A combined high-throughput and high-content platform for unified on-chip synthesis, characterization and biological screening

Abstract

Acceleration and unification of drug discovery is important to reduce the effort and cost of new drug development. Diverse chemical and biological conditions, specialized infrastructure and incompatibility between existing analytical methods with high-throughput, nanoliter scale chemistry make the whole drug discovery process lengthy and expensive. Here, we demonstrate a chemBIOS platform combining on-chip chemical synthesis, characterization and biological screening. We developed a dendrimer-based surface patterning that enables the generation of high-density nanodroplet arrays for both organic and aqueous liquids. Each droplet (among > 50,000 droplets per plate) functions as an individual, spatially separated nanovessel, that can be used for solution-based synthesis or analytical assays. An additional indium-tin oxide coating enables ultra-fast on-chip detection down to the attomole per droplet by matrix-assisted laser desorption/ionization mass spectrometry. The excellent optical properties of the chemBIOS platform allow for on-chip characterization and in-situ reaction monitoring in the ultraviolet, visible (on-chip UV-Vis spectroscopy and optical microscopy) and infrared (on-chip IR spectroscopy) regions. The platform is compatible with various cell-biological screenings, which opens new avenues in the fields of high-throughput synthesis and drug discovery.

High-throughput screening of nanoparticles in drug delivery

“…In the HTS performed in the last 20 years, the following cellular readouts have been reported: (i) gene knockdown, 91,92 (ii) gene knockout, 93,94 (iii) cell viability, 98,99 and (iv) expression of a cellular reporter. 95,96 In most of these HTS studies, the effect of the nanoformulations was evaluated by optical methods including absorbance, 100 fluorescence, 101 and luminescence, 28,56 using plate readers or high content microscopes. 102,103 …”

Liquid Wells as Self‐Healing, Functional Analogues to Solid Vessels

“…[ 9–15 ] Development of omniphobic–omniphilic or superoleophobic patterned substrates made it possible to confine droplets of low‐surface‐tension liquids (LSTLs) and significantly improved the capabilities of surface‐templated liquids. [ 16 ] The preparation of omniphobic or superoleophobic surfaces typically requires perfluorinated chemicals for surface modification or lubricant infused surfaces (LISs). [ 17 ] However, the use of perfluorinated chemicals is environmentally questionable due to their biopersistence, whereas LISs are often not durable due to partial miscibility of the lubricants in LSTLs.…”

Controlling Surface Wettability for Automated In Situ Array Synthesis and Direct Bioscreening

“…[ 4 ] Regarding the second approach, high‐density peptide arrays (>100 000 cm −2 ) can be generated on glass by printing the polymer particles containing preactivated building blocks, [ 12–15 ] utilizing photolabile protecting groups, [ 16,17 ] or generating prepatterned omniphilic/omniphobic surfaces. [ 18 ] However, they are also associated with drawbacks. Many methods require special chemistry or in‐house‐developed instrumentations, such as amino acid carrier ink, [ 13 ] as well as laser‐based transferring, [ 14 ] scanning probe lithography‐based, [ 15 ] or maskless lithography techniques.…”

“…[ 19 ] Therefore, the modulation of surface wettability has been explored to increase the spot density for array synthesis. [ 18 ] In addition to the chemical synthesis, the compatibilities of the resulting molecule array with various biochemical and cell‐adhesion assays are also important.…”