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.

BioScript: programming safe chemistry on laboratories-on-a-chip

“…The DMFB ISA can be extended by integrating sensors [Alistar and Gaudenz 2017;Barsoukov and Macdonald 2005;Bhattacharjee and Najjaran 2012;Cooreman et al 2005;Gao et al 2013;J. Schertzer et al 2012;Lederer et al 2012;Li et al 2014Li et al , 2015Murran and Najjaran 2012;Ren et al 2004;Sadeghi et al 2012;Shih et al 2013Shih et al , 2011Suni 2008], optical detectors [Luan et al 2008[Luan et al , 2012Srinivasan et al 2004;White Royal et al 2013], heaters [Luo et al 2015], or online video monitoring capabilities [Basu 2013;Hu et al 2013;Li et al 2017;Shin and Lee 2010;Vo et al 2017]. Sensors and actuators create a łcyber-physicalž feedback loop between the host PC controller and the DMFB.…”

CoSyn: Efficient single-cell analysis using a hybrid microfluidic platform

“…Cyberphysical synthesis techniques have enabled online error recovery [15], [16], volume precision [17], termination of biochemical applications such as qPCR [18], and protocols for multiple samples [19]. However, a key limitation of the above methods is that they fail to support heterogeneous singlecell analysis, and considerable manual effort is required to coordinate biochemical procedures.…”

Simulation of feedback-driven PCR assays on a 2D electrowetting array using a domain-specific high-level biological programming language

“…The probability model developed by Luo et al [18], which we adopt, assumes this exponential growth trend and introduces Eq. (1) below to calculate the confidence percentage p i at cycle i.…”

“…Secondly, control is provided exclusively through electricity, which eliminates the need for external pressure sources, which significant inhibit the ability to remove other LoCs from the laboratory for usage in the field. Thirdly, the electrical interface provided by a DMFB is a natural match for computer control; thus, there has been interest in the development of programming languages, compiler technology and software control of DMFBs in recent years [5,9,11,14,18,27,28].…”

“…The assays that we simulate are PCR variants: one uses sensory feedback to terminate thermocycling early when the initial droplet contains insufficient Microelectronic Engineering 148 (2015) 110-116 product for amplification [18]; the other uses integrated sensors to detect droplet evaporation during thermocycling in an air-matrix digital microfluidic system, and performs just-in-time replenishment using droplets of solvent to ensure that the reaction volume remains within an acceptable window [14]. This study establishes the viability and validity of software-driven programming of digital microfluidic EWoD systems, and serves to motivate further research on this topic.…”