Biomedical Sensing Technologies

IEEE SENSORS JOURNAL, VOL. 3, NO.
3, JUNE 2003
251
Emerging Biomedical Sensing Technologies and

Their Applications
Gerard L. Cot, Senior Member, IEEE, Ryszard M. Lec, Member, IEEE, and Michael V. Pishko
AbstractRecent progress in biomedical sensing technologies

has resulted in the development of several novel sensor products
and new applications. Modern biomedical sensors developed with
advanced microfabrication and signal processing techniques are
becoming inexpensive, accurate, and reliable. A broad range of
sensing mechanisms has significantly increased the number of
possible target measurands that can be detected. The miniaturization of classical bulky measurement techniques has led to the
realization of complex analytical systems, including such sensors
as the BioChemLab-on-a-Chip. This rapid progress in miniature devices and instrumentation development will significantly
impact the practice of medical care as well as future advances
in the biomedical industry. Currently, electrochemical, optical,
and acoustic wave sensing technologies have emerged as some
of the most promising biomedical sensor technologies. In this
paper, important features of these technologies, along with new
developments and some of the applications, are presented.
I. INTRODUCTION
HE ongoing mergence of the 20th century revolution in

information technology with the 21st century revolution
in biotechnology poses considerable demand for new sensors,
in particular new biomedical sensors. Currently, the recent
advances in the microelectronics industry, the availability of
advanced microfabrication technologies down to the microand nanoscale, and inexpensive signal processing systems have
made the development of a variety of novel biomedical sensors
possible.
A good indication of that demand is the growing use of personal monitoring devices such as glucose sensors for diabetics
or the recently developed sensors for HIV detection. Biomedical sensors can also make medical care more personal and tailored to the individual needs of a patient. In the near future,
a treatment procedure could be adjusted to address a patients
unique metabolism and biological rhythms. For example, the
dose of a drug could be correctly determined in order to optimize the healing process and minimize its side effects. In addition, biomedical sensors will enable a broad range of medical
Manuscript received May 23, 2001; revised June 10, 2002. The associate editor coordinating the review of this paper and approving it for publication was
Prof. Henry Baltes.
G. L. Cot is with the Department of Biomedical Engineering Program,
Texas A&M University, College Station, TX 77843-3120 USA (e-mail:
cote@tamu.edu).
R. M. Lec is with the The School of Biomedical Engineering, Science
and Health Systems, and the Department of Electrical and Computer
Engineering, Drexel University, Philadelphia, PA 19104 USA (e-mail:
rlec@cbis.ece.drexel.edu).
M. V. Pishko is with the Department of Chemical Engineering, Pennsylvania State University, University Park, PA 16802 USA (e-mail:
mpishko@engr.psu.edu).
Digital Object Identifier 10.1109/JSEN.2003.814656
services at a patients home using a variety of systems that employ a personal computer and the Internet. One may envision
a dedicated home-based analytical diagnostic system interfaced
with a computer that could monitor and store medical data over
the life time of the person. In such a case, specialized application
software would be capable of recognizing incoming health problems and could notify a person in advance of her or his health
conditions.
A modern biomedical sensor is a device which consists of
a biologically or biophysically-derived sensing element integrated with a physical transducer that transforms a measurand
into an output signal. The requirements for any good biomedical
sensor are specificity or the ability to pick out one parameter
without interference of the other parameters, sensitivity or the
capability to measure small changes in a given measurand,
accuracy or closeness to the true measurement, time response,
biocompatibility, aging characteristics, size, ruggedness and
robustness, and low cost. In addition, the sensor must have
compatibility with the chemical, optical, optoelectronic, or
electronic integrated circuit (IC) technology. The above listed
features have been researched comprehensively over the last
two decades and critical knowledge has been accumulated
and the challenges have been identified. One may claim that
the biomedical sensor field has matured enough to be poised
for commercial success. In this paper, an overview of three of
the primary biomedical sensor technologies; electro-chemical,
optical and acoustic are discussed along with many of the
biomedical applications.
II. MODERN BIOMEDICAL SENSORS
A conceptual model of a biomedical sensor and its important design elements are shown in Fig. 1. This model presents
a complete biomedical sensor scheme in which, in addition to a
sensing section of a biomedical sensor, microfluidic, signal processing and packaging units are included. Simultaneous analysis
and design of all these elements are essential for the development of marketable biomedical sensors.
The principle of operation of such a biomedical sensor can
be inferred by following its sensing path. A measurand is introduced to a biomedical sensor using sample delivery system
or by bringing the sensor to the patient, as with implantable
or indwelling biomedical sensor probes. Next, the measurand
passes through a preprocessing section, such as semi-permeable
membrane, which performs a initial selective screening of possible interfering factors. After that, the measurand is exposed
to the sensing element, a biologically active substance which
is selective to the measurand of interest (i.e., DNA, antibodies,
1530-437X/03$17.00 2003 IEEE
252
IEEE SENSORS JOURNAL, VOL. 3, NO. 3, JUNE 2003
Fig. 1. General diagram of a biomedical sensor system. It should be noted that the biomedical sensor could be an array that would allow for simultaneous detection
of multiple measurands.
enzymes, or cellular components). When a measurand interacts with the sensing element, microscopic physical, chemical,
and/or biochemical changes are produced. These microscopic
changes cause the macroscopic physical changes in the sensing
element, which are converted by the physical transducer into an
output electric signal. The electric signal is conditioned, processed, and displayed. The processing can include such important sensor features as self-calibration, self-diagnostics, and advanced pattern recognition analyses. All these functional design
elements can be enclosed in the sensor package that provides
measurement integrity to the device.
In recent years significant progress has been made in all areas
listed above. However, the widest researched area has been on
the sensing elements and sensing mechanisms. Below is a short
overview of the current state in these areas with an emphasis
on the optical, electrochemical and acoustic biomedical sensing
technologies.
III. BIOMEDICAL TRANSDUCER TECHNOLOGIES
AND APPLICATIONS
Biomedical sensor development has in a large part depended
upon technologies primarily developed for other purposes.
The silicon-based microfabrication (IC) and micromechanical
(MEMS) techniques have been successfully applied for the
fabrication of a large range of miniature electrochemical
biomedical sensors. Similarly, the progress in optical biomedical sensors has been founded on fibers and devices purposed
for fiberoptic communication. Also, acoustic/piezoelectric
biomedical sensors capitalized on the decades-long growth of
RF telecommunication technologies. Piezoelectric elements
utilized in radar, cellular phones, electronic watches, etc.,

have been well applied to biomedical sensors. Other types of
biomedical sensors based on calorimetric, magnetic techniques,
etc. have also been effected significantly by modern IC and
MEMS techniques.
Currently, electrochemical, optical, and acoustic wave transducer technologies have emerged as some of the most promising
biomedical sensor technologies. In the following sections, important features of these technologies, some applications and
new trends and developments are presented.
A. Electrochemical Biomedical Sensing Technologies
Electrochemical biomedical sensors have been the subject of
research for a number of decades, with the vast majority of devices consisting of enzymes coupled to an electrode. These devices typically can be operated in two modes: potentiometric or
amperometric. Amperometric devices are by far the most prevalent and have seen commercialization for measurands such as
glucose and lactic acid. In an amperometric enzyme electrode,
an enzyme is immobilized on the surface of an electrode and
the product of the enzymatic reaction detected at the electrode
surface anodically or cathodically. For example, the commercially available Yellow Springs Instruments glucose electrode
uses the enzyme glucose oxidase immobilized on a membrane
placed over a platinum electrode. Glucose oxidase catalyzes
the reaction shown at the bottom of the page. One product of
this reaction, hydrogen peroxide, is oxidized at 700 mV (versus
a saturated calomel reference electrode) on the platinum electrode surface, producing a current that is directly proportional to
the amount of glucose in sample. Amperometric enzyme electrodes for other measurands such as lactate operate in a sim-
COT et al.: EMERGING BIOMEDICAL SENSING TECHNOLOGIES
ilar fashion. Amperometric glucose sensors have been by far

the greater commercial success and can be found on most pharmacy shelves in the form of home glucose test meters, such as
the Freestyle meter from Therasense and the One Touch meter
from Lifescan.
In addition to in vitro enzyme electrodes based on this detection scheme, the FDA has recently approved a subcutaneously
implantable glucose sensor [1], [2] based on the same principles.
Miniature needle-type amperometric glucose sensors have been
commercialized by MiniMed Corporation (Slymar, CA) for
the short-term monitoring of interstitial fluid glucose (Fig. 2).
Despite considerable efforts to develop a membrane and enzyme
system that is minimally affected by the foreign body response,
most subcutaneous sensors develop significant drift immediately following implantation. A rapid and progressive loss of
sensitivity can be attributed to protein/cellular fouling of the
membrane, enzyme dysfunction due to heavy metal toxicity, and
unstable levels of oxygen in the subcutaneous tissues. Accurate
real-time monitoring in the clinical setting requires frequent
recalibration of the in vivo sensor using an external glucose measurement reference method [3]. Markwell Medical Corporation
(Madison, WI) has developed a miniature implantable enzyme
based amperometric sensor with telemetry capable of measuring
interstitial fluid glucose long-term. Unique to this technology is a
multilayer protective membrane that promotes angiogenesis and
prevents the formation of a diffusion limiting fibrous capsule [4].
An iontophoretic transdermal glucose sensor [5][7] developed
by Cygnus, Inc. (Redwood City, CA) also used similar glucose
detection chemistry, but uses an electric field to extract interstitial
fluid from the skin and uses the sensor to measure glucose in this
field. Thus, the issue of a foreign body response is removed, but
significant extraction times (great than 7 min) are required to
remove enough interstitial fluid for a measurement.
Medical Research Group Corporation (Slymar, CA) has
developed a glucose sensor for long-term implantation within
the blood stream [8]. This device is also based on glucose oxidase
immobilized on a Pt electrode. However, the consumption of
oxygen is measured rather than the production of peroxide.
The miniature system looks like a pacemaker generator with
two flexible intravascular leads. An external patient module
provides a data display, visual and audible alarms for hypo- and
hyperglycemia, data storage, and telemetry for recalibration. The
protective membranes are reported to be relatively unaffected by
protein deposition and thrombosis by placing the catheter-based
sensor within the large vein of the chest (vena cava). Oxygen
sensors are used to measure the decrease in oxygen that occurs
in proportion to the oxidation of glucose. Venous blood oxygen
levels are measured by a second reference oxygen sensor to
provide enhanced specificity for glucose. Excellent long-term
stability has been demonstrated in human testing, requiring
infrequent recalibration. Eventual fouling of the protective
membranes and enzyme depletion limits the current system to
six months of continuous use. Methods to safely remove the
old system and surgically implant a new intravenous system are
beingdeveloped.Anintegratedsensor-controlledinsulindelivery
system (artificial endocrine pancreas) is being developed by
MRG consisting of the vena cava glucose sensor, an implantable
insulin pump and an adaptive computer control algorithm.
253
Fig. 2. Example of a typical bio-chemical sensing system (minimed

continuous glucose monitoring system; http://www.minimed.com/files/
cgms/patient_pg2.htm).
A number of research programs have sought to minimize the

