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By Julia Boguslavsky

March 17, 2004
| The manufacture of ultradense bioarrays depends critically on the ability to control the chemistry of surfaces on the nanometer scale, while generating surface patterns with multiple distinct molecules.

Dip pen nanolithography (DPN), a process developed by Chad Mirkin, director of the Northwestern University Nanotechnology Institute, is a direct-write patterning technique based on scanning probe technology. A molecule-coated probe tip — which also becomes a "pen" — is used to deposit "ink" material onto the chemically engineered surface. DPN is compatible with a variety of ink-substrate combinations, including small organic molecules or biological polymers patterned on metals or insulators.

"Because DPN is compatible with soft matter, it is ideal for making the next-generation gene chips and proteomic arrays," Mirkin says. "This will be invaluable for high-throughput drug discovery and medical diagnostics with massive multiplexing capabilities and small sample-volume requirements." The DPN process is currently being commercialized for nanoscale manufacturing by Chicago-based NanoInk.

The tip of the dip pen.

The Upside of Downsizing

The DPN process offers numerous advantages when scaling up from the research laboratory to an industrial setting, including:

· Direct-write. Since DPN patterning deposits material directly onto a surface rather than using masks or stencils, it does not destroy any part of the substrate or DPN pens.

· Ultrahigh resolution. NanoInk's DPN system is capable of producing structures with diameters of less than 15 nanometers (compared to photolithography's 120nm line width).

· Flexibility. Direct fabrication is possible with many substances, from oligonucleotides to metals.

· Ease of use. DPN experiments may be performed by non-specialized personnel with minimal training.

· Accuracy. Highly accurate atomic force microscope (AFM) technology provides the means to determine the exact placement of the features on the substrate, thus allowing integration of multiple component nanostructures.

Ubiquitous nanoscale positioning control offered by scanning probes provides the ability to produce high-quality nanolithographic patterns. The ability of the same scanning probe to write and read patterns allows researchers to achieve an alignment registry between consecutively written nanoscale chemical patterns, or between a DPN pattern and microscale device structures. Multiple pens and inks may be used in combination to produce complex DPN patterns. Because it can precisely align multiple structures consisting of distinct chemical or biomolecule functionalities, DPN is the tool for bottom-up nanofabrication.

"DPN is the only direct-write scanning probe lithographic process out there," Mirkin says. "All others are indirect and often involve surface damage or the use of resist layers. This allows DPN to be transformed into a massively parallel, resist-less process. At present, we have 1-million-pen arrays, but this is by no means the limit."

Mirkin says the resolution of DPN is comparable to e-beam lithography. "But unlike e-beam, which requires ultrahigh-vacuum and clean-room environments for operation, DPN can be carried out by personnel with minimal training under ambient conditions," he says. DPN works well with soft matter (proteins and DNA) as well as hard matter (semiconductors and metals). "This capability makes it extremely versatile and opens up applications not accessible via conventional techniques that are limited to semiconductor processing," Mirkin adds.

The scanning probe technology provides the foundation for the hardware platform of NanoInk's DPNWriter systems. The NScriptor DPNWriter is the company's first tool that allows dedicated DPN experiments based on a fully functional, commercial scanning probe microscope system, featuring both molecular writing and reliable image acquisition.

DPN is an attractive tool for patterning biological structures because it offers high resolution and alignment registration, as well as direct-write printing in ambient or inert environments (without exposure to ionizing UV or electron-beam radiation). Different kinds of molecules may be deposited on the same surface without exposing the substrate to harsh solvents or chemical etchants, and without introducing cross-contamination.

NanoInk was recently awarded a two-phase, $1.3-million Small Business Innovation Research grant from the National Institutes of Health to support the development of DPN for ultra-miniaturization of DNA arrays, which may eventually serve the growing point-of-care diagnostics and biodefense markets.

NanoInk and Northwestern researchers have already demonstrated two chemistry schemes for building oligo nanoarrays: acrylamide-modified oligos bound to an oxidized silicon substrate, and alkanethiol-modified oligos bound to a polycrystalline-gold surface. The oligo binding was detected with standard fluorescence labeling and detection, gold nanoparticle probes imaged on an optical microscope, and the only method that was compatible with feature sizes of 100 nm and smaller: a scanning probe microscope to detect topography changes associated with the binding of a complementary probe or analyte.

Similarly, in a recent article in the Journal of the American Chemical Society, Mirkin's team demonstrated the potential of applying DPN to the manufacturing of protein nanoarrays. Researchers created two-component nanoarrays of native proteins (lysozyme and immunoglobulin gamma) that are biologically active and capable of recognizing a biological complement in solution. Feature size could be controlled (from 45 nm to several microns) by manipulating the tip-substrate contact time.

"The primary challenge is user acceptance," Mirkin says. "Once people use it, they are usually sold on its benefits and capabilities." In 1999, only one laboratory used DPN. In 2004, it is used in dozens of labs. "The user base of DPN has more than doubled during every year of its existence," Mirkin says. "I expect this trend to continue and the corresponding applications to scale with the increasing user base."



Julia Boguslavsky is conference director for Cambridge Healthtech Institute. E-mail: julia@thebiotechwriter.com.








For reprints and/or copyright permission, please contact  Jay Mulhern, (781) 972-1359, jmulhern@healthtech.com.