Disease Detectives
Biochips have the potential to quickly and reliably identify infectious diseases.
Recent advances in microarray technology and the emerging technology of biologically based sensors have increased the speed and sensitivity with which viral infections can be detected. Biochips combine these technologies with microelectronics to form complete infectious disease detection systems. These biochips have the potential to be used in hospitals, labs, and in the field as point-of-care diagnostic systems that would save time and money compared to current systems which require sending samples to a centralized lab for confirmatory diagnoses.
The current method employed to detect infectious diseases is enzyme-linked immunosorbent assay, or ELISA. This method is able to detect the presence of antigens or antibodies in a sample. Antigens are molecules that the immune system sees as threats, and antibodies are the immune system’s reaction to these threats. ELISA is straightforward: an enzyme is added to a sample that activates a visible colored dye in the presence of a particular antigen or antibody. The visible signal is analyzed, identifying the unknown antigen or antibody. Although ELISA is a tried and true method, it may take days between obtaining a sample and getting meaningful results. Researchers need to shorten the time between sample collection and disease identification, and this is where biochips have great potential.
Biochip beads and drops
Researchers at Argonne National Laboratory, Ill., are developing a biochip that will be used to identify human and veterinary infectious diseases. Currently, the device can identify infectious disease strains in less than 15 min when testing protein arrays and in less than two hours when testing nucleic acid arrays. “The benefits of using biochips are minimal sample volume measurements, parallel analysis of multiple diseases/agents, shorter assay times, internal redundancy, and better controls for statistics and minimizing false positive and negative results,” says Dan Schabacker, leader of the biochip group at Argonne.
Argonne’s biochip contains hundreds to thousands of gel drops that are about 100 µm in diameter. A segment of DNA, protein, peptide, or antibody is inserted into each drop, tailoring that drop to recognize a specific biological agent or biochemical signature. The drops are in known locations on the biochip so that when the sample reacts with the drops, the position of the drop is detected, identifying the sample.
“The array of gel drops can be tailored to detect specific strains of infectious diseases or other biological organisms,” says Schabacker. “Each drop can detect trace quantities of the agents for which they are specific.”
This biochip exploits polymerase chain reaction (PCR), a method for replicating billions of copies from one piece of material. PCR allows trace quantities of DNA to be replicated to a level where they can be detected in the biochip system. The sample to be tested is applied to the biochip, and the chip is then put into the reader and scanned using side illumination laser technology to detect the reaction sites. Automated algorithms determine the agents present in the sample.
Improvements currently under development include shortening the sample preparation time to 10 min and increasing system sensitivity, allowing full analysis for nucleic acid arrays in less than an hour. Beads are also used in biochips to help detect disease. Researchers at the Univ. of California, Berkeley, are developing a 2-mm square biochip, the ImmunoSensor, that uses magnetic beads along with microelectronics to detect disease. A drop of blood or serum is placed in a microscale well on the chip and comes into contact with an array of small sensors that are coated with a viral protein or a specific antigen associated with a particular disease. If disease-specific antibodies are present in the sample, they will bind to the antigen and any number of the magnetic beads on the chip. A magnetic field is then applied, which causes the beads that are not attached to the antigens to be pulled away from the array, a process called magnetic washing. Sensors then check for a small magnetic field from the remaining beads, indicating whether the disease is present.
The ImmunoSensor takes a bit more than a minute to complete this process. It is currently being used to test for Dengue fever, and researchers are creating a version for HIV detection.
Illuminating diseases
Researchers at Oak Ridge National Laboratory (ORNL), Tenn., are developing a multifunctional biochip which uses fluorescence to identify diseases. It is highly selective and sensitive with the ability to distinguish between a bacterium and a virus or between a chemical or biological organism. It can simultaneously detect a variety of biomedical targets, and it can process up to 100 samples in 30 min.
The chip contains a sampling platform, an excitation source, and electro-optical sensor arrays. It uses DNA to identify the virus in a sample. Short DNA strands are attached to the sampling platform, each with a different sequence of chemical bases. The chip site and the sequence of each fragment is known. The sample under test is processed for viral or bacterial material, and the DNA fragments of unknown substances in the sample are tagged with fluorescent dye. Once the sample under test is applied to the chip, the unknown DNA sequences will link up with their mirror images, or hybridize, with the affixed DNA fragments having the complementary sequence. The unattached fragments are washed away, and a diode laser or LED (light-emitting diode) illuminates the array, causing fluorescence of the paired DNA fragments. Electronics on the chip then determine the total sequence of the captured DNA fragments and compares them with known sequences of various bacteria and viruses, and issues a diagnosis.
The ORNL biochip can currently detect HIV, tuberculosis bacillus, and cancer.
Scientists at the Univ. Laval, Quebec City, Canada, are building an infectious disease identifying biochip that is also fluorescence-based. It uses an array of DNA strands attached to a polymer film on a glass chip. When a protein from the sample under test sticks to the biochip DNA array, the attachment distorts the underlying polymer molecules, changing their optical properties and making them fluoresce. This fluorescence is then measured with standard fluorescence techniques, and the disease is identified based on the fluorescence signature.
This chip is built from specific DNA strands called aptamers that stick only to a specific protein. This enables the chip to detect a single protein, even in a mixture of other molecules that would otherwise interfere with the sensing process and give false positives. This biochip takes anout an hour to identify diseases.
Looking to the future
Most infectious disease biochips are still under development in labs, and many improvements must take place before they are widely used in hospital environments or in the field. “Biochip use is currently limited to highly trained technicians because of the multi-reagent/multi-step processes required,” says Schabacker. Improved sample preparation would also increase their acceptance into mainstream use. “Easy point-of-care devices such as biochips embedded into fluidic cartridges with all sample preparation on-board is an improvement that I would like to see,” adds Schabacker.
