ABSTRACT
A biochip is a collection of miniaturized test sites (microarrays) arranged on a solid
substrate that permits many tests to be performed at the same time in order to achieve
higher throughput and speed. Like a computer chip that can perform millions of
mathematical operations in one second, a biochip can perform thousands of biological
reactions, such as decoding genes, in a few seconds. Biochips helped to dramatically
accelerate the identification of the estimated 80,000 genes in human DNA, an ongoing
world-wide research collaboration known as the Human genome project. Developing a
biochip plat-form incorporates electronics for addressing, reading out, sensing and
controlling temperature and, in addition, a handheld analyzer capable of multiparameter
identification. The biochip platform can be plugged in a peripheric standard bus of the
analyzer device or communicate through a wireless channel. Biochip technology has
emerged from the fusion of biotechnology and micro/nanofabrication technology.
Biochips enable us to realize revolutionary new bioanalysis systems that can directly
manipulate and analyze the micro/nano-scale world of biomolecules, organelles and cells.
INTRODUCTION
What is a biochip?
A biochip is a collection of miniaturized test sites (microarrays) arranged on a solid
substrate that permits many tests to be performed at the same time in order to achieve
higher throughput and speed. Typically, a biochip's surface area is no larger than a
fingernail. Like a computer chip that can perform millions of mathematical operations in
one second, a biochip can perform thousands of biological reactions, such as decoding
genes, in a few seconds. Biochip is a broad term indicating the use of microchip
technology in molecular biology and can be defined as arrays of selected biomolecules
immobilized on a surface. Biochip will also be used in animal and plant breeding, and in
the monitoring of foods and the environment. Biochip is a small-scale device, analogous
to an integrated circuit, constructed of or used to analyze organic molecules associated
with living organisms. One type of theoretical biochip is a small device constructed of
large organic molecules, such as proteins, and capable of performing the functions (data
storage, processing) of an electronic computer. The other type of biochip is a small device
capable of performing rapid, small-scale biochemical reactions for the purpose of
identifying gene sequences, environmental pollutants, airborne toxins, or other
biochemical constituents.
Fig : Biochip
HISTORY/GENERATION
The development of biochips has a long history, starting with early work on the
underlying sensor technology. One of the first portable, chemistry-based sensors was the glass
pH electrode, invented in 1922 by Hughes (Hughes, 1922). Measurement of pH was
accomplished by detecting the potential difference developed across a thin glass membrane
selective to the permeation of hydrogen ions; this selectivity was achieved by exchanges between
H+ and SiO sites in the glass. The basic concept of using exchange sites to create perm selective
membranes was used to develop other ion sensors in subsequent years. For example, a K+ sensor
was produced by incorporating valinomycin into a thin membrane (Schultz, 1996). Over thirty
years elapsed before the first true biosensor (i.e. a sensor utilizing biological molecules)
emerged. In 1956, Leland Clark published a paper on an oxygen sensing electrode(Clark,
1956_41). This device became the basis for a glucose sensor developed in 1962 by Clark and
colleague Lyons which utilized glucose oxidase molecules embedded in a dialysis membrane
(Clark, 1962). The enzyme functioned in the presence of glucose to decrease the amount of
oxygen available to the oxygen electrode, thereby relating oxygen levels to glucose
concentration. This and similar biosensors became known as enzyme electrodes, and are still in
use today.
In 1953, Watson and Crick announced their discovery of the now familiar double helix structure
of DNA molecules and set the stage for genetics research that continues to the present day
(Nelson, 2000). The development of sequencing techniques in 1977 by Gilbert (Maxam, 1977)
and Sanger (Sanger, 1977) (working separately) enabled researchers to directly read the genetic
codes that provide instructions for protein synthesis. This research showed how hybridization of
complementary single oligonucleotide strands could be used as a basis for DNA sensing. Two
additional developments enabled the technology used in modern DNA-based biosensors. First, in
1983 Kary Mullis invented the polymerase chain reaction (PCR) technique (Nelson, 2000), a
method for amplifying DNA concentrations. This discovery made possible the detection of
extremely small quantities of DNA in samples. Second, in 1986 Hood and co-workers devised a
method to label DNA molecules with fluorescent tags instead of radiolabels (Smith, 1986), thus
enabling hybridization experiments to be observed optically.
