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Small and Smaller: Protein Nanoarrays Described and Validated in Science Article

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If you thought microarrays were tiny, brace yourself for the next small thing: nanoarrays. In this week’s Science, Chad Mirkin and colleagues from Northwestern University and the University of Chicago describe their protein arrays with feature sizes of 100 to 350 nanometers — about 100,000 times smaller than state-of-the-art DNA arrays, which have 18-micrometer features.

Besides higher density and novel detection methods, these chips open “a fundamentally new way of studying biorecognition,” said Mirkin, who serves as director of Northwestern’s Institute of Nano-technology.

The researchers used an atomic force microscope (AFM) “like a quill pen” to deposit organic molecules with affinity for proteins in dots or grids on a gold layer. After passivating the remaining surface with another organic solution that repels proteins, they immersed the chip in protein solution, so protein molecules stuck only to the features. The process goes by the name of dip-pen nanolithography (DPN) and can also be used to array oligonucleotides or other types of biomolecules, Mirkin said.

With feature sizes in the range of the wavelength of light, optical detection methods are no longer possible. “The good news here is that by going small, you can start using scanning probe methods, and screening the arrays based upon height and stickiness and shape changes that accompany a biomolecule binding event on one of the active features of the array,” said Mirkin. In the paper, he and his colleagues determined the binding of an antibody in a mixture of four different proteins to another antibody immobilized on the chip surface by measuring the increase in height.

As an example of how the arrays could be used to study molecular recognition, the scientists immobilized a cell adhesion molecule, added live cells, and assayed for cellular binding, “proving that small features can support cell adhesion,” said Mirkin.

In the future Mirkin wants to use the nanochips to find “anatural receptors” for biomolecules, by screening them against arrays of simple organic molecules that together form a unique pattern. “If you wanted to develop new receptors for cells, you can make patterns using the dip-pen nanolithography process, and you can discover in combinatorial format what the best receptor is for a given biostructure of interest,” he said. These synthetic receptors may then be used “on any sort of signal transduction device,” he added.

Though the current study was just a proof of concept one, “dip-pen nanolithography is now quickly becoming a routine type of technique, a technique that can be adopted by anybody,” claimed Mirkin. All a researcher needs, he said, is a conventional atomic force microscope with closed-loop scanning and a single commercially available type of AFM tip. “It becomes easier and faster if you have access to software that we have,” he added.

A Chicago-based company called NanoInk, of which Mirkin is a co-founder, is currently commercializing the DPN process, he said, “and they will be selling and distributing all of the writers and software within a three- to six-month time frame.” The company also wants to scale up the process from one pen up to maybe a thousand pens. “Dip-pen nanolithography actually impacts both the life sciences and also the semiconductor industries,” said Mirkin, “but both industries require a tool that’s faster than the current AFM.”

— JK

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