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.

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 30% when errors occur during the implementation of the bioassay.

Protein crystallization is a commonly used technique for protein analysis and subsequent drug design. It predicts the 3-D arrangement of the constituent amino acids, which in turn indicates the specific biological function of a protein. Protein crystallization experiments are typically carried out in well-plates in the laboratory. As a result, these experiments are slow, expensive, and error-prone due to the need for repeated human intervention. Recently, droplet-based ¿digital¿ microfluidics have been used for executing protein assays on a chip. Protein samples in the form of nanoliter-volume droplets are manipulated using the principle of electrowetting-on-dielectric. We present the design of a multi-well-plate microfluidic biochip for protein crystallization; this biochip can transfer protein samples, prepare candidate solutions, and carry out crystallization automatically. To reduce the manufacturing cost of such devices, we present an efficient algorithm to generate a pin-assignment plan for the proposed design. The resulting biochip enables control of a large number of on-chip electrodes using only a small number of pins. Based on the pin-constrained chip design, we present an efficient shuttle-passenger-like droplet manipulation method and test procedure to achieve high-throughput and defect-tolerant well loading.

Testing is essential for digital microfluidic biochips that are used for safety-critical applications such as point-of-care health assessment, air-quality monitoring, and food-safety testing. However, the effectiveness of recently proposed test techniques for biochips is limited by the fact that current design methods do not consider testability. We introduce the concept of design-for-testability (DFT) for microfluidic biochips and propose a DFT method that incorporates a test plan into the fluidic operations of a target bioassay protocol. By using the testability-aware bioassay protocol as an input to the biochip design tool, the proposed DFT method ensures a high level of testability, defined as the percentage of the electrodes or functional units on the synthesized chip that can be effectively tested. We evaluate the DFT method using a representative multiplexed bioassay and the polymerase chain reaction.

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 two-dimensional 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 PCB 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. Another limitation of prior work is that the mapping of control pins to electrodes is only applicable for a specific bioassay. We present a broadcast-addressing-based design technique for pin-constrained multi-functional 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. The proposed method is evaluated using a multifunctional chip designed to execute a set of multiplexed bioassays, the polymerase chain reaction, and a protein dilution assay.

Proteins crystallization is a commonly used technique for protein analysis and subsequent drug design. It predicts the three-dimensional arrangement of the constituent amino acids, which in turn indicates the specific biological function of a protein. Protein crystallization experiments are typically carried out manually on multi-well plates in the laboratory. These experiments are slow, expensive, and error-prone. We present the design of a multi-well plate microfluidic biochip for protein crystallization; this biochip can transfer protein samples, prepare candidate solutions, and carry out crystallization automatically. To reduce the manufacturing cost of such devices, we present an efficient algorithm to generate a pin-assignment plan for the proposed design. The resulting biochip enables control of a large number of on-chip electrodes using only a small number of pins. Based on the pin-constrained chip design, we present an efficient shuttle-passenger-like droplet manipulation method to achieve high-throughput and defect-tolerant well loading.

Digital microfluidic biochips, as referred to as lab-on-a-chip, are revolutionizing DNA sequencing, immunoassays, and clinical diagnostics. Bioassays steps are mapped to a sequence of microfludic operations on a two dimensional array of electrodes. The number of independent input pins used to control the electrodes is an important cost-driver, especially for disposable PCB devices that are being developed for clinical and point-of care diagnostics. We review two design-automation methods for such pin-count-constrained biochips. The first design procedure relies on a droplet-trace-based array partitioning scheme and an efficient pin assignment technique, referred to as the "Connect-5 algorithm". The second pin-constrained design method relies on cross-referencing addressing based on "rows" and "columns" to access electrodes. An efficient droplet manipulationmethod is presented for this cross-referencing technique based on a mapping of the droplet-movement problem to the clique-partitioning problem from graph theory

Dependability is an important system attribute for microfluidic lab-on-chip. Structural test and functional test are needed to detect defects and malfunctions, respectively. Previously proposed techniques for reading test outcomes and for pulse-sequence analysis are cumbersome and error-prone. We present a built-in self-test (BIST) method for digital microfluidic lab-on-chip. This method utilizes digital microfluidic logic gates to implement the BIST architecture; AND, OR and NOT gates are used to compress test-outcome droplets into one droplet signature. This approach obviates the need for capacitive sensing test-outcome circuits for analysis. An efficient diagnosis method based on a microfluidic encoder is also proposed to locate a single defective electrode in a microfluidic array. Finally, reconfiguration is used during test and diagnosis to enable BIST with low area overhead.

Microfluidic biochips are revolutionizing high-throughput DNA sequencing, immunoassays, and clinical diagnostics. As high-throughput bioassays are mapped to digital microfluidic platforms, the need for design automation techniques is being increasingly felt. Moreover, as most applications of biochips are safety-critical in nature, defect tolerance is an essential system attribute. Several synthesis tools have recently been proposed for the automated design of biochips from the specifications of laboratory protocols. However, only a few of these tools address the problem of defect tolerance. In addition, most of these methods do not consider the problem of droplet routing in microfluidic arrays. These methods typically rely on postsynthesis droplet routing to implement biochemical protocols. Such an approach is not only time consuming, but also imposes an undue burden on the chip user. Postsynthesis droplet routing does not guarantee that feasible droplet pathways can be found for area-constrained biochip layouts; nonroutable fabricated biochips must be discarded. We present a synthesis tool that integrates defect tolerance and droplet routing in the design flow. Droplet routability, defined as the ease with which droplet pathways can be determined, is estimated and integrated in the synthesis procedure. Presynthesis and postsynthesis defect-tolerance methods are also presented. We use a large-scale protein assay as a case study to evaluate the proposed synthesis method.