The rapid technological advances of the biochemistry and semiconductor fields in the 1980s led
to the large scale development of biochips in the 1990s. At this time, it became clear that
biochips were largely a "platform" technology which consisted of several separate, yet integrated
components. Figure 1 shows the make up of a typical biochip platform. The actual sensing
component (or "chip") is just one piece of a complete analysis system. Transduction must be
done to translate the actual sensing event (DNA binding, oxidation/reduction, etc.) into a format
understandable by a computer (voltage, light intensity, mass, etc.), which then enables additional
analysis and processing to produce a final, human-readable output. The multiple technologies
needed to make a successful biochip — from sensing chemistry, to microarraying, to signal
processing — require a true multidisciplinary approach, making the barrier to entry steep. One of
the first commercial biochips was introduced by Affymetrix. Their "GeneChip" products contain
thousands of individual DNA sensors for use in sensing defects, or single nucleotide
polymorphisms (SNPs), in genes such as p53 (a tumor suppressor)
and BRCA1 and BRCA2 (related to breast cancer) (Cheng, 2001). The chips are produced
using microlithography techniques traditionally used to fabricate integrated circuits (see below
Biochips are a platform that require, in addition to microarray technology, transduction and
signal processing technologies to output the results of sensing experiments.
Today, a large variety of biochip technologies are either in development or being
commercialized. Numerous advancements continue to be made in sensing research that enable
new platforms to be developed for new applications. Cancer diagnosis through DNA typing is
just one market opportunity. A variety of industries currently desire the ability to simultaneously
screen for a wide range of chemical and biological agents, with purposes ranging from testing
public water systems for disease agents to screening airline cargo for explosives. Pharmaceutical
companies wish to combinatorially screen drug candidates against target enzymes. To achieve
these ends, DNA, RNA, proteins, and even living cells are being employed as sensing mediators
on biochips (Potera, 2008). Numerous transduction methods can be employed including surface
Plasmon resonance, fluorescence, and chemiluminescence. The particular sensing and
transduction techniques chosen depend on factors such as price, sensitivity, and reusability
STRUCTURE AND WORKING OF AN ALREADY
IMPLANTED SYSTEM
Biochip Architecture
The biochip implant system consists of two components; a transponder and a reader or scanner.
The transponder is the actual biochip implant. The biochip system is radio frequency
identification (RFID) system, using low-frequency radio signals to communicate between the
biochip and reader. The reading range or activation range, between reader and biochip is small,
normally between 2 and 12 inches.
Size:
The size of Biochip is of a size of an uncooked rice grain size. It ranges from 2inches to
12inches.
Fig: Actual size of chip
The transponder:
The transponder is the actual biochip implant. It is a passive transponder, meaning it contains no
battery or energy of its own. In comparison, an active transponder would provide its own energy
source, normally a small battery. Because the passive contains no battery, or nothing to wear out, it
has a very long life up to 99 years, and no maintenance. Being passive, it is inactive until the
reader activates it by sending it a low-power electrical charge. The reader reads or scans the
implanted biochip and receives back data (in this case an identification number) from the biochips.
The communication between biochip and reader is via low-frequency radio waves. Since the
communication is via very low frequency radio waves it is not at all harmful to the human body.
The biochip-transponder consists of four parts; computer microchip, antenna coil,
capacitor and the glass capsule.
Computer microchips:
The microchip stores a unique identification number from 10 to 15 digits long. The storage
capacity of the current microchips is limited, capable of storing only a single ID number. AVID
(American Veterinary Identification Devices), claims their chips, using a nnn-nnn-nnn format, has
the capability of over 70 trillion unique numbers. The unique ID number is “etched” or encoded
via a laser onto the surface of the microchip before assembly. Once the number is encoded it is
impossible to alter. The microchip also contains the electronic circuitry necessary to transmit the
ID number to the “reader”.
