Design Automation and Test Solutions for Digital Microfluidic Biochips
Summary (3 min read)
Introduction
- Digital Object Identifier 10.1109/TCSI.2009.2038976 and reagent volumes, higher levels of system integration, and less likelihood of human error.
- This tutorial paper is focused on droplet-based “digital” microfluidic biochips.
- Next the paper describes emerging computer-aided design (CAD) tools for the automated synthesis and optimization of biochips from bioassay protocols.
- Recent advances on fluidic-operation scheduling, module placement, droplet routing, testing, and dynamic reconfiguration are also presented.
II. TECHNOLOGY PLATFORMS
- Early biochips were based on the concept of a DNA microarray, which is a piece of glass, plastic or silicon substrate on which pieces of DNA, i.e., probes, have been affixed.
- There are a number of commercial microarrays available in the marketplace today, e.g., GeneChip DNAarray from Affymetrix, NanoChip microarray from Nanogen, and DNA microarray from Agilent.
- A drawback of these arrays is that they are “passive chips”; they are neither reconfigurable nor can they be used for sample preparation.
- The basic idea of a microfluidic biochip is to integrate all necessary functions for biochemical analysis using microfluidics technology.
- Integrated functions include assay operations, detection, and sample preparation.
A. Continuous-Flow Microfluidics
- Traditional (continuous-flow) microfluidic technologies are based on the continuous flow of liquid through micro-fabricated channels [8], [10]–[16].
- Continuous-flow systems are inherently difficult to integrate because the parameters that govern flow field (e.g. pressure, fluid resistance, electric field strength) vary along the flow-path, making the flow at any location dependent upon the properties of the entire system.
- Moreover, unavoidable shear flow and diffusion in microchannels make it difficult to eliminate intersample contamination and dead volumes.
- Furthermore, since structure and functionality are so tightly coupled, each system is only appropriate for a narrow class of applications.
B. Digital Microfluidics
- A digital microfluidic biochip utilizes electrowetting on dielectric (EWOD) to manipulate and move microliter or nanoliter droplets containing biological samples on a two-dimensional electrode array [2]–[4], [17], [23]–[26].
- The bottom plate contains a patterned array of individually controlled electrodes, and the top plate is coated with a continuous ground electrode.
- The digital microfluidic platform offers dynamic reconfigurability, since fluidic operations can be performed anywhere on the array.
- As in the case of today’s integrated circuits, such multifunctional chips facilitate mass production and lower product cost.
- Many droplet operations, e.g., droplet dispensing and mixing, have been demonstrated to be repeatable with high accuracy [27].
A. Scheduling and Module Placement
- To ensure the integrity of assay results, it is therefore desirable to minimize the time that samples spend on-chip before assay results are obtained.
- Since digital microfluidics-based biochips enable dynamic reconfiguration of the microfluidic array during run-time, they allow the placement of different modules on the same location during different time intervals.
- Non-reconfigurable devices such as reservoirs and detectors also have to be considered.
- The top-down synthesis flow described above unifies architecture level design with physical-level module placement.
IV. PIN-CONSTRAINED CHIP DESIGN
- Early design-automation techniques relied on the availability of a direct-addressing scheme.
- For large arrays, direct-addressing schemes lead to a large number of control pins, and the associated interconnect routing problem significantly adds to the product cost.
- Thus, the design of pin-constrained digital microfluidic arrays is of great practical importance for the emerging marketplace.
A. Droplet-Trace-Based Array Partitioning
- An array-partitioning-based pin-constrained design method of digital microfluidic biochips proposed in [56].
- This method uses array partitioning and careful pin assignment to reduce the number of control pins.
- The droplet trace, defined as the set of cells traversed by a single droplet, serves as the basis for generating the array partitions.
- The solution to this problem is to make the overlapping region a new partition, referred to as the overlapping partition, and use direct addressing (one-to-one mapping) for it.
- This method requires detailed information about the scheduling of assay operations, microfluidic module placement, and droplet routing pathways.
B. Cross-Referencing-Based Droplet Manipulation
- This method allows control of an grid array with only control pins.
- In order to drive a droplet along the X-direction, electrode rows on the bottom plate serve as driving electrodes, while electrode rows on the top serve as reference ground electrodes.
- The roles are reversed for movement along the Y-direction.
- The manipulation of multiple droplets is ordered in time; droplets in the same group can be moved simultaneously without electrode interference, but the movements for the different groups must be sequential.
- The problem of finding the minimum number of groups can be directly mapped to the problem of determining a minimal clique partition from graph theory [37].
C. Broadcast-Addressing Method
- One drawback of the cross-reference driving scheme is that this design requires a special electrode structure (i.e., both top and bottom plates contain electrode rows), which results in increased manufacturing cost.
- Compatible sequences can be generated from a single signal source.
- The number of control pins can be reduced by connecting together electrodes with mutually-compatible activation sequences, and addressing them using a single control pin.
- The problem of finding an optimal partition that leads to the minimum number of groups can be easily mapped to the problem of determining a minimal clique partition from graph theory [37].
