Nanobiosensor And Biosensor Packaging Biology Essay


Nanotechnology is one of the greatest achievements in engineering field attempt to function the systems in molecular scales. Nanotechnology now becomes dominant in environmental, health and safety issues, military application such as biological warfare and implants for soldiers and nanosensors and nanoprobes with submicron-sized dimensions that are suitable for intracellular measurements. Nanotechnology is opening of a new horizon for the development of nanosensors and nanoprobes. Despite of recent advances in medical field, the detection traces of biological species in medical diagnosis remains a challenge such as in European level [1]. Biosensors, one of the most useful tool in detection trace still need further progress as not only new technological solutions but also application of new ideas and more sensitive methods.

This bottleneck probably can be removed by low-cost label free detection devices which have a very high sensitivity and selectivity if on a wide scale used. But their complexity, the design of such devices requires an interdisciplinary collaboration as complementary expertises between the research groups could not be found at a single laboratory level. Hence researches and project works have been working with aim to develop highly sensitive and specific nanobiosensor with extraordinary optical signal enhancement dedicated to the in vitro proteins detection and disease (cancer, cardiovascular or infectious diseases) diagonosis.

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The nanobiosensor technology is an integrated bioelectronics technology. Bioelectronics, including biosensors, is basically an emerging interdisciplinary field and encompassing of bioscience, chemistry, physics, material science, electronics, and engineering. This technology has being widely used in the health care industry, forensic medicine, home-land security, food and drink industries, environmental protection, genome analysis of organisms and communications.

The biosensing electronics building blocks are biosensing, signal conversion and signal processing, and biosensing mecha­nisms. By being made use of smart nanomaterials such as Zinc oxide (ZnO) nanowire and carbon nanotubes (CNTs) in fabrication of biosensors, nanbiosensor technology is more and more effective. Biological probe design, probe preparation and interfacing with signal transducer element of the biosensor are some critical accounts playing important role in nanobiosensor technology.

The earliest concept of biosensor was introduced by Dr. Leland C Clark in the early 1960's [3]. Enormous technical development in mass-production provided a great help to develop integration of multi-analyte sensors which has great capability of comprehensive analyses to detect glucose, lactate and potassium. These technical developments also enabled the development of miniaturization of integrated biosensors. Miniaturization also allowed additional analytical tools to be added to the biosensor, such as chromatography or capillary electrophoresis. The newest generation of biosensors includes miniaturized multi-analyte immunosensor devices with high-throughput capabilities and more than 1000 individually addressable electrodes per square centimetre [3]. These instruments can detect analytes present in the attomole range. Modern fabrication techniques such as ink-jet printing, photolithography, microcontact printing, and self-assembly continue to contribute to more advanced biosensors, and the next type of devices to emerge may include miniature biosensors with high-density ligands, selfcontained lab-on-a-chip capabilities, and nanoscale biosensors.

1.2 Fundamentals of Biosensor

Biosensor is prominent bioelectronics device because of its enormous application potentials. Biosensors are can be used for detection, identification, quantification, and analysis of target molecules.

Figure 1.1 Schematic diagram of a typical biosensor [4]

A typical biosensor is composed of three basic parts. They are namely biosensing, transducer or signal conversion, and signal processing elements.

Figure 1.2 Principle of Biosensor [4]

Protein, peptide, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), whole cell or tissue are biosensing elements which interact specially with its complementary target or analyte molecules.

The transducer or signal conversion is a device such as an electrode, piezoelectric crystal, photosensitive element, nanobelts/wire, carbon nanotubes (CNTs) or thermistor. It interfaces with the recognition element, and converts the magnitude of the biological relevant information or response signal into an electronic signal.

Based on the location of lodging of the device, biosensors can be divided into two main types [4]:

in vivo or implantable biosensor- if inserted into the cell, tissue, or body for sensing the analyte; and

in vitro biosensors- if placed in an artificial environment external to the cell, tissue, or body.