—Martha Walz
Recent advances in microarray technology and the emerging technology of biologically based sensors have increased the speed and sensitivity with which viral infections can be detected. Biochips combine these technologies with microelectronics to form complete infectious disease detection systems. These biochips have the potential to be used in hospitals, labs, and in the field as point-of-care diagnostic systems that would save time and money compared to current systems which require sending samples to a centralized lab for confirmatory diagnoses.
The current method employed to detect infectious diseases is enzyme-linked immunosorbent assay, or ELISA. This method is able to detect the presence of antigens or antibodies in a sample. Antigens are molecules that the immune system sees as threats, and antibodies are the immune system’s reaction to these threats. ELISA is straightforward: an enzyme is added to a sample that activates a visible colored dye in the presence of a particular antigen or antibody. The visible signal is analyzed, identifying the unknown antigen or antibody. Although ELISA is a tried and true method, it may take days between obtaining a sample and getting meaningful results. Researchers need to shorten the time between sample collection and disease identification, and this is where biochips have great potential.
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Researchers at Argonne National Laboratory, Ill., are developing a biochip that will be used to identify human and veterinary infectious diseases. Currently, the device can identify infectious disease strains in less than 15 min when testing protein arrays and in less than two hours when testing nucleic acid arrays. “The benefits of using biochips are minimal sample volume measurements, parallel analysis of multiple diseases/agents, shorter assay times, internal redundancy, and better controls for statistics and minimizing false positive and negative results,” says Dan Schabacker, leader of the biochip group at Argonne.
Argonne’s biochip contains hundreds to thousands of gel drops that are about 100 µm in diameter. A segment of DNA, protein, peptide, or antibody is inserted into each drop, tailoring that drop to recognize a specific biological agent or biochemical signature. The drops are in known locations on the biochip so that when the sample reacts with the drops, the position of the drop is detected, identifying the sample.
“The array of gel drops can be tailored to detect specific strains of infectious diseases or other biological organisms,” says Schabacker. “Each drop can detect trace quantities of the agents for which they are specific.”
This biochip exploits polymerase chain reaction (PCR), a method for replicating billions of copies from one piece of material. PCR allows trace quantities of DNA to be replicated to a level where they can be detected in the biochip system. The sample to be tested is applied to the biochip, and the chip is then put into the reader and scanned using side illumination laser technology to detect the reaction sites. Automated algorithms determine the agents present in the sample.
Improvements currently under development include shortening the sample preparation time to 10 min and increasing system sensitivity, allowing full analysis for nucleic acid arrays in less than an hour. Beads are also used in biochips to help detect disease. Researchers at the Univ. of California, Berkeley, are developing a 2-mm square biochip, the ImmunoSensor, that uses magnetic beads along with microelectronics to detect disease. A drop of blood or serum is placed in a microscale well on the chip and comes into contact with an array of small sensors that are coated with a viral protein or a specific antigen associated with a particular disease. If disease-specific antibodies are present in the sample, they will bind to the antigen and any number of the magnetic beads on the chip. A magnetic field is then applied, which causes the beads that are not attached to the antigens to be pulled away from the array, a process called magnetic washing. Sensors then check for a small magnetic field from the remaining beads, indicating whether the disease is present.
The ImmunoSensor takes a bit more than a minute to complete this process. It is currently being used to test for Dengue fever, and researchers are creating a version for HIV detection.
Illuminating diseases
Researchers at Oak Ridge National Laboratory (ORNL), Tenn., are developing a multifunctional biochip which uses fluorescence to identify diseases. It is highly selective and sensitive with the ability to distinguish between a bacterium and a virus or between a chemical or biological organism. It can simultaneously detect a variety of biomedical targets, and it can process up to 100 samples in 30 min.
The chip contains a sampling platform, an excitation source, and electro-optical sensor arrays. It uses DNA to identify the virus in a sample. Short DNA strands are attached to the sampling platform, each with a different sequence of chemical bases. The chip site and the sequence of each fragment is known. The sample under test is processed for viral or bacterial material, and the DNA fragments of unknown substances in the sample are tagged with fluorescent dye. Once the sample under test is applied to the chip, the unknown DNA sequences will link up with their mirror images, or hybridize, with the affixed DNA fragments having the complementary sequence. The unattached fragments are washed away, and a diode laser or LED (light-emitting diode) illuminates the array, causing fluorescence of the paired DNA fragments. Electronics on the chip then determine the total sequence of the captured DNA fragments and compares them with known sequences of various bacteria and viruses, and issues a diagnosis.
The ORNL biochip can currently detect HIV, tuberculosis bacillus, and cancer.
Scientists at the Univ. Laval, Quebec City, Canada, are building an infectious disease identifying biochip that is also fluorescence-based. It uses an array of DNA strands attached to a polymer film on a glass chip. When a protein from the sample under test sticks to the biochip DNA array, the attachment distorts the underlying polymer molecules, changing their optical properties and making them fluoresce. This fluorescence is then measured with standard fluorescence techniques, and the disease is identified based on the fluorescence signature.
This chip is built from specific DNA strands called aptamers that stick only to a specific protein. This enables the chip to detect a single protein, even in a mixture of other molecules that would otherwise interfere with the sensing process and give false positives. This biochip takes anout an hour to identify diseases.
Looking to the future
Most infectious disease biochips are still under development in labs, and many improvements must take place before they are widely used in hospital environments or in the field. “Biochip use is currently limited to highly trained technicians because of the multi-reagent/multi-step processes required,” says Schabacker. Improved sample preparation would also increase their acceptance into mainstream use. “Easy point-of-care devices such as biochips embedded into fluidic cartridges with all sample preparation on-board is an improvement that I would like to see,” adds Schabacker.
—Martha Walz
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