Antenna Coil:
This is normally a simple, coil of copper wire around a ferrite or iron core. This tiny,
primitive, radio antenna receives and sends signals from the reader or scanner.
Tuning Capacitor:
The capacitor stores the small electrical charge (less than 1/1000 of a watt) sent by the
reader or scanner, which activates the transponder. This “activation” allows the transponder to
send back the ID number encoded in the computer chip. Because “radio waves” are utilized to
communicate between the transponder and reader, the capacitor is tuned to the same frequency as
the reader.
Glass Capsule:
The glass capsule “houses” the microchip, antenna coil and capacitor. It is a small capsule,
the smallest measuring 11 mm in length and 2 mm in diameter, about the size of an uncooked grain
of rice. The capsule is made of biocompatible material such as soda lime glass.
After assembly, the capsule is hermetically (air-tight) sealed, so no bodily fluids can touch
the electronics inside. Because the glass is very smooth and susceptible to movement, a material
such as a polypropylene polymer sheath is attached to one end of the capsule. This sheath provides
a compatible surface which the boldly tissue fibers bond or interconnect, resulting in a
permanent placement of the biochip.
Fig: Biochip & Syringe
The biochip is inserted into the subject with a hypodermic syringe. Injection is safe and
simple, comparable to common vaccines. Anesthesia is not required nor recommended. In dogs
and cats, the biochip is usually injected behind the neck between the shoulder blades.
The Reader:
The reader consists of an “exciter coil” which creates an electromagnetic field that, via
radio signals, provides the necessary energy (less than 1/1000 of a watt) to “excite” or “activate”
the implanted biochip. The reader also carries a receiving coil that receives the transmitted code or
ID number sent back from the “activated” implanted biochip. This all takes place very fast, in
milliseconds. The reader also contains the software and components to decode the received code
and display the result in an LCD display. The reader can include a RS-232 port to attach a
computer.
Cost:
Biochips are not cheap, though the price is falling rapidly. A year ago, human biochips
cost $2,000 per unit. Currently human biochips cost $1,000, while chips for mice, yeast, and fruit
flies cost around $400 to $500. The price for human biochips will probably drop to $500 this
year. Once all the human genes are well characterized and all functional human SNPs are known,
manufacture of the chips could conceivably be standardized. Then, prices for biochips, like the
prices for computer memory chips, would fall through the floor.
How it works
The reader generates a low-power, electromagnetic field, in this case via radio signals,
which “activates” the implanted biochip. This “activation” enables the biochip to send the ID code
back to the reader via radio signals. The reader amplifies the received code, converts it to digital
format, decodes and displays the ID number on the reader’s LCD display. The reader must
normally be between 2 and 12 inches near the biochip to communicate. The reader and biochip can
communicate through most materials, except metal.
BIOCHIPS CURRENTLY UNDER DEVELOPMENT
Oxy Sensors:
A working model of an oxy sensor uses the same layout. With its current circuitry, it is
about the size of a large shirt button but the final silicon wafer will be less than a millimeter
square. The oxygen sensors will be useful not only to monitor breathing inside intensive care units,
but also to check that packages of food, or containers of semiconductors stored under nitrogen gas
remain airtight.
Another version of an oxygen sensing chip currently under development sends light pulses
out into the body. The light absorbed to varying extends, depending on how much oxygen is
carried in the blood, and this chip detects the light that is left. The rushes of blood pumped by the
heart are also detected, so the same chip is a pulse monitor. A number of companies already make
large scale versions of such detectors.
The transition of certain semiconductors to their conducting state is inherently sensitive to
temperature, so designing the sensor was simple enough. With some miniature radio frequency
transmitters, and foam-rubber earplugs to hold the chip in place, the device is complete.
Applications range from sick children, to chemotherapy patients who can be plagued by sudden
rises in body temperature in response to their anti-cancer drugs.
Brain surgery with an on-off switch:
Sensing and measuring is one thing, but can we switch the body on and off? Heart
pacemakers use the crude approach: large jolts of electricity to synchronize the pumping of the
heart. The electric pulses of Active implant, made by US-based Medtronic’s Inc., are directed not
at the heart but at the brain. They turn off brain signals that cause the uncontrolled movements, or
tremors, associated with disease such as Parkinson’s.
