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How To Pin Down 55,000 Virus Particles

Nanotechnology gets a speed boost with a new tool made of thousands of pens.
September 29, 2006

Researchers have developed a device that uses 55,000 perfectly aligned, microscopic pens to write patterns with features the size of viruses. The tool could allow researchers to study the behavior of cells at a new rate of speed and level of detail, potentially leading to better diagnostics and treatments for diseases such as cancer.

Researchers have made an array of 55,000 pens that can simultaneously draw 55,000 identical nanoscale images. (Courtesy of Chad Mirkin, Northwestern University)

The device builds on a technique called dip-pen nanolithography, which was first developed in 1999 by Chad Mirkin, professor of chemistry, medicine, and materials science and engineering at Northwestern University. In that system, the tip of a single atomic force microscope (AFM) probe is dipped in selected molecules, much as a quill pen would be dipped in ink. Then the molecules slip from the tip of the probe onto a surface, forming lines or dots less than 100 nanometers wide. Their size is controlled by the speed of the pen.

Because it operates at room temperature, the dip-pen tool is particularly useful for working with biological materials, such as proteins and segments of DNA that would be damaged by high-energy methods like electron beam lithography. Also, the patterns it makes can be easily programmed, making it “probably the best rapid-prototyping system for nanostructures out there,” Mirkin says.

The method addresses “one of the biggest problems in nanoscience,” according to Mirkin. “How do I get fingers small enough to manipulate something so small I can only see it with an electron microscope?” Because the tool can work at that scale “routinely,” he says, “I think it’s going to turn everything upside-down.”

So far, applications of the single-pen device, which is already being sold through NanoInk, a company based in Chicago, have been limited because of the speed of the process. “The drawback of [dip-pen nanolithography] in its early years was that it was slow if you wanted to prepare substrates that were patterned over large areas,” on the scale of a square centimeter, says Milan Mrksich, professor of chemistry at the University of Chicago (who was not involved with the work).

Mirkin and colleagues have overcome this problem by creating a massive array of pens using conventional photolithography. “The 55,000-pen array greatly accelerates the patterning rate,” Mrksich says, “increasing the throughput by orders of magnitude.” Mirkin says the pens can now write “hundreds of millions of features on a minute time-scale.”

In a paper appearing online now in the journal Angewandte Chemie, Mirkin described test runs with the array that show the complexity of the patterns that are possible. For example, he simultaneously printed 55,000 identical microscopic nickels in an area smaller than a dime. The dots outlining Jefferson’s face are each only 80 nanometers wide.

The device might turn out to be a boon in many fields. It could be used to study how individual cells interact with other things in their environment, such as viruses. “I can make a spot so small that it can act as a piece of glue for a single virus particle, and the shape of the spot can be used to control its orientation,” Mirkin says. Viruses in a several different positions could then be exposed to individual cells, with thousands of identical experiments performed at the same time to get statistically significant results.

Researchers could also study the size and distribution of patches of proteins on a cell’s surface that are responsible for anchoring it in place, says Mrksich. This could help them understand how cancer cells detach from a tumor and spread throughout the body, which could suggest new cancer treatments. Stem cell research might also benefit, Mrksich says, since the tool would allow researchers to study how cell attachments can influence how stem cells specialize into particular types of mature cells.

The technology might also have applications outside the lab; for example, it could tag pharmaceuticals with invisible codes to help drug companies identify counterfeit pills, says Mrksich.

Although such a precise method of printing might seem like a good fit for the electronics industry as well, in the past, many have been skeptical about its use there because of the slow speed of dip-pen nanolithography with a single pen.

Calvin Quate, professor of electrical engineering at Stanford University, says the 55,000-pen array “would go a long way” to changing his mind. But he warns that Mirkin will face stiff competition. “The thing that startles me is optical lithography has made such huge progress” that even with the added speed, the resolution of the technique may need to improve before it could compete.

So, at least for now, the best bet for dip-pen nanolithography may be in creating miniscule patterns of molecules suited to revealing the most detailed workings of life.

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