B. Structural Test Techniques
- A unified test methodology for digital microfluidic biochips has recently been presented, whereby faults can be detected by controlling and tracking droplet motion electrically [45].
- On the other hand, if the authors move a test droplet across the faulty cells affected by an electrode-short fault, the test droplet may or may not be stuck depending on its flow direction.
- This approach uses only one droplet to traverse the microfluidic array, irrespective of the array size.
- Such a diagnosis method is inefficient since defect-free cells are tested multiple times.
- More recently, a cost-effective testing methodology referred to as “parallel scan-like test” has been proposed [58].
C. Functional Testing Techniques
- Functional testing involves test procedures to check whether groups of cells can be used to perform certain operations, e.g., droplet mixing and splitting.
- Functional test methods to detect the defects and malfunctions have recently been developed.
- Functional test methods were applied to a PCB microfluidic platform for the Polymerase Chain Reaction (PCR), as shown in Fig.
- The bottom row was first targeted and five test droplets were dispensed to the odd electrodes, as shown in Fig. 9(a).
D. Built-In Self-Test (BIST) Techniques
- Previous test methods for digital microfluidic platforms use capacitive sensing circuits to read and analyze test outcomes.
- This approach requires an additional step to analyze the pulse sequence to determine whether the microfluidic array under-test is defective.
- Using the principle of electrowetting-ondielectric, microfluidic AND, OR and NOT gates are implemented through basic droplet-handling operations such as transportation, merging, and splitting.
- Fig. 10 shows the operation of the OR gate for two inputs .
- The electrodes represent the last row/column where the pseudosinks are located.
E. Design for Testability
- Previous pin-constrained design methods achieve a significant reduction in the number of input pins needed for controlling the electrodes.
- Note that the reduction in testability is due to the conflicts between the fluidic operation steps required by functional test and the constraints on droplet manipulations introduced by the mapping of pins to electrodes.
- For each electrode in the array, its activation sequence during the test procedure is added to that for the target bioassay to form a longer sequence.
- The broadcast-addressing method is then applied to generate the eventual pin assignment according to sequences in T3.
- By applying pin-constrained design to the testability-aware bioassay protocol, the proposed method ensures that the resulting chip layout supports the effective execution of test-related droplet operations for the entire chip.
VI. CONCLUSION
- The authors have presented a survey of research on design automation and test techniques for digital microfluidic biochips.
- Practical design techniques for achieving high throughout with a small number of control pins have been presented.
- Testing and design-for-testability techniques have also been presented.
- These design techniques are expected to pave the way for the deployment and use of biochips in the emerging marketplace.
- As the next step for research in this field, there is a need to integrate Authorized licensed use limited to: DUKE UNIVERSITY.
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Citations
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Cites methods from "Design Automation and Test Solution..."
..., LOC systems, can automate biological computations or experiments by integrating a diverse set of biological sensors and manipulating fluids at the picolitre [18,19] and nanolitre scales [20]....
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76 citations
67 citations
Cites background from "Design Automation and Test Solution..."
...Moreover, the assistance of CAD tools will facilitate the integration of fluidic components with a microelectronic component in next-generation system-on-chips (SOCs) [6, 7, 12, 32]....
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...Continuing growth of various applications have dramatically complicated chip/system integration and design complexity [7, 12], rendering traditional manual designs infeasible, especially under time-to-market constraints....
[...]
References
[...]
6,255 citations
2,311 citations
"Design Automation and Test Solution..." refers methods in this paper
...Architectural-level synthesis is then used to generate a macroscopic structure of the biochip; this is analogous to a structural register-transfer level (RTL) model in electronic CAD [40]....
[...]
...It describes emerging computer-aided design (CAD) tools for the automated synthesis and optimization of biochips from bioassay protocols....
[...]
...Next the paper describes emerging computer-aided design (CAD) tools for the automated synthesis and optimization of biochips from bioassay protocols....
[...]
...In this section, we examine a progression of CAD problems related to biochip synthesis....
[...]
...Index Terms—Chip layout, computer-aided design (CAD), droplet routing, lab-on-chip, synthesis, testing and diagnosis....
[...]
1,522 citations
1,471 citations
"Design Automation and Test Solution..." refers methods in this paper
...A digital microfluidic biochip utilizes electrowetting on dielectric (EWOD) to manipulate and move microliter or nanoliter droplets containing biological samples on a two-dimensional electrode array [2]–[4], [17], [23]–[26]....
[...]
1,124 citations
"Design Automation and Test Solution..." refers background in this paper
...Demonstrated applications of digital microfluidics include the on-chip detection of explosives such as commercial-grade 2,4,6-trinitrotoluene (TNT) and pure 2,4-dinitrotoluene [6], automated on-chip measurement of airborne particulate matter [21], [22], and colorimetric assays [7]....
[...]
...A film of silicone oil is used as a filler medium to prevent cross contamination and evaporation [7], [27]....
[...]