Drug therapy of Parkinson’s disease aims to replace the brain messenger dopamine, a
product of brain cells that are dying. But eventually the drug’s effects wear off, and the erratic
movements come charging back.
The Activa implant is a new alternative that uses high-frequency electric pulses to
reversibly shut off the thalamus. The implantation surgery is far less traumatic than thalamatomy,
and if there are any post-operative problems the stimulator can simply be turned off. The implant
primarily interferes with aberrant brain functioning.
Adding sound to life:
The most ambitious bioengineers are today trying to add back brain functions, restoring
sight and sound where there was darkness and silence. The success story in this field is the
cochlear implant. Most hearing aids are glorified amplifiers, but the cochlear implant is for patients
who have lost the hair cells that detect sound waves. For these patients no amount of amplification
is enough.
THE CLARION COCHLEAR IMPLANT
THE CIRCUITRY OF THE IMPLANTED PART OF THE COCHLEAR IMPLANT
The cochlear implant delivers electrical pulses directly to the nerve cells in the cochlea, the
spiral-shaped structure that translates sound in to nerve pulses. In normal hearing individuals,
sound waves set up vibrations in the walls of the cochlea, and hair cells detect these vibrations.
High-frequency notes vibrate nearer the base of cochlea, while low frequency notes nearer the top
of the spiral. The implant mimics the job of the hair cells. It splits the incoming noises into a
number of channels (typically eight) and then stimulates the appropriate part of the cochlea.
The two most successful cochlear implants are ‘Clarion’ and ‘Nucleus’.
[Abstract]Experiments with lost sight
With the ear at least partially conquered, the next logical target is the eye. Several groups
are working on the implantable chips that mimic the action of photoreceptors, the light-sensing
cells at the back of the eye. Photoreceptors are lost in retinitis pigmentosa, a genetic disease and in
age related macular degeneration, the most common reason for loss sight in the developed world.
Joseph Rizzo of the Massachusetts Eye and Ear Infirmary, and John Wyatt of Massachusetts
Institute of Technology have made a twenty electrode 1mm-square chip, and implanted it at the
back of rabbit’s eyes.
The original chip, with the thickness of human hair, put too much stress on the eye, so the
new version is ten times thinner. The final setup will include a fancy camera mounted a pair of
glasses. The camera will detect and encode the scene, then send it into the eye as a laser pulse,
with the laser also providing the energy to drive the chip.
Rizzo has conformed that his tiny array of light receivers (photodiodes) can generate
enough electricity needed to run the chip. He has also found that the amount of electricity needed
to fire a nerve cell into action is 100-fold lower than in the ear, so the currents can be smaller, and
the electrodes more closely spaced.
For now the power supply comes from a wire inserted directly in the eye and, using this
device, signals reaches the brain.
Eugene de Jaun of Hopkins Wilmer Eye Institute is trying electrodes, electrodes inserted
directly in to the eyes, are large and somewhat crude. But his result has been startling. Completely
blind patients have seen well-defined flashes, which change in position and brightness as de Jaun
changes the position of the electrode or amount of current.
In his most recent experiments, patients have identified simple shapes outlined by multiple
electrodes.
In one US project chips are implanted on the surface of the retina, the structure at the back
of the eyes. The project is putting its implants at the back of the retina, where the photoreceptors
are normally found.
THE AGILENT 2100 BIOANALYZER
The Agilent 2100 bioanalyzer is the industry’s only platform with the ability to analyze
DNA, RNA, proteins and cells. Through lab-on-a-chip technology the 2100 bioanalyzer integrates
sample handling, separation, detection and data analysis onto one platform. It moves labs beyond
messy, time consuming gel preparation and the subjective results associated with electrophoresis.
And now, with our second generation 2100 bioanalyzer, we have integrated an easier way to
acquire cell based parameters from as few as 20,000 cells per sample.
