Diagnostics & Imaging Week Washington Editor

WASHINGTON — The second day of the conference on nanotechnology hosted by the National Academy of Sciences (Washington) included discussions of a number of healthcare applications of nanomaterials, including cancer and heart disease.

Among the presentations was one that described the work going toward exploration of the most exotic and delicate organ of all, the human brain.

Herc Neves, PhD, principal scientist for biomedical systems for IMEC (Leuven, Belgium), gave an overview of the dilemmas faced in the effort to use nanotechnology to deal with neurological conditions. He said that IMEC is the largest research center in Europe for micro- and nano-electronics that operate on a scale of 45 nanometers or smaller.

Science has a fairly successful history of electrically interacting with biological tissues, Neves said, but he noted that monitoring chemical activity on such a small scale is a different task, especially over extended periods of time. Such uses of nanotechnology open up what he called “a Pandora’s box, because you have a lot of new problems to tackle.”

When attempting to record any kind of synaptic activity, the rule is the same as that for real estate: location, location, location. Ideally, the signal from a single synapse is all that an electrode will pick up, but the electrode “can pick up data from nearby neurons” as well if the placement is imprecise, he said.

Neves worked on sensor tip arrays for peripheral nervous system use while at the University of California at Los Angeles, and while he said that work was on a larger scale than his current endeavor, the electrodes he and others engineered at that time provided a better signal-to-noise ratio. This then enabled researchers to move into the central nervous system (CNS).

He said, “The justification for doing brain recordings is that the techniques that we use today, such as functional MRI,” do not allow researchers to map brain cell activities.

Management of movement disorders, such as Parkinson’s, is a huge opportunity, as is localization of pathological activity to aid surgical excision in intractable epilepsy.

Neves said that signals recorded from the motor cortex could lead to an intervention that might facilitate motor control in neurologically damaged patients, but such neural interface systems are several years away.

One of the practical considerations in neurological implants is fairly simple: Such devices can be fixed in place reliably, but “the brain moves over time,” Neves said, and any effort to zero in on single-nerve action potentials demands that electrodes be set no farther away than 150 nanometers of the target synapse.

Neves noted that the late John C. Lilly, MD, had described other well-known hurdles in this area of research in 1940. Among these are the need to manufacture electrodes that are sufficiently small to pick up synaptic signals without damaging adjacent tissue.

The other side of the size dilemma is that too small an electrode is subject to impedance that will distort the signal. Hence the probe’s size must be closely matched to the size of the target synapse.

Other difficulties include the need to ensure the long-term stability of the probe, and the tendency of foreign matter to damage brain tissue, which can result in signal impedance. For some purposes, single-electrode probes do not draw in sufficient data, but as might be expected, researchers have found that multi-electrode probes are more damaging.

Biocompatibility is a much bigger issue in an organ as sensitive as the brain than it is for other organs, according to Neves. “As soon as you insert something into the brain, you start a reaction,” he said, including absorption of proteins onto the implant.

“Your best chances are to reduce cell adhesion” by using materials such as dextran, a polysaccharide, to coat the probe and reduce interaction. “If this process [of adhesion] persists, there is encapsulation of the probe,” which will fend off any signals, Neves noted.

On the other hand, “when you stimulate the brain, you lose electrode material to the brain,” a fact of which researchers were unaware until recently.

“The brain is just as chemical as it is electrical,” Neves said, and researchers are interested in acetylcholine and glutamate because of their relationships to several conditions, including Alzheimer’s and schizophrenia.

At present, one must use cholinesterase inhibitors to examine levels of acetylcholine, which creates problems because of the tendency of cholinesterase inhibitors to suppress cardiac and respiratory function. The neurotransmitter glutamate’s role in schizophrenia is well known, but the locations of interest include the limbic system, which is located deep in the brain, creating a new set of dilemmas in terms of access and device stability.

The shapes of probes are also problematic in that “[i]n the first seconds of use, you need a needle,” but Neves said that he wished “I had something that ceases to be a needle and acquires a more flexile form” after insertion, which is the kind of thinking “we desperately need” where electrode design is concerned.

Despite the long list of headaches, medical science is “at a very good time for this,” Neves said, partly because Moore’s law should start kicking in for miniaturization of electrodes.

Described in 1965 by Intel (Santa Clara, California) co-founder Gordon Moore, this principal states that scientists should be able to double the number of transistors on an integrated circuit every 12 to 24 months. (A web search suggests, however, that the period of doubling referred to by Moore is the subject of debate).

“The problem we see more and more now, no pun intended, is that Moore’s law deals with only about 10% of the system,” Neves said, namely the sensors in the electrodes and not the other elements required to detect synaptic function. A similar law regarding systems integration is said to lag behind Moore’s law, but it “is catching up very quickly,” according to Neves.

As for alternate shapes and materials, Neves said that IMEC is “very interested in using diatoms as building materials” for probes.

Diatoms are marine flora as small as 10 nanometers that leave behind a skeleton of silicon dioxide in a stunning array of shapes, featuring scales and spikes with potential uses in this area. And Neves pointed to the possibility of genetically engineering their shapes to grow diatoms in large numbers with features that are uniquely suited to this kind of research.

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