-
tivity. Both linear-scan or square-wave voltammetric
modes [17] or constant-current chronopotentiometry
[18] can be used to detect the association of the redox
indicator with the surface duplex.
Mikkelsen’s group, that pioneered the use of redox
indicators, demonstrated its utility for detecting the
cystic fibrosis
F508 deletion sequence associated
with 70% of cystic fibrosis patients [19]. A detection
limit of 1.8 fmol was demonstrated for the 4000-base
DNA fragment in connection to a Co(bpy)3 3+ marker.
High selectivity towards the disease sequence—but
not to the normal DNA—was achieved by performing
the hybridization at an elevated temperature of 43 ◦ C.
 J. Wang / Analytica Chimica Acta 469 (2002) 63–71 67

Such use of the electrochemical transduction mode

requires that proper attention be given to the choice of
the indicator and its detection scheme. Our laboratory
demonstrated the use of the Co(phen)3 3+ indicator,
in connection to a carbon-paste chronopotentiometric
transducer and PNA probes, for detecting single-base
imperfections in the p53 gene [20]. Other useful
redox-active indicators include bisbenzimide dyes
such as Hoecht 33258 [21] or anthracycline antibi-
otics such as daunomycin [22]. A daunomycin-based
chronopotentiometric biosensor was combined with
PCR amplification of DNA extracted from whole
blood for the genetic detection of apolipoprotein E
polymorphism [23].
New electroactive indicators, offering better distinc-
tion between ss- and ds-DNA have been developed for
attaining higher sensitivity. Very successful has been
the recent use of a threading intercalator ferrocenyl
naphthalene diimide (FND) [24] that binds to the DNA
duplex more tightly than usual intercalators and dis- Fig. 3. Differential pulse voltammograms for the ferrocenyl naph-
plays a negligible affinity to the single-stranded probe. thalene diimide indicator at the dT20 -modified electrode before (a)
and after (b) hybridization with dA20 . Also shown, the chemical
This duplex-specific threading indicator resulted in a structure of the indicator (from [24] with permission).
detection limit of 10 zmol in connection to differen-
tial pulse voltammetric monitoring of the hybridiza-
tion event (Fig. 3). The oligonucleotide probe was It is possible also to employ metal nanoparticle labels,
chemisorbed onto gold electrodes through a thiol an- and to quantitate them following the hybridization and
chor. Table 1 summarizes common redox-active in- acid dissolution by a highly-sensitive electrochemical
dicators used in electrochemical DNA hybridization stripping protocol [28].
biosensors. Oligonucleotides bearing electroactive re-
porter molecules, such as ferrocene or anthraquinone 2.3.2. Use of enzyme labels for detecting
tags, have also been considered for electrical detec- DNA hybridization
tion of surface hybridization [25,26]. Ferrocene tags Enzyme labels have been widely used in bioaffin-
are being used in a new hand-held device, the CMS ity sensors, particularly in immunosensors. The use
eSensorTM system of Motorola Inc., that can detect of enzyme labels to generate electrical signals offers
up to 48 different sequences in connection to elegant also great promise for ultrasensitive electrochemi-
surface chemistry (combining self-assembly of thio- cal detection of DNA hybridization. Lumley et al.
lated probes and phenylacetylene “molecular wires”) [29] demonstrated that a direct low-potential sensi-
and a highly-sensitive ac voltammetric detection [27]. tive amperometric monitoring of the hybridization

Table 1
Examples of redox-active indicators used for the biosensing of DNA hybridization
Indicator Detection mode transducer Electrode Ep,a vs. Ag/AgCl (V) Reference

Co(bpy)3 3+ Cyclic voltammetry Carbon paste 0.15 [17]