oxygen dependency and improve the signal to noise level of
enzyme electrodes by replacing oxygen in the enzyme catalyzed
reaction with an electron acceptor/donor also called a mediator
[9]. In the case of glucose oxidase, the reaction becomes the
following:
where
is the mediator in its oxidized form and
is the
mediator in its reduced form. These mediators are typically
in the form of organometallic complexes such as ferrocene
and its derivatives and Os(imidazole) (bis-bipyridine) .
The mediators have lower oxidation potentials than hydrogen
peroxide and thus can be operated at lower potentials (200500
mV versus saturated calomel). Thus they are less suspectible
to interference from electroactive compounds such as ascorbic
acid and uric acid that are pervasive in vivo and in bodily fluids.
This type of chemistry has lead to commercial home glucose
test meters such as those manufactured by Abbott Laboratories,
Therasense, Roche, and Bayer.
A number of biomedical sensors based upon redox polymers
coupled to oxidoreductases have also been studied. In these
studies, the polymer served to immobilize the enzyme via formation of an insoluble protein/polymer complex, through the
physical entrapment of the enzyme in a polymer film and/or
through the covalent crosslinking of the enzyme and polymer.
These polymers are suitable as mediators for implantable sensors because they are less susceptible to mediator leaching from
the sensor as compared to small molecule mediators. Amperometric biomedical sensors based on redox polymer/enzyme
complexes were shown to be miniaturizable and could measure
desired species either intravenously or subcutaneously when implanted in rats, primates and human volunteers [10][12]. Because of the high current density these sensors exhibit, they can
be calibrated in vivo using a one-point calibration, i.e., the
device is calibrated from a blood glucose measurement and the
sensor current at one point in time.
A significant area recently has been in the development of
biomedical sensor arrays using nanostructured materials, for
both redundant sensing of a single analyte or multianalyte
sensing with a single device. Recent research on patterning
biomolecules on surfaces has focused primarily on self-assembled monolayers (SAMs) and tethered biomolecules on
surfaces that may potentially form addressable patterned arrays.
254
Amperometric patterned enzyme electrodes were formed using

SAMs patterned by scanning electrochemical microscopy
[13] or via microcontact printing followed by the electrostatic
assembly of a multilayer enzyme/redox polymer thin film [14].
Willner and colleagues reported amperometric glucose sensors
based on pyrroloquinoline quinone/glucose dehydrogenase
SAMs that exhibited high current densities [15][19]. These
surfaces are easily formed, particularly using alkane thiols and
their derivatives on gold-coated surfaces. SAMs also permit the
site specific immobilization and orientation of biomolecules
on a surface. However, two-dimensional approaches such as
SAMs may limit the number of biomolecule recognition sites
on the sensor surface and thus may have low signal levels
and require shielding or other measures to reduce noise. The
structure of self-assembled molecules on a surface can also
result in defects or pinholes in the monolayer and contribute
to instability, particularly at applied potentials. The current adhesion chemistry used in the fabrication of SAMs also permits
monolayer formation only on a limited number of surfaces,
most commonly gold. In addition to monolayers, photolithography and other photoinduced patterning chemistries were
highlighted in a few studies, demonstrating the formation of
patterned biomolecule surfaces and micropatterned polymers
for optical chemical sensing.
Electrode arrays can be fabricated using various methods,
however, thin film technology adopted from microelectronics
has been the predominant approach due to ease, quality,
reproducibility and low cost of manufacturing. Electrode
arrays have been photolithographically microfabricated on
thermally oxidized silicon, polyimide, and other insulating
substrates. Methods of immobilizing sensing components for
glucose and lactate detection onto electrode arrays, include
electrodeposition of proteins such as glucose oxidase and
the casting of proteins over the array surface. These studies
demonstrated the potential for fabricating successful sensor
arrays, however, there is still a need for a reproducible and
simple way of immobilization of sensing elements which also
allows for oxygen-free, mediated glucose, and lactate monitoring. One approach which affords excellent reproducibility
and control over architecture of the deposited species is based
upon multilayer electrostatic assembly [20]. This scheme
has been used to deposit oppositely charged redox polymers
and enzymes on electrode surfaces. Specifically, ferrocene
and osmium based cationic redox polymers were stacked
alternately with with anionic oxidoreductases such as pyruvate
oxidase (for pyruvate biosensors) and lactate oxidase, both of
which as polyanions at neutral pH. Resultant sensors yielded
reproducible current responses and showed no saturation for
physiologically relevant concentrations of analytes such as
glucose lactate and pyruvate. Examination of the nanostructure
of these thin films suggest that there is significant intercalation
between the cationic and anionic layers leading to a very
compact and stable nanocomposite structure.
B. Optical Biosensing Technologies
Recent advances in optic and electronic technologies have
lead to the research and development of many optic and fiber
Fig. 3. Michelson interferometer using bulk optics. The beam splitter is often
replaced with fiber optics.
optic biomedical devices. Indeed, there has been much enthusiasm as well as a strong effort by newly formed medical device companies, established medical device industry leaders,
and universities to investigate optical technologies for a host
of diagnostic and sensing procedures, including both bio-chemical and bio-physical based sensors. Examples of some optical
bio-physical sensors include the measurement of body temperature, blood velocity and intracranial pressure measurements
while the optical bio-chemical sensor examples include blood
chemical detection, blood micronutrient monitoring, and cancer
detection. In terms of optical biomedical sensors for monitoring
these parameters remotely into the body, fiberoptic probes can
be used. The utility of fiberoptic probes is that they offer the potential for miniaturization, good biocompatability for the visible
and near-infrared wavelengths, fast speed since light is used,
and safety, since no electrical connections to the body are required. In this section, we will briefly outline the latest mechanisms being explored for biomedical optical sensing today including interferometry, infrared absorption, scattering, luminescence and polarimetry.
1) Interferometric Biomedical Sensing: The phenomenon
of interference is a method by which physical light interaction
takes place and it depends on the superposition of two or more
individual waves, typically originating from the same source.
There are several variations for producing light interference
using both bulk optics and fiber optics but the Michelson
interferometer is the most common instrument used today
(Fig. 3), especially in the Fourier transform infrared (FTIR)
machines used for absorption spectroscopy and the relatively
new field of optical coherence tomography [21]. One example
of a fiber optic based interferometric sensor is the commercially available intracranial fluid pressure monitoring system
for patients with severe head trauma or a condition known as
hydrocephalus, which is an increased amount of cerebral spinal
fluid in the ventricles and/or subarachnoid spaces of the brain
[22]. In addition, the Michelson interferometer is currently
being investigated for sensing other biophysical parameters
such as tissue thickness, particularly for corneal tissue as
feedback for the radial keratectomy procedure, which is laser
removal or shaving of the cornea to correct vision [23], [24].
As mentioned, this interferometric approach, when used with
a low coherent light source and scanning or imaging array

technology, has been shown to produce morphological data
in vivo by a process known as optical coherence tomographic
(OCT) imaging [21], [25], [26]. Optical coherence tomography
is a fundamentally new sensing technology that allows visualization through tissue at very high resolution. It measures the
intensity of backreflected infrared light and allows resolutions
of 1020 m, but with a very limited depth of field, typically
12 mm. This approach has been used to investigate several
ocular diseases including macular disease, genetic retinal
disease, retinal detachment and retinoschisis, choroidal tumors,
optic nerve disorders, and glaucoma [25]. In addition, OCT
is useful over approximately the same distance of a biopsy
at high resolution and in real time. Consequently, the most
attractive applications for OCT are those where conventional
biopsies cannot be performed or are ineffective [21]. This
interferometric-based imaging approach could also be used in
cardiology for guiding coronary procedures [27], [28].
2) Absorption-Based Biomedical Sensing: Research in the
area of bio-chemically based optical sensing and, in particular,
infrared (IR) absorption-based sensing has been fueled in
a large part by the glucose sensing market. However, the
optical monitoring approaches currently clinically available
are the pulse oximeter, IR ear thermometer, hemoglobin and
hematocrit meter, and the new IR bilirubin sensor. The pulse
oximeter is based on the detection of changes in the strong
optical absorption peaks of oxygenated and de-oxygenated
hemoglobin and are available from vendors such as Criticare,
Datex-Ohmeda, Invacare, Novametrix, and Nellcor, to name
a few [29], [30]. The ear thermometer is based on receiving
infrared light from the tympanic membrane and is available
from vendors such as Becton Dickinson, Braun, Omron, and
Safety 1st [31]. Through the work of Groner, Winkelman, et
al. [32], and recently commercialized by Cytometrics, Inc.
as the Hemoscan 1000 [33], a noninvasive optical approach
has become available which has the potential to monitor
hemoglobin and hematocrit as an indicator of iron deficiency
in a clinical or field setting. The approach is based on imaging
the near-infrared absorption spectral peaks of hemoglobin but
using a polarized light input and been referred to as orthogonal
polarization spectral (OPS) imaging. The images are striking
but the key to this technology becoming truly useful as a field
device for blood monitoring is in the software development to
provide quantifiable data. The new bilirubin sensor is a near
infrared approach pioneered through the early work of Jacques
et al. [34], [35] and commercially developed by scientists at
SpectRx Inc.
In general, light absorption in a sample is governed by the
Beer-Lambert law in which the transmitted light is dependent on
the wavelength and intensity of the incident light, the path length
and the absorption coefficient or rather the sum of the multiplication of the molar absorptivity times the concentration of all the
different components in the measurand [36]. The primary means
for varying the wavelength of the light include dispersive and
nondispersive methods. The optical filter-based nondispersive
NIR systems are more commonly being developed by several
companies [37], [38], in particular for glucose sensing, because
they can be configured inexpensively and generally can have
255
better throughput if all the light is passed through the sample.