Digital microfluidic biochips are revolutionizing high-throughput DNA, immunoassays, and clinical diagnostics. As high-throughput bioassays are mapped to digital microfluidic platforms, the need for design automation techniques for pin-constrained biochips is being increasingly felt. However, most prior work on biochips computer-aided design has assumed independent control of the underlying electrodes using a large number of (electrical) input pins. We propose a droplet-manipulation method based on a ldquocross-referencingrdquo addressing method that uses ldquorowrdquo and ldquocolumnsrdquo to access electrodes. By mapping the droplet-movement problem on a cross-referenced chip to the clique-partitioning problem from graph theory, the proposed method allows simultaneous movement of a large number of droplets on a microfluidic array. Concurrency is enhanced through the use of an efficient scheduling algorithm that determines the order in which groups of droplets are moved. The proposed design-automation method facilitates high-throughput applications on a pin-constrained biochip, and it is evaluated using random synthetic benchmarks and a set of multiplexed bioassays.

Microfluidic biochips are revolutionizing many areas of biochemistry and biomedical sciences. Several synthesis tools have recently been proposed for the automated design of biochips from the specifications of laboratory protocols. However, only a few of these tools address the problem of droplet routing in microfluidic arrays. These methods typically rely on post-synthesis droplet routing to implement biochemical protocols. Such an approach is not only time-consuming, but it also imposes an undue burden on the chip user. Moreover, post-synthesis droplet routing does not guarantee that feasible droplet pathways can be found for area-constrained biochip layouts; non-routable fabricated biochips must be discarded. We present a droplet-routing-aware automated synthesis tool for microfluidic biochips. Droplet routability, defined as the ease with which droplet pathways can be determined, is estimated and integrated in the synthesis flow. The proposed approach allows architectural-level design choices and droplet-routing-aware physical design decisions to be made simultaneously. We use a large-scale protein assay as a case study to evaluate the proposed synthesis method.

Digital microfluidic biochips are revolutionizing high-throughput DNA sequencing, immunoassays, and clinical diagnostics. As high-throughput bioassays are mapped to digital microfluidic platforms, the need for design automation techniques for pin-constrained biochips is being increasingly felt. However, most prior work on biochips CAD has assumed independent control of the underlying electrodes using a large number of (electrical) input pins. The authors propose a droplet manipulation method based on a "cross-referencing" addressing method that uses "row" and "columns" to access electrodes. By mapping the droplet movement problem to the clique partitioning problem from graph theory, the proposed method allows simultaneous movement of a large number of droplets on a microfluidic array. This in turn facilitates high-throughput applications on a pin-constrained biochip. The authors use random synthetic benchmarks and a set of multiplexed bioassays to evaluate the proposed method

Dependability is an important attribute for microfluidic biochips that are used for safety-critical applications such as point-of-care health assessment, air-quality monitoring, and food-safety testing. Therefore, these devices must be adequately tested after manufacture and during bioassay operations. Moreover, since disposable biochips are being targeted for a highly competitive and low-cost market segment, test and diagnosis methods should be inexpensive, quick, and effective. We propose a cost-effective testing methodology referred to as "parallel scan-like test", and a rapid diagnosis method based on test outcomes, for droplet-based microfluidic devices. The proposed method allows testing using parallel droplet pathways in both on-line and off-line scenarios. The diagnosis outcome can be used to reconfigure a droplet-based biochip such that faults can be easily avoided, thereby enhancing chip yield and defect tolerance. We evaluate the proposed test and diagnosis methods using complexity analysis as well as experiments using a fabricated biochip.

Dependability is an important attribute for microfluidic biochips that are used for safety-critical applications such as point-of-care health assessment, air-quality monitoring, and food-safety testing. Therefore, these devices must be adequately tested after manufacture and during bioassay operations. Known techniques for biochip testing are all function-oblivious, i.e., while they can detect and locate defect sites on a microfluidic array, they cannot be used to ensure correct operation of functional units. In this paper, we introduce the concept of functional testing of microfluidic biochips. We address fundamental biochip operations such as droplet dispensing, droplet transportation, mixing, splitting, and capacitive sensing. Long electrode actuation times are avoided to ensure that there is no electrode degradation during testing. We evaluate the proposed test methods using simulations as well as experiments for a fabricated biochip.

Microfluidics-based biochips, also referred to as lab-on-a-chip, are devices that integrate fluid-handling functions such as sample preparation, analysis, separation, and detection. This emerging technology combines electronics with biology to open new application areas such as point-of-care diagnosis, on-chip DNA analysis, and automated drug discovery. We propose a design automation method for pin-constrained biochips that manipulate nanoliter volumes of discrete droplets on a microfluidic array. In contrast to the direct-addressing scheme that has been studied thus far in the literature, we assign a small number of independent control pins to a large number of electrodes in the biochip, thereby reducing design complexity and product cost. The design procedure relies on a droplet-trace-based array partitioning scheme and an efficient pin assignment technique, referred to as the “Connect-5 algorithm.” The proposed method is evaluated using a set of multiplexed bioassays.