Co(phen)3 3+ Chronopotentiometry Carbon paste 0.15 [18]
Hoecht 33258 Pulse voltammetry Gold 0.58 [21]
Daunomycin Chronopotentiometry Screen printed 0.45 [22]
Ferrocenyl naphthalene diimide Pulse voltammetry Gold 0.50 [24]
68 J. Wang / Analytica Chimica Acta 469 (2002) 63–71
event could be achieved in connection to the use of
horseradish-peroxidase (HRP) labeled target and an
electron-conducting redox polymer. In this system,
the hybridization of enzyme labelled oligo(dA)25 tar-
get with oligo(dT)25 probe, covalently attached to
electron-conducting redox hydrogel resulted in the
‘wiring’ of the enzyme to the transducer, and in a con-
tinuous hydrogen-peroxide electroreduction current.
A single-base mismatch in an 18-base oligonucleotide
was thus detected using a 7 ␮m-diameter carbon-fiber
transducer. A HRP label has been combined by Patol-
sky et al. [30] with a biocatalytic precipitative accu-
mulation of the enzyme-generating product to achieve
multiple amplifications and hence, extremely low
detection limits. Chronopotentiometry and faradaic
impedance spectroscopy were employed for detect-
ing the biocatalyzed deposition reaction. Applica-
bility for the detection of mutations relevant to the
Tay–Sachs genetic disorder was demonstrated. En-
hanced amplification of DNA sensing processes was
achieved also by using liposomes labeled with HRP
in connection to faradaic impedance spectroscopic
detection [31] (e.g. Fig. 4). Such use of functionalized
Fig. 4. Amplified electrical detection of DNA hybridization using HRP-functionalized liposomes and biocatalytic precipitation of the
product of the enzymatic reaction (from [31] with permission).
liposomes resulted in a dramatic signal amplification
(of ca. 105 ). The same enzyme label was employed for
quantitative pulse amperometric monitoring of PCR
amplification [32] and for differential pulse measure-
ments of sequences related to human cytomegalovirus
DNA [33]. The coupling of enzyme-based DNA as-
says with an efficient magnetic removal of unwanted
sample constituents has been illustrated in our labo-
ratory [34]. Enhanced “wiring” of enzyme labels is
anticipated through the emerging use of nanoparticle
superstructures [35].
2.3.3. Label-free electrochemical biosensing
of DNA hybridization
Increased attention has been given recently to direct
label-free electrochemical detection schemes, in which
the hybridization event triggers a change in an electri-
cal signal. Such protocols greatly simplify the sensing
protocol (as they eliminate the need for the indicator
addition/association/detection steps) and offers an in-
stantaneous detection of the duplex formation. Such
direct, in situ detection can be accomplished by mon-
itoring changes in the intrinsic redox activity of the
 J. Wang / Analytica Chimica Acta 469 (2002) 63–71
nucleic acid target or probe or changes in the electro-
chemical properties of the interface. For example, it is
possible to exploit changes in the intrinsic electroac-
tivity of DNA accrued from the hybridization event
[36–39]. Among the four nucleic acids bases, the gua-
nine moiety is most easily oxidized and is most suit-
able for such indicator-free hybridization detection.
To overcome the limitations of the probe sequences
(absence of G), guanines in the probe sequence were
substituted by inosine residues (pairing with C’s) and
the hybridization was detected through the target DNA
guanine signal [36]. A greatly amplified guanine sig-
nal, and hence, hybridization response can be obtained
by using the electrocatalytic action of a Ru(bpy)3 2+
redox mediator [37]. This involves the following cat-
alytic cycle:
Ru(bpy)3 2+ → Ru(bpy)3 3+ + e− (1)
Ru(bpy)3 3+ + G → Ru(bpy)3 2+ + G+ (2)
The presence of a guanine-containing nucleic acid
target thus creates a catalytic cycle that results in
a large current output. The ability of this approach
to detect mutations or deletions involving guanine
bases has been demonstrated [40]. This technology
is currently being used in a commercial nucleic acid
detection system (of Xanthon Inc.) that uses a 96-well
microtiter plate format, where each well contains
seven separate probe-coated indium–tin oxide elec-
trodes (two of which are used as controls) [41]. A
single microtiter plate thus allows 672 measurements
(480 tests and 192 controls). In addition to anodic
measurements of the target guanine, it is possible
to use cathodic stripping measurements of the target
adenine for sensitive detection of DNA hybridization
[39].
It is possible also to exploit different rates of
electron transfer through ss- and ds-DNA for prob-
ing hybridization (including mutation detection) via
the perturbation in charge migration through DNA.
Barton and coworkers demonstrated that such charge
transport is disrupted by the presence of a single-base
mismatch [42,43]. Such disruption and point muta-
tion were detected, using a gold electrode modified
with thiolated DNA, by monitoring changes in the
charge transport between an electroactive methylene
blue intercalator and a ferricyanide redox species.
A substantially smaller electrocatalytic signal was
69
observed in the presence of the single-base mismatch.
Prospects for designing electronic circuits based on
manipulation of charge transport through DNA were
discussed [44].
Direct, label-free, electrical detection of DNA hy-
bridization has also been accomplished by monitoring
changes in the conductivity of conducting polymer
molecular interfaces, e.g. using DNA-substituted
or doped polypyrrole films [45,46]. For example,
Korri-Youssoufi et al. [45] has demonstrated that
a 13-mer oligonucleotide-substituted polypyrrole
(PPy) film displays a decrease current response
during the duplex formation. Such change in the
electronic properties of PPy has been attributed to
bulky conformational changes along the polymer
backbone due to its higher rigidity following the
hybridization.
New avenues for generating the hybridization
signal are currently being explored in several lab-
oratories. Siontorou et al. [47] reported on the use
of self-assembled bilayer lipid membranes (BLMs)
for the direct monitoring of DNA hybridization. A
decrease in the ion conductivity across the lipid mem-
brane surface, containing the single-stranded probe,
was observed during the formation of the duplex. This
was attributed to alterations in the ion permeation as-
sociated with structural changes in the BLM accrued
by the desorption of the ds-DNA. The mechanism of
interaction between oligonucleotides and BLM films
was examined by Hianik et al [48]. Aoki et al. de-
veloped a novel ion-channel protocol for the indirect
biosensing of DNA hybridization [49]. The system
relied on the electrostatic repulsion of the diffusing
ferrocyanide redox marker, accrued from the hy-
bridization of the negatively-charged target DNA and
the neutral PNA probe (Fig. 5). High specificity to-
wards mismatch oligonucleotides was demonstrated.
A related approach for amplifying DNA hybridiza-
tion signals, based on the use of negatively-charged
liposomes, was described by Patolsky et al. [50].
Such liposomes bind to the bound target to form a
‘giant’ negatively-charged interface that repels the
anionic redox probe. The resulting barrier to the in-
terfacial electron transfer was monitored by Faradaic
impedance spectroscopy.
Berggren et al. demonstrated that changes in the
capacitance of a thiolated-oligonucleotide modified
gold electrode, provoked by hybridization to the
70 J. Wang / Analytica Chimica Acta 469 (2002) 63–71

