biosensors based on piezoelectric crystal detectors_ theory and application
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TABLE OF CONTENTS
INTRODUCTION
PIEZOELECTRIC BIOSENSORS:
BACKGROUND
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
CONCLUSIONS
ACKNOWLEDGEMENTS
References
Figure 1. Schematic diagram of a
biosensor device.
This article is one of five papers to be presented exclusively on the web as part of the October 2000JOM-ethe
electronic supplement to JOM.
The following article appears as part of JOM-e, 52 (10) (2000),
http://www.tms.org/pubs/journals/JOM/0010/Kumar/Kumar-
0010.html
JOMis a publication of The Minerals, Metals & Materials Society
Biosensors Based on Piezoelectric Crystal
Detectors: Theory and Application
Ashok Kumar
Biosensors are chemical sensors that take advantage of the high
selectivity and sensitivity of a biologically active material. It is wellknown that the resonant frequency of an oscillating piezoelectric
crystal can be affected by a change in mass at the crystal surface.
Piezoelectric immunosensors are able to measure a small change in
mass. This paper describes the construction of an antibody-based
piezoelectric sensor capable of detecting mycobacterial antigen in
diluted cultures of attenuated M. tuberculosis.
INTRODUCTION
A biosensor is an analytical tool consisting of biologically active materialused in close conjunction with a device that will convert a biochemical
signal into a quantifiable electrical signal. Biosensors have many
advantages, such as simple and low-cost instrumentation, fast response
times, minimum sample pretreatment, and high sample throughput.
Although biosensors are beginning to move toward field testing and
commercialization in the United States, Europe, and Japan, relatively
few have been commercialized. Increased research in this area demands
the development of novel materials, new and better analytical
techniques, and new and improved biosensors.7-11
Some potential
applications of biosensors are agricultural, horticultural and veterinary
analysis; pollution, water and microbial contamination analysis; clinicaldiagnosis and biomedical applications; fermentation analysis and
control; industrial gases and liquids; mining and toxic gases; explosives
and military arena; and flavors, essences and pheromones.1-6
A biosensor has two components: a receptor and a detector. The receptor is responsible for the selectivity of
the sensor. Examples include enzymes, antibodies, and lipid layers. The detector, which plays the role of the
transducer, translates the physical or chemical change by recognizing the analyte and relaying it through an
electrical signal. The detector is not selective. For example, it can be a pH-electrode, an oxygen electrode or a
piezoelectric crystal. Figure 1describes a typical biosensor configuration that allows measurement of the
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target analyte without using reagents. The device incorporates a biological-sensing element with a traditional
transducer. The biological-sensing element selectively recognizes a particular biological molecule through a
reaction, specific adsorption, or other physical or chemical process, and the transducer converts the result of
this recognition into a usable signal, which can be quantified. Common transduction systems are optical,
electro-optical, or electrochemical; this variety offers many opportunities to tailor biosensors for specific
applications.1-6
For example, the glucose concentration in a blood sample can be measured directly by a
biosensor (which is made specifically for glucose measurement) by simply dipping the sensor into the sample.
The objective of the research described here is to use biosensor technology to develop a rapid method for the
diagnosis of tuberculosis and other infections caused by mycobacteria. The work encompassed here describes
the construction of antibody-based piezoelectric crystals capable of detecting mycobacterial antigens in
diluted cultures of attenuated M. tuberculosis in an immunologically specific manner. The antigen were
detected in either liquid or vapor phase.
