Researchers at the National Institute of Standards and Technology (NIST) and the NIH say they have developed a shape-shifting probe, which is capable of sensitive, high-resolution remote biological sensing that is not possible with current technology. If eventually put into widespread use, the probe, about one-hundredth as wide as a human hair, could have a major impact on research in medicine, chemistry, and biology and might be used in clinical diagnostics, according to the scientists.

To date, most efforts to image highly localized biochemical conditions such as abnormal pH and ion concentration, which are critical markers for many disorders, rely on various nanosensors that are probed using light at optical frequencies. But the sensitivity and resolution of the resulting optical signals decrease rapidly with increasing depth into the body. That has limited most applications to less obscured, more optically accessible regions.

The new probe devices, described in an article (“Shape-changing magnetic assemblies as high-sensitivity NMR-readable nanoprobes”) in Nature, reportedly are not subject to those limitations. They make it possible to detect and measure localized conditions on the molecular scale deep within tissues, and to observe how they change in real time.

“Our design is based on completely different operating principles,” says NIST's Gary Zabow, Ph.D., who led the research with colleagues at the NIH. “Instead of optically based sensing, the shape-changing probes are designed to operate in the radio frequency (RF) spectrum, specifically to be detectable with standard nuclear magnetic resonance (NMR) or magnetic resonance imaging (MRI) equipment. In these RF ranges, signals are, for example, not appreciably weakened by intervening biological materials.”

As a result, they can get strong, distinctive signals from small dimensions at substantial depths or in other locations impossible to probe with optically based sensors, notes Dr. Zabos.

“The sensors can be made from biocompatible materials, are themselves detectable down to low concentrations, and offer potential responsive NMR spectral shifts that are close to a million times greater than those of traditional magnetic resonance spectroscopies,” wrote the investigators.

The novel devices, called geometrically encoded magnetic sensors (GEMs), are microengineered metal-gel sandwiches about 5 to 10 times smaller than a single red blood cell. Each consists of two separate magnetic disks that range from 0.5 to 2 micrometers in diameter and are just tens of nanometers.

Between the disks is a spacer layer of hydrogel, a polymer network that can absorb water and expand significantly; the amount of expansion depends on the chemical properties of the gel and the environment around it. Conversely, it can also shrink in response to changing local conditions. Swelling or shrinking of the gel changes the distance (and hence, the magnetic field strength) between the two disks, and that, in turn, changes the frequency at which the protons in water molecules around and inside the gel resonate in response to radio-frequency radiation.

In the experiments reported in Nature, the scientists tested the sensors in solutions of varying pH, in solutions with ion concentration gradients, and in a liquid growth medium containing living canine kidney cells as their metabolism went from normal to nonfunctional in the absence of oxygen. That phenomenon caused the growth medium to acidify, and the change over time was sensed by the GEMs and recorded through real-time shifting in resonant frequencies. Even for the un-optimized, first-generation probes used, the frequency shifts resulting from changes in pH were easily resolvable and orders of magnitude larger than any equivalent frequency shifting observed through traditional magnetic resonance spectroscopy approaches.

“The idea is that you could design different sensors to measure different things, effectively measuring a panel of potential biomarkers simultaneously, rather than just one, to better differentiate between different pathologies,” explains Dr. Zabow. “We think that these sensors can potentially be adapted to measure a variety of different biomarkers, possibly including things such as glucose, local temperatures, various ion concentrations, possibly the presence or absence of various enzymes and so forth.”
 








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