Fig. 5. An ion-channel sensor based on a PNA probe immobilized on gold electrode, and detection of the hybridization based on the
electrostatic repulsion of a negatively-charged redox marker (shown as an octahedron) (from [49] with permission).

complementary strand (and the corresponding dis-
placement of solvent molecules from the surface), can
be used for monitoring in high sensitivity and speed
the hybridization event [51].
3. Conclusions and outlook
Over the past decade, we have witnessed a tremen-
dous progress towards the development of electro-
chemical nucleic acid biosensors. Such devices are of
considerable interest due to their tremendous promise
for obtaining sequence-specific information in a faster,
simpler, and cheaper manner compared to traditional
nucleic acid assays. In addition to excellent economic
prospects, such devices offer innovative routes for in-
terfacing (at the molecular level) the DNA-recognition
and signal-transduction elements, i.e. an exciting op-
portunity for fundamental research. The realization
of instant decentralized (medical, environmental, or
forensic) DNA testing would require additional devel-
opmental work. Particular attention should be given
to the major challenges of mismatch discrimination,
signal amplification, non-specific adsorbates, as well
as integration of various processes, including sample
collection, DNA extraction and amplification, with the
actual hybridization detection, on a single microchip
platform containing multiple functional elements and
related microfluidic network. Such integration and
miniaturization should lead to significant advantages
in terms of cost, speed, sample/reagent consumption,
simplicity, and automation. The integration of mul-
tiple biosensors in connection to DNA microarrays
should lead to the simultaneous analysis of multiple
nucleic acid sequences, and hence, to the generation of
characteristics hybridization patterns and acquisition
of expression information. Screening of DNA-protein
or DNA-drug interactions would also benefit from
such DNA microarrays. The rapid progress that elec-
trical detection for DNA hybridization has made in
the last decade suggests the major impact it may have
in the present decade. It is envisioned that future re-
search will lead to new electrical detection strategies,
that coupled with major technological advances, will
result in powerful, miniaturized, easy-to-use instru-
ments for DNA diagnostics. Such instruments will
undoubtedly accelerate the realization of large-scale
genetic testing.
 J. Wang / Analytica Chimica Acta 469 (2002) 63–71
Acknowledgements
The author gratefully acknowledges financial sup-
port from the US Army Medical Research (Award no.
DAMD17-00-1-0366) and the National Institutes of
Health (Grant no. R01 14549-02).
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