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Design Automation and Test Solutions for Digital Microfluidic Biochips

01 Jan 2010-IEEE Transactions on Circuits and Systems I-regular Papers (IEEE)-Vol. 57, Iss: 1, pp 4-17
TL;DR: This tutorial paper describes emerging computer-aided design (CAD) tools for the automated synthesis and optimization of biochips from bioassay protocols and recent advances in fluidic-operation scheduling, module placement, droplet routing, pin-constrained chip design, and testing are presented.
Abstract: Microfluidics-based biochips are revolutionizing high-throughput sequencing, parallel immunoassays, blood chemistry for clinical diagnostics, and drug discovery. These devices enable the precise control of nanoliter volumes of biochemical samples and reagents. They combine electronics with biology, and they integrate various bioassay operations, such as sample preparation, analysis, separation, and detection. Compared to conventional laboratory procedures, which are cumbersome and expensive, miniaturized biochips offer the advantages of higher sensitivity, lower cost due to smaller sample and reagent volumes, system integration, and less likelihood of human error. This tutorial paper provides an overview of droplet-based ?digital? microfluidic biochips. It describes emerging computer-aided design (CAD) tools for the automated synthesis and optimization of biochips from bioassay protocols. Recent advances in fluidic-operation scheduling, module placement, droplet routing, pin-constrained chip design, and testing are presented. These CAD techniques allow biochip users to concentrate on the development of nanoscale bioassays, leaving chip optimization and implementation details to design-automation tools.

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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4 IEEE TRANSACTIONS ON CIRCUITS AND SYSTEMS—I: REGULAR PAPERS, VOL. 57, NO. 1, JANUARY 2010
Design Automation and Test Solutions for Digital
Microfluidic Biochips
Krishnendu Chakrabarty, Fellow, IEEE
(Invited Tutorial)
Abstract—Microfluidics-based biochips are revolutionizing
high-throughput sequencing, parallel immunoassays, blood chem-
istry for clinical diagnostics, and drug discovery. These devices
enable the precise control of nanoliter volumes of biochemical
samples and reagents. They combine electronics with biology,
and they integrate various bioassay operations, such as sample
preparation, analysis, separation, and detection. Compared to
conventional laboratory procedures, which are cumbersome and
expensive, miniaturized biochips offer the advantages of higher
sensitivity, lower cost due to smaller sample and reagent volumes,
system integration, and less likelihood of human error. This
tutorial paper provides an overview of droplet-based “digital”
microfluidic biochips. It describes emerging computer-aided
design (CAD) tools for the automated synthesis and optimiza-
tion of biochips from bioassay protocols. Recent advances in
fluidic-operation scheduling, module placement, droplet routing,
pin-constrained chip design, and testing are presented. These
CAD techniques allow biochip users to concentrate on the de-
velopment of nanoscale bioassays, leaving chip optimization and
implementation details to design-automation tools.
Index Terms—Chip layout, computer-aided design (CAD),
droplet routing, lab-on-chip, synthesis, testing and diagnosis.
I. INTRODUCTION
A
DVANCES in digital microfluidics have led to the
promise of miniaturized biochips for applications such
as immunoassays for point-of-care medical diagnostics, DNA
sequencing, and the detection of airborne particulate matter
[1]–[8]. These devices enable the precise control of nanoliter
droplets of biochemical samples and reagents, and integrated
circuit (IC) technology can be used to transport and process
“biochemical payload” in the form of tiny droplets. Biochips
facilitate the convergence of electronics with the life sciences,
and they integrate on-chip various bioassay operations, such as
sample preparation, analysis, separation, and detection [1], [4].
Compared to conventional laboratory procedures, which are
cumbersome and expensive, miniaturized biochips offer the ad-
vantages of higher sensitivity, lower cost due to smaller sample
Manuscript received September 25, 2009; revised November 21, 2009. First
published December 31, 2009; current version published January 13, 2010. This
work was supported in part by the National Science Foundation under Grant IIS-
0312352, Grant CCF-0541055, and Grant CCF-0914895, and by the National
Institute of General Medical Sciences of the National Institute of Health under
Grant R44GM072155. this paper was recommended by Associate Editor W. A.
Serdijn.
The author is with the Department of Electrical and Computer Engineering,
Duke University, Durham, NC 27708, USA (e-mail: krish@ee.duke.edu).
