Design and optimization of a cyberphysical digital-microfluidic biochip for the polymerase chain reaction

Abstract

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 the neighboring devices and the cost of droplet transportation. We present an integrated design solution to optimize the complete PCR procedure, including: 1) DNA amplification and termination control; 2) resource placement that satisfies proximity constraints; and 3) droplet transportation. Based on the sensor feedback data, a statistical model is developed to optimize and control the DNA amplification sequence in real-time on a cyberphysical biochip. Next, we present a geometric algorithm for avoiding device interference and for reducing droplet routing cost. A novel optical sensing system is deployed based on the physical visibility of droplets. Simulation results for 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.