Moreover, based on the types of molecules detected into nucleic acid sensors and DNA chips, it can be categorized as- biosensor devices have immunosensors, enzyme-based biosensors, organism and whole cell-based biosensors, natural and synthetic receptors-based biosensors (see Figure 1.3).

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Figure 1.3 Different types of Biosensors

Innovative signal transduction technology, systems integration, proteomics, bioelectronics, and nanoanalytical systems are essential for the development of smart biosensors [4].

The bottleneck of conventional detection system is when labeling of the probe molecules,

requirement of large amount of target molecules to enable detection, and elaborate signal detection methods. Moreover, the conventional technologies are based on the "top-down" approaches which are difficult to continue to scale down due to limitations in lithography and interconnect schemes for design and fabrication of biosensors.

The innovative combinations of properties possessed by nanostructured materials are utilized for fabrication of nanobiosensors. New technology made used of "bottom-up" approach is incorporating with integration of nanotechnology with biology and bioelectronics constitutes the third generation of smart biosensors (Figure 3).

Figure 1.4 Integration of nanotechnology with biology and bioelectronics to produce nanotechnology based biosensors

Recently nanoscience and nanotechnology involves in manipulating the materials at the

scale of 100 nm or less. This improvement in micro/nanofabrication technologies enables fabrication and packaging of varieties of functional devices using nanomaterials for biological and nonbiological applications. The applications range across material science, information technologies, environmental protection, and medicine. With help of micro and nanoscale in the cell and subcellular systems for biological function, the nanodevices have potential life science applications including improved drug and gene delivery, biocompatible materials for implants,and advanced sensors for early disease detection of diseases and therapies[4]. These nanodevices made with smart nanomaterials are efficient, cost effective, and easily implantable.

1.2 Application of Biosensors

The importance of critical detection of hazardous pathogen and toxic molecules in the environment was realized by the events of September 11, 2001 attack on US soil, and the subsequent anthrax attacks, and ricin (a potent poison from castor beans) attacks in the United Kingdom, which highlighted the value of using sensitive biosensors and bioelectronics all over the world. The important applications of biosensors are clinical diagnostics, drug discovery, drug abuse genome analysis, food hygiene, industrial bioprocess control and monitoring environmental safety [4].

Function of Tranducers in Biosensors and Challenges

As mentioned in Chapter 1,in biosensor sensing process, the biosignals are converted into electrical, optical, and electromagnetic signals. There are a variety of signal conversion methods as described below [4]:

Electrochemical (conductimetric, amperometric, and potentiometric)


Acoustic wave

Microelectromechanical (resonant)

Magnetic, and


Electrochemical Method

In electrochemical method, electrochemical fluid cell is used for the field-effect transistor (FET) to detect DNA or protein. The process involves electrical impedance measurements of the probe and target molecules by using a three-electrode [4]:

Working electrode in which contains electrochemical cells of DNA or protein-modified Si sample

Ag/AgCl reference electrode and

Pt counter electrode

A poly dimethylsiloxane (PDMS) fluid cell (5μl volume) is pressure sealed between DNA-modified Si sample (8 Ã- 4 mm) and the Pt counterelectrode. Impedance value can be measured by using a three-electrode potentiostat coupled to an impedance analyzer. All electrochemical potentials considered with respect to the saturated Ag/AgCl reference electrode [5]. The multiwalled carbon nanotubes dispersed on the working electrode forms the efficient working electrode (see Figure 2.1). The impedance is proportional to the target-probe molecular hybridization.

Figure 2.1 Three-electrode chemical fluid cell biosensor. 1 - Potentiostat; 2 - platinum foil counterelectrode; 3 - working electrode as DNA-modified silicon sample (Source: Courtesy of Cai et al., 2003)

Optical Method

In optical signal conversion method, the bioprobe and target hybridization signals are converted into optical signals. Surface plasmon resonance (SPR) is an advanced optical signal conversion technique. In SPR configuration, it consists of a prism or glass slide coated with a thin metal film, usually silver or gold (see Figure 2.2).

