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6/21/2004

Developers Aim to Bring Laboratory Tests to the Point of Care

Cheryl A. Thompson

Imagine the ease for patients of a tiny blood glucose monitor that fits in the eye, of a disposable coagulation monitoring system that reads like a thermometer. Or the convenience to clinicians of devices that can quickly and relatively simply detect disease-specific DNA and protein.

Making clinical laboratory testing more convenient for health care professionals and patients was the theme of the April 29 and 30 conference "Pushing the Technology Envelope," convened in San Jose, California, by the American Association for Clinical Chemistry.

Nanotechnology. Some of the advances being made in clinical laboratory testing come courtesy of the National Aeronautics and Space Administration (NASA), the National Institutes of Health (NIH), and the Department of Homeland Security, said Jun Li of the Center for Nanotechnology at NASA's Ames Research Center near San Jose.

These government groups "need something cheaper, faster, and simpler for biomolecular detection" than is currently available, he said. The NASA space program in particular wants technology that provides highly sensitive measurements with little sample preparation because of the lack of clinical laboratories in outer space. The Department of Homeland Security needs devices that instantly detect pathogens. NIH seeks speedy DNA and RNA analysis for early cancer detection and point-of-care instruments for disease screenings and selection of patients likely to respond to pharmacogenomics-based medication.

Li said nanotube electrodes, or nanoelectrodes, do a much better job than traditional electrodes of detecting signals from molecules and distinguishing the signal of interest from background noise. And, as with a computer chip, size matters when it comes to speed.

Li's research team has been building high-density arrays of multiple-walled nanoelectrodes topped with DNA probes to detect short nucleotide segments and laboratory-amplified portions of BRCA1, a gene that has been linked to breast cancer in certain women. The new laboratory method, which needs further development, combines "ultrahigh sensitivity" and good control and reproducibility with simple operation and instrumentation—all without the addition of a fluorescent dye or radioactive isotope, Li said.

Sanford A. Asher, a chemistry professor at the University of Pittsburgh in Pennsylvania, said his research group uses 100-nm colloidal particles to build "photonic crystal sensors" for measuring the concentration of glucose in tear fluid. Research conducted elsewhere, he said, determined that there is a direct correlation between the concentrations of glucose in tear fluid and the approximately 15-fold higher amounts in blood.

Asher's research team isolates a special group of negatively charged colloidal particles that, by virtue of their electrostatic repulsion when in close quarters, self-assemble into a crystal that diffracts light in the visible range. Because of the overall composition of the sensor, the wavelength of the light exiting the crystal depends on the concentration of glucose but not other sugars.

Users, he said, will wear a hard contact lens or ophthalmic insert embedded with the sensor. Whenever they want to measure their blood glucose concentration, they will do so indirectly by gazing at a special compact that has a mirror for viewing the color of the tiny lens or insert at a specific distance. Encircling the mirror is a chart for converting the sensor's color to milligrams of glucose per deciliter of blood.

The device has been licensed to Glucose Sensing Technologies LLC.

Disposable coagulation monitor. Wai Tak Law, with four-year-old PortaScience Inc. in New Jersey, said the PortaPT, once fully developed, will allow health care providers to monitor patients' coagulation status with a small, lightweight, disposable device that lacks electronics and moving parts. "Simple to make, simple to use," as he described it.

The 1 x 9 cm test device has four basic parts: a plastic top cover, a round reagent pad, a capillary channel for controlling the flow of the blood sample, and a plastic base with a scale for reading the International Normalized Ratio (INR) in increments of 0.25.

A single drop of whole blood is sufficient to rehydrate the recombinant thromboplastin in the reagent pad, Law said. Simultaneously, the blood sample enters the capillary channel and flows through it until clotting occurs. The endpoint of blood flow is seen as a red bar whose length is proportional to the INR. According to the company, the INR can be read less than 30 seconds after placing a "normal sample" on the reagent pad.

Law reported that, for a blood sample having a mean INR of 0.9 when measured repeatedly by Roche Diagnostics's CoaguChek and Hanson Medical Systems Inc.'s ProTime, two commercially available point-of-care instruments, his company's device gave a mean reading of 1.0 with a precision of 9.3%. The comparative devices had precisions of 8.7% and 6.7%.

In a study conducted at a physician's office, he said, the PortaPT had an accuracy of 94% for the blood samples from 36 patients, 25 of whom were receiving anticoagulation therapy.

Glucose levels at the touch of a finger. Because body heat, blood flow, and oxygenation influence blood glucose concentration, "metabolic heat conformation" offers a noninvasive method for estimating patients' glucose level, said Katushiko Kuwa from Japan's Tsukuba University.

Kuwa and collaborators at Hitachi Limited in Japan and PhiScience GmbH in Germany are working on a 17 x 11.5 x 6.3 cm device that estimates blood glucose concentration from the touch, not prick, of a finger.

Beneath the device's sensor pad where a patient places his or her finger is a thermopile, three thermistors, six light-emitting diodes (LEDs) in the near-infrared and visible spectra, and three photodiodes, Kuwa explained. The amount of heat generated from the finger is detected by the thermophile and thermistors, he said, and the blood flow rate is determined from the rate of heat transfer from the finger to the pad. Oxygenation is measured by the LEDs and photodiodes in a manner similar to that of commonly used finger oximeters.

Kuwa said initial testing with four women and four men, some of whom were insulin users, showed a direct relationship, with a correlation coefficient of 0.91, between blood glucose concentrations of 54–405 mg/dL estimated by the noninvasive device and the values determined with a hexokinase photometric method for plasma samples. Repeated testing with the experimental device of healthy fasting persons having a blood glucose concentration of 100 mg/dL revealed a standard deviation of 5—6 mg/dL.

"These data provide preliminary evidence that the [metabolic heat conformation] method can be used to estimate blood glucose concentrations noninvasively," Kuwa said. "Clinical studies are currently ongoing to further characterize the performance of this technology as a valuable tool for home monitoring of glucose by diabetic patients."