Digital Object Identifier 10.1109/TCSI.2009.2038976
and reagent volumes, higher levels of system integration, and
less likelihood of human error. As a result, non-traditional
biomedical applications and markets are opening up funda-
mentally new uses for ICs. For example, the worldwide market
for in vitro diagnostics in 2007 was estimated at $38 billion
[70], and 1.5 billion diagnostic tests/year worldwide has been
predicted for malaria alone [71].
However, continued growth in this emerging field depends
on advances in chip/system integration. In particular, design
methods are needed to ensure that biochips are as versatile as
the macro-labs that they are intended to replace. The few com-
mercial biochips available today (e.g., from Agilent, Fluidigm,
Caliper, I-Stat, BioSite, etc.) are specific to an application and
they offer no flexibility to the user. Intel recently announced the
Health Guide PHS6000 product for home patients, but the un-
derlying technology does not exploit the benefits of reconfig-
urable microfluidics.
This tutorial paper is focused on droplet-based “digital”
microfluidic biochips. The digital microfluidics platform offers
the flexibility of dynamic reconfigurability and software-based
control of multifunctional biochips. Next the paper describes
emerging computer-aided design (CAD) tools for the auto-
mated synthesis and optimization of biochips from bioassay
protocols. Recent advances on fluidic-operation scheduling,
module placement, droplet routing, testing, and dynamic re-
configuration are also presented. These CAD techniques allow
biochip users to concentrate on the development of nanoscale
bioassays, leaving chip optimization and implementation de-
tails to design-automation tools.
It is expected that an automated design flow will transform
biochip research and use, in the same way as design automation
revolutionized IC design in the 1980s and 1990s. This approach
is, therefore, especially aligned with the vision of functional
diversification and “More than Moore”, as articulated in the
International Technology Roadmap for Semiconductors (ITRS)
2007, which highlights “Medical” as being a “System Driver”
for the future [9]. Biochip users will adapt more easily to
emerging technology if appropriate design methods/tools and
in-system automation methods are available. A limitation of
current CAD techniques is that they do not adequately consider
unique constraints that arise due to the fluidic aspects of the
underlying technology, the likelihood of cross-contamination
between different bio-molecules, and the limited availability of
stock solutions for use in assay protocols in biochemistry.
The rest of this paper is organized as follows. Section II
describes biochip technology platforms, including digital mi-
crofluidics. Section III presents synthesis techniques, including
1549-8328/$26.00 © 2010 IEEE
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CHAKRABARTY: DESIGN AUTOMATION AND TEST SOLUTIONS FOR DIGITAL MICROFLUIDIC BIOCHIPS 5
solutions published in the literature for operation scheduling,
module placement, and droplet routing. Section IV describes
pin-constrained chip methods. Section V presents advances
in testing, diagnosis, and dynamic reconfiguration. Finally,
Section VI concludes the paper.
II. T
ECHNOLOGY
PLATFORMS
Early biochips were based on the concept of a DNA mi-
croarray, 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 prepa-
ration. Product cost is also a problem; for example, while the mi-
croarray chips from Affymetrix cost in the range of $500–$2000
each, the accompanying instrument and licensing/royalty fees
can be as high as $175 000.
The basic idea of a microfluidic biochip is to integrate all nec-
essary functions for biochemical analysis using microfluidics
technology. These micro-total-analysis-systems are more ver-
satile than microarrays. Integrated functions include assay op-
erations, 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, unavoid-
able shear flow and diffusion in microchannels make it difficult
to eliminate intersample contamination and dead volumes. Fur-
thermore, since structure and functionality are so tightly cou-
pled, each system is only appropriate for a narrow class of ap-
plications.
B. Digital Microfluidics
A digital microfluidic biochip utilizes electrowetting on di-
electric (EWOD) to manipulate and move microliter or nano-
liter droplets containing biological samples on a two-dimen-
sional electrode array [2]–[4], [17], [23]–[26]. A unit cell in the
array includes a pair of electrodes that acts as two parallel plates.
The bottom plate contains a patterned array of individually con-
trolled electrodes, and the top plate is coated with a continuous
ground electrode. A droplet rests on a hydrophobic surface over
an electrode, as shown in Fig. 1. It is moved by applying a
control voltage to an electrode adjacent to the droplet and, at
the same time, deactivating the electrode just under the droplet.
Using interfacial tension gradients, droplets can be moved to
any location on a two-dimensional array. A film of silicone oil
is used as a filler medium to prevent cross contamination and
evaporation [7], [27]. In Fig. 1(a), the electrode pitch is 1.5 mm
and the gap height is 600
m. Recent work has demonstrated
chips with an electrode pitch of 60
m and 19.2 m height. To
Fig. 1. Fabricated digital microfluidic arrays. (a) Glass substrate [25]. (b) PCB
substrate [57].
dispense a 105 pl droplet, an actuation voltage of 80 V is re-
quired [74].