Figure 2.2 Schematic of optical biosensor. Gold and silver nanoparticles are deposited on a quartz substrate. The substrate is coated with mercaptosilane adhesion layer and functionalized using gold or silver nanoparticles, self-assembled monolayers of functional thiols, antibodies, and antigen. The resulting absorption spectrum increase upon binding of analytes to the functional nanoparticles (Courtesy of A. Campitelli, C. Van Hoof, IMEC)

DNA or protein bioprobe is immobilized on thin gold film. When the light is passed through the prism and incident onto to the gold surface with angles and wavelengths near the surface plasmon resonance condition. The optical reflectivity of the gold changes very sensitively in the presence of the gold surface. Similar effect also can be found when using quartz substrate which is coated with gold and silver nanoparticles. Efficient collective excitation of conduction electrons near the gold surface made the optical response highly sensitive.

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The optical components in an optical sensor could be fiber optics, wave guides, photodiode, spectroscopy, charge-coupled device (CCD), and interferometers. The changes in intensity, frequency, phase shift, and polarization are needed to be measured. Measurements involved are absorbance (oligo - 260 nm, peptide - 280 nm), fluorescence, refractive index, and light scattering. Surface plasmon resonance, which are particularly useful for the detection of biological molecules: (1) they can be extremely sensitive (nanomoles or less) and (2) they are nondestructive to the sample. Optical conversion technique offers an inexpensive system for the detection of heavy metals, particularly the high toxic arsenic in the environment [6]. In optical method, no reference electrode is needed, and there is no electrical interference.

Acoustic Wave Method

Acoustic wave is a kind of wave used in piezoelectric component, such as crystal, in circuits. In acoustic wave signal conversion method, radio frequency is applied to crystal which produces mechanical stress in it. As a result surface acoustic wave (SAW) is induced. When electrodes receive SAW, it can translate SAW to voltage (see in Figure. 2.3). The hybridization of probe and target molecular on the surface of quartz platform causes signal conversion and can be changed into the voltage. These are typical signal conversion components that detect the presence of low mass such as single molecule or cell.

Figure 2.3 Schematic Diagram of acoustic wave biosensor- probe and target molecule

binding on the surface of quartz platform caused difference in the voltage

Electromechanical Method

Nanocantilevers and quartz crystal microbalance sensors are extremely sensitive mass sensors. They are capable of measuring attogram (10-18 g) mass sensitivity. When target binding is occurred between protein, DNA or RNA target molecules, and probe molecules on the cantilever beam, change of adsorption is directly related to the cantilever deflection. Tension of binding surface causes bending of cantilever beam and deflection of the beam is measured optically (see Figure 2.4).

Figure 2.4 Piezoelectric cantilever (Source: Courtesy of Drs. Il-Han Hwang and Jong-Hyun


In piezoelectric cantilever, resonance frequency varies as a function of mass loading. Nanobelts, nanorings, and nanosprings with piezoelectric properties can be used as nanoscale transducers, actuators, and sensors by being synthesized.

Nanobelts/wires are quasi-onedimensional semi-conducting and piezoelectric nanostructures. They can be used to fabricate field effect transistor (FET). Single-crystal zinc oxide (ZnO) and SnO2 nanobelts that spontaneously rolled them up for piezoelectricity into helical structures with widths in the range of 10-60 nm wide and 5-20 nm thick. These nanobelts induce a field effect in the presence of charged biological molecules such as proteins, peptides, DNA, and RNA. The ZnO and Si nanowires [8], and Si microresonators are recently use for nanobiosensor devices fabrication. The FET-based devices have potentials of advanced technique for in situ, real-time, wireless, and implantable biosensors [9]. These devices facilitate detection of subnanomolar quantities of proteins, DNA, and RNA from anthrax, salmonella, smallpox, AIDS virus, and other pathogens and toxins, including ricin.