However, they have had limited success in producing repeatable and quantifiable results in vivo. The lack of repeatability of
the NIR signal in vivo both within and especially between patients is because the signal variations in most instances are not
fully understood or accounted for in the system. The primary
known drawbacks to taking this technology from an in vitro to
an in vivo monitoring device include the pathlength variability
of a pliable tissue, temperature variability of the peripheral site
such as the finger or earlobe and the presence of other chemically confounding substances (protein, urea, cholesterol, alcohols, etc.).
The latest technology in the IR biosensing field is in the development of clinical and chemical laboratories, in particular at
the Oak Ridge National Lab (ONRL), in which researchers have
miniaturized an infrared microspectrometer to the size of a sugar
cube [39]. Carved out of a solid block of plastic, the device measures 1.5 cm on a side and has no moving parts. It can be used
for blood chemistry analysis, as well as a number of nonmedical
processes. The plastic device uses a light source to excite certain types of compounds in gases, liquids and solids. These excited compounds give off infrared light of various wavelengths.
The measured emissions wavelengths are fed into a microchip,
which determines the concentrations of chemicals in a sample.
3) Biomedical Sensing Using Scattered Light: There are
fundamentally two types of optical scattering for diagnostics
and monitoring, elastic and inelastic. The elastic scattering
can be described using Mie theory (or Rayleigh scattering
for particles small compared to the wavelength), in which
the intensity of the scattered radiation can be related to the
concentration, size, and shape of the scattering particles. This
type of scatter is broadband and not typically specific enough
for biosensing [36], [40]. However, as a diagnostic screening
tool for cancer detection, measurement of the scatter in thin
tissues or cells may hold promise [41]. Many of the changes in
tissue due to cancer are morphologic rather than chemical and
thus occur with changes in the size and shape of the cellular
and subcellular components. Thus, the changes in elastic light
scatter should occur with morphologic tissue differences. If the
wavelength of the elastic light scattering is carefully selected
so as to be outside the major absorption areas due to water and
hemoglobin and if the diffusely scattered light is measured
as a function of angle of incidence, there is potential for this
approach to aid in pathologic diagnosis of disease [36].
One inelastic scattering approach in which the polarization
of the particle is not constant is known as Raman scattering,
which is observed when monochromatic (single wavelength) radiation is incident upon the media. The shift is associated with
transitions between rotational, vibrational, and electronic levels.
As with infrared spectroscopic techniques, Raman spectra can
be utilized to identify molecules since these spectra are characteristic of variations in the molecular polarizability and dipole
moments. The Raman signal in general is weak but the technology has advanced, with the replacement of slow photomultiplier tubes with faster CCD arrays, as well as the manufacture of higher power near infrared laser diodes, to allow for
biomedical sensing. However, this technology is still bulky and
expensive for most biomedical sensor applications and thus cur-
256
rently in the bench top study phase. The technology has allowed researchers to consider the possibility of distinguishing
normal and abnormal tissue types as well as studying a variety
of biological molecules including proteins, enzymes and immunoglobulins, nucleic acids, nucleoproteins, lipids and biological membranes, and carbohydrates quantifying blood chemicals in near-real time [42][49]. The diagnostic approaches look
for the presence of different spectral peaks and/or intensity differences in the peaks due to different chemicals present in, for
instance, cancerous tissue. For monitoring, investigators have
applied statistical methods such as partial least squares (PLS) to
aid in the estimation of biochemical concentrations from Raman
spectra [45], [46].
In addition to normal Raman scattering, biomedical sensors
have been developed using surface-enhanced Raman spectroscopy (SERS) that allows for orders of magnitude increase
in sensitivity. In particular, the ONRL group has developed
surface-enhanced Raman gene (SERG) probes that can locate
free DNA molecules that have hybridized to other DNAs fixed
on a surface [39]. This group uses a hybridization method in
which DNA is transferred from the nylon membrane to a glass
strip coated with tiny silver spheres. The dye labels attached
to the DNA bases have unique Raman infrared spectra, but the
normally weak Raman lines are greatly enhanced by the presence
of the silver spheres. This enhancement allows DNA bases to be
detected at sufficient sensitivity to be useful for DNA sequencing
studies. Using a silver colloid, SERS has also been used to detect
elevated levels of amino acids, in particular glutamate, in cerebral
spinal fluid after head trauma [50]. These elevated levels could
cause further damage and thus need to be quantifiably measured
in order to provide for pharmaceutical intervention.
4) Use of the Luminescence Property of Light for Biomedical
Sensing: Luminescence is the absorption of photons of electromagnetic radiation (light) at one wavelength and re-emission of
photons at another wavelength. The luminscent effect can be
referred to as fluorescence or phosphorescence. Fluorescence
is luminescence that has energy transitions that do not involve
a change in electron spin and therefore the re-emission occurs
much faster. Consequently, fluorescence occurs only during excitation while phosphorescence can continue after excitation.
The measurement of fluorescence has been used for both diagnostic and monitoring purposes. Obtaining diagnostic information, in particular with respect to cancer diagnosis or the
total plaque in arteries, has been attempted using the intrinsic
fluorescence of tissue [51], [52]. The intrinsic fluorescence is
due to the naturally occurring proteins, nucleic acids, and nucleotide coenzymes while extrinsic fluorescence is induced by
several mechanisms. For instance, antibody-based extrinsic fluorescent biomedical sensors have been developed for number
of biomedical applications including cancer diagnosis [53]. In
fact, such fluorescent biomedical sensor probes can be made at
the nanometer scale in which a laser beam (blue) that penetrates
a living cell is used with monoclonal antibodies that recognize
and bind to benzo(a)pyrene tetrol (BPT), indicating that the cell
has been exposed to a cancer-causing substance [54]. Extrinsic
fluorescence has also been investigated to monitor such measurands as glucose, intracellular calcium, proteins, and nucleotide
coenzymes [36]. Unlike the use of fluorescence in dilute solu-
tions, the intrinsic or autofluorescence of tissue as well as the

scattering and absorption of the tissue act as a noise source for
the extrinsic approach.
Most extrinsic fluorescent biomedical sensors are based on
either the measurement of intensity or lifetime, in which the
lifetime can be measured in the time or frequency domain
[55][58]. Bench-top systems typically are bulky and include
dual monochromators (grating based wavelength separation
devices) are used with either a photomuliplier tube as the
detector or a CCD array detector. However, once the optimal
configuration for a particular biomedical application, such
as cervical cancer detection or glucose sensing, has been
investigated using the bench-top machine, an intensity or phase
lifetime measurement system can be designed with a simpler,
more robust, configuration. Such a system can be designed
with wavelength specific filters instead of monochromators and
made to work at two or more discrete wavelengths. In addition,
optical fibers can be used for delivery and collection of the
light to the remote area [58]. Since the excitation wavelength
and fluorescent emission wavelengths are different, the same
fiber or fibers can be used to both deliver and collect the light.
As with many of the optical approaches discussed, a number
of novel fluorescence-based techniques seem to have evolved
from the glucose sensing application. Unlike many of the other,
noninvasive, optical approaches being investigated, because the
fluorescent glucose sensing approaches have to be in contact
with the sample, they have the advantage of being highly specific to the glucose. Those approaches that seem to have demonstrated the most promise generally fall into two categories: the
glucose-oxidase based sensors and the affinity-binding sensors
[43]. In the first category the sensors use the enzyme catalyzed
oxidation of glucose by glucose-oxidase (GOX), similar to the
electrochemical sensors but in this case they generate an optically detectable glucose-dependent signal. Several methods for
optically detecting the products of this reaction and hence the
concentration of glucose driving the reaction have been devised
[59], [60]. The primary drawback to GOX based sensors is that
their response depends not only on glucose concentration but on
local oxygen tension as well [43].
The affinity-based sensors do not depend on local oxygen;
however, many of the earlier affinity-binding techniques were
investigated for short term use since they required indwelling
probes [57], [58], [61][63]. In more recent work, these and
other investigators have exploited the phenomenon of fluorescence resonance energy transfer (FRET) whereby an acceptor in
close proximity to a fluorescent donor can induce fluorescence
quenching in the latter. Most recently, Russell et al. has reported
the use of poly(ethylene glycol) or PEG particles to encapsulate
the FRET assay [55]. In the work of Russell, it was reported that
it is possible to create a microparticle-based fluorescent glucose
assay system potentially suitable for subcutaneous implantation.
In addition to the above application, high sensitivity, short
collection time requirements, lack of sample contact, and
capability of scanning large areas/volume render fluorescence
methods an attractive alternative for microbial detection. One
fluorescence-based approach uses the intrinsic fluorescence
of tryptophan, other amino acids, and DNA which are excited
and fluoresce in the UV (200300 nm excitation, 300400 nm
257
Fig. 4. Schematic diagram of a biochip system (adapted from the virtual poster presentation of ORNL [http://www.ornl.gov/virtual/biomedical sensors/]).
emission). Observation of these markers is a sensitive indicator

of the presence of biological materials. However, all biological
materials contain these building blocks and, in addition, particles, such as dust, pollen, smoke, etc., preferentially scatter
UV/blue radiation (Raleigh scattering). These interferences
significantly reduce the utility of these markers. However, a
variety of microbial cell components exhibit intrinsic fluorescence: NAD[P]H, tryptophan, tyrosine, DNA, lumazines,
pterins, flavoproteins, and other secondary metabolites [64]. Of
these, NAD[P]H (360 nm excitation, 450/475 nm emission) has
been the most extensively studied. Other DPNH metabolites
have excitation and emission energies near that of NAD[P]H
and these metabolic signals can be obtained by integration
of the 425500-nm region fluorescence. This fluorescence is
directly proportional to the concentration of the metabolite,
e.g., NAD[P]H and related to the number of live (metabolizing) cells. Other components, such as flavoproteins and
cytochromes, have some absorption in this region, but their
concentrations are factors of 10100 less in living cells. In fact,
there are no interferences of biological origin in this region and
this fact has made redox fluorimetry based on NAD[P]H/DPNH
a vital tool in the investigation of cellular metabolism and
tissue oxygenation [65]. One method and prototype device for
the detection of microbial life on surfaces, such as foods, glass,
plastics, cloth, stainless steel, etc., developed by Estes et al.,
in environmental
has resulted in a sensitivity of
conditions [66].
Last, the latest research in luminescent sensing is a new

generation of reagents that report on specific molecular events
in living cells, called fluorescent protein biomedical sensors or
rather bioluminescent chips. These biomedical sensors have
evolved from in vitro fluorescence spectroscopy and fluorescent
analogue cytochemistry. The various probe designs measure the
molecular dynamics of macromolecules, metabolites, and ions
in single cells emerge from the integrative use of contemporary
synthetic organic chemistry, biochemistry, and molecular
biology [67]. For instance, a simple device consisting of a
coating of bioluminescent bacteria on top of a light-sensitive
integrated circuit can be used to emit light in direct correlation
to an measurand concentration [68]. The overall biochip design
can be represented as shown Fig. 4, as adapted from the virtual
poster presentation of ORNL [69].
5) Biomedical Sensing Using Light Polarization Properties: Two of the emerging applications of polarized light
are for biochemical quantification such as glucose and tissue
characterization, in particular, to aid in cancer identification
[70][73].
The concept behind these devices for measurand quantification is that the amount of rotation of polarized light by an optically active substance depends on the thickness of the layer traversed by the light, the wavelength of the light used for the measurement, the temperature, the pH of the solvent, and the concentration of the optically active material [43]. For polarimetry
to be used as a noninvasive technique, for instance in blood glu-
258
cose monitoring, the signal must be able to pass from the source,
through the body and to a detector without total depolarization
of the beam. Since the skin possesses high scattering coefficients, which causes depolarization of the light, maintaining polarization information in a beam passing through a thick piece of
tissue (i.e., 1 cm), which includes skin, would be very difficult,
if not impossible, although at least one company is attempting
this approach [74]. Tissue thickness of less than 4 mm that include skin have been tried [75] and may potentially be used but
the polarimetric sensing device must be able to measure millidegree rotations in the presence of greater than 95% depolarization
of the light due to scattering from the tissue. As an alternative to
transmitting light through the skin, the aqueous humor of the eye
has been investigated as a site for detection of in vivo glucose
concentrations since this sensing site is a clear biological optical
media [70], [71]. It is also known that glucose concentration of
the aqueous humor of the eye correlates well with blood glucose levels, with a minor time delay (on the order of minutes),
in rabbit models [71]. The eye as a sensing site, however, is not
without its share of potential problems. For instance, potential
problems with using the eye include corneal birefringence and
eye motion artifact [70]. In most tissues, including the eye, the
change in rotation due to other chiral molecules such as proteins needs to be accommodated in any final instrument. In addition, most other tissues also have a birefringence associated
with them that would need to be accounted for in a final polarimetric glucose sensor.
It is the birefringence and retardation of the polarized light, as
well as polarized scattering of the cells and tissue, that is the signal
rather than the noise when using polarized light for tissue characterization. It has been shown that scanning laser polarimetry provides statistically significant higher retardation for normal eyes
in certain regions over eyes with glaucoma. In addition to retardation in the retinal nerve fiber layer, images generated from the
scatteringofvariousformsofpolarizedlighthavealsobeenshown
to be able differentiate between cancer versus normal fibroblast
cells in vitro [76]. Using a simplified, cross-polarized system, the
potential of polarized light to not only distinguish between pigmented nevus and a freckle but also to retrospectively identify the
true border around a patient with a sclerosing basal cell carcinoma
has been tested in vivo [73], [77].
C. Acoustic Biomedical Sensors
Acoustic waves have been used to study physico-chemical
properties of gases, liquids, and solids for decades [78], [79].
In recent years, there has been an increase in efforts to utilize
acoustic waves for the development of biomedical sensors
[80][83]. Acoustic wave transducer technology provides
a wide range of devices that are sensitive, accurate, small,
portable, robust, and have excellent aging characteristics. In
addition, such transducers can be produced using standard
photolithography and hence are inexpensive. Acoustic waves
can be generated and received by a variety of means including
piezoelectric, magnetostrictive, optical, and thermal techniques
[84]. The piezoelectric transduction effect almost exclusively
has been utilized for generation and reception acoustic waves
in sensor applications.
Acoustic biomedical sensors are typically designed to operate

