2011
251660288251659264251662336251661312
Magnetic Bead
Technology
History, Applications, and Marketability
University of Massachusetts-Lowell
Shiv Sharma
Garo Yessayan
Zachary Nicoll
George Chahwan
Jason Tarantino
Abstract
The objective of this review is to track the on-going progress and evolution of the
biotechnological field through the experimentation with magnetic bead technology and its
applications to modern society. With the large demand for lower costing health care, In Vitro
companies have been looking for newer technologies that will make the overhead costs of
clinical tests and diagnostics cheaper. As a result, recent research has elucidated the pros of
magnetic bead technology. Magnetic beads are polymer-encapsulated shells with a magnetic
pigment mostly made up of iron oxide. The polymer surface of the beads permit chemical
derivatization of magnetic particles; this allows for the conversion of the magnetic particles into
a binding agent for testing and application. The review will look at the history of magnetic bead
technology, from its development to its current applications, its effect on the scientific
community, and its marketability.
Introduction
Background
Magnetic Bead Technology has been around since the 1970’s when Norwegian scientists
were trying to implement magnetism into biological studies. A standardized form was discovered
in 1976 when Norwegian scientist John Ugelstad was first able to create spherical, polystyrene
beads of exactly the same size. This technique had only previously been accomplished by NASA
in the weightless conditions of space. It centers on the concept of magnetic bead-based
separation. The initial upside to this discovery was that it allowed for previously unattainable lab
results to be accurately observed. It led to the idea that magnets can be used to more accurately
perform the techniques already in place. Magnetic beads are based around the use of super
paramagnetic materials that exhibit magnetic properties in the presence of a magnetic field with
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no residual magnetism once the field is removed. This material trait allows for the beads to be
magnetically separated from a mixture and then studied individually. The beads themselves are a
polymer encapsulated shell with a magnetic pigment, usually iron oxide, inside. What makes
them so special is the polymer surface allows for biological substances to be bound to their
surface. Major companies have become interested in the development and application of the
technology so it has been able to grow rapidly. The major upsides of this technology are that it is
significantly cheaper, requires less labor and is widely applicable. These advantages are the
driving forces behind the conception and development of the magnetic bead technology. Some of
the applications are highly interesting and can be productive in the medical field. Bar-coded
magnetic bead (BMB) technology is new, upcoming and is currently being introduced to society.
This technology can help in the medical field by assisting doctors with bacteria testing. Bacteria
can be quickly identified and can also get accurately matched up with the best possible antibody.
This can cut days off the old methods of testing which can not only improve a patient’s health
faster, but can also hinder anti-body resistance by picking the strongest medication for the job. In
addition, these advancements will offer new opportunities for automated, low-cost and fast
cancer diagnosis.
DynaBeads
Dynabeads have become the industry standard for all magnetic beads and are the ones
used by scientists in their experiments. John Ugelstad, the Norwegian scientist, invented the
early form of these beads with the intention of creating uniformly distributed bead surfaces. The
Dynal company eventually progressed the technology to the point where they are capable of
creating unique batch-to-batch, reproducible beads. The process in which they are formed gives
them all the same shape, texture and size, which allows for tests results to be reproduced. The
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outside polymer shell also allows bioreactive substances to be absorbed or coupled to their
surface and they can later be separated from the biological materials. The overall process allows
bioreactive materials to be copied onto the surface of the beads, and then the beads are
magnetically removed from whatever solution they are in, then the bioreactive materials can be
separated and studied. A standardized version of the magnetic beads is an essentially part to
their development and continued use in future experiments.
The Needs and Opportunities
Lately, there has been a seemingly eternal quest for improved medical care at lower costs.
