High-throughput screening at the picoliter scale by combining Dip Pen Lithography with Inkjet printing

Abstract

Drug screening is a complex, expensive and time consuming field consisting of diseasebased target identification in conjunction with high-throughput screening of chemical and natural product libraries. Conventional drug screening technology is usually time and reagent consuming (micro-, nanoliter scale) and is based on complex liquid handling robotics. In this work, we show a low-cost and miniaturized drug screening methodology based on direct bio-printing methodologies like Inkjet Printing and Dip Pen Lithography. We show the possibility to precisely deliver femtoliter scale droplets of protein targets by Dip Pen Lithography by finely tuning deposition parameters. This allows obtaining microscale droplet arrays where picoliter volumes of drug candidates solutions are readily deposited by inkjet printing. Exact and accurate pattern alignment is shown. Modulation of deposition procedure allows producing gradients of drug target concentration directly on-chip. A fluorescence confocal microscope is used to quantify drug-ligand interaction by means of standard intensity based imaging and fluctuation techniques which allows mapping concentration and diffusion coefficients of fluorolabeled ligands at nanomolar concentration. Outputs obtained on different systems by means of this new method are compared with the ones obtained by established microliters volumes samples, confirming the ability of our “chip printing” technique to discriminate ligand-target interactions for different compounds.