in a resonant type sensor configuration implemented as an oscillator. In this case, the output sensor signal is the resonant frequency shift, which is a function of the magnitude of the measurand. This is an important feature, since one can measure frequency relatively easily. In addition, the frequency can be considered as a quasidigital signal, which facilitates the subsequent
signal processing operations. Sensors configured as an oscillator can be equipped with an antenna for remote sensing and
control. Several recent oscillator circuits include an option for
measuring sensor losses which significantly expands measurement capabilities of portable acoustic sensors [80], [85]. Another advantageous feature of using piezoelectric materials is
that the same electro-mechanical transduction mechanism can
be used not only for sensing but also for actuation. This property
is essential for the design of piezoelectric surgical microcutters
[86] or liquid microflow systems [87]. Therefore, it is possible
to develop smart biostructures in which both sensing and actuating are realized within the same piezoelectric technology platform. Recently, a piezoelectrically-based Chem-Lab-on-a Chip
capable of detecting a variety of hazardous chemicals has been
reported [88]. In summary, the piezoelectric sensing platform
offers a very versatile technology base for the development of
sensors, actuators and smart structures.
1) Acoustic Waves, Piezoelectric Transducers and Acoustic
Sensing Mechanisms: There are different types of acoustic
wavesthatcanbeusedforbiomedicalsensing.Knowledgeof their
properties is important for the selection of the optimal acoustic
wave for a given measurand. Acoustic waves can be considered
as a source of distributed force acting on a medium. The resultant
deformation of a medium can be compressional or shear, or
consists of a combination of both. The type of the deformation
accompanying the wave is important because it determines
resultant acoustic sensing processes.Compressional deformation
is associated with the structural relaxational processes in the
medium, while shear is coupled with medium viscoelastic
properties and therefore they are sensitive to different molecular
processes [78], [79]. Compressional deformations are easily
transmitted through any gaseous, liquid or solid media. Shear
deformation, on the other hand, propagates only through solids
and penetrates only into liquids and gases. This last feature
is very favorable because it makes shear waves sensitive to
a numerous interfacial phenomena and this configuration is
utilized in most acoustic wave biomedical sensors. The wave
penetration depth, which depends on the frequency of the wave
and the density and viscoelastic properties of the medium,
ranges from microns to nanometers. Therefore, required sample
volumes for sensing are small and the sensitivity of the sensor
is high. In addition to mechanical phenomena, acoustic wave
sensors can also sense electrical properties of a medium. Electric
field probing of a medium is either generated by acoustic wave
displacement (via the piezoelectric effect) or is provided by a
sensor electrode structure. As a result, acoustic wave sensing
mechanisms are very broad and acoustic sensors are capable
of measuring the changes in mass/density, elastic modulus,
viscosity, electrical conductivity, and dielectric constant.
There are several types of waves that can be excited by
piezoelectric transducers and they can be classified as bulk and
259
Fig. 5. Classification of acoustic waves (bold-marked acoustic waves already have been used in biomedical sensors).
surface generated waves. The bulk generated waves are usually

excited by metalized bulk piezoelectric elements such as disks
or rods, whereas the surface generated acoustic waves are
excited by an interdigital system of metallic electrodes (IDT)
placed on the surface of piezoelectric materials. The electrodes
are used to connect the transducer with electronic circuitry
for the excitation and/or reception of acoustic waves. Two of
the most common configurations of piezoelectric transducers
include a thin metalized disk used for the excitation of bulk
waves which excite thickness shear modes (TSM) and an
interdigital transducer (IDT), which is applied for the excitation
of a surface Rayleigh wave (SRW), a surface transverse wave
(STW), a shear-horizontal acoustic plate mode (SH-APM), and
a flexural plate wave (FPW). The STWs form a large family of
various waves and include shear horizontal SAW (SH-SAW),
surface skimming bulk wave (SSBW), and Love wave modes
[83], [90]. In Fig. 5, a general acoustic wave classification
diagram is presented. Knowledge of the properties of acoustic
waves is important for the optimal design of a biomedical
sensor [80], [89], [91]. Specific properties of these waves, such
as the type of accompanying mechanical displacement, spatial
distribution of mechanical and electrical fields, susceptibility
to spurious mode coupling and the sensitivity of the wave to
ambient conditions such as temperature, pressure, etc., depend
on the cut of piezoelectric materials from which transducers are
made. There are many available materials for manufacturing
piezoelectric transducers including crystals, composites, and
hybrid structures, which provide a wide range of possible
sensing material design options. The most often used material
is quartz, which is chemically inert, has superior mechanical
properties and is temperature compensated [80], [81]. ATquartz cut orientation is routinely utilized for fabrication
of TSM-based resonator biomedical sensors. In Fig. 6, a
schematic presentation of a distribution of shear mechanical
displacement generated by a disk-shaped AT-cut transducer
immersed in water is given when the transducer operates at the
fundamental (a) and harmonic frequencies (b). As a general
rule, acoustic transducers can slice a biological interface at
Fig. 6. Conceptual model for a TSM transducer exposed on one side to water.
(Top) Sensor operating at the fundamental frequency. (Bottom) Sensor operating
at the fundamental frequency and higher harmonics.
different depths [Fig. 6(b)], hence providing important spatial

,
information. For SAW based devices various cuts of
and
crystals are used [80], [83]. Here, commonly
[82], ZX
[83] and ST-90
a 36Y rotated
[86] materials are utilized. In the case of the APF sensors a
silicon-ZnO hybrid structure is employed [80].
In a typical biomedical sensor, piezoelectric transducers are
integrated with biological sensing films in order to obtain a
required specificity (Fig. 1). Many biological materials such
as proteins (enzymes, antibodies, receptors), organelles, cells,
and tissue (microorganizms, animal and plant cells, and tissues)
have been used as molecular recognition elements in piezoelectric biomedical sensors. An important issue impacting the
260
Fig. 7.
Typical acoustic sensing process.
sensor performance is a proper attachment of a biological film to

the sensor surface. In addition to classical immobilization techniques [90], several novel bio-deposition techniques have been
recently developed and are successfully used with piezoelectric
sensors. Examples include SAMs [92], molecularly imprinted
polymers (MIPS) techniques for immobilization of antibodies
[93], and soft lithography patterning for proteins and cells [94].
A typical acoustic sensing process is schematically presented
in Fig. 7 and the corresponding measurement systems are
depicted in Fig. 8. When a measurand interacts with the sensing
element, microscopic physical, chemical and/or biochemical
changes are produced. These microscopic changes cause the
macroscopic acoustical/mechanical or electrical changes in the
sensing element. Specifically, the density, viscosity, elasticity,
electric conductivity, or dielectric constant of the sensing element undergo changes, which in turn modify the acoustic field
quantities of the acoustic wave transducer. The acoustic wave
transducer, which consists of a piezoelectric element with an
array of metal electrodes, acts as a converter which transducts
measurands into an output electric signal. For example, in
the acoustic immunosensors, the antibodies are immobilized
in the form of a thin film at the surface of the acoustic wave
transducer. When the target antigen is introduced into the
sensor environment, the elasticity, density, and viscosity of the
film vary and these variations modify the acoustic parameters
of the sensor, which finally leads to the changes in the output
sensor signal. Molecular interpretation of the sensor response
could be very simple or very complicated. When the sensing
film is rigid and acoustically thin, then the sensor response can
be related directly to mass accumulation of the measurand at
the interface [80], [96]. Examples include gas absorption by
thin rigid polymer films [83] and thin metal oxide films [97], or
some immunological reactions [98]. However, when the film
is acoustically thick then, in addition to mass effects, the film
viscous and elastic properties make significant contributions
to the sensor response and the relationship between the sensor
response and molecular events could be very complex [80],
[99], [100]. Also, other factors such as the type of the boundary
conditions or the topography of a sensor surface come into
importance and influence sensor response, as well [101], [102].
Therefore, different biological systems and measurement
conditions should be carefully studied in order to select or to
develop the correct sensor model representation. Modeling of
the sensor response is an area of ongoing, very active research,
and though significant progress has been made in the last several years, many issues still need to be addressed [103], [104].
Among them are the molecular nature of the electro-bio-mechanical boundary conditions, interfacial viscoelasticity, and
the development of dedicated computational techniques.
Acoustic biomedical sensors, from an electronic measurement
point of view, can be referred to as electrical radio-frequency (RF)
components such as resonators, filters, or delay lines. Therefore,
standard laboratory microwave measurement techniques based
on network analyzers, vector voltmeters, and impedance meters
are routinely used for the characterization of biomedical sensors
(Fig. 8). However, the resolution of these techniques is limited
and they are not applicable for real-life applications because of
the cost and size. Therefore, in recent years, a lot of effort has
been placed on the development of small portable biomedical
sensor measurement systems. Several designs allowing simultaneous measurement of the transducer frequency and dissipation
change have been proposed that are based on the frequency
and amplitude measurements (oscillators) [85], the decay time
and amplitude [87] or their combinations [91], but the overall
performance of these systems is only satisfactory [80]. Finally, a
very difficult and rather neglected issue is that of an enclosure for
a sensor. The separation of a fluid-based biological environment
from the electronic circuitry poses a very difficult task. Though
several ingenious mechanical measurement cell designs have
been devised [104] and various electrical passivating techniques
layers [96] and deposited polymer
utilizing sputtered thin
films [97] have been successfully tested, the complete design
that is commercially viable with an appropriate fluidic delivery
system still needs to be developed.
2) New Acoustic Sensing Devices and Applications: A
novel monolithic piezoelectric sensor (MPS) has been recently
presented for the detection of chemical and biochemical measurands [105]. This new sensor overcomes several deficiencies
associated with the typical two electrode system of a bulk TSM
(QCM) sensor, while still employing a well-characterized,
temperature-stable thickness-shear mode (TSM) response. This
new three-electrode structure, depicted in Fig. 9, is applicable
to both gaseous and liquid phase measurements; however, the
principal benefit of the MPS is in liquid phase measurements.
In these applications, it offers the ability to operate simple,
yet stable, oscillator circuits in relatively viscous media. This
novel MPS structure should accelerate the commercialization
of piezoelectric sensor technology, particularly in such areas as
biomedical, biochemical and environmental testing.
261
(a)
(b)
Fig. 9. Physical structure of the MPS. (a) The two active electrodes (upper
surface) each have area, A and are seperated by a gap width g. (b) The MPS
equivalent circuit consists of two TSM equivalent circuits with mechanical
coupling (modeled as mutual inductance) and a parasitic capacitance. (c)
Experimental amplitude (solid) and phase (square) response of the prototype
MPS with various viscous water-glycerol mixture loading [105].
Fig. 8. Laboratory and portable electronic measurement systems utilized with