Table I. Some Common Biosensor Materials
Analytes Examples
Respiratory Gases O2, CO2
Anesthetic Gases N2O, Halothane
Toxic Gases H2S, Cl2, CO, NH3
Flammable Gases CH4
Ions H+, Li
+, K
+, Na
+, Ca
+, Phosphates, Heavy Metal Ions
Metabolites Glucose, Urea
Trace Metabolites Hormones, Steroids, Drugs
Toxic Vapors Benzene, Toluene
Proteins and Nucleic Acids DNA, RNA
Antigens and Antibodies Human Ig, Anti-human Ig
Microorganisms Viruses, Bacteria, Parasites
PIEZOELECTRIC BIOSENSORS: BACKGROUND
Two classes of bio-recognition processes-bio-affinity recognition-and bio-metabolic recognition, offer
different methods of detection. Both processes involve the binding of a chemical species with another, which
has a complementary structure. This is referred to as shape-specific binding. In bio-affinity recognition, the
binding is very strong, and the transducer detects the presence of the bound receptor-analyte pair. The most
common types of processes are receptor-ligand and antibody-antigen binding. In bio-metabolic recognition,the analyte and other co-reactants are chemically altered to form the product molecules. The biomaterials that
can be recognized by the bio-recognition elements are as varied as the different reactions that occur in
biological systems. Table Ilists a number of common analytes that could prove attractive for developing
biosensors of appropriate specificity and sensitivity. Almost all types of biological reactions, (chemical or
affinity), can be exploited for biosensors. The concept of shape-specific recognition is commonly used to
explain the high sensitivity and selectivity of biological molecules, especially antigen-antibody systems. The
analyte molecule has a complementary structure to the antibody, and the bound pair is in a lower energy state
than the two separate molecules. This binding is very difficult to break. Table IIsummarizes a variety of
biosystem-transducer combinations in terms of transducer, measurement mode and potential application.
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Figure 2. Schematic diagram of an
immunosensor device.
Table II. Biosensor Components
Transducer System Measurement Mode Typical Applications
Ion-Selective Electrode Potentiometric Ions in biological media, enzyme electrodes
Gas-Sensing Electrodes Potentiometric Gases, enzyme, organelle, cell or tissue electrodes
Field-Effect Transistors Potentiometric Ions, gases, enzyme substrates immunological analytesOptoelectronic and Fiber-Optic Devices Optical pH; enzymes; immunological analytes
Thermistors Calorimetric Enzyme, organelle, gases, pollutants, antibiotics, vitamins
Enzyme Electrodes Amperometric Enzymes, immunological systems
Conductimeter Conductance Enzyme substrates
Piezoelectric Crystals Acoustic (mass) Volatile gases and vapors, antibodies
The interaction of antibodies with their corresponding antigens is an attractive reason for attempting to
develop antibody-based chemical biosensors, i.e. immunosensors. Theoretically, if an antibody can be raised
against a particular analyte, an immunosensor could be developed to recognize it. Despite the high specificityand affinity of antibodies towards complementary ligand molecules, most antibody-antigen interactions do not
cause an electronically measurable change. However, the remarkable selectivity of antibodies has fueled
much research to overcome this intrinsic problem. The piezoelectric effect in various crystalline substances is
a useful property that leads to the detection of analytes. Figure 2 shows a schematic diagram of an
immunosensor device.12-21
The piezoelectric immunosensor is thought to be one of the most
sensitive analytical instruments developed to date, being capable of
detecting antigens in the picogram range. Moreover, this type of
device is believed to have the potential to detect antigens in the gasphase as well as in the liquid phase.
Almost all current methods of diagnosing tuberculosis (TB) have
drawbacks. They tend to be either nonspecific or too time-consuming.
In most cases of pulmonary and extrapulmonary TB, diagnosis
depends upon culturing the mycobacterial organism, a process
requiring 4-8 weeks. Significant attention has been devoted to
developing more rapid diagnostic methods for TB, but some of them
do not have the high specificity or sensitivity required for proper
diagnosis.22-29
A piezoelectric sensor that could reliably detect the mycobacterial antigen in biological fluids would be of
enormous use. For instance, detection of the antigen in saliva could constitute a noninvasive method of
screening high-risk populations. One tested piezoelectric crystal sensor gives results within a couple of hours
after exposing the electrode to a liquid containing the antigen. The apparatus would be quite portable, so the
immunological tests could be performed virtually anywhere, and the results could be obtained very quickly.
The feasibility of using piezoelectric immunosensors to diagnose TB based upon the detection of
mycobacterial antigens in liquid depends upon the degree of sensitivity and specificity that can be achieved
and upon overcoming any problems caused by potentially interfering substances in biological fluids. The
feasibility of gas- or vapor-phase detection of antigen depends upon these same factors, plus any difficulties
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that may be unique to gas-phase antigen capture by antibodies.
Theoretical Principals
The basic equations describing the relationship between the resonant frequency of an oscillating piezoelectric
crystal and the mass deposited on the crystal surface have been derived by Sauerbrey, 30Stockridge,31and
Lostis.32Each followed a different path, but their final equations are similar, the Sauerbrey equation being the
most widely accepted. In 1959, Sauerbrey developed an empirical equation for AT-cut quartz crystalsvibrating in the thickness shear mode that describes the relationship between the mass of thin metal films
deposited on quartz crystals and the corresponding change in resonant frequency of the crystal:
(1)
where, DF = frequency change in oscillating crystal in Hz, F = frequency of piezoelectric quartz crystal in
MHz, DM = mass of deposited film in g, and A = area of electrode surface in cm2.