With an aging US population In Vitro Diagnostic (IVD) companies are scrambling to find
biological solutions that will bring down the price of improved medical care. Due to this urge,
the IVD industry is rapidly evolving. In a nutshell, the need for improved care at a low cost
entails improved diagnostic methods. Therefore, a lot of recent research is focused in figuring
out more efficient and precise
diagnostic methods. An example
would include improved testing
sensitivity. Improvements in this
phase of the diagnostic method will lead to better diagnosis, a better clinical management, and
inevitably reduced costs of clinical care. Thus, IVD companies have been looking at numerous
technologies such as magnetic beads to help if finding a solution to the needs of consumers.
Magnetic beads, in the last twenty years have exponentially progressed to now be
considered the “golden standard” in the magnetic microspheres and magnetic nanospheres field.
Magnetic beads are an essential component of immunoassay diagnostic kits for analyzers in
clinical labs. These microspheres are actually polymer shells with a magnetic pigment; here, the
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magnetic material is mainly iron oxide. Functional groups of the polymer surface permit
chemical derivatization of magnetic particles. This process allows the conversion of magnetic
particles into a binding agent for tests using immunoassays.
In the biomedical field, magnetic beads range in size anywhere between 1um-100um,
being 1um-2um in size on average. The iron content of these beads also varies between 15%60%; this amount determines the response to an applied magnetic field, facilitating the
manipulation of any phase in any biomedical test.
Instrumentation
Turbo Beads
Turbo Beads are the next generation of
magnetic beads; they are magnetic nanobeads that
have a core and shell structure. The beads core is
constructed of metal, and its shell is made out of
carbon. The metal core is used because of its highly
magnetic properties, and the carbon is used to provide
a chemical stability. This new technology provides a fast and efficient way to separate various
compound from one another.
This technology began by taking highly
reactive metal nanomagnetics and coating them in
graphene- carbon. The binding of the beads is a
carbon to carbon bond. This covalent bond allows
for no ligands to be lost. A ligand is an atom that is
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bonded to the central metal atom. The graphene-carbon allows the beads to have high thermal
stability. This means that the beads can be used in areas that had low pH levels (Acids) and high
temperatures without oxidation of the core.
That is not the only positive property of the turbo bead. Due to the combination of the
metal core and carbon shell these beads display a large increase in their magnetic properties.
Below is an image that demonstrates how much more reactive the turbo bead is compared to a
ferrite based bead.
In the image on the left we can see that the ferrite based bead is located to the left and is in a red
color; whereas the turbo bead is located to the right and is in a black
color. In the middle of the two tubes is a standard magnet. It is clear
that after forty seconds the turbo bead concentration is comparatively
much greater than the ferrite bead concentration.
The picture on the side is another example demonstrating how
quickly the turbo beads can separate from a substance. In this image
there is a substance that contains the turbo beads. It can be seen that
once a magnet is applied to the vessel (bottom left corner) it only takes five minutes for the turbo
beads to completely separate from the
substance.
The chemical properties of the turbo
beads allow them to have a selective
separation
of
precious
metals
at
low
concentrations. Also, their highly magnetic
properties allow for high recyclability of
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magnetic chemicals, which permits them to be reused.
Today these turbo beads are being used for toxin management in water streams. Given
that the beads are highly reactive and chemically stable, they can be used for the selective
separation of heavy metals. The compounds that create the magnetic bead result in reagents for
swift removal of toxins that can be found in contaminated water.
The picture on the left is a graph that shows the amount of cadmium that is in water before and
after the use of turbo beads. It can be seen that using the turbo beads significantly decrease the
amount of cadmium found in contaminated water. This means that turbo beads allow the
purification to go down to drinking water standards.
CardioGenics Magnetic Beads
CardioGenics’ bead is a type of magnetic bead that was developed to improve testing
sensitivity. Most commercial magnetic beads have a dark color to them, and approximately 80%
of the light they generate is lost, causing them to have a low testing sensitivity.
The CardioGenics magnetic bead is a lighter colored bead that is used to optimize and
collect light signals in binding tests. These beads are a lighter color than the generic bead
because they are coated with a thin layer of silver before they are covered with a polymer shell.
