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Harvard Group's Nanowire Arrays May Allow Higher Throughput Neuronal Drug Discovery

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A team of scientists from Harvard has developed high-density silicon nanowire transistor arrays capable of recording, stimulating, or inhibiting signals from individual axons and dendrites of single live mammalian neurons, according to a recent study published in Science.
 
The technology has several advantages over traditional electrophysiology techniques, such as high-throughput patch clamping and microfabricated electrode arrays, and may be adapted to high-throughput, real-time cellular assays for neuronal drug discovery and testing, according to the researchers.
 
Current methods for recording electrophysiological measurements from living cells are relatively limited and have not changed much for the last several decades. The basic concept of using a voltage clamp to measure ion currents across cell membranes in bulk was refined in the late 1970s to patch clamping, which allows similar measurements to be made on single cells.
 
Several variations on patch clamping have been devised for higher throughput basic research and drug discovery, and companies such as Molecular Devices (widely considered the market leader), Axon Instruments (now a part of MDCC), Cellectricon, Nanion, Flyion, and Sophion have all developed instruments or tools for high-throughput or automated patch clamping.
 
But all of these techniques have limitations such as a high level of invasiveness, the inability to record electrical activity from single cells, or incomplete or unreliable voltage seals.
 
Other techniques include microfabricated electrode arrays, which have been used to monitor general cellular physiological activity in addition to electrical impulses. These types of arrays, which are more popular in basic research, still have size or sensitivity limitations, according to Charles Lieber, corresponding author on the nanowires paper and a professor of chemistry in the division of engineering and applied sciences at Harvard.
 
As described in the August 25 issue of Science, the researchers adapted field-effect transistor arrays made with silicon nanowires to inhibit, stimulate, and measure electrical signals in live mammalian neurons. Lieber and colleagues had previously shown that the nanowire FETs could detect chemical and biological species, including single virus particles, in solution, the researchers wrote in the paper.
 
In an e-mail to CBA News, Lieber said that he suspected the FET sensors would work for electrophysiological measurements because they “can respond to changes in charge, [such as] binding of biomolecules; or [the] potential of membranes during [the] propagation of spikes in neurons.”
 
Because the silicon nanowires are so thin – with widths of just tens of nanometers – the Harvard researchers were able to interface as many as 50 individual probes to the surface of single cells. Most current electrophysiology techniques allow for only one probe per cell.
 
“We are working on a completely different scale,” Lieber wrote. “The size of our probes is orders of magnitude smaller; that is, we can make measurements from individual axons and dendrites – and in future synapses – that are simply inaccessible to [other] technology.”
 
In order to make arrayed chips for multiple simultaneous measurements, the researchers patterned polylysine as an adhesion and growth factor so that cultured neurons overlapped with the silicon nanowire elements.
 
In addition, the scientists had to specially treat the metal nanowires, which would typically corrode and fail under the relatively harsh conditions of neuronal cell culture. Their preparation technique allowed the devices to survive continuous cell culture conditions at 37° C for at least 10 days with greater than 90-percent yield.
 

“The size of our probes is orders of magnitude smaller; that is, we can make measurements from individual axons and dendrites – and in future synapses – that are simply inaccessible to [other] technology.”

Other important features of the technology include the ability to repeat any array design on chips for individual cells depending on the goal of the study, and the ability to “easily diversify the elements in each sub-array to not only measure potential but also to measure chemical and biological species expressed at the cell surface or changing in the extracellular region immediately adjacent to the outer membrane,” Lieber wrote.
 
“These capabilities could be used to investigate multiple nanowire inputs and outputs to a single soma and to study synaptic processing in neural networks with nanowire-neurite junctions used to reversibly inhibit or stop signal propagation along specific pathways while simultaneously mapping signal flow in dendrites and axons in the network,” the researchers wrote in the paper.
 
In addition, “the demonstrated reproducibility of the nanowire-cell devices and ability to integrate these hybrid structures on chips in a multicell array format has implications for developing flexible real-time cellular assays, for example, for drug discovery and testing,” they added.
 
Lieber added that the technology could be used to screen potential therapeutics because “by multiplexing measurements on each cell it should be possible to assay several important physiological indicators of the cell. And because it is noninvasive, it should also be possible to screen multiple compounds per cell as long as the cell does not die.”
 
Lieber and colleagues have applied for several patents on the silicon nanowire production methods both preceding and related to the neuronal measurement work, he wrote.
 
The group does have an interest in commercializing the arrays for such a purpose, but it might not be the highest priority due to a lack of direct funding, Lieber said. It is unclear whether the group is actively seeking commercialization partners.
 

Other potential application areas for the nanowire arrays include basic electrophysiology research and hybrid cellular-nanowire circuits for implantable medical devices.

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