acoustic biomedical sensors.
As well as the acoustic transducer technology, novel interfaces are also being developed. Biological recognition
elements require appropriate immobilization on the surface of a
transducer in order to maintain their bioactivity and specificity
of biointeraction. Several immobilization techniques, surface
modification methods, and a variety of novel intermediate materials supporting the attachment have been studied extensively
[106]. In particular, several polymer-based interfaces have been
proposed [107], [108]. One technique is a new very promising
polymer nanofiber structure for cell immobilization [109].
Nanofiber architecture closely resembles a natural collagen
structure which supports and promotes growth and proliferation
of tissue cells.
In addition to the aforementioned novel acoustic sensor
device and the artificial biomedical sensor interfaces, there
have been several new applications for acoustic sensors. These
include antibody-based, nucleic acid-based, enzyme-based,
and cell-based acoustic biomedical sensors. Antibody-based
or immunosensors have been the most explored and the most
advanced class of acoustic biomedical sensors. The interest
results from the fact that antibodies can be obtained against
almost any substance, antibody immobilization techniques are
numerous and well developed and the pertinent acoustic sensing
mechanism is simple and mostly determined by mass accumulation [110]. The detection process of antigens does not require
labeling, which is the obvious advantage. However, in a case
when nonspecific binding may interfere with detection, special
care needs to be taken to eliminate it [111]. Other advantages
of piezoelectric immunosensors are that they are reusable with

no noticeable degradation in performance [112]. In addition,
piezoelectric immunosensors can operate in optically opaque
media. Furthermore, piezoelectric sensors are inexpensive,
easy-to-use, and feature rapid response; hence, they may allow
for wide screenings and the development of effective preventive
strategies for a broad range of diseases. Such sensors are used
to determine the concentration of immunoglobulin IgM and
C-reactive protein [112]; human cells such as T-lymphocytes
[113], erythrocytes [114], herbicides in drinking water [115];
bacteria such as E.coli [116], Stalphylococcus aureus [117];
drugs (methamphetamine) in human urine [118]; and viruses
such as human herpes [119], hepatitis [120], African swine
fever [121], and HIV [122]. In particular, piezoelectric sensors
facilitated the detection of antibodies that are specific against
HIV within a few minutes in human serum sample. It is worth
noting that the selectivity and sensitivity was on a par with that
of a licensed HIV ELISA and a typical HIV sensor response
is given in Fig. 10 [122].
Exploiting advances in genetic sequence information technology and utilizing an inherent strong affinity interaction
between complementary nucleic acid strands, nucleic acid,
or DNA sensors are emerging as a very important class of
biomedical sensors [123], [124]. Unlike immunosensors,
which are susceptible to nonspecific binding, DNA sensors
provide higher selectivity and reliability. Similar to acoustic
immunosensors, no label is required for the detection of DNA.
However, much more complex immobilization procedures
challenge development of DNA sensors. DNA biomedical
sensors typically employ an immobilized single-stranded DNA
molecule for hybridizing with the complementary strand in
a given sample. Recently, a TSM quartz sensor was used
to monitor hybridization and affinity of several synthesized
antisense oligonucleotides [125]. Antisense oligonucleotides
are potential therapeutic agents used against cancer and viral
262
(a)
(b)
Fig. 10. (a) Resonance frequency change versus the time of a TSM HIV
immunosensor and (b) comparison of the results measured with the TSM HIV
sensor and with licensed ELISA [122].
diseases. A combination of a piezoelectric biomedical sensor

with PCR-amplified real Aeromonas bacteria samples allowed
detection of hybridization using only 205 bp fragments of
extracted DNA [126]. Genetic defects were identified with a
TSM biomedical sensor by measuring a single mismatch in a
15mer single-strand target of the p53 suppresser gene [127].
Other work reports a successful study on denaturation of DNA
[128], the detection of DNA polymorphisms [129] and the
real-time monitoring of enzymatic cleavage of nucleic acids
[130]. In comparison to traditional DNA analysis methods
[123], acoustic sensors offer a rapid and marker-free detection
of nucleic acid hybridization. Acoustic DNA sensors should
find a broad application in medical area for fast and inexpensive
screening of variety of diseases, in the pharmaceutical industry
during drug development process and also address many
sensing needs in monitoring environmental conditions.
Enzymes provide another important interface capable of
highly specific reactions with a variety of biological substances.
Though enzymes are biocatalysts, they participate in biological
transduction processes and have been extensively used for
biomedical sensor development. Enzymes catalyze bioreactions at a very high reaction rate, have well-characterized
mechanisms of action, are easily immobilized, are available
for broad range of applications and are inexpensive [131].
Several AT-cut TSM quartz glucose sensors using immobilized
hexokinaze [132] and glucose oxidase [133] have been studied.
In the last case, glucose levels were measured in situ and the
sensor responded in 80100 s with a linear relation to glucose
in the concentration range between 30200 uM. Chang and