The process is simple: load sample, run analysis, and view data. The 2100 bioanalyzer is
designed to streamline the processes of RNA isolation, gene expression analysis, protein
expression, protein purification and more. One platform for entire workflow!
Human interface to Biochip
Biochips provide interfaces between living systems and electro-mechanical and
computational devices. These chips may be used in such varied applications as artificial sensors,
prosthesis, portable/disposable laboratories or even as implantable devices to enhance human
life. Biochips promise dramatic changes in future medical science and human life in general.
With the advances of bio and nano technologies two strong paradigms of integrated electronic
and life are emerging. Biosensor chips can provide the construction of sophisticated human
sensing systems such as nose and ears. The second paradigm is chips for sensing biology that
will provide for interactions with living bodies and build new diagnosis tools (such as diabetes
glucose meters) or new medicines (such as a bio-assay chip). A tiny microchip, the size of a
grain of rice, is simply placed under the skin. It is so designed as to be injected simultaneously
with a vaccination or alone."
The biochip is inserted into the subject with a hypodermic syringe. Injection is safe
and simple, comparable to common vaccines. Anesthesia is not required nor recommended. In
dogs and cats, the biochip is usually injected behind the neck between the shoulder blades.
Trovan, Ltd., markets an implant, featuring a patented "zip quill", which you simply press in, no
syringe is needed. According to AVID "Once implanted, the identity tag is virtually impossible
to retrieve. . . The number can never be altered."
Fig:Human interfacing of Biochip
First Implant of Biochip :
On May 10 2002, three members of a family in Florida ("medical pioneers," according to
a fawning report on the CBS Evening News) became the first people to receive the implants.
Each device, made of silicon and called a VeriChip™, is a small radio transmitter about the size
of a piece of rice that is injected under a person's skin. It transmits a unique personal ID number
whenever it is within a few feet of a special receiver unit. VeriChip's maker describes it as "a
miniaturized, implantable, radio frequency identification device (RFID) that can be used in a
variety of security, emergency and healthcare applications.
ADVANTAGES & DISADVANTAGES
Advantages :
.The ability to detect multiple viral agents in parallel e.g. differential diagnosis of agents
from other diseases that cause similar clinical symptoms, or the recognition of complex mixtures
of agents. .Clarification of syndromes of unknown aetiology .Increase speed of diagnosis of
unknown pathogens ("future proofed" surveillance tools).
.Viral typing (AIV, FMDV, Rabies)
.Drive policy for diagnostics and disease control.
.Epidemiological tracing
.Interagency collaboration. The consortium consists of National, EU and OIE reference
laboratories and has access to real sample material from a wide selection of hosts and viruses.
Disadvantages
.These methods have problems that a DNA chip cannot be fabricated at high density and mass
production is limited. Thus, these methods are applicable to fabrication of a DNA chip for study.
.Meanwhile, the DNA chip and the DNA microarray have different fabrication methods but are
similar in that different oligonucleotides are aligned on a square spot having a certain size in a
check pattern.
Applications of Biochip
Genomics :
Genomics is the study of gene sequences in living organisms and being able to read and interpret
them. The human genome has been the biggest project undertaken to date but there are many
research projects around the world trying to map the gene sequences of other organisms. The use
of Biochip facilitate: Automated genomic analysis including genotyping, gene expression DNA
isolation from complex matrices with aim to increase recovery efficiency DNA amplification by
optimizing the copy numberDNA hybridization assays to improve speed and stringency
Proteomics
Proteome analysis or Proteomics is the investigation of all the proteins present in a cell, tissue or
organism. Proteins, which are responsible for all biochemical work within a cell, are often the
targets for development of new drugs. The use of Biochip facilitates:
High throughput proteomic analysis
Multi-dimensional
micro separations (pre LC/MS) to achieve high plate number
Electro kinetic sample injection for fast, reproducible, samples
Stacking or other preconcentration methods (as a precursor to biosensors) to improve
detection limits
Kinetic analysis of interactions between proteins to enable accurate, transport-free kinetics
Cellomics:
Every living creature is made up of cells, the basic building blocks of life.. Cells are used widely
by for several applications including study of drug cell interactions for drug discovery, as well as
in biosensing. The use of Biochip facilitates:
Biochip /Applications of Biochip
Design/develop
"lab-in-cell" platforms handling single or few cells with nanoprobes in carefully
controlledenvironments.
