Magnetism holds the key

A new approach could revolutionise point-of-care testing with its robust and remote properties

BRINGING the diagnostic power of the laboratory to the patient requires that complex protocols be reduced to simple robust tests. Current clinical technologies are not amenable to the challenges of bedside and on-location use while simple inexpensive tests are as yet unable to produce sensitive and precise results for critical diagnoses. What is required is an upgrade for the common immunoassay that will fill the role of complex and costly clinical laboratory techniques.

The use of magnetic beads in rapid Point of Care (POC) diagnostics is a relatively new approach to this challenge. Magnetic beads offer several advantages over other labels, which make them attractive reagents. Their magnetic properties are very stable over time as they are not affected by reagent chemistry or subject to photo-bleaching. From a detection standpoint, there is not usually a significant magnetic background present in a biomolecular sample. In addition, magnetism may be used to remotely manipulate the particles for concentration and separation in solution. A number of magnetic field detection devices have been developed that claim to be suitable for biosensing applications, including giant magnetoresistive (GMR) sensors and spin valves, piezo-resistive cantilevers, inductive sensors, superconducting quantum interference devices (SQUIDs), anisotropic magnetoresistive rings, and miniature Hall crosses. But due to various reasons, none of them are widely used in the diagnostics industry. They are either embodied in over-engineered instruments requiring moving parts or liquid nitrogen refrigeration, or they require expensive consumables embedded electronics, connections or microfluidics.

This article presents a technology that promises to make magnetic bead-based detection the new standard for rapid testing. MIAtek effectively distinguishes signal from noise without complex or cumbersome instrumentation. Detecting an entirely new signal due to the unique behaviour of nanometric sized magnetic particles (superparamagnetism), it takes advantage of the magnetic field's intrinsic ability to pass through materials such as plastic, water and nitrocellulose, allowing for true volumetric measurements.

The magic of MIAtek lies in the reader instrument, not in the test. Common lateral flow tests can be accommodated with the substitution of a magnetic bead in place of the gold colloid, blue latex or fluorescent label. Due to reduced engineering constraints, the reader is compact with low power consumption and is amenable to mass production. A reading head based on simple copper coils is all that is required - this instrument does not require any moving parts. In addition, because it provides true volumetric reading capability and geometric versatility, the instrument can accommodate a variety of assay formats such as lateral-flow strip tests, large volume cartridges that combine immunoconcentration and volumetric detection, and flow systems for continuous multi-agent monitoring. The attraction of the magnetic beads to a field in a solution permits integrated concentration and detection in a single phase. This allows for the development of simpler tests with integrated sample preparation; a limitation of rapid tests.

Contrary to conventional methods usually used in physics which measure the susceptibility (χ) of these ‘superparamagnetic’ materials, MIAtek only measures their non-linear impact on the magnetic field applied by the reader. The advantage of doing so is to offset the impact of linear diamagnetic materials such as sample matrix, consumable plastics and/or nitrocellulose. When one is investigating very tiny quantities of superparamagnetic materials, on the nanogram scale or below, the background signal generated by ancillary materials is significant. In most approaches, magnetic signal is obscured by this background magnetic noise, which can be several orders of magnitude greater than the signal. MIAtek eliminates the contribution of external diamagnetic noise by measuring only the unique signal generated by the target beads. Another benefit of this technology is that external magnetic fields such as Earth field, motors or magnets have no influence on the signal. Serial dilution tests have demonstrated a remarkably precise calibration over a broad dynamic range. A linear signal response curve has been obtained for six orders of magnitude magnetic sample dilution.

The feasibility of multi-parametric assays using magnetic beads as labels has been developed: it has been shown that one can use a set of magnetic beads differing by their magnetic properties for the investigation of a single sample potentially containing a plurality of targets, with no need for aliquoting or spatial resolution. Not only can one detect the presence or the absence of each target, but also quantify each individually in a mixed sample of varying concentration and target proportion. Several families of magnetic materials with unique construct signatures have already been identified and characterised in the MIAplex technology.

A device that can read planar biochips or microfluidic cartridges by using a number of small coils with a 0.5-1mm radius is also being developed. Such coils can count magnetic nanoparticles inside a semisphere of the same radius, which allows the separation of electronics from biochips or microfluidic cartridges that can be analysed externally through 0.1mm-thick glass or plastic. Such magnetic biochips can be very affordable consumables for clinical diagnostics.

Even though a rapid diagnostic would be useful for many applications, current technologies have not resulted in the development of simple tests with adequate performance for these targets of interest - MIAtek may offer the potential to provide an answer for these unmet needs.

Advances in rapid POC testing technology promise to improve patient outcomes and reduce healthcare costs. Higher performance field tests can help contain disease outbreaks, increase safety and reduce testing cost. Between the simple strip test and the ideal of real-time and personalised molecular medicine lies a myriad of applications waiting for an improved diagnostic solution. More intelligent medical decisions and effective targeted therapies depend on increasing the quality and speed of information gathering.

MIAtek technology presents an opportunity for the next evolution in POC testing, offering the possibility to develop a high performance simple test - not a labour-intensive lab method jammed into a small package. A MIAtek based diagnostic will provide the performance of radioimmunoassay and the sensitivity of ELISA for safe and simple rapid testing. The physics behind MIAtek permits a high performance result without hazardous, high cost reagents or complex consumables.

The technology has demonstrated that it could be a useful tool for in vivo investigations. When compared to the detection of 59Fe isotope for monitoring ferrite-based particles in rat blood, preliminary experiments with MIAtek demonstrated comparable sensitivity, which could be further improved by optimising the device geometry. This approach is more convenient, safer, less expensive, and provides real-time measurements in vivo. Quantified multiparametric magnetic staining is also a possibility in which spatial concentration of particular antibodies or DNA probes can be not only identified but also quantified on a slide.

MIAtek meets the specific needs of such markets as bacteriology and food safety testing. With larger volume samples and the need to accommodate thick or high viscosity samples, this technology could determine a limit of detection where it has not been possible before. For bacterial detection, MIAtek, utilising the high volume flow through format MIAflo, is sufficiently sensitive that in many cases it is not necessary to culture bacteria, thus providing a meaningful POC result in minutes rather than days.

The increased diagnostic performance obtained by integrating MIAtek into the common lateral-flow format increases the utility of such simple tests. For example, applications such as avian flu testing in birds are being developed. Such a field test, which is lower cost and provides greater testing confidence, could help to contain outbreaks of the disease by providing an earlier warning. Such screening tests that are currently relegated to a non-critical role can become clinically important methods for enhancing healthcare delivery due to increased sensitivity, decreased demands on the user, and secure non-interpretative results. As an example, a test for determining tetanus immunity status (MIAtetanos) is close to market launch in the European Union.

MIAtek could also make possible rapid field tests for remote diagnosis by a qualified medical practitioner, even if the test operator may not be medically trained. In the developing world, such remote diagnosis translates into the ability to screen vast low population areas from a small number of centrally located clinics. In developed countries, such as the United States with its requirements to receive a waiver under the Clinical Laboratory Improvement Amendments (CLIA), MIAtek enables the development of clinically critical tests that can be administered by technicians and nurses without involving a physician. With a secure quantified data output, MIAtek is compatible with GPS mapping and integrated patient monitoring systems.

The technology has been demonstrated for the identification of multiple targets with positive results. In a simple lateral flow strip test format, MIAtek has demonstrated two to three orders of magnitude increased sensitivity over existing tests relying on visual detection of a gold colloid label. There are currently several tests in development based on the MIAtek diagnostic platform with many possible applications across multiple markets.