Since these beads are lighter they become more sensitive to light; which in turn maximizes light
collection. The CardioGenics can vary in size from 1 to 50 microns, and have seven times more
light sensitivity than a generic magnetic bead. Due to the increase in light sensitivity these beads
improve the testing sensitivity.
Below are two images that show the different amounts of silver coating that can be added
in order to change the color of the beads. The lighter the beads are the more sensitive they are to
light.
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Asynchronous Magnetic Beads
A new promising technology is asynchronous magnetic bead rotation (AMBR). In order
for this technology to be useful in the field of pharmaceuticals and medicine, the beads need to
be extremely sensitive because they have to examine
various biomolecules in the nano scale.
This breakthrough technology was elucidated
through monitoring the continuous growth of individual
bacteria by direct observation using optical imaging.
Unfortunately,
direct
observation
has
numerous
limitations such as optical diffraction and a limit to the
number of cells that could be continuously monitored. The technology started off testing beads at
a low frequency, around 2-25 Hz, due to limitations on the
magnetic fields. Advances have been made to increase the
rotational speed of the AMBR to 145 Hz, which allows the
bead to have a detection limit of 59nm. There is a direct
correlation between increasing the rotational speed to an
increase in sensitivity. Such precision could be used to measure
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nanoscale growth dynamics of individual bacterial cells.
AMBR sensors operating at high frequencies of 145 Hz allow for higher resolution,
which is important while dealing with molecules on a very small scale. Even though other
technologies like electron microscopy and cantilevers already offer high resolution monitoring,
the drawback of using electron microscopy and cantilevers is that they give optimal results in
vacuum or air and that the AMBR technology has a higher resolution capability. AMBR sensors
will make real time single bacterium growth monitoring and single virus detection possible in
their given fluid environment.
A rotating magnetic field controls the rotation of a ferromagnetic bead. The bead rotation
becomes asynchronous with the magnetic field at a critical frequency Ωc. The critical frequency
depends on the magnetic momentum of the bead m, the magnetic field strength B, the kinetic
viscosity ɳ, the volume of the bead V, and the shape factor k (for a sphere, the shape factor is 6)
Applications
Turbo Beads/ CardioGenics Magnetic Beads Applications
With magnetic beads being such a new but fast growing technology, there is no doubt
that this technology can be applied to numerous fields shown in the figure below. A few fields
include clinical diagnostics, drug targeting, cell isolation, purification, nucleic acid purification
and detection.
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A very popular application of magnetic beads
would be providing more efficient assay platforms
compared to suspension bead based assay platforms.
Immunoassays are used to investigate the roles of
biomolecules. Immunoassays help with trying to stop
the progression of diseases such as HIV, Alzheimer’s
disease, and numerous cancers. Immunoassays can
use both magnetic bead platforms or suspension
platforms but there are numerous reasons as to why
magnetic beads are a better choice.
At a glance, there are various drawbacks to
suspension
beads.
Though
these
beads
offer
numerous advantages in the areas of sensitivity and
cost, there are many unintended consequences that
are elucidated during the process of use. Examples
include the vacuum that is used to wash and remove liquid from the microscopic beads cause
pressure that can fluctuate between wells and plates. This can ultimately skew data results. Also,
human error is a major influence on the results in suspension bead tests are a lot of manual caretake is involved.
On the contrary, magnetic beads just make the whole testing process more efficient and
precise. The magnetic bead based assay platforms use a series of magnetic beads that have
different dyes and emit at varied wavelengths. This is done to create a unique spectral address for
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each bead. These beads then serve as solid phases to capture analytes. The figure on the side
describes the process of the magnetic beads in the assay platform.
Using magnetic beads to carry out the process of magnetic separation in an automated
wash eliminates the variables that cause skewed answers with suspension bead use. Additionally,
with magnetic bead technology, assays can be completed in 3-4 minutes and do not require
additional user training. Conclusively, the benefits of using magnetic beads outweigh those of
suspension beads.