Cell handling, which involve sorting and positioning of the cells optimally using
DEP,optical traps etc.
.
Field/reagent based cell lysis, where the contents of the cell are expelled out by breaking
the membrane,or increase the efficiency of transfection using reagents/field
Intracellular processes to obtain high quality safety/toxicity ADME/T data
Biodiagnostics and (Nano) Biosensors:
Biodiagnostics or biosensing is the field of sensing biological molecules based on
electrochemical, biochemical, optical, luminometric methods. The use of Biochip facilitate:
Genetic/Biomarker Diagnostics, development of Biowarfare sensors which involves optimization
of the platform, reduction in detection time and improving the signal-to-noise ratio
Selection of detection platform where different formats such as lateral flow vs.
microfluidics are compared for ease/efficiency Incorporation of suitablesensing modality
by evaluating tradeoffs and downselect detection modes(color / luminometric,
electrochemical, biochemical, optical methods) forspecific need.
Protein Chips for Diagnosis and Analysis of Diseases
The Protein chip is a micro-chip with its surface modified to detect various disease
causing proteins simultaneously in order to help find a cure for them. Bio-chemical
materials such as antibodies responding to proteins, receptors, and nucleic acids are to be
fixed to separate and analyze protein.
Biochips can detect cancers before symptoms develop
Biochips contain grids of small wells or "dots," each of which contains a protein, antibody or
nucleic acid that can bind to a target antigen or DNA sequence.
In their fight against cancer, doctors have just gained an impressive new weapon to add to
their arsenal. Researchers at the U.S. Department of Energy's Argonne National
Laboratory have developed a chip that can save lives by diagnosing certain cancers even
before patients become symptomatic.
The new technology, known as a biochip, consists of a one-centimeter by one centimeter array
that comprises anywhere between several dozen and several hundred "dots," or small drops. Each
of these drops contains a unique protein, antibody or nucleic acid that will attach to a particular
DNA sequence or antigen.
A tumor, even in its earliest asymptomatic phases, can slough off proteins that find their way into
a patient's circulatory system. These proteins trigger the immune system to kick into gear,
producing antibodies that regulate which proteins belong and which do not.
"Antibodies are the guardians of what goes on in the body," said Tim Barder, president of
Eprogen, Inc., which has licensed Argonne's biochip technology to search for new biomarkers
that indicate cancer. "If a cancer cell produces aberrant proteins, then it's very likely that the
patient will have an antibody profile that differs from that of a healthy person. You can look for
similarities and differences in autoantibody profiles to look for clues and markers that provide
early indicators of disease."
In their hunt for cancer indicators, Eprogen uses a process called 2-dimesional protein
fractionation, which sorts thousands of different proteins from cancer cells by both their
electrical charge and their hydrophobicity or "stickiness."
The 2-D fractionation process creates 960 separate protein fractions, which are then arranged in a
single biochip containing 96-well grids. Eprogen scientists then probe the microarrays with
known serum or plasma "auto-antibodies" produced by the immune systems of cancer patients.
By using cancer patients' own auto-antibodies as a diagnostic tool, doctors could potentially
tailor treatments based on their personal autoantibody profile. "This technology is really
designed to take advantage of the information contained within the patient's own biology,"
Barder said. "What makes this technique unique is that scientists can use the actual expression of
the patient's disease as a means of obtaining new and better diagnostic information that doctors
could use to understand and fight cancer better.
CONCLUSION
Within ten years you will have a biochip implanted in your head consisting of financial
status, employment and medical records.
Even in a grocery store, sensor will read the credit chip and will automatically debit the
account for purchase.
A biochip implanted in our body can serve as a combination of credit ca5rd, passport,
driver’s license and personal diary. And there is nothing to worry about losing them.
It is said that by 2020 all members of typical American family including there pets will
have microchips under their skin with ID and medical data
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