These relationships not only apply to film deposition but also to particulate deposition. When vibrating in the
thickness-shear mode, the oscillating frequency of an AT-cut quartz crystal is given by:
(2)
where F is the frequency of the crystal, N is the material constant (N = 1.66 MHz-mm for AT-cut quartz
crystal), and a is the thickness of the crystal plate. Thus,
(3)
for finite amount of change, we may write
(4)
Dividing Equation 4by Equation 2gives:
(5)
If the thickness is defined as
(6)
where M is the mass of the electrically driven portion of the crystal, A is the area of the electrically driven
portion of the crystal, and r is the density of the crystal.
Assuming constant density, we have:
(7)
If the changes are finite,
(8)
Using Equation 6yields
(9)
Thus,
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(10)
Since F and M are constants, we may say:
DF = -k DM (11)
The oscillating frequency of the crystal changes linearly with the change in mass on the crystal. The mass
change occurs due to deposition of materials on the surface of the crystal. This relationship is only valid for
small mass changes. For larger mass changes, it would be invalid since the density would change.
Equation 10may also be stated as:
(12)
This shows that the term DFDM
would increase if the base oscillating frequency of the crystal is increased. The term itself is the sensitivity of
the crystal sensor, and Equation 12shows that sensitivity is directly proportional to the base frequency of the
crystal.
If a gas stream is sent flowing over the surface of the piezoelectric crystal and if it contains an analyte withconcentration C, then
(13)
where C is the concentration of the analyte in the gas stream, DM is the mass of analyte in the gas stream,
and V is the volume of the gas in the stream. The volume of the gas stream is related to the sampling time by
the following relationship:
V = q t (14)
where q is the flow rate of the gas stream, and t is the sampling time. Equation 13can be rewritten as:
(15)
where E is the collection efficiency of the coating material. If E is assumed to be equal to one and substituting
Equation 15into Equation 12, we may say
(16)
or
(17)
Thus, the change in the oscillating frequency of the crystal is related to both the sampling time and the
concentration of the particles in the carrier gas. If we keep the sampling time, career gas flow rate and the
mass of the analyte in the gas stream constant, we may restate Equation 17as
DF = K C (18)
Equation 18shows that the change in frequency of the crystal is directly proportional to the concentration of
the analyte in the gas stream flowing over it.
The piezoelectric crystal detector can be a very powerful analytical tool because of the relationship shown for
the change in frequency to the analyte concentration with high sensitivity. Conversely, the above explanation
shows that the crystal detector indiscriminately changes frequency due to the deposition of mass of any
material on its surface. Thus, it is the task of the researcher to choose a coating that will undergo a highly
selective chemical or physical binding with the substance to be detected. Only then can a highly selective
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Figure 3. Quartz crystal and holder.
Figure 4. Experimental apparatus for
a piezoe lectric sensor.
Figure 5. Schematic diagram of the
antibody-antigen binding.
sensor be constructed that will be sensitive to the subject to be detected.
EXPERIMENTAL PROCEDURES
Electrode Fabrication Process
The most frequently used detector crystal is alpha quartz. These crystals are
most suitable for piezoelectric application because they are insoluble inwater and resistant to high temperatures. Alpha quartz crystals can be
resistant to temperatures up to 579C with no loss of piezoelectric
properties. The resonant frequency of quartz crystal depends on the physical
dimensions of the quartz plate and the thickness of the electrode deposited.
AT and BT-cut crystals are most useful as piezoelectric detectors. These cuts
refer to the orientation of the plate with respect to the crystal structure. The
AT-cut crystal is the most stable, with a temperature coefficient of 1 ppm
per degree centigrade over a temperature range of 10C to 50C. The
crystals usually take the form of discs, squares, and rectangles.
All crystals in this investigation were general-purpose 10 MHz AT-cut quartzcrystals with an electrode coating deposited on each side using sputtering
method. The crystal was mounted on a holder with stainless steel with leads.
