Optimization of Polymerase Chain Reaction on a Cyberphysical Digital Microfluidic Biochip

The amount of DNA strands available in a biological sample is a major limitation for many genomic bioanalyses. To amplify the traces of DNA strands, polymerase chain reaction (PCR) is widely used for conducting subsequent experiments. Compared to conventional instruments and analyzers, the execution of PCR on a digital microfluidic biochip (DMFB) can achieve short time-to-results, low reagent consumption, rapid heating/cooling rates, and high integration of multiple processing modules. However, the PCR biochip design methods in the literature are oblivious to the inherent randomness and complexity of bioanalyses, and they do not consider the interference among on-chip devices and the cost of droplet transportation. We present, for the first time, an integrated design method to optimize the complete PCR procedure, including (i) DNA amplification and termination control, (ii) resource placement that satisfies physical constraints needed to avoid interference, and (iii) droplet transportation needed for mixing and detection. We propose a statistical model for sensor feedback-driven (cyberphysical) on-line decision making in order to optimize and control the execution sequence for DNA amplification. Next, we present a geometric algorithm for layout design to avoid device interference and reduce the cost of droplet routing. Simulation results on three laboratory protocols demonstrate that the proposed design method results in a compact layout and produces an execution sequence for efficient control of PCR operations on a cyberphysical DMFB.