An alternative method for digital microfluidics, namely di-
electrophoresis (DEP), relies on AC actuation [28]–[31]. How-
ever, excessive Joule heating is often seen as a problem for DEP.
In contrast to DEP actuation, Joule heating is virtually elimi-
nated in EWOD because the dielectric layer covering the elec-
trodes blocks DC electric current.
The division of a volume of fluid into discrete, independently
controllable “packets” or droplets, provides several advan-
tages over continuous-flow. The reduction of microfluidics
to a set of basic repeated operations (i.e., “move one unit of
fluid one distance unit”) allows a hierarchical and cell-based
design approach to be utilized. By varying the patterns of
control-voltage activation (a clock signal with logic-high and
logic-low values), many fluid-handling operations such as
droplet merging, splitting, mixing, and dispensing can be easily
executed. The digital microfluidic platform offers dynamic
reconfigurability, since fluidic operations can be performed
anywhere on the array. Droplet routes and operation scheduling
results are programmed into a microcontroller that drives elec-
trodes in the array. As a result, there is no need for dedicated
on-chip reaction chambers. Reservoirs are included on the
array boundary, from which droplets can be easily dispensed
[4]. The disposable nature of these chips precludes multiple
uses over long periods of time; nevertheless, reconfigurability
allows the same chip design and fabrication method to be used
for multiple applications. As in the case of today’s integrated
circuits, such multifunctional chips facilitate mass production
and lower product cost.
To address the need for low-cost, printed circuit board (PCB)
technology has been employed for inexpensive fabrication [32].
Using a copper layer for the electrodes, solder mask as the insu-
lator, and a Teflon AF coating for hydrophobicity, the microflu-
idic array can be fabricated using an existing PCB process. A
typical coplanar digital microfluidic chip has an electrode pitch
of 1.5 mm, with a gap of 90
[73]. Actuation voltages of
around 220 V are applied for fluidic operation. Power supplies
are, therefore, external to the microfluidic chip.
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]. Measured performance
metrics for such colorimetric assays have been reported in prior
work, e.g., [2], [7]. Digital microfluidic biochips are being
designed for on-chip gene sequencing through synthesis [4],
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6 IEEE TRANSACTIONS ON CIRCUITS AND SYSTEMS—I: REGULAR PAPERS, VOL. 57, NO. 1, JANUARY 2010
and integrated hematology, pathology, molecular diagnostics,
cytology, microbiology, and serology on the same platform
[18]. A prototype has been developed for pyrosequencing
[4], which targets the simultaneous execution of 106 fluidic
operations and the processing of billions of droplets. Other
lab-on-chip/biochip systems are being designed for protein
crystallization, which requires the concurrent execution of
hundreds of operations [33], [34]. A commercially available
droplet-based (using dielectrophoresis) lab-on-chip embeds
more than 600,000 20
mby20 m electrodes with integrated
optical detectors [35]. Experimental work using digital mi-
crofluidics has been focused on in vitro and ex vivo techniques,
as opposed to in vivo methods.
A limitation of digital microfluidics is the nonspecific adsorp-
tion of reagents and samples to the electrode surface. Therefore,
design techniques must be developed to avoid cross-contamina-
tion. Another limitation today is the difficulty in ensuring accu-
racy and reproducibility for the droplet split operation. Finally,
the world-to-chip interface is a challenge since it is difficult to
deliver reagents and samples to such biochips. Nevertheless,
these issues are being studied in ongoing research, e.g., [72],
[74], and there is considerable enthusiasm for this emerging
technology. Many droplet operations, e.g., droplet dispensing
and mixing, have been demonstrated to be repeatable with high
accuracy [27].
In a recent review paper on the use of microfluidics for pro-
tein crystallization [36], the following question was posed: can
we purchase identical crystallization devices, produced under
adequate quality control? The authors go on to say, “Drawing
upon integrated circuits as an analogy, microfluidics devices
may be reducible to a standard set of discrete operations which
can then be custom assembled to form more complex operations
as needed. With this approach, the success of manufacturing in-
vestment does not have to rest upon a single application.”
The discrete droplet-based biochip described in this paper
is perfectly suited as a platform technology, since it avoids
the common pitfall of custom devices offered by other contin-
uous-flow microfluidic technologies.
