Thursday, December 31, 2009

Massively Parallel Dip Pen Nano-Lithography Using Two-Dimensional Pen Arrays Enables Patterned Phospholipid Membranes for Biochemical Sensors, Drug Screening and Delivery

U. S. Patent Application 20090325816 details Northwestern University’s instrument for massively parallel dip pen nano-lithography using two-dimensional pen arrays.  The device has a patterning rate between 100,000 to 4 million dots per minute. Patterns can be created with lines and dots as small as 20 nanometers. Substrates can be coated and patterned with, for example, 25 million structures, to 1 billion structures to form devices for use in biosensors, drug discovery, drug delivery and other biochemical applications.

Inventors Northwester University Dr. Chad A. Mirkin  (Director of the International Institute for Nanotechnology), with Peng Sun, Yuhuang Wang and Steven Lenhert developed instruments for massive parallel printing of structures and nanostructures, including lipids, at high speed with high resolution and high quality using two dimensional arrays comprising cantilevers and tip-based transfer of material to a surface.

Micro- and nanoscopic heterogeneities, such as lipid rafts and focal adhesions, are vital to the biological function of lipid bilayer membranes. Lithographically patterned phospholipid membranes can be used as cell-surface models and have been used in several applications, including biochemical sensors, drug screening and delivery, the analysis of cell-cell interactions, and to address fundamental biological questions in membrane trafficking.  

Northwestern's  method allows both high-resolution patterning and parallel deposition of different phospholipid materials over large areas. Massively parallel lithography with two-dimensional pen arrays is suitable for the rapid fabrication and integration of large-scale phospholipid nanostructure libraries on a variety of substrates.

The array is designed so only tips touch the surface. This can be accomplished by long tips and bent cantilevers and alignment. The instrument includes: a two-dimensional array of a plurality of cantilevers, wherein the array comprises a plurality of base rows, each base row comprising a plurality of cantilevers, wherein each of the cantilevers comprise tips at the cantilever end away from the base, wherein the number of cantilevers is greater than 250, and wherein the tips have an apex height relative to the cantilever of at least four microns, and a support for the array. Combinatorial arrays and bioarrays can be prepared. The arrays can be manufactured by micromachining methods.

FIG. 1. Dip Pen Nanolithography (DPN)  patterning with 55,000 AFM cantilevers in parallel: (a) Optical micrograph of part of the 2D array of cantilevers used for patterning. Inset shows an SEM image of the tips. (b) Large area SEM image (left) of part of an 88,000,000 gold dot array (40.times.40 within each block) on an oxidized silicon substrate. A representative AFM topographical image (right) of part of a block. (c) Representative optical micrograph (inset shows AFM image) of .about.55,000 features drawn in the form of the face of the 2005 US five cent coins. The coin bears a picture of Thomas Jefferson, who helped develop the polygraph, a macroscopic letter duplicator that relies on an array of pens. 

The instruments can be used to control multi-bilayer stacking (FIG. 1); phospholipid patterns including fluorophore doping (FIG. 2); parallel writing of multiple inks including for testing membrane fluidity; and generation of fluorescent micrographs. DPN printing makes can use an atomic force microscope tip to directly deposit molecular inks onto a surface, reproducibly allowing line widths below 20 nm in the case of alkanethiols on gold.

FIG. 2. A schematic diagram of the fabrication process for 2D cantilever arrays.

The ability for DPN to operate under ambient conditions makes it particularly well suited to the fabrication of biomolecular arrays. This unique capability has been demonstrated by the fabrication of DNA and protein arrays with sub-100-nm lateral resolution. The fabrication of small spot sizes locally concentrates the analyte, which enables the detection of very low bulk analyte concentrations.

 Importantly, DPN has an advantage over other types of lithography in that many different chemical functionalities can be integrated onto a single surface without the risk of feature cross-contamination, as in the previously used indirect methods. Since the line widths and spot sizes in DPN are independent of the contact force of the microscope tip on the substrate, the technique can be readily carried out in parallel with arrays of cantilevers over centimeter length scales. 

FIG. 3. Optical micrograph of part of a 2D 55,000 pen array. Insets are SEM images of the pen array from side view (top), and top view (bottom), respectively.

FIG. 9. SEM image of single dip pen pyramidal tip, where the measured tip apex height is 8.8 microns and the base is 11.0 microns.

FIG. 10. Illustrating measurement of angle of cantilever bending and distance of cantilever bending.

Professor Mirkin is a chemist and a world renowned nanoscience expert, who is known for his development of nanoparticle-based biodetection schemes, the invention of Dip-Pen Nanolithography, and contributions to supramolecular chemistry, nanoelectronics, and nanooptics. He is the author of over 400 manuscripts and over 360 patents and applications, and the founder of three companies, Nanosphere, NanoInk, and Aurasense which are commercializing nanotechnology applications in the life science and semiconductor industries.  NanoInk is commercializing Dip Pin Nanolithography. 


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