Shih [134] developed a fullerene-cryptan-coated piezoelectric
membrane glucose enzyme sensor by measuring gluconic acid,
a product of glucose oxidase in glucose aqueous solutions.
They found that the interference from various common species
found in the human blood was negligible. Piezoelectric glucose
meters are in a position to pose an alternative solution to well
known electrochemical portable glucometers.
Last, acoustic biomedical sensors incorporating living cells
are capable of delivering functional information in contrast
to previously discussed protein-based sensors, which provide
analytical data. Functional information, i.e., information about
the physiological effect of a measurand on a living system, is
often desired in many important applications in pharmacology,
toxicology, cell biology, and environmental measurements
[135]. Important properties of cultured animal cells such as
attachment, proliferation and cell-substrate interaction under
different conditions were successfully monitored using TSM
sensors. In particular, extracellular matrix deposition, the
integrity of the actin cytoskeleton, cell-substrate separation
distance, and mechanical properties of the narrow cleft between cell and substrate were determined [136]. Steinem et al.
[137] utilized acoustic sensors for analysis of the interactions
ganglioside-lectin and ganglioside-toxin (cholera, tetanus, pertusis). Because a cell-based sensing process is physiologically
relevant to natural cellular machinery, these sensor types will
experience growing significance in the near future.
IV. CONCLUSION
About $20 billion per year are spent for analytical testing
worldwide. Specialized laboratories located away from a
patient, doctor, or hospital perform nearly all of the testing
causing significant time delays in reporting results. Modern
biomedical sensors developed with advanced microfabrication
and signal processing techniques are becoming inexpensive,
accurate, and reliable and, with an average detection time on
the order of a few minutes, can significantly reduce the delay
time as well as bring the testing to doctors offices and patients
homes. As a result, the wide use of biomedical sensors may
lead to more individualized health care services that will be
tailored for the needs of a patient and will match a specific
genotype. Indeed, one may envision using biomedical sensors
for optimizing drug doses, monitoring the effectiveness of
treatments, and monitoring health conditions over persons
life time. In addition to decreased time delays, miniaturization of biomedical sensors and integration with microfluidic
devices is yielding advanced analytical microsystems such as
a BioChemLab-on-a-Chip. Integration of several sensors on
a single substrate produces transducer arrays. A few recent
examples include electronic noses and tongues that are capable
of performing multimeasurand detection in a few minutes.
For a more complete listing of various biomedical, biological,
and biosensing applications, the authors refer the reader to
the following references [138][140]. Overall, these exciting
developments forecast a biomedical sensor revolution that
could dramatically change the way in which the medical,
pharmaceutical, and environmental industries practice their
fields in the future.
REFERENCES
[1] J. J. Mastrototaro et al., An Electroenzymatic Glucose Sensor Fabricated
on a Flexible Substrate, pp. 300302, 1990.
, An electroenzymatic glucose sensors fabricated on a flexible sub[2]
strate, Sens. Actuators B, vol. 5, pp. 139144, 1991.
[3] W. K. Ward and J. E. Troupe, Assessment of chronically implanted
subcutaneous glucose sensors in dogs: The effect of surrounding fluid
masses, ASAIO 45, pp. 555561, 1999.
[4] S. J. Updike, B. J. Gilligan, M. C. Shults, and R. K. Rhodes, A subcutaneous glucose sensor with improved longevity, dynamic range and stability of calibration, Diabetes Care, vol. 23, no. 2, pp. 208214, 2000.
[5] G. Rao et al., Reverse iontophoresis: Noninvasive glucose monitoring
in vivo in humans, Pharm. Res., vol. 12, no. 12, pp. 18691873, 1995.
[6] J. Tamada, N. Bohannon, and R. Potts, Measurement of glucose in diabetic subjects using noninvasive transdermal extraction, Nature Med.,
vol. 1, no. 11, pp. 11981201, 1995.
[7] J. Tamada et al., Noninvasive glucose monitoring. Comprehensive clinical results, J. Amer. Med. Assoc., vol. 282, no. 19, pp. 18391844,
1999.
[8] J. C. Armour, J. Y. Lucisano, B. D. McKean, and D. A. Gough, Application of chronic intravascular blood glucose sensor in dogs, Diabetes,
vol. 39, pp. 15191526, 1990.
[9] A. E. G. Cass et al., Ferrocene-mediated enzyme electrode for amperometric determination of glucose, Anal. Chem., vol. 56, pp. 66771,
1984.
[10] E. Csoregi et al., Design, characterization and one-point in vivo calibration of a subcutaneously implanted glucose electrode, Anal. Chem.,
vol. 66, pp. 31313138, 1994.
[11] E. Csoregi, D. Schmidtke, and A. Heller, Design and optimization
of a selective subcutaneously implantable glucose electrode based on
wired glucose oxidase, Anal. Chem., vol. 67, pp. 12401244, 1995.
[12] C. P. Quinn et al., Kinetics of glucose delivery to subcutaneous tissue
in rats: A study utilizing amperometric biosensors, Amer. J. Physiol.,
vol. 269, no. 32, p. E155, 1995.
[13] G. Wittstock and W. Schuhmann, Formation and imaging of microscopic enzymatically active spots on an alkanethiolate-covered gold
electrode by scanning electrochemical microscopy, Anal. Chem., vol.
69, pp. 50595066, 1997.
[14] K. Sirkar and M. Pishko, Amperometric biosensors based on oxidoreductases immobilized in photopolymerized poly(ethylene glycol) redox
polymer hydrogels, Anal. Chem., vol. 70, pp. 28882894, 1998.
[15] A. N. J. Moore, E. Katz, and I. Willner, Immobilization of pyrroloquinoline quinone on gold by carbodiimide coupling to adsorbed
polyamines: Stability comparison to attachment via a chemisorbed thiol
monolayer, Electroanal., vol. 8, no. 12, p. 1092, 1996.
[16] A. Riklin et al., Improving enzyme-electrode contacts by redox modification of cofactors, Nature, vol. 376, pp. 672675, 1995.
[17] I. Willner et al., Electrical wiring of glucose oxidase by reconstitution
of FAD-modified monolayers assembled onto au-electrodes, J. Amer.
Chem. Soc., vol. 118, pp. 10 32110 322, 1996.
[18] I. Willner and B. Willner, Electrical communication of redox proteins
by means of electron relay-tethered polymers in photochemical, electrochemical and photoelectrochemical systems, React. Polym., vol. 22,
pp. 267279, 1994.
[19] I. Willner, E. Katz, and B. Willner, Electrical contact of redox enzyme
layers associated with electrodes: Routes to amperometric biosensors,
Electroanal., vol. 9, no. 13, pp. 965977, 1997.
[20] K. Sirkar, A. Revzin, and M. Pishko, Glucose and lactate biosensors
based on redox polymer/oxidoreductase nanocomposite thin films,
Anal. Chem., vol. 72, no. 13, pp. 29302936, 2000.
[21] D. Huang, E. A. Swanson, C. P. Lin, J. S. Schumann, W. G. Stinson,
W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J.
G. Fujimoto, Optimal coherence tomography, Science, vol. 254, pp.
11781181, 1991.
[22] R. A. Wolthuis, G. L. Mitchell, E. Saaski, J. C. Hartl, and M. A. Afromowitz, Development of medical pressure and temperature sensors employing optical spectrum modulation, IEEE Trans. Biomed. Eng., vol.
38, pp. 97481, Oct. 1991.
[23] C. K. Hitzenberger, A. Baumgartner, W. Drexler, and A. F. Fercher, Interferometric measurement of Corneal thickness with micrometer precision, Amer. J. Ophthal., vol. 118, no. 4, pp. 468476, 1994.
[24] J. Merchant, Optical Coherence Reflectometry for the Measurement of
Collagen Thickness, Masters thesis, Dept. Biomed. Eng., Texas A&M
Univ., College Station, 1998.
263
[25] P. Hrynchak and T. Simpson, Optical coherence tomography: An introduction to the technique and its use, Optom. Vis. Sci., vol. 77, no. 7, pp.
34756, July 2000.
[26]
Light Lab Imaging, Westford, MA. [Online]. Available:
http://www.lightlabimaging.com/oct.html
[27] M. E. Brezinski, G. J. Tearney, B. E. Bouma, J. A. Izatt, M. R. Hee, E.
A. Swanson, J. F. Southern, and J. F. Fujimoto, Optical coherence tomography for optical biopsy, Properties Demonstration Vasc. Pathol.,
Circ., vol. 93, no. 6, pp. 120613, Mar. 1996.
[28] M. E. Brezinski, G. J. Tearney, N. J. Weissman, S. A. Boppart, B. E.
Bouma, M. R. Hee, A. E. Weyman, E. A. Swanson, J. F. Southern, and
J. G. Fujimoto, Assessing atherosclerotic plaque morphology: Comparison of optical coherence tomography and high frequency intravascular
ultrasound, Heart, vol. 77, no. 5, pp. 397403, May 1997.
[29] Profox Oximetry Software. PROFOX Associates, Inc., Escondido, CA.
[Online]. Available: http://www.profox.net/pages/2compdevs.html
[30] Pulse Oximetry. Novametrix Medical Systems Inc., Wallingford, CT.
[Online]. Available: http://www.novametrix.com/ix_ox.html
[31] Ear Thermometer Review From Epinions Inc., Brisbane, CA. [Online].
Available: http://www.epinions.com/well-Supplies-Home_DiagnosticsThermometers-All-Ear
[32] W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K.
Messmer, and R. G. Nadeau, Orthogonal polarization spectral imaging:
A new method for study of the microcirculation, Nat. Med., vol. 5, no.
10, pp. 120912, Oct. 1999.
[33] Hemoscan 1000 Noninvasive Optical Monitor for Hemoglobin and
Hematocrit. Cytometrics Inc., Philadelphia, PA. [Online]. Available:
http://www.cytometrics.com/
[34] I. S. Saidi, S. L. Jacques, and F. K. Tittel, Monitoring neonatal bilirubinemia using an optical patch, in Proc. SPIE Opt. Fibers Med. V, vol.
1201, A. Katzir, Ed., 1990, pp. 569578.
[35] I. S. Saidi, S. L. Jacques, M. Keijzer, and F. K. Tittel, Optical fiber probe
monitor for neonatal bilirubinemia, in Proc. 11th Int. Conf. IEEE Eng.
Med. Biol. Soc. 2, 1989, pp. 120102.
[36] J. Enderle, S. Blanchard, and J. Bronzino, Introduction to biomedical
engineering, in Biomed. Optics and Lasers Contributed, G. L. Cot, S.
Rastegar, and L. Wang, Eds. New York: Academic, 2000, ch. 17, pp.
843903.
[37] K. Day, SEC accuses Futrex Incorporated of fraud, Washington, DC,
1996.
[38] P. Sabatini, Biocontrols Diabetes monitor still faces hurdles,
Burlington, MA, 1996.
[39] B. K. Jacobson. Biosensors and Other Medical and Environmental
Probes. ONRL Center for Biotechnology. [Online]. Available:
http://www.ornl.gov/ORNLReview/rev29_3/text/biosens.htm
[40] G. L. Cot, Noninvasive optical glucose sensingAn overview, J.
Clinical Eng., vol. 22, no. 4, pp. 2539, 1997.
[41] J. R. Mourant, M. Canpolat, C. Brocker, O. Esponda-Ramos, T. M.
Johnson, A. Matanock, K. Stetter, and J. P. Freyer, Light Scattering
From Cells: The Contribution of the Nucleus and the Effects of
Proliferative Status, vol. 5, no. 2, pp. 13137, Apr. 2000.
[42] A. Mahadevan-Jansen and R. Richards-Kortum, Raman spectroscopy
for the detection of cancers and precancers, J. Biomed. Opt., vol. 1, no.
1, pp. 3170, 1996.
[43] R. J. McNichols and G. L. Cot, Optical glucose sensing in biological
fluids: An overview , J. Biomed. Opt., vol. 5, no. 1, pp. 516, Jan. 2000.
[44] A. J. Berger, I. Itzkan, and M. S. Feld, Feasibioity of measuring
blood glucose concentration by near infrared Raman spectroscopy,
Spectrochim. Acta A., vol. 53, no. 2, pp. 28792, 1997.
[45] M. J. Goetz Jr., G. L. Cot, W. F. March, R. Erckens, and M. Motamedi,
Application of a multivariate technique to Raman spectra for quantification of body chemicals, IEEE Trans. Biomed. Eng., vol. 42, pp.
72831, July 1995.
[46] J. Lambert, M. Storrie-Lombardi, and M. Borchert, Measurement
of physiological glucose levels using Raman spectroscopy in a rabbit
aqueous humor model, IEEE-LEOS Newslett., vol. 12, no. 2, pp.
1922, 1998.
[47] R. V. Tarr, The non-invasive measure of D-glucose in the ocular
aqueous humor using stimulated Raman spectroscopy, Ph.D. dissertation, Georgia Inst. Technol., Atlanta, 1991.
[48] S. Y. Wang et al., Analysis of metabolites in aqueous solutions by using
laser Raman spectroscopy, Appl. Opt., vol. 32, no. 6, pp. 925929,
1993.
[49] J. P. Wicksted, R. J. Erkens, M. Motamedi, and W. F. March, Monitoring of aqueous humor metabolites using Raman spectroscopy, in
Proc. SPIE, vol. 2135, 1994, pp. 264274.
264
[50] D. P. ONeal, M. Motamedi, J. Chen, and G. L. Cot, Surface-enhanced

Raman spectroscopy for the near real-time diagnosis of brain trauma
in rats, in Proc. SPIE Int. Symp. Biomed. Opt., Optical Diagnostics of
Biological Fluids V3918, San Jose, CA, Jan. 2228, 2000.
[51] U. Utzinger, E. V. Trujillo, E. N. Atkinson, M. F. Mitchell, S. B. Cantor,
and R. Richards-Kortum, Performance estimation of diagnostic tests
for cervical precancer based on fluorescence spectroscopy: Effects of
tissue type, sample size, population and signal-to-noise ratio, IEEE
Trans. Biomed Eng., vol. 46, pp. 1293303, Nov. 1999.
[52] A. L. Bartorelli, M. B. Leon, Y. Almagor, L. G. Prevosti, J. A. Swain,
C. L. McIntosh, R. F. Neville, M. D. House, and R. F. Bonner, In
vivo human atherosclerotic plaque recognition by laser-excited fluorescence spectroscopy, J. Amer. Coll. Cardiol., vol. 17, no. 6 Suppl B, pp.
160B168B, May 1991.
[53] M.-C. Moreno-Bondi, J. Mobley, J.-P. Alarie, and T. Vo-Dinh, Antibody-based biosensor for breast cancer with ultrasonic regeneration, J.
Biomed. Opt., vol. 5, no. 3, pp. 35054, July 2000.
[54]
Nanosensor Probes Single Living Cells. ONRL Center for
Biotechnology. [Online]. Available: http://www.ornl.gov/ORNLReview/rev32_3/nanosens.htm
[55] R. Russell, C. Gefrides, M. McShane, G. Cote, and M. Pishko, A fluorescence-based glucose biosensor based on concanavalin A and dextran
encapsulated in a Poly(ethylene glycol) hydrogel, Anal. Chem., vol. 71,
no. 15, pp. 31263132, 1999.
[56] E. M. Sevick-Muraca, J. S. Reynolds, T. L. Troy, G. Lopez, and D. Y.
Paithankar, Fluorescence lifetime spectroscopic imaging with measurements of photon migration, Ann. N.Y. Acad. Sci., vol. 838, pp. 4657,
Feb. 1998.
[57] J. R. Lakowicz and B. Maliwal, Optical sensing of glucose using phasemodulation fluorimetry, Anal. Chim. Acta, vol. 271, pp. 15564, 1993.
[58] J. S. Schultz, S. Mansouri, and I. J. Goldstein, Affinity sensor: A new
technique for developing implantable sensors for glucose and other
metabolites, Diabetes Care, vol. 5, no. 3, pp. 245253, 1982.
[59] Z. Rosenzweig and R. Kopelman, Analytical properties and sensor size
effects of a micrometer-sized optical fiber glucose biosensor, Anal.
Chem., vol. 68, no. 8, pp. 140813, 1996.
[60] B. P. Schaffar and O. S. Wolfbeis, A fast responding fiber optic glucose
biosensor based on an oxygen optrode, Biosens. Bioelectron., vol. 5,
no. 2, pp. 13748, 1990.
[61] R. Ballerstadt and J. S. Schultz, Competitive-binding asay method
based on fluorescence quenching of ligands held in close proximity by
a multivalent receptor, Anal. Chim. Acta, vol. 345, pp. 20312, 1997.
[62] S. Mansouri and J. S. Schultz, A miniature optical glucose sensor based
on affinity binding, Biotechnol., pp. 88590, 1984.
[63] D. L. Meadows and J. S. Schultz, Design, manufacture and characterization of an optical fiber glucose affinity sensor based on an homogeneous fluorescence energy transfer assay system, Anal. Chim. Acta, vol.
280, pp. 2130, 1993.
[64] R. Dalterio, W. Nelson, D. Britt, J. Sperry, J. Tanguay, and S. Suib, The
steady-state and decay characteristics of primary fluorescence from live
bacteria, Appl. Spectrosc., vol. 41, p. 234, 1987.
[65] C. Barlow and B. Chance, Ischemic areas in perfused rat hearts: Measurement by NADH fluorescence photography, Science, vol. 193, p.
909, 1976.
[66] C. Estes, A. Duncan, B. Wade, and L. Powers, Real-time multiwavelength microbe detection instrument, in Abstract for Poster Presentation at the EMBS/BMES Joint Conf., Atlanta, GA, Oct. 1316, 1999.
[67] K. A. Giuliano, P. L. Post, K. M. Hahn, and D. L. Taylor, Fluorescent
protein biosensors: Measurement of molecular dynamics in living cells,
Annu. Rev. Biophys. Biomol. Struct., vol. 24, pp. 40534, 1995.
[68] G. Spera, Biosensor research targets medical diagnostics, MDDI, Nov.
1997.
[69] T. Vo-Dinh. Virtual Poster Session: Biosensors and Biochips for
Environmental and Biomedical Applications. Advanced Monitoring
Development Group, Life Sciences Division, Oak Ridge Nat.
Lab., Oak Ridge, TN. [Online]. Available: http://www.ornl.gov/virtual/biosensors/
[70] B. D. Cameron, H. Gorde, B. Satheesan, and G. L. Cot, The use of polarized laser light through the eye for noninvasive glucose monitoring,
Diabetes Technol. Therapeutics, vol. 1, no. 2, pp. 13543, 1999.
[71] W. F. March, B. Rabinovitch, and R. L. Adams, Noninvasive glucose
monitoring of the aqueous humor of the eye: Part II animal studies and
the scleral lens, Diabetes Care, vol. 5, no. 3, pp. 259265, 1982.
[72] M. J. Rakovic, G. Kattawar, M. Mehrubeoglu, B. D. Cameron, L. V.
Wang, S. Rastegar, and G. L. Cote, Light backscattering polarization
patterns from turbid media: Theory and experiment, Appl. Opt., vol.
38, no. 15, pp. 33993408, May 1999.
[73] S. L. Jacques, J. R. Roman, and K. Lee, Imaging superficial tissues with