Magtration Technology
Magtration technology in simple terms is the filtration for a nucleic solution by means of
a magnetic force. When studying these nucleic acids, one can learn much about how cells
function, research diseases, discover new medicines, and countless more applications. Nucleic
acids are known as the building blocks of life and contain different types of DNA and RNA.
These are found inside every animal cell and we can now separate nucleic acids by implementing
magtration technology.
Every cell is surrounded by a cell membrane which must be broken down first in order to
get to the inside of the cell where nucleic acids are found. To do this, there are certain toxins and
detergents that will break down a cell membrane but not harm the internal parts of the cell. A
separate solution containing these paramagnetic beads is added to the lysis solution. These
paramagnetic beads are coated with silica with is a natural attraction for the nucleic acid. This
new mixture is shot up and down a pipette in which the magnetic beads are trapped up against
the wall where a magnet is placed. Now that the magnetic beads and the nucleic acid trapped in
the pipette, it must go through separate washing solutions. Several wash cycles should be
preformed to maximize the purification process. From here, the beads are moved into a new
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container containing a low ionic strength solution. When this solution is warmed up, it separates
the beads from the nucleic acid. Then the final step is to remove the beads from the solution by
use of a magnet and aspirating the solution up and down to collect the beads as done earlier and
what remains is the purified nucleic acid.
Asynchronous Magnetic Bead Applications
As mentioned earlier, researchers are looking to operate AMB’s at a high frequency
because that would mean a higher resolution and a higher sensitivity caused by changes in
diameter. Many current applications would benefit from a higher critical frequency; examples
include micro-mixing and growth studies. Using a ferromagnetic bead to reach a bead frequency
of 145 Hz (shown in graph 1) that allows a detection limit of 59 nm; this is sensitive enough to
study single bacterial growth.
Graph 1
(1)
The rotational frequency of the bead is calculated using the following formula:
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Many applications use the sensors to monitor the growth of individual bacteria. In a
recent experiment the sensors were used to monitor the growth of bacteria and its susceptibility
to a particular drug. The Escherichia coli also known as E coli bacteria along with the
antibacterial ampicillin were used for the experiment (2).
The experiment showed that the AMBR sensor was able to detect changes at even 80nm
in a single E coli cell. The sensor was also able to detect the response of the E coli cell to the
antibacterial used. What is also worth mentioning is the fact that the experiment was done in
water; this shows that the sensor is able to work in an aqueous environment unlike previous
technologies like electron microscopy that would work best in a vacuum environment. The
success of this experiment has extended the method to similar single cell studies like cancer
cells.
Finally, we can conclude that asynchronous magnetic bead rotation technology has a lot
of potential. It has the ability to speed up treatment of bacterial infections by allowing us to find
antimicrobials for infections in minutes instead of days. Another field where the technology
could be of vital use would be for studying the response of individual cancer cells; such tests
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could equal huge advances in drug development and treatment. The AMBR technology will help
get faster results at a cheaper price hence saving more lives.
Radiation Checking Magnetic Beads
Professor Lawrie Challis, chairman of Mobile telecommunications and health and
research program, has been looking into the affects of mobile phone radiation and alternatives.
Mobile phones output electromagnetic radiation
which, at 10^(-8) Hertz resemble the frequency of
microwaves. Cell phones are not the only technology
to emit such radiation; in fact any type of wireless
communication device will use the same technology.
Excessive use of these devices can lead to many
health risks. Two of the leading problems are developing brain tumors, and break down of the
blood brain barrier. The blood brain barrier protects the brain from incurring harmful substances
that are within the body. When it breaks down it makes your brain susceptible to many health
dangers. Two leading diseases that are related to the BBB breakdown include Alzheimer’s
disease and Parkinson’s disease.
Other smaller risks include constant headaches, sleep
disturbances, memory loss, learning disabilities, and infertility.
Every device has a specific absorption rate which is the measure of the amount of radio
frequency energy is absorbed by one’s body when
using these device headsets which determine the
danger of the device.
