Although magnetic sensors are not newcomers to the field of biological diagnostics, their use has been limited by their size and sensitivity. Now, with the development and use of GMR sensors, all that is changing.
Carl H. Smith,
Robert W. Schneider, and Mark Tondra,
Nonvolatile
Electronics, Inc.
Photo 1. A custom GMR sen-
sor array, which consists of 10 sensors, is shown with several 2.8 µm paramagnetic dynabeads. Each sensor measures
2 µm by 10 µm. (Photo courtesy of Jing Ni and Mike Granger, Iowa State University).
In the past, the magnetic sensors used in biological diagnostics (e.g., superconducting quantum interference detectors [SQUIDs]) limited the deployment of such systems to the field because of their size and power requirements. But solid-state magnetic sensors now promise to change all this with the advent of miniaturized systems. The barrier created by the limited sensitivity of solid-state magnetic sensors is being overcome by the use of giant magnetoresistance (GMR) materials.[1]
These highly sensitive near-micrometer-sized sensing elements stand on the cutting edge of biological diagnostics research.[2] Spin-dependent tunneling (SDT) sensors--a new technology also being developed for high-density, hard-disk read heads--promise further reduction in size and power consumption.
Magnetic Biosensors
Magnetic particles have been used for many years in biological assays. A wide variety of biological species--such as cells, proteins, antibodies, pathogens, toxins, and DNA--can be labeled by attaching them to superparamagnetic microbeads. These particles range in size from a few nanometers to a few microns, and their composition varies from pure ferrite to small percentages of ferrite encapsulated in plastic or ceramic spheres. The beads are coated with a chemical or biological species (e.g., DNA or antibodies) that selectively binds to the target analyte. To date, these types of particles have been used primarily to separate and concentrate analytes for offline detection. Now these labeled species can be biochemically immobilized on specific regions of chips and detected using magnetic sensors integrated into the chip/array. This technology can be used for medical/clinical analysis, DNA analysis, scanning for pathogens in municipal water treatment facilities, and pollution detection in public waterways.
Figure 1. Researchers can detect antigens by flowing them over a sensor coated with antibodies. The magnetic, particle-labeled antibodies bind to the antigens, providing a magnetic indication of the presence of the antigens.
You can use the selectivity of the sample and the target as a rapid, sensitive detection strategy with the online integration of a magnetic detector. This integration is facilitated by the development of solid-state GMR sensors that can be used as the magnetic detectors in these applications. These sensors enjoy the advantage of being compatible with silicon IC fabrication technology, resulting in the placement of a single detector--or even multiple detectors--on a chip with the required electrical circuitry. Laboratory findings and the results from theoretical modeling show that GMR detectors can resolve single micrometer-sized magnetic beads.
Figure 2. In a multisensor array, the coating of each location will bond to a different antigen. The diagram shows beads on three of the four locations.
In a proof-of-concept experiment, physicists constructed an 80 µm by 5 µm array of sensing elements from sandwich GMR material. Each element was coated with biological molecules that bonded to specific materials being assayed. A quantity of 1 µm beads consisting of nonometer-sized iron oxide particles, which have little or no magnetization in the absence of an applied field, were coated with the analytes of ineterest and placed in suspension. The beads were allowed to settle on the sensor array, where specific beads bonded to specific sensors only if the materials were designed to attract each other (see Photo 1, and Figure 1). Nonbinding beads were removed by a small magnetic field. The beads were then magnetized at 200 Hz by an AC electromagnet. A lock-in amplifier extracted the signal that occurred at twice the exciting frequency from a Wheatstone bridge. The bridge consisted of two GMR sensing elements (one of which was used as a reference) and two normal resistors. High-pass filters eliminated offset and the necessity of balancing the two GMR sensing elements. With this detection system, the presence of as few as one microbead could be detected. The size of GMR sensing elements makes it possible to construct an array that can simultaneously test for multiple biological molecules (see Figure 2).
Several groups have tried to use commercial GMR sensors as biosensors that detect coated magnetic beads. But the plastic encapsulation used to protect the underlying sensor chip inhibits the performance of the sensors. The 8-pin SOIC package used by Nonvolatile Electronics, Inc., for commercial GMR sensors has a spacing between the GMR element and the top of the package of 0.5 mm and an even greater distance from the element to the end of the package.
Figure 3. The field of the permanent magnet has no horizontal component along the sensor's sensitive axis, but the field at the magnetic bead has a small horizontal component. The sensor detects the field of the magnetized bead.
When magnetized by an external field, magnetic microbeads develop a dipole field proportional to the volume of magnetic material and inversely proportional to the distance cubed. Detecting small fields be-comes more difficult as the distance from the bead to the sensor increases. The rapid decrease in the field with distance requires that the sensitive area be of similar size as the microbeads. If the sensitive area is much larger than the bead, only the portion of the magnetoresistive material close to the bead will be affected. Therefore, the fractional change in resistance--and hence the sensitivity--will be maximized by matching the size of the sensor to the size of the bead.
The quest for smaller active sensor area leads to spin-dependent tunneling materials--GMR materials that function as a re-sult of electrons tunneling through an insulating layer. These materials can be fabricated with high sensitivity and high resistivity in very small footprints. Developers will use these materials to optimize the re-sponse of future arrays of magnetic biosensors.
There are several variations of the relative orientation of the beads, GMR detectors, and excitation fields. One important variation of the excitation field geometry is to apply a field normal to the plane of the GMR sensor (see Figure 3). Thin-film GMR sensors are ~1000 times harder to magnetize in the direction normal to its sensitive axis than parallel to it, so a much larger
magnetizing field can be applied to the beads without saturating the GMR sensors. Another important variation from an instrumentation standpoint is to have a differential sensor or bridge sensor setup in which one or two GMR resistors are exposed to fields from the beads while the rest are not or are exposed to fields in the opposite direction.
Figure 4. In an integrated GMR sensor, the field that magnetizes the immobilized bead can be generated by a strap located in the sensor itself. The chip can also include the processing electronics.
An integrated GMR sensor can include the sensors; the processing electronics; and even the current straps, which provide the field to magnetize the microbeads on the same substrate. Figure 4 shows a cross section of such a sensor.
What Next
As sensor development progresses, the next challenge is to combine integrated GMR sensors with fluid-handling systems. If we can do that, then we can build compact systems that automatically analyze biological materials in the field, eliminating the necessity of using extensive laboratory equipment.
References
1. Carl H. Smith and Robert W. Schneider. Sept. 1999. "Low-Field Magnetic Sensing with GMR Sensors, Part 1: The Theory of Solid-State Sensing," Sensors, Vol. 16, No. 9: 76-83.
2. M. Tondra et al. "Detection of Immobilized Superparamagnetic Nanosphere Assay Labels Using Giant Magnetoresistive Sensors," (American Vacuum Society Conf., Seattle, WA, October 25, 1999, to be published in J. Vac. Sci. & Tech.).
3. D.R. Baselt et al. 1998. "A Biosensor Based on Magneotoresistance Technology," Biosensors & Bioelectronics, Vol 13:731-739.
Acknowledgment
We would like to acknowledge the information and assistance received from Marc Porter, R Lipert, Jing Ni, and Mike Granger of the Microanalytical Research Center at Iowa State University. *
Carl H. Smith is Senior Physicist, Robert W. Schneider is Director of Marketing, and Mark Tondra is Physicist at Nonvolatile Electronics, Inc., 11409 Valley View Rd., Eden Prairie, MN 55344, 612-829-9217, fax 612-996-1600, lowfield@nve.com