polarized light, lasers in surgery and medicine, vol. 26, pp. 119129,
2000.
[74] F. Madarasz. The Photonic Molecular Probe, a Noninvasive Blood Glucose Meter. International Diagnostic Technologies, Inc., Madison, AL.
[Online]. Available: http://www.idtscience.com/Default.htm
[75] V. Kupershmidt, Method and Apparatus for Non-Invasive Phase
Sensitive Measurement of Blood Glucose Concentration, U.S. Patent,
5 448 992, Sept. 1995.
[76] A. H. Hielscher, J. R. Mourant, and I. J. Bigio, Influence of particle
size and concentration on the diffuse backscattering of polarized light
from tissue phantoms and biological cell suspensions, Appl. Opt., vol.
36, pp. 12535, 1997.
[77] S. L. Jacques. (1998) Video Imaging With Polarized Light
Finds Skin Cancer Margins not Visible to Dermatologists.
Oregon Medical Laser Center NewsEtc.. [Online]. Available:
http://omlc.ogi.edu/news/feb98/polarization/index.html
[78] A. J. Matheson, Molecular Acoustic. New York: Wiley-Interscience,
1971.
[79] A. B. Bathia, Ultrasonics Absorption. London, U.K.: Clarendon,
1967.
[80] D. S. Ballantaine, R. M. White, S. J. Martin, A. J. Ricco, E. T. Zellers, G.
C. Frye, and Wohltjen, Acoustic Wave Sensors. New York: Academic,
1997.
[81] R. L. Bunde, E. J. Jarvi, and J. Rosentreter, Piezoelectric quartz crystal
biosensors, Talanta, vol. 46, pp. 12231236, 1998.
[82] R. M. Lec and P. A. Lewin, Acoustic wave biosensors, Proc. 20th
Annu. IEEE Eng. Med. Biol. Soc., vol. 20, no. 6, pp. 27852790, 1998.
[83] J. C. Andle and J. F. Vetelino, Acostic wave biosensors, Sens. Actuators A, vol. 44, pp. 167176, 1994.
[84] M. G. Silk, Ultrasonic Transducers for Nondestructive Testing. New
Yorkl: Adam Hilger, 1984.
[85] F. Eichelbaum, R. Borngraber, J. Schroder, and R. Lucklum, Interface
circuits for quartz-crystal microbalance sensors, Rev. Sci. Instrum., vol.
70, no. 5, pp. 211, 1999.
[86] H. Takeuchi, H. Abe, and K. Yamanouchi, Ultrasonic micromanipulation of small particles in liquid using VHF-range leaky wave transducer,
in Proc. Ultrason. Symp., Cannes, France, 1994, pp. 607611.
[87] A. Lal, Silicon-Based ultrasonic surgical actuators, Proc. 20th Annu.
IEEE Eng. Med. Biol. Soc., vol. 20, no. 6, pp. 27852790, 1998.
[88] Sandias Tiny Acoustic Wave Sensors Will Detect Minute Traces of
Dangerous Chemicals, Sandia Nat. Lab. News Releases, Albuquerque,
NM, 1999.
[89] G. McHale, M. I. Newton, M. K. Banerjee, and J. A. Cowen, Acoustic
wave-liquid interactions, Mater. Sci. Eng. C, vol. 12, pp. 1722, 2000.
[90] M. Vellekoop, Acosutic wave sensors and their technology, Ultrason.,
vol. 36, pp. 714, 1998.
[91] F. Josse, R. Dahint, J. G. Schmacher, J. C. Andale, and J. F. Vetelino, On
the mass sensitivity of acoustic-plate-mode sensors, Sens. Actuators A,
vol. 53, pp. 243248, 1996.
[92] X. Su, F. Chew, and S. F. Y. Li, Self-assembled monolayer-based piezoelectric crystal immonosensor for the quantification of total human immunoglobulin E, Anal. Biochem., vol. 273, pp. 6672, 1999.
[93] J. Rickert, T. Weiss, W. Kraas, G. Jung, and W. Gopel, A new affinity
biosensor: Self-assembled thiols as selective monolayers coatingd
of quartz crystal microbalances, Biosens. Bioelectron., vol. 11, pp.
591598, 1996.
[94] L. I. Andersson, Molecular imprinting: Developments and applications
in the analytical chemistry field, J. Chromatography B, vol. 745, pp.
313, 2000.
[95] R. S. Kane, S. Takayama, E. Ostuni, D. E. Ingber, and G. M. Whitesides,
Patterning proteins and cells using soft lithography, Biomater., vol. 20,
pp. 23632376, 1999.
[96] R. Lucklum, C. Behling, and P. Hauptmann, Role of mass accumulation
and viscoelastic film properties for the response of acoustic-wave-based
chemical sensors, vol. 71, pp. 24882496, 1999.
[97] C. Behling, R. Lucklum, and P. Hauptmann, Response of quartz-crystal
resonators to gas and liquid measurand exposure, Sens. Actuators A,
vol. 68, pp. 388398, 1998.
[98] R. Lucklum, C. Behling, and P. Hauptmann, Gravimetric and nongravimetric chemical quartz resonators, Sens. Actuators B, vol. 65, pp.
277283, 2000.
[99] B. Knig and M. Grtzel, A piezoelectric immunosensor for hepatitus
viruses, Anal. Chim. Acta, vol. 309, pp. 1925, 1995.
[100] S. J. Martin and G. C. Frye, Dynamics and response of polymer-coated
acoustic devices, solid-state sensor and actuator workshop, in 5th Tech.
Dig., 1992, pp. 2731.
[101] T. W. Schneider and S. J. Martin, Influence of compressional wave generation on thickness-shear mode resonator responses in a fluid, Anal.
Chem., vol. 65, no. 18, pp. 33243335, 1995.
[102] M. Urbakh and L. Daikhin, Surface Morphology and The Quartz
Crystal microbalance response in Liquids, Coll. Surf. A, vol. 134, pp.
7584, 1998.
[103] W. C. Duncan-Hewitt, Four-layer theory for the acoustic shear wave
sensor in liquids incorporating interfacial slip and liquid structure,
Anal. Chem., vol. 64, pp. 94105, 1992.
[104] N. M. McHale, M. Banerje, and S. Rowan, Interaction of surface
acoustic waves with viscous liquids, Faraday Discuss, vol. 107, pp.
1526, 1997.
[105] M. G. Schwyer, J. A. Hilton, J. E. Munson, J. C. Andle, J. M. Hammond,
and R. M. Lec, A novel monolithic piezoelectric sensor, in Proc. IEEE
Int. Freq. Contr. Symp., Orlando, FL, May 2931, 1997, pp. 3241.
[106] T. Wessa, M. Rapp, and H. J. Ache, New immobilization method
for SAW-biomedical sensors: Covalent attatchment of antibodies via
CNBr, Biomed. Sens. Bioelectron., vol. 14, pp. 9398, 1999.
[107] N. Bari, M. Rapp, H. Sigrist, and H. J. Ache, Covalent photolinker-mediated immobilization of an intermediate dextran layer to
polymer-caoted surfaces for biosensing applications, Biomed. Sens.
Bioelectron., vol. 13, pp. 855860, 1998.
[108] B. Ratner, Surface modification of polymers: Chemical, biological
and surface analytical challenges, Biosens. Bioelectron., vol. 10, pp.
797804, 1995.
[109] S. J. Kwoun, R. M. Lec, B. Hun, and F. Ko, A novel polymer nanofiber
interface for chemical sensor applications, in Proc. IEEE/EIA Int. Freq.
Contr. Symp., Kansas City, MO, 2000, pp. 5257.
[110] S. P. Sakti, S. Rosler, L. Lucklum, P. Hauptmann, F. Bhling, and S.
Ansorge, Thick polystylene-coated quartz crystal microbalanece as a
basis of a cost effective immunosensor, Sens. Actuators A, vol. 76, pp.
98102, 1999.
[111] N. Barie, H. Sigrist, and M. Rapp, Development of immunosensors
based on commercially available surface acoustic wave (SAW) devices,
Analusis, vol. 27, pp. 622629, 1999.
[112] X. Chiu, J. Jiang, G. Shen, and R. Yu, Simultaneous immunoasssay
using piezoelectric immunosensor array and robust method, Anal.
Chim., vol. 336, pp. 185193, 1996.
[113] B. Konig and M. Gratzel, Detection of human T-lymphocytes with a
piezoelectric immunosensor, Anal. Chim. Acta, vol. 281, pp. 1318,
1993.
, Development of piezoelectric immunosensor for the detection of
[114]
human erythrocytes, Anal. Chim. Acta, vol. 276, pp. 329233, 1993.
[115] K. Yokoyama, Ikebukuro, E. Tamiya, I. Karube, N. Ichiki, and Y.
Arikawa, Highly sensitive quartz immunosesnors for multisample
detection of herbicides, Anal. Chim. Acta, vol. 304, pp. 139145, 1995.
[116] H. Maramatsu, Y. Watanabe, M. Hikuma, I. Ataka, E. Tamiya, and
I. Karube, Piezoelectric crystal biosensor system for detection of E.
coli., Anal. Lett., vol. 229, pp. 21552166, 1989.
[117] D. Le, H. Feng, J. Tai, N. Lihua, and S. Yao, A goat-anti-human modified piezoimmunosesnor for staphylococcus aureus detection, J. Microbiol. Methods, vol. 23, pp. 229234, 1996.
[118] N. Miura, H. Higobashi, G. Sakai, A. Takeyashu, T. Uda, and N. Yamazoe, Piezoelectric crystal immunosensor for sensitive detection of
methamphetamine in (stimulant drug) in human urine, Sens. Actuators
B, vol. 13, pp. 188191, 1993.
[119] B. Konig and M. Gratzel, A novel immunosensor for herpes viruses,
Anal. Chem., vol. 68, pp. 341344, 1994.
, A piezoelectric immunosensor for hepatitis viruses, Anal. Chim.
[120]
Acta, vol. 309, pp. 1925, 1995.
[121] E. Uttenthaler, C. Kolinger, and S. Drost, Characterization of immobilization methods for African swine fever virus protein and antibodies
with a piezoelectric immunosensor, Biosens. Bioelectron., vol. 13, pp.
12791286, 1998.
[122] F. Arberl and H. Wolf, HIV serology using piezoelectric immunosensors, Sens. Actuators B, vol. 1819, pp. 271275, 1994.
[123] C. M. Roth and M. L. Yarmush, Nucleic acid biotechnology, Annu.
Rev. Biomed. Eng., vol. 01, pp. 265297, 1999.
[124] J. Wang, DNA biosensors based on peptide nucleic acid (PNA) recognition layers, Biosens. Bioelectron., vol. 13, pp. 752762, 1998.
[125] T. Ketterer, H. Stadler, E. Rickert, E. Bayer, and W. Gpel, Detection
of oligonucleotide sequences with quartz crystal oscillators, Sens. Actuators B, vol. 65, pp. 7375, 2000.
265
[126] T. Sara, M. Marco, S. Cristina, and A. P. F. Turner, A DNA piezoelectric biosensor assay coupled with a polymerase chain reaction for bacterial toxicity determination in environmental samples, Anal. Chim. Acta,
vol. 418, pp. 19, 2000.
[127] P. Wittung-Stafshede, M. Rodahl, B. Kasemo, P. Nielson, and B.
Norden, Detection of point mutations in DNA by PNA-based
quartz-crystal biosensor, Coll. Surf., vol. 174, pp. 269273, 2000.
[128] Y. Wu, A. Zhou, Q. Xie, and S. Yao, A piezoelectric quartz crystal
impedance study on denaturation of herring DNA, Microchem. J., pp.
6774, 2000.
[129] S. Tombelli, M. Mascini, L. Braccini, M. Anichini, C. Anichini, and A.
P. Turner, Coupling of a DNA piezoelectric biosensor and polymerase
chain reaction to detect apolipoprotein E polymorphism, Biosens.
Bioelelcron., vol. 15, pp. 363370, 2000.
[130] J. Wang, M. Jiang, and E. Palecek, Real-time monitoring of enzymatic
clevage of nucleic acids using a quartz crystal microbalance, vol. 48,
pp. 477480, 1999.
[131] R. Freitag, Utilization of enzyme-substrate interactions in analtical
chemistry, J. Chromatography B, vol. 722, pp. 279301, 1999.
[132] S. J. Lasky and D. A. Butry, Chemical sensors and instrumentation, in
ACS Symposium Series 43.
[133] S. M. Reddy, J. P. Jones, T. J. Lewis, and P. M. Vadgama, Development
of an oxidase-based glucose sensor using thicknerss-shear-mode quartz
crystals, Anal. Chim. Acta, vol. 363, pp. 203213, 1998.
[134] M. Chang and J. Shih, Fullerence-cryptand-coated piezoleectric
crystal membrane glucose enzyme sensor, Sens. Actuators B, vol. 67,
pp. 275281, 2000.
[135] J. J. Pancrazio, J. P. Whelan, D. A. Borkholder, W. Ma, and D. A.
Stenger, Development and application of cell-based biosensors, Ann.
Biomed. Eng., vol. 27, pp. 697711, 1999.
[136] C. Steinem, A. W. Janshoff, W. Ulrich, W. Willenbrink, and G. H. Sieber,
Impedance and shear wave resonance analysis of ligand-receptor interactions at functionalized syrfaces and of cell monolayers, Biosens. Bioelectron., vol. 12, no. 8, pp. 787808, 1997.
[137] A. Janshoff, C. Steinem, M. Sieber, A. Bay, M. Schmidt, and H. Galla,
Quartz crystal microbalance investigation of the interaction of bacterial
toxins with ganglioside containing solid supported membranes, Eur.
Biophys. J., vol. 26, pp. 261270, 1997.
[138] J. Biosens. Bioelectron. (formerly Biosens.), Elsevier.
[139] Europtrodes Conf. Proc., Anal. Chem., Biosens. Bioelectron., Sens. Actuators B.
[140] SPIE Photonics West BiOS Conf. Proc.
Gerard L. Cot (SM98) received the B.S.E.E.

