IEEE transactions on computer-aided design of integrated circuits and systems : a publication of the IEEE Circuits and Systems Society

Droplet-based digital microfluidics technology has now come of age, and software-controlled biochips for healthcare applications are starting to emerge. However, today's digital microfluidic biochips suffer from the drawback that there is no feedback to the control software from the underlying hardware platform. Due to the lack of precision inherent in biochemical experiments, errors are likely during droplet manipulation; error recovery based on the repetition of experiments leads to wastage of expensive reagents and hard-to-prepare samples. By exploiting recent advances in the integration of optical detectors (sensors) into a digital microfluidics biochip, we present a physical-aware system reconfiguration technique that uses sensor data at intermediate checkpoints to dynamically reconfigure the biochip. A cyberphysical resynthesis technique is used to recompute electrode-actuation sequences, thereby deriving new schedules, module placement, and droplet routing pathways, with minimum impact on the time-to-response.

/pdf/error-recovery-in-cyberphysical-digital-microfluidic-11183246ec.pdf

Error Recovery in Cyberphysical Digital Microfluidic Biochips

VLSI physical design automation: theory and practice

The invention is directed to droplet actuator devices and assay methods for multiplexed newborn testing for metabolic disorders. The methods include, among other things, droplet-based enzymatic assays and immunoassays for testing for metabolic disorders. The invention includes methods and devices for conducting multiple assays for different metabolic disorders on a single droplet actuator, as well as multiple assays for the same metabolic disorder using samples from different subjects and/or multiple samples from the same subject on a single droplet actuator. In various embodiments, the invention includes methods for conducting enzymatic activity assays and/or immunoassays in a single fresh blood and/or plasma samples and dried blood and/or plasma samples.

Enzyme assays on a droplet actuator

A microfluidic device having a substrate with an electrically conductive element made using a conductive ink layer underlying a hydrophobic layer.

Droplet actuator devices and methods

Recent advances in digital microfluidics have enabled droplet-based biochip devices for DNA sequencing, immunoassays, clinical chemistry, and protein crystallization. Since cross-contamination between droplets of different biomolecules can lead to erroneous outcomes for bioassays, the avoidance of cross-contamination during droplet routing is a key design challenge for biochips. We propose a droplet-routing method that avoids cross-contamination in the optimization of droplet flow paths. The proposed approach targets disjoint droplet routes and synchronizes wash-droplet routing with functional droplet routing, in order to reduce the duration of droplet routing while avoiding the cross-contamination between different droplet routes. In order to avoid cross-contamination between successive routing steps, an optimization technique is used to minimize the number of wash operations that must be used between successive routing steps. Two real-life biochemical applications are used to evaluate the proposed droplet-routing methods.

/pdf/cross-contamination-avoidance-for-droplet-routing-in-digital-4kdg7wtskq.pdf

Cross-Contamination Avoidance for Droplet Routing in Digital Microfluidic Biochips

Recent advances in digital microfluidics have led to tremendous interest in miniaturized lab-on-chip devices for biochemical analysis Synthesis tools have also emerged for the automated design of lab-on-chip from the specifications of laboratory protocols However, none of these tools consider control flow or address the problem of recovering from fluidic errors that can occur during on-chip bioassay execution We present a synthesis method that incorporates control paths and an error-recovery mechanism in the design of a digital microfluidic lab-on-chip Based on error-propagation estimates, we determine the best locations for fluidic checkpoints during biochip synthesis A microcontroller coordinates the implementation of the control-flow-based bioassay by intercepting the synthesis results that are mapped to the software programs Real-life bioassay applications are used as case studies to evaluate the proposed design method For a representative protein assay, compared to a baseline chip design, the biochip with a control path can reduce the completion time by 30p when errors occur during the implementation of the bioassay

/pdf/integrated-control-path-design-and-error-recovery-in-the-2nm5y4g2gm.pdf

Integrated control-path design and error recovery in the synthesis of digital microfluidic lab-on-chip

Digital microfluidic biochips are being utilized in many areas of biochemistry and biomedical sciences. Since cross-contamination between droplets of different biomolecules can lead to erroneous outcomes for bioassays, it is essential to avoid cross-contamination during droplet routing. We propose a wash-operation synchronization method to manipulate wash droplets to clean the residue that is left behind by sample and reagent droplets. We also synchronize wash-droplet routing with sample/reagent droplet-routing steps by controlling the arrival order of droplets at cross-contamination sites. The proposed method minimizes droplet-routing time without cross-contamination, and it is especially effective for tight chip-area constraints. A real-life application is used for evaluation.

/pdf/synchronization-of-washing-operations-with-droplet-routing-3th3zb3bua.pdf

Synchronization of washing operations with droplet routing for cross-contamination avoidance in digital microfluidic biochips

Recent advances in digital microfluidics have enabled lab-on-a-chip devices for DNA sequencing, immunoassays, clinical chemistry, and protein crystallization. Basic operations such as droplet dispensing, mixing, dilution, localized heating, and incubation can be carried out using a 2-D array of electrodes and nanoliter volumes of liquid. The number of independent input pins used to control the electrodes in such microfluidic “biochips” is an important cost-driver, especially for disposable printed circuit board devices that are being developed for clinical and point-of-care diagnostics. However, most prior work on biochip design-automation has assumed independent control of the electrodes using a large number of input pins. We present a broadcast-addressing-based design technique for pin-constrained multifunctional biochips. The proposed method provides high throughput for bioassays and it reduces the number of control pins by identifying and connecting control pins with “compatible” actuation sequences. We also describe two scheduling methods to map fluidic operations on the pin-constrained design, in order to minimize the completion time while avoiding pin-actuation conflicts. The proposed methods are evaluated using multifunctional chips designed to execute a set of multiplexed bioassays, the polymerase chain reaction, and a protein dilution assay.

Broadcast Electrode-Addressing and Scheduling Methods for Pin-Constrained Digital Microfluidic Biochips

Recent advances in droplet-based digital microfluidics have enabled biochip devices for DNA sequencing, immunoassays, clinical chemistry, and protein crystallization. Since cross-contamination between droplets of different biomolecules can lead to erroneous outcomes for bioassays, the avoidance of cross-contamination during droplet routing is a key design challenge for biochips. We propose a droplet-routing method that avoids cross-contamination in the optimization of droplet flow paths. The proposed approach targets disjoint droplet routes and minimizes the number of cells used for droplet routing. We also minimize the number of wash operations that must be used between successive routing steps that share unit cells in the microfluidic array. Two real-life biochemical applications are used to evaluate the proposed droplet-routing methods.

/pdf/cross-contamination-avoidance-for-droplet-routing-in-digital-5erv81apdz.pdf

Yang Zhao

Papers

Cross-Contamination Avoidance for Droplet Routing in Digital Microfluidic Biochips

Integrated control-path design and error recovery in the synthesis of digital microfluidic lab-on-chip

Synchronization of washing operations with droplet routing for cross-contamination avoidance in digital microfluidic biochips

Broadcast Electrode-Addressing and Scheduling Methods for Pin-Constrained Digital Microfluidic Biochips

Cross-contamination avoidance for droplet routing in digital microfluidic biochips