Design automation of microfluidic single and double emulsion droplets with machine learning.

Droplet microfluidics enables kHz screening of picoliter samples at a fraction of the cost of other high-throughput approaches. However, generating stable droplets with desired characteristics typically requires labor-intensive empirical optimization of device designs and flow conditions that limit adoption to specialist labs. Here, we compile a comprehensive droplet dataset and use it to train machine learning models capable of accurately predicting device geometries and flow conditions required to generate stable aqueous-in-oil and oil-in-aqueous single and double emulsions from 15 to 250 µm at rates up to 12000 Hz for different fluids commonly used in life sciences. Blind predictions by our models for as-yet-unseen fluids, geometries, and device materials yield accurate results, establishing their generalizability. Finally, we generate an easy-to-use design automation tool that yield droplets within 3 µm (<8%) of the desired diameter, facilitating tailored droplet-based platforms and accelerating their utility in life sciences.

Versatility and stability optimization of flow-focusing droplet generators via quality metric-driven design automation.

Droplet generation is a fundamental component of droplet microfluidics, compartmentalizing biological or chemical systems within a water-in-oil emulsion. As adoption of droplet microfluidics expands beyond expert labs or integrated devices, quality metrics are needed to contextualize the performance capabilities, improving the reproducibility and efficiency of operation. Here, we present two quality metrics for droplet generation: performance versatility, the operating range of a single device, and stability, the distance of a single operating point from a regime change. Both metrics were characterized in silico and validated experimentally using machine learning and rapid prototyping. These metrics were integrated into a design automation workflow, DAFD 2.0, which provides users with droplet generators of a desired performance that are versatile or flow stable. Versatile droplet generators with stable operating points accelerate the development of sophisticated devices by facilitating integration of other microfluidic components and improving the accuracy of design automation tools.

Machine learning for microfluidic design and control.

Microfluidics has developed into a mature field with applications across science and engineering, having particular commercial success in molecular diagnostics, next-generation sequencing, and bench-top analysis. Despite its ubiquity, the complexity of designing and controlling custom microfluidic devices present major barriers to adoption, requiring intuitive knowledge gained from years of experience. If these barriers were overcome, microfluidics could miniaturize biological and chemical research for non-experts through fully-automated platform development and operation. The intuition of microfluidic experts can be captured through machine learning, where complex statistical models are trained for pattern recognition and subsequently used for event prediction. Integration of machine learning with microfluidics could significantly expand its adoption and impact. Here, we present the current state of machine learning for the design and control of microfluidic devices, its possible applications, and current limitations.

Machine learning enables design automation of microfluidic flow-focusing droplet generation.

Droplet-based microfluidic devices hold immense potential in becoming inexpensive alternatives to existing screening platforms across life science applications, such as enzyme discovery and early cancer detection. However, the lack of a predictive understanding of droplet generation makes engineering a droplet-based platform an iterative and resource-intensive process. We present a web-based tool, DAFD, that predicts the performance and enables design automation of flow-focusing droplet generators. We capitalize on machine learning algorithms to predict the droplet diameter and rate with a mean absolute error of less than 10 µm and 20 Hz. This tool delivers a user-specified performance within 4.2% and 11.5% of the desired diameter and rate. We demonstrate that DAFD can be extended by the community to support additional fluid combinations, without requiring extensive machine learning knowledge or large-scale data-sets. This tool will reduce the need for microfluidic expertise and design iterations and facilitate adoption of microfluidics in life sciences.

Rapid and inexpensive microfluidic electrode integration with conductive ink.

Electrode integration significantly increases the versatility of droplet microfluidics, enabling label-free sensing and manipulation at a single-droplet (single-cell) resolution. However, common fabrication techniques for integrating electronics into microfluidics are expensive, time-consuming, and can require cleanroom facilities. Here, we present a simple and cost-effective method for integrating electrodes into thermoplastic microfluidic chips using an off-the-shelf conductive ink. The developed conductive ink electrodes cost less than $10 for an entire chip, have been shown here in channel geometries as small as 75 µm by 50 µm, and can go from fabrication to testing within a day without a cleanroom. The geometric fabrication limits of this technique were explored over time, and proof-of-concept microfluidic devices for capacitance sensing, droplet merging, and droplet sorting were developed. This novel method complements existing rapid prototyping systems for microfluidics such as micromilling, laser cutting, and 3D printing, enabling their wider use and application.

Performance tuning of microfluidic flow-focusing droplet generators.

The required step in all droplet-based devices is droplet formation. A droplet generator must deliver an application-specific performance that includes a prescribed droplet size and generation frequency while producing monodisperse droplets. The desired performance is usually reached through several cost- and time-inefficient design iterations. To address this, we take advantage of a low-cost rapid prototyping method and provide a framework that enables researchers to make informed decisions on how to change geometric parameters and flow conditions to tune the performance of a microfluidic flow-focusing droplet generator. We present the primary and secondary parameters necessary for fine-tuning droplet formation over a wide range of capillary numbers and flow rate ratios. Once the key parameters are identified, we demonstrate the effect of geometric parameters and flow conditions on droplet size, generation rate, polydispersity, and generation regime. Using this framework, a wide range of droplet diameters (i.e., 30-400 µm) and generation rates (i.e., 0.5-800 Hz) was achieved.