All these risks decrease
vastly with increased distance from the device to
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your body. This is why hands free devices are very good based on the fact that they cut down
immensely the amount of radiation that is absorbed into your body. Unfortunately, they do not
eliminate these harmful risks.
Professor Challis has done much research and found that attaching a magnetic bead to the
wire or antenna of the phone. This type of bead is called a ferrite bead because it acts as a
suppressant to the high frequency noise in the device; it stops any current from passing it on the
outside of the wire. In simple terms it means that no radiation is pulsing out of the phone and is
unable to reach the head. This technology can be used as a marketing technique that will
promote certain phones that contain the beads as “health safe phones”.
There is ongoing debate on whether these magnetic beads are a necessity within the cell phone
unit. There are two main arguments against the use of magnetic beads in cell phones: one is that
the cell phones pass a government safety test which regulates the amount of radiation a phone
can legally have; the United States requires a 1.6 watt per kilogram SAR rating (specific
absorption rate). The other argument against the use of magnetic beads in cell phones is that
since the effect of the radiation takes a very long time to develop, not all scientists are convinced
that there is a link between the radiation and any illnesses. The scientists argue that these
illnesses can be caused by many effects and not just radiation poisoning.
3D Micro Incubator
Magnetic bead technology has also been linked with the purification and detection of
timorous cells. Mixing magnetic bead technology and micro-electro-mechanicals-systems
(MEMS) has resulted in the ability to detect tumor cells rapidly and it also has the capability of
collecting and purifying them. The magnetic beads allow specific antibodies to be incorporated
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onto their surface to target and recognize the desired tumor cells in the clinical body fluids. The
whole idea is based around the technology developed called a 3D micro-incubator. The machine
itself was developed for the incubation and mixing
process, and it has the ability, using the vortex
effect, to mix large amounts of bio-samples
efficiently and rapidly. It has also successfully
detected ovarian and lung cancer cells by
performing on-chip identification. The resulting
mixture of magnetic beads and the 3D micro-incubator leads to a new ability for rapid
purification and detection of cancer cells.
The need for a means of detecting cancerous cells has long been a top priority in the
scientific field since no known cure exists. Currently we are capable of detecting cancerous cells
using biomarkers of tumor cells, cell biopsy and magnetic resonance imaging (MRI), but these
methods of detection take a long time and require complicated machinery and procedures.
Therefore the need for a rapid means of detection exists. It is known that an early detection of
cancerous cells is crucial to the prevention of the cells metastasizing, so a technology enabling
very early detection is highly sought after. With the
emergence of MEMS technology we have been
able to miniaturize biomedical devices and
systems. The combination of MEMS technology
and its use in Biology has led to the emergence of a
new field called lab-on-a-chip technology (LOC).
This technology means that a whole host of
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procedures and devices can be placed onto a single microchip, and it also reduces the amount of
time it takes to diagnose because the process of analysis and preparation have been reduced to
an automatic function. Using these LOC devices, scientists have been able to perform cancer
analysis using cell sorting, separation and spectroscopy techniques. This technology may
possibly lead to the ability to specify treatments to individuals, however the process still requires
lots of bulk equipment that are needed to perform the identification of the cancer cells. This is
where the implementation of magnetic beads comes in to play. We are able to surface-modify
magnetic beads, which allows for a specific type of cell to be detected rapidly, and when
combined with the previous technologies the overall process becomes much quicker.
An actual experiment for the purification and detection of tumor cells was performed to
accurately test the hypothesized outcomes. First they extracted body fluid in large amounts,
around 20mL. The body fluids were then pre-centrifuged and collected. The next step involved
re-suspending them with phosphate buffered saline into a 1 mL volume in an eppendorf tube.
The samples were then incubated with magnetic beads specifically coded to recognize the tumor
cells which could then be purified by using a magnetic field. The actual purification process is
performed by using a vacuum pump to suck out all of the interference substances, leaving only
the magnetized beads behind. The target mRNA can then be reverse transcripted and amplified
using a built-in-self-compensated temperature control module.