degree from the Rochester Institute of Technology,
Rochester, NY, in 1986 and the M.S. and Ph.D.
degrees in bioengineering from the University of
Connecticut, Storrs, in 1987 and 1990, respectively.
He is a Professor and faculty member of the Department of Biomedical Engineering and the Director
of the Optical Biosensing Laboratory, Texas A&M
University, College Station. His primary research interests focus on the use of optics for medical diagnostics such as cancer and optical biosensing including
various analytes (glucose, excitatory amino acids, lactate, nitric oxide, oxygen,
etc.). He has over 120 publications.
Dr. Cot has been the Chair of several conference tracks and sessions and has
served as a reviewer on several government panels. He is also an Associate Editor of the IEEE SENSORS JOURNAL. He is a member of the SPIE Biomedical Optics Group, the Biomedical Engineering Society (BMES), the American Society
for Engineering Education (ASEE), and Tau Beta Pi Engineering Honor Society.
He is the recipient of several awards, including the ASA Statistics in Chemistry
Award, the JDRFI Mary Jane Kugel Award, the Faculty Distinguished Achievement Award in Teaching, and the TEES Senior Fellow Award.
266
Ryszard M. Lec (M88) received the Ph.D. degree

from the Warsaw University of Technology, Warsaw,
Poland, in 1978.
He is a Professor at the School of Biomedical
Engineering, Science and Health Systems, Drexel
University, Philadelphia, PA. From 1980 to 1981,
he was Visiting Scientist at the Department of
Electrical Engineering at the University of Marine,
Poland. He then joined the Institute of Fundamental
Technological Research, Warsaw, where he was
Head of the Ultrasonic Spectroscopy Laboratory
from 1981 to 1986. From 1986 to 1990, he was Visiting Professor in the
Electrical and Computer Engineering Department, University of Marine.
From 1991 to 1998, he was Research Professor of electrical and computer
engineering, University of Marine, and Technical Leader of the Industrial
Process Control Sensor System Program, College of Engineering, University of
Marine. He has been active in the areas of material science and instrumentation
for more than 20 years. Specifically, his research efforts have been devoted to
the study of viscoelastic, acoustooptic (AO), ultrasonic properties, and liquid
and solid media, with a focus on biomedical applications. In addition, he has
developed several associated electronic instrumentations, including ultrasonic
spectrometers, AO Q-switches and filters, and acoustic resonant systems.
Since the mid-1980s, his interests have been in the application of acoustic,
piezoelectric, ultrasonic, and optical technologies for the development of
sensors. In particular, he has designed and fabricated a variety of sensors
for the medical, biochemical, chemical, and automotive industries, including
immunosensors, micro-viscometers, engine oil quality sensors, gas sensors,
and sensors for monitoring the kinetics of chemical reactions.
Dr. Lec has been a Vice Chairman of the Technical Program Committee of
the IEEE International Frequency Control Symposium and a co-Chairman of the
IEEE UFFC Standard Sub-Committee on Sensors since 1997. He was a member
of the IEEE Sensor Council from 1998 to 2000, and he has authored and co-authored over 50 publications and one book and is co-inventor of three issued U.S.
patents.
Michael V. Pishko received the B.S. and M.S. degrees in chemical engineering from the University of
Missouri, Columbia, and the Ph.D. degree in chemical engineering from the University of Texas, Austin.
He was a postdoctoral associate at the Massachusetts
Institute of Technology, Cambridge.
He is an Associate Professor in the Departments
of Chemical Engineering and Materials Science and
Engineering, The Pennsylvania State University,
University Park. His research interests include
biosensing, biomaterials, and drug delivery. He has
over 50 publications and 18 issued U.S. patents.
Dr. Pishko is a member of the editorial board and an Associate Editor of the
IEEE SENSORS JOURNAL. He has received several awards, including an Alfred
P. Sloan Research Fellowship and the JDRFI Mary Jane Kugel Award.

Biomedical Sensing Technologies

Enviado por

Dados do documento

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

Biomedical Sensing Technologies

Enviado por

Direitos autorais:

Formatos disponíveis

IEEE SENSORS JOURNAL, VOL. 3, NO.

Emerging Biomedical Sensing Technologies and

AbstractRecent progress in biomedical sensing technologies

HE ongoing mergence of the 20th century revolution in

1530-437X/03$17.00 2003 IEEE

IEEE SENSORS JOURNAL, VOL. 3, NO. 3, JUNE 2003

utilized in radar, cellular phones, electronic watches, etc.,

COT et al.: EMERGING BIOMEDICAL SENSING TECHNOLOGIES

ilar fashion. Amperometric glucose sensors have been by far

Fig. 2. Example of a typical bio-chemical sensing system (minimed

A number of research programs have sought to minimize the

Amperometric patterned enzyme electrodes were formed using

IEEE SENSORS JOURNAL, VOL. 3, NO. 3, JUNE 2003

COT et al.: EMERGING BIOMEDICAL SENSING TECHNOLOGIES

a low coherent light source and scanning or imaging array

better throughput if all the light is passed through the sample.

IEEE SENSORS JOURNAL, VOL. 3, NO. 3, JUNE 2003

tions, the intrinsic or autofluorescence of tissue as well as the

COT et al.: EMERGING BIOMEDICAL SENSING TECHNOLOGIES

emission). Observation of these markers is a sensitive indicator

Last, the latest research in luminescent sensing is a new

IEEE SENSORS JOURNAL, VOL. 3, NO. 3, JUNE 2003

Acoustic biomedical sensors are typically designed to operate

COT et al.: EMERGING BIOMEDICAL SENSING TECHNOLOGIES

surface generated waves. The bulk generated waves are usually

different depths [Fig. 6(b)], hence providing important spatial

IEEE SENSORS JOURNAL, VOL. 3, NO. 3, JUNE 2003

Typical acoustic sensing process.

sensor performance is a proper attachment of a biological film to

COT et al.: EMERGING BIOMEDICAL SENSING TECHNOLOGIES

Fig. 8. Laboratory and portable electronic measurement systems utilized with

of piezoelectric immunosensors are that they are reusable with

IEEE SENSORS JOURNAL, VOL. 3, NO. 3, JUNE 2003

diseases. A combination of a piezoelectric biomedical sensor

in the concentration range between 30200 uM. Chang and

COT et al.: EMERGING BIOMEDICAL SENSING TECHNOLOGIES

[50] D. P. ONeal, M. Motamedi, J. Chen, and G. L. Cot, Surface-enhanced

IEEE SENSORS JOURNAL, VOL. 3, NO. 3, JUNE 2003

[73] S. L. Jacques, J. R. Roman, and K. Lee, Imaging superficial tissues with

COT et al.: EMERGING BIOMEDICAL SENSING TECHNOLOGIES

Gerard L. Cot (SM98) received the B.S.E.E.

Ryszard M. Lec (M88) received the Ph.D. degree

IEEE SENSORS JOURNAL, VOL. 3, NO. 3, JUNE 2003

Você também pode gostar