Magnetic Method

Force-amplified biological sensor (FABS) used magnetic nanoparticles to label antibodies, sequence-specific DNA or RNA. Atomic force microscope (AFM) is employed to pull on and measure the strength of single DNA-DNA or antibody-antigen bonds [10]. Thus, the detection of binding and hybridization events of probe and target molecules is done by using magnetic nanoparticles (see Figure 2.5).

Figure 2.5 Magnetic biosensor, in which the antibodies labelled magnetic particles are

attracted in the magnetic field (Source: Courtesy of Drs. Baselt et al. 1998) 638 D.G. Janagama and R.R. Tummala

The magnetic particles used for FABS must be smooth and spherical in order to bind entire surface of each particle to the flat cantilever surface. Irregular particles effectively could have a reduced active area. The particles should apply a uniform force in a magnetic field, and a high magnetic moment for maximum signal. They should not corrode when immersed in physiological salt solutions; low density and initially nonmagnetic to avoid coagulation of the solution.

Chemical and Enzymatic Method

Variety of glucose oxido-reductases and lactic dehydrogenases are used as a component

for various enzyme sensors. Electron mediator-dependent glucose dehydrogenases (GDH) are ideal constituents of mediator-type enzyme sensors. The dehydrogenases utilize the NAD+/NADH couple. The NADH generated (Figure 2.6) is detected by using the amperometric method.

Figure 2.6 Enzymes catalyzing oxido-reductions. The electrons produced in the reaction

are a measure of glucose

In simple glucose biosensors, the enzymatic oxidation of glucose produces hydrogen peroxide, which in turn generates electrons by electrode reaction. The current density is used as a measure of glucose in the sample (see Figure 2.7).

Figure 2.7 The selective membrane in contact with glucose and the enzyme acts as a


Thermal Method

The thermal biosensor is an enzyme thermistor which is modified for split-flow analysis. A miniaturized thermal biosensor involves in a flow-injection analysis system for the determination of glucose in whole blood. The blood glucose is determined by measuring

the heat evolved when samples containing glucose passed through a small column with immobilized glucose oxidase and catalase. A sample of whole blood as small as 1μl can be measured directly using this thermal biosensor [11].

3 Nanostructures, Biomolecules, and Cells as Components of Biosensors

Discovery of nanostructured materials open new horizon of several possibilities toward fabricating advanced nanobiosensors which possess superior sensitivity and specificity. Recently, single-walled carbon nanotubes (SWNTs) and multiwalled carbon nanotubes (MWNTs) exhibit the potentials of chemical stability, good mechanical properties, outstanding charge-transport characteristics, and high surface area that make them ideal for the design of nanobiosensors for detecting sub-femtogram quantities of target protein, DNA, and RNA.

Among the approaches of applying nanotechnology in medicine, nanoparticles can provide some unique advantages as sensing, image enhancement, and delivery agents [12].

The remarkable biorecognition capabilities of the biomolecules such as DNA,RNA, and proteins can be utilized for the fabrication of ultra miniature biological electronic sensing devices, by conjugating them with nanoscale solids (particles,dots, or wires). Varieties of nanoparticles are available commercially, including polymeric nanoparticles, metal nanoparticles, liposomes, micelles, quantum dots,dendrimers, and nanoassemblies. The gold nanoparticles of size 1.4 nm are used in the fabrication biosensors. In the fabrication of immunosensors, the nanoparticles are conjugated with the protein probe, which involves in antigen-antibody immune complex formation. Nanoparticles are also used for conjugating DNA or RNA probe involving sequence-specific DNA or RNA hybridization detection, in the construction of nucleic acid probes. Nanoparticles-based biosensors are sensitive, inexpensive, noninvasive detection systems for measuring biological molecules, and advanced over the existing technologies due to their nanosize, smart performance, and constituting the third-generation biosensors. Aptamers are oligonucleotides (DNA and RNA) that can bind with high affinity and specificity to wide range of target molecules (proteins, peptides, drugs, vitamins, and other organic or inorganic compounds). The biosensors fabricated with resonant oscillating quartz crystal can detect minute changes in resonance frequency when probe ss-DNA hybridizes with target DNA. DNA-based supramolecular chemistry allowed the replacement of natural bases in the DNA molecule with artificial nucleotides or nucleotide mimics [26]. Further, new generation of such nucleotide mimics was reported in which the hydrogen bonding interactions were replaced by metal-mediating base pairs [27].The metal incorporation into the interior of the DNA confers DNA metal-based functions such as thermal stability and magnetic properties (Fig. 28).

