Development of a digital acoustofluidic system for automating liquid handling in biomedical research

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PROJECT SUMMARY This R01 application is responsive to the NIH initiative PAR-19-253 “Focused Technology Research and Development”. Automated liquid handling technologies are valuable in many areas of biomedical research. For example, robotic pipetting systems have been extensively utilized to automate assays, thereby eliminating errors associated with manual pipetting and significantly improving reproducibility. However, the majority of automated liquid handling technologies suffer from a fundamental constraint: they rely on physical contact with a solid structure in order to manipulate liquid reagents. Therefore, traces of a reagent inevitably adsorb onto the contact surface and can possibly later dissolve into another liquid sample. Thus, the risk of cross-contamination due to this undesirable “fouling of the surface” limits the transport surfaces to a single type of working liquid plus reagent combination. Recently, we invented digital acoustofluidics (DAF), an acoustic-based, programmable, contact- free, liquid handling technology, which overcomes the key obstacles associated with the existing liquid handling methods. In this R01 project, we will develop and validate a DAF fluid processing system with the following features: (1) Rewritability, programmability, and ability to perform complex, cascade reactions: We will demonstrate the ability of DAF to transport and mix ‘fluidic bits’ (i.e., droplets) along prescribed, arbitrary routes without cross-contamination, leading to a 104-fold increase in the number of allowable combinations of reagent inputs on a single device (as compared with conventional platforms); (2) Biocompatibility: Instead of being directly subjected to strong acoustic pressure or high electric fields, the droplets are manipulated in a contactless, gentle manner. Our preliminary results show that the DAF platform has no significant effect on the viability of cells; (3) Versatility: DAF is not restricted to fluids with specific acoustic, electrical, hydrodynamic, or magnetic properties. This versatility makes DAF suitable for handling a wide range of liquids, even for challenging samples such as low-polarity fluids (e.g., organic solvents), sticky or viscous samples (e.g., blood and sputum), and solids (e.g., fecal samples and model organisms); (4) Miniaturization and convenient integration: Our DAF platform provides an unprecedented level of miniaturization and cost-effectiveness compared with existing robotic liquid handling systems. In addition, it is designed to be integrated with a variety of multi-well plates, enabling it to be seamlessly integrated into existing biomedical research laboratories. With the aforementioned advantages, the proposed DAF technology has the potential to exceed current industry standards, address unmet needs in the field, and provide a compelling platform for the development of a robust, rewritable, high- throughput, and digitally-programmable fluidic processor. We will validate its performance across two established biomedical applications: protein crystal chemistry, and high-throughput drug screening. In this regard, we aim to demonstrate the far-reaching potential of DAF to enable improved research in areas ranging from clinical chemistry to fundamental biology.