The overall layout of the system is comprised of three main units; the 3D microincubator, a micro fluidic control module and a nucleic acid amplification module. The 3D
micro-incubator has three layers of PDMS structures which allow large quantities of fluids to be
mixed quickly. Each layer has a thick PDMS structure and a thin pneumatically-driven PDMS
membrane which generates the mixing effect. The thick PDMS structure is made up of two air
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chambers with a connecting chamber. It has a built in electromagnetic valve capable of driving it
via a digital controller and a vacuum pump. The vacuum pump generates the vortex flow in the
mixing chamber, which is what is needed for the incubation process. For final proof, two kinds
of cancer cells were incubated with magnetic beads, ovarian cancer and lung cancer. The
magnetic beads were conjugated with the correct antibodies and placed in the incubator. Using a
magnetic the beads were attracted and the unwanted substances were sucked out with a vacuum.
It was recorded that almost all of the cancer cells were captured and purified by the experiment.
On average about 92% of tumor cells are capable of being specifically targeted by this
technology. The use of this technology will hopefully bring about the ability to detect and
prevent cancer, that way we can avoid the need to cure it.
Bar-coded Magnetic Bead Technology:
Bar-coded magnetic bead (BMB) technology is new,
upcoming and is currently being introduced to
society. The technology works through a
combination of photolithographic barcodes and
molecular chemistry. The optical bar-coded beads
are functionalized with nucleic acids, proteins, and
probe molecules. The bar code patterns on the beads
transmit high contrast signals to improve the
isolation and identification capacity of in-vitro
diagnostics. The beads themselves are decoded using
two analyzers from an imaging based system. The
bar-code patterns allow for the variation in the florescence signal during analyzation to be
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minimal; therefore, offering a near 100% decoding accuracy. As a result, the bar-coded beads
allow for highly multiplexed assays to be carried out in homo/heterogeneous media. This
technology can help us in the medical field by assisting doctors in the bacteria testing
department. Bacteria can be quickly identified and can also get accurately matched up with the
best possible antibody. This can cut days off the old methods of testing which can not only
improve a patient’s health faster, but can also hinder anti-body resistance by picking the
strongest medication for the job. In addition, these advancements will offer new opportunities for
automated, low-cost and fast cancer diagnosis.
Marketability
Magnetic beads are the most
widely
used
solid
phase
for
automated methods for isolation
and detection of biomolecules. In
fact, 9/10 top IVD companies use
magnetic beads in their automated
analyzers.
Additionally,
binding
tests (such as immunoassays and molecular tests) combine for 1/3 of the clinical tests done in the
market. These tests use magnetic beads as the primary component. This market is also valued at
USD $42 billion as of 2008. Magnetic beads themselves have a market of $1 billion for
immunoassay and molecular diagnosis.
Furthermore, Dynal, a leading magnetic bead manufacturer claims that while the IVD
market is fast growing, the magnetic beads market is growing exponentially faster. In the same
report, Dynal explains that immunoassays make up $4 billion if the IVD market where magnetic
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beads are once again the golden
standard. Moreover, nucleic acid testing
makes a smaller portion, roughly $2
billion of the IVD market; here,
magnetic beads are the most common
solid phase employed. Even areas such
as genomics that include DNA and RNA extraction and purification (a $2.3 billion market) have
started using magnetic beads at a growing pace.
Conclusion
Magnetic Bead technology is becoming influential in the field of medicine and
biosensors. Having been in the market for only a few years, magnetic beads have gone from
niche experimentation to a staple in the biomedical field. With its numerous practical
applications such as asynchronous bead rotation, radiation sensing abilities and biomolecules
separating abilities, magnetic beads are a technology that will be implemented for numerous
years to come. Even from a marketing point of view, the technology has a lot of room to grow in
the market; based on a simple cost analysis it can be seen that this technology will only rise
monetarily for the fore coming future.
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