A silver composite was used to connect the electrode to wire. The crystals
were 14 mm in diameter, and the electrodes on both sides of the crystal
were 8 mm in diameter. The crystals were mounted on size HC6/u holders.
Figure 3shows the schematic diagram of the fabricated crystal attached to
the base.
Figure 4is a block diagram of the apparatus used for the biosensor
experiment. The piezoelectric quartz crystal was driven by a low-frequency
transistor oscillator, powered by a 1-30 V d.c. regulator power supply andset at 9 V d.c. The frequency of the vibrating crystal was monitored by a
Protek multifunction frequency counter. The crystal mounted on its holder
was connected to the oscillator circuit and the frequency counter was
connected to the oscillator device. After each step in the coating
process-first with the various metal depositions and then with the
biomolecular analytes-the frequency reading was recorded.33
Immunosensing
The crystal electrodes were first modified with a 5 ml coating of protein A
for better adhesion of the antibodies to the surface of the transducer. ProteinA is a polypeptide isolated from Staphylococcus aureusthat binds specifically to the immunoglobulin
molecules, especially IgG antibodies, without interacting at the antigen site. This property permits the
formation of tertiary complexes consisting of protein A, antibody, and antigen. Prior to modification, the
electrodes were anodically oxidized at constant current in 0.5 M NaOH. They were then cleaned in 0.5 M
HCl and 0.5 M HCrO2. They were dried in an incubator for one hour, and the antibody (IgG) coating was
then applied to the protein A coating. Using a pipette, 10 ml of antibody was applied on both sides of the
crystal. After another hour of drying, 10 ml of antigens were coated onto the crystal, and they were
methodically dried again. After each step, the frequency of the crystal was recorded, and the crystal was
washed as a precaution against non-specific binding.
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Control crystals and experimental crystals were coated with antibodies. The former were coated with an
irrelevant antibody (HBV-honey bee antibody), one specific for an antigen not present in the solution
containing the analyte. The experimental sample was coated with antibody (M. tuberculosis) specific for
binding to the antigen. Both were exposed to the solution containing the analyte. Then the difference in
frequency change between the control and experimental crystals were compared, reflecting the
immunologically specific binding of analyte. This procedure was carried out first with crystal with gold
substrate, and then using crystals coated with magnetic materials. A magnetic field was induced during the
investigation of the latter. The nature of the binding of antigen to antibody to the surface of the transducer isshown in Figure 5. The protein helps the antibody to bind to the electrode and the antigen in gaseous state
binds to specific antibody.33
RESULTS AND DISCUSSION
Figure 6shows the x-ray diffraction patterns of the gold films deposited on quartz. The gold film is
polycrystalline in nature. The theoretical values at varying gold thicknesses, compared with experimental
values at different thicknesses, are shown in Figure 7, which clearly shows that the experimental and
theoretical values of change in frequency are almost equal for different thicknesses of electrode coating. The
deposited coating changes the frequency approximately in agreement with the projections made by Sauerbrey.
Figure 6. X-ray diffraction pattern of gold
electrode coating on a quartz substrate.
Figure 7. Frequency change (experimental and
theoretical) vs. thickness for the deposited gold
coating.
Although platinum is a more noble (non-reactive) material compared to the gold, the adherence of the
platinum films was very poor on quartz substrates and the platinum reacted with different buffer solutions,
(e.g. HCl and NaOH) during the specimen preparation for antigen-antibody binding. Thus, gold electrodes are
preferred due to superior adhesion and non-reactive properties. The optimum thickness of the gold electrodelayer was estimated at 1,000 Angstroms. Although the binding between antigen and antibody did show a
change in frequency, the results were not always reproducible. The antibody binding to the protein layer was
critical to achieve desirable results. The use of magnetic materials underneath the gold coating helped make
the antigen detectable.33-35
CONCLUSIONS
These results are preliminary. More analysis is needed to shed more light on the optimum binding
characteristics of the antigen and antibody to the piezoelectric transducer.
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ACKNOWLEDGEMENTS
This research was supported by aNational Science Foundationgrant. The author thanks S. Perlaky, I.
Hussain, and A. Mangiaracina for their contributions in doing research at the University of South Alabama.
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Ashok Kumar is with theDepartment of Mechanical Engineeringand Center for Microelectronic Research
at the University of South Florida.
For more information, contact Ashok Kumar, University of South Florida, Department of MechanicalEngineering and Center for Microelectronics Research, Tampa, Florida 33620.
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