III. S
YNTHESIS METHODS
In this section, we examine a progression of CAD problems
related to biochip synthesis.
A. Scheduling and Module Placement
Recent years have seen growing interest in the automated
design and synthesis of microfluidic biochips [39], [44],
[47]–[51], [53]–[56], [59]–[61], [63]–[67], [69]. Optimization
goals here include the minimization of assay completion time,
minimization of chip area, and higher defect tolerance. The min-
imization of the assay completion time, i.e., the maximization
of throughput, is essential for environmental monitoring ap-
plications where sensors can provide early warning. Real-time
response is also necessary for surgery and neonatal clinical
diagnostics. Finally, biological samples are sensitive to the
environment and to temperature variations, and it is difficult to
maintain an optimal clinical or laboratory environment on chip.
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.
Increased throughput also improves operational reliability.
Long assay durations imply that high actuation voltages need
to be maintained on some electrodes, which accelerate insulator
degradation and dielectric breakdown, reducing the number of
assays that can be performed on a chip during its lifetime.
One of the first published methods for biochip synthesis
decoupled high-level synthesis from physical design [44],
[54]. Architectural-level synthesis for microfluidic biochips
can be viewed as the problem of scheduling assay functions
and binding them to a given number of resources so as to
maximize parallelism, thereby decreasing response time. A
behavioral model for a set of bioassays is first obtained from
their laboratory protocols. 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]. On the other hand, geometry-level syn-
thesis (physical design) addresses the placement of resources
and the routing of droplets to satisfy objectives such as area or
throughput. It creates the final layout of the biochip, consisting
of the placement of microfluidic modules such as mixers and
storage units, the routes that droplets take between different
modules, and other geometrical details [53].
As in the case of high-level synthesis for integrated circuits,
resource binding in the biochip synthesis flow refers to the
mapping from bioassay operations to available functional
resources. Note that there may be several types of resources
for any given bioassay operation. For example, a 2
2 array
mixer, a 2
3 array mixer and a 2 4 array mixer can be
used for a droplet mixing operation, but with different mixing
times. In such cases, a resource selection procedure must be
used. On the other hand, resource binding may associate one
functional resource with several assay operations; this neces-
sitates resource sharing. Once resource binding is carried out,
the time duration for each bioassay operation can be easily
determined. Scheduling determines the start times and stop
times of all assay operations, subject to the precedence and
resource-sharing constraints.
A key problem in the geometry-level synthesis of biochips is
the placement of microfluidic modules such as different types
of mixers and storage units. 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. A
simulated annealing-based heuristic approach has been devel-
oped to solve the NP-complete problem in a computationally
efficient manner [53]. Solutions for the placement problem can
provide the designer with guidelines on the size of the array
to be manufactured. If module placement is carried out for a
fabricated array, area minimization frees up more unit cells for
sample collection and preparation.
Architectural synthesis is based on rough estimates for place-
ment costs such as the area of the microfluidic modules. These
estimates provide lower bounds on the exact biochip area, since
the overheads due to spare cells and cells used for droplet trans-
portation are not known a priori. However, it cannot be ac-
curately predicted if the biochip design meets system specifi-
cations, e.g., maximum allowable array area and upper limits
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CHAKRABARTY: DESIGN AUTOMATION AND TEST SOLUTIONS FOR DIGITAL MICROFLUIDIC BIOCHIPS 7
Fig. 2. An example illustrating system-level synthesis [47].
on assay completion times, until both high-level synthesis and
physical design are carried out. [47] proposed a unified system-
level synthesis method for microfluidic biochips based on par-
allel recombinative simulated annealing (PRSA), which offers
a link between these two steps. This method allows users to de-
scribe bioassays at a high level of abstraction, and it automati-
cally maps behavioral descriptions to the underlying microflu-
idic array.
The design flow is illustrated in Fig. 2. First, the different
bioassay operations (e.g. mixing and dilution), and their mutual
dependences are represented using a sequencing graph. Next,
a combination of simulated annealing and genetic algorithms
are used for unified resource binding, operation scheduling, and
module placement. A chromosome is used to represent each
candidate solution, i.e., a design point. The word chromosome
is derived from genetics, and it encodes the characteristics of
an individual in the population. In each chromosome, opera-
tions are randomly bound to resources. Based on the binding
results, list scheduling is used to determine the start times of op-
erations, i.e., each operation starts with a random latency after
its scheduled time. Finally, a module placement is derived based
on the resource binding and the schedule of fluidic operations.
A weighted sum of area- and time-cost is used to evaluate the
quality of the design. The design is improved through a