Fig. 28 Schematic of copper metal-mediating DNA base pairing. The cell-based biosensors are composed of two transducers, where the primary transducer is cellular and the secondary transducer is typically electrical. It is known that olfactory neurons respond to odorant molecules, and the retinal neurons in the eye are triggered by photons. These cells in the body act as primary transducers capturing the signals and in turn passed on to the secondary transducer.

7.4 Nanowire

Semiconducting and piezoelectric nanostructures such as single-crystal zinc oxide

(ZnO) nanobelts (Fig. 32) are used as sensitive signal conversion components,

capable of measuring signal conversion from a single molecule or cell. ZnO

nanobelts/wires (10-60 nm wide and 5-20 nm thick) induce a field effect in

the presence of charged biological molecules such as proteins, peptides, DNA,

and RNA [32]. ZnO and Si nanowires are used as efficient signal conversion

components [33].

Fig. 32 (a) Single-crystal

zinc oxide (ZnO) nanobelts;

(b) ZnO nanowire mounted

between the electrodes

(Source: Courtesy of Dr. ZL

Wang, Georgia Institute of


7.5 Carbon Nanotubes (CNTs)

The carbon nanotubes and silicon nanowires and actinyl peroxide self-assembled

structures are the products of novel innovative technologies. Self-assembled carbon

nanotubes produced in the arc discharge process are widely used in catalytic

processes [34]. Based on the wall structure of the nanotubes, two types of tubes

are categorized: single-walled and multiwalled. A single-walled carbon nanotube

(SWNTs) consists of a single graphene cylinder, whereas a multi-walled carbon

nanotube (MWNTs) comprises several concentric graphene cylinders. SWNTs can

possess efficient electrical conductivity. The carbon atoms are strongly (covalently)

bound to each other (carbon-carbon distance 0.14 nm). As shown in Fig. 33, rolling

up the sheet along one of the symmetry axis gives either a zig-zag (m = 0) tube or

an armchair (n = m) tube.

The carbon nanotubes (CNTs) possess unique properties such as chemical stability,

good mechanical properties, high surface area, and outstanding charge-transport

characteristics that make them ideal for fabrication of nanobiosensors.

Nanobiosensing Electronics and Nanochemistry for Biosensor Packaging 645

Fig. 33 Structure of carbon nanotubes (Courtesy of Technion, Department of Physics, Israel

University (∼talimu/structure.html )

8.5 Biosensor Device Fabrication Methods

The nanodevices are fabricated using one or more of the following common


• Soft lithography, which is a new high-resolution patterning technique

• Thermal diffusion bonding of structural ceramics to superalloys

Nanobiosensing Electronics and Nanochemistry for Biosensor Packaging 655

• UV laser micromachining for 2D and 3D medical devices.

• Deep reactive ion etching in the substrate.

• Electronic pick and place for heterogeneous integration

• Microfabricated fluidic nanotiterplate

• Micromechanical milling

• Microplastic injection molding

• Polymer embossing, and polymer injection molding

• Micromanufacturing of cellular systems

8.5.1 Fabrication Nanowire-Based Biosensors

The ZnO nanowire is synthesized through a high-temperature vapor-solid (VS) process

that has been developed in Georgia Tech [44] and used for fabrication of ZnO

nanowire-based biosensor system for detection of biological molecules and cancer

cells [45]. The system setup is shown in Fig. 43.

Fig. 43 The setup of the

vapor-solid (VS) synthesis

process (Courtesy of PRC,

Georgia Tech)

The setup of the vapor-solid (VS) synthesis process consists of a horizontal hightemperature

tube furnace with the length of ∼50 cm, an alumina tube of ∼75 cm,

a rotary pump, and a gas-controlling system. About 2 g of the mixture of commercial

ZnO powder (Alfa Aesar) and carbon powder is loaded into a polycrystalline

Al2O3 boat, which is placed in the center of the alumina tube. The furnace is heated

up to ∼1400â-¦C in a ramp rate of 20°C/min from room temperature. Gas Ar at a

flow rate of 50 stand. cubic centimeters per minute (sccm) is introduced into the

tube as carrying gas. After holding at ∼1400°C for about 2 h, the furnace is slowly

cooled down to room temperature. Polycrystalline Al2O3 substrates which are positioned

∼11 cm from the ZnO source at the downstream side are used to collect the

as-synthesized ZnO nanowires. The whole system is maintained at a pressure of

∼200 mbar throughout. The as-synthesized sample is then inspected under a LEO

1530 field-emission scanning electron microscope (SEM) operated at 5 kV.

656 D.G. Janagama and R.R. Tummala

8.5.2 Fabrication of Microelectrochemical Biosensors

As shown in Fig. 44, microelectrochemical sensor device is fabricated patterning the

Pt electrodes using lift-off process. The patterning of the silver electrode is done by

a semiadditive process (Evaporate Ti/Ag, photoresist patterning, electroplating Ag,

photoresist, and seed layer removal). Chloridized in FeCl3 to form Ag/AgCl [46].

Fig. 44 Three-electrode

structure of electrochemical

biosensor (Courtesy of PRC,

Georgia Tech)

Sol-Gel System for Encapsulation of the Enzyme

Sol-gel chemistry is gaining importance in acting as an interface between biological

materials and nonbiological components in biosensors. Zirconia/Nafion sol-gel

encapsulation of enzyme is used in fabrication of enzyme-based sensors. The zirconia

sol-gel solution is prepared by mixing 8.0 ml of deionized water with 1.0 ml of

0.12M ZrOpr dissolved in isopropanol and 0.25 ml of 11 M HCl solution. The zirconia/

nafion composite is prepared by mixing zirconia solution with nafion. Glucose

oxidase enzyme at 100 mg/ml is prepared in 0.05Mphosphate buffer at pH 7.0. The

enzyme encapsulating matrix is prepared by mixing 40 μl of zirconia/nafion stock

solution and 40μl of the enzyme solution, casted on the working electrode (Fig. 45).

The advantage of the sol-gel encapsulation are as follows:

Fig. 45 FESEM micrographs of zirconia-nafion gels before (top) and after (bottom) enzyme

entrapment (Courtesy of PRC, Georgia Tech)

Nanobiosensing Electronics and Nanochemistry for Biosensor Packaging 657

• It resists chemical attack and withstands high temperature.

• Nafion is highly conductive to cations, making it ideal for many membrane


• Pure nafion films revealed large calcification and instability of the cast films.

• Incorporate zirconia into anionic nafion assembly in order to prevent


• Encapsulation of the enzyme with the sol-gel protects from heat and

8.6 Micro-fluidic Channels

Microfluidics system is the manipulation of liquids in channels having crosssectional

dimensions on the order of 10-100μm. Microfluidic channels are essential

for guiding and helping biofluids carrying the target or the sample to be tested onto

sensing element of the biosensor. As all biological molecular reaction takes place

in liquid environment, microfluidic channels facilitate controlled flow of microquantities

of fluids containing desired test molecules (Fig. 46, 47). The common

fluids used as target in microfluidic devices include whole blood samples, bacterial

cell suspensions, protein or antibody solutions, and various buffers. Fluidics carries

the biological molecules without involving mechanical moving parts that will

wear out.

Fig. 46 Planar

microelectrodes: (a) without

CNTs and sol-gel enzyme;

(b) CNTs and sol-gel

enzyme, open microfluidic

channel; (c) CNTs and

sol-gel enzyme, sealed

microfluidic channel

Materials for implantable devices and microfluidic channels need to be biocompatible,

which is not producing a toxic, injurious, or host response in living

tissue. Biocompatible materials such as polydimethylsiloxane (PDMS), LCP materials

are commonly used for fabrication of microfluidics. Further, laminated plastic

microfluidic components made of polyimide, poly methylmethacrylate (PMMA),

and polycarbonate materials with thickness between 25 and 125μm have also been

developed and used. These devices can be potentially manufactured in high volume

with low unit cost because of advancements in the materials and chemical processes

such as high-speed full-field excimer laser ablation process (Anvik Incorporated) to

generate the fluidic channels. Low-cost PDMS adhesive-based bonding is used to

seal the channels. Fabrication of both the sub-micron features of the photonic crystal

sensor structure and the >10μm features of a flow channel network in one step at

room temperature on a plastic substrate was demonstrated [47,48]. Polymer-based

658 D.G. Janagama and R.R. Tummala

Fig. 47 (a) Schematic of microfluidics integrated, multiplexed biosensor system; (b) cross section

of the device

microfluidic devices can be created by combining lithographic and conventional

manufacturing techniques (e.g., injection molding or embossing). Polymeric channels

can also be made transparent in the UV, visible, and IR ranges. This property

enables the use of generic off-chip detection systems, thereby reducing the cost and

complexity of a microanalysis chip. As an example, laminated plastic microfluidic

components of polyimide, poly (methylmethacrylate) (PMMA), and polycarbonate

materials with thickness between 25 and 125μm have been developed [49]

These devices can be potentially manufactured in high volume with low unit cost

because of advances in the materials and processing tools made by the electronic


8.7 Biosensor Packaging

The highly miniaturized electronic system technology mostly relies on integrated

circuits (IC) integration (Moore's law) for performance improvement and cost

reduction. System-on-package (SOP) technology paradigm (the second law of electronics)

pioneered by Georgia Tech Packaging Research Center, since the early

1990s provides system-level miniaturization in a package size that makes today's

hand-held devices into megafunctional systems, with applications ranging from

computing, wireless communications, health care, and personal security. The SOP

is a system miniaturization technology that ultimately integrates nanoscale thin film

components for batteries, thermal structures, active and passive components in lowcost

organic packaging substrates, leading to micro-scale to nanoscale modules and

systems. True miniaturization of products should take place not only at IC but also

at system level, the latter made possible by thin film batteries, thermal structures,

Nanobiosensing Electronics and Nanochemistry for Biosensor Packaging 659

and embedded actives and passives in package-size boards. This is the fundamental

basis for the SOP concept. The traditional packaging by which components are integrated

into systems today, presents several sets of barriers in cost, size, performance,

and reliability. The SOP concept overcomes these barriers by the best of both the

IC and the package integration at system level, the IC for transistor density and the

system package for component density of RF, optical, digital, and biofunctions. In

addition to miniaturization, such a concept leads to lower cost, higher performance,

and better reliability of all electronic systems including biosensor systems described

in this chapter. The attributes of traditional electronic system are bulky, poor reliability,

moderate performance, medium cost compared to SOP-based systems, which

show miniaturized, 3Ã- improvement in reliability, high performance, and low cost.

SOP-based biosensor systems can be greatly enhanced in terms of the functionalities

in both clinical and nonclinical domains. As shown in Fig. 48, the energy source

for many biomedical microsystems is through an external RF link. The system communicates

with the outside world over an inductively coupled bidirectional wireless

link [50].

Fig. 48 (a) Schematic of a wireless integrated microsystem; (b) implantable version of the same

microsystem (Courtesy of Dr. Kensall D. Wise, University of Michigan)

9 Characterization of Functionalized Biosensor Structures

The functionalized electrode surface is characterized by transmission electron

microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), fluorescent

microscopy, X-ray photoelectron spectroscopy (XPS), scanning electron

microscopy (SEM), and atomic-force microscopy (AFM). Fourier transform

infrared spectroscopy (FT-IR) is used to identify specific types of chemical bonds

or functional groups based on their unique absorption signatures.

Transmission electron microscopy (TEM) is used to study the morphology and

size of the particles.

660 D.G. Janagama and R.R. Tummala

Energy-dispersive X-ray spectrometer is used to confirm the composition of

particles immobilized on gold surface. The ellipsometry is a real-time optical measurement

technique, which is used to study several material characteristics such

as layer thickness, optical constants (refractive index and extinction coefficient),

and optical anisotropy. It is used for quantification and visualization of the lateral

thickness distribution of thin (0-30 nm) transparent layers on solid substrates. The

thinness of the biofunctionalized molecules on a nanodevice surface is measured at

the same time with a high lateral resolution.

Atomic-force microscope (AFM) is used to take three-dimensional images of

resolution on the order of 1-2 nm. It consists of cantilever tip assembly, piezo tube

scanner, and laser deflection system (Fig. 49). The attachment of the biomolecules

such as proteins and DNA, and the molecular hybridization events on the biosensor

devices can be characterized using AFM [51].

Fig. 49 Schematic of the atomic force microscope (Source: Courtesy of Hafner et al., 2001)

10 Future Trends and Summary

The tremendous advancements in the sensor technologies are due to the great

technological demand for rapid, sensitive, and cost-effective biosensor systems

in vital areas of human activity such as health care, genome analysis, food and

drink, the process industries, environmental monitoring, defense, and security. In

fact, nanobioconjugates that consists of various functional nanoparticles or nanostructures

linked to biological molecules revolutionized the biosensor systems.

Biosensors have enormous potentials and prospects in wide range of applications.

These nanobioelectronic devices will revolutionize the detection system and signal

processing, and enrich the quality of life.

At present, the nanotechnology-based biosensors are at the early stage of development.

The vast applications of nanotechnology in such diverse fields such

as semiconductors, biological and medical devices, polymer composites, optical

Nanobiosensing Electronics and Nanochemistry for Biosensor Packaging 661

devices, dispersions, and coatings are amazing. With the discovery of novel materials

and innovated approaches, it may progress by leaps and bounds, as in the case

of the computer industry after the development of integrated circuits. As biosensors

are essentially involved in revealing molecular information, they form a part

of important information technology. The potentials and prospects of biosensors are

effectively attracting myriad start-ups to the Fortune 500 companies to manufacture

these devices.

In summary, the building blocks of biosensors, biomechanisms, biofunctionalization

of nanodevices, search for suitable interfaces between biological material

and electronics, intelligent signal processing of information transmitted by biosensors

and other related issues are discussed. The methods for protein and DNA and

RNA molecular probe design and syntheses, and microfabrication methods of the

biosensor devices are enumerated. A detailed account on application of nucleic

acid sensors and DNA chips, immunosensors, enzyme-based biosensors, organism

and whole cell-based, ion sensors, natural and synthetic receptors for biosensors,

new signal transduction technology, systems integration, proteomics and single-cell

analysis, bioelectronics, nanoanalytical systems, and importance of nanoscale target

molecular detection in cancer, AIDS and other diseases are discussed. The issues of

technical challenges in designing and fabricating the smart biosensors, and integration

of nanobiosensors with system-on-package (SOP) are discussed. Emphasis is

made on nanochemistry applications for biosensor packaging. The potentials and

prospects of biosensors, and their commercial value are mentioned.

Today biosensor packaging technology become dealt with integrated functional active and passive components, such as biosensing elements, biosignal conversion elements, signal processing elements, microfluidic systems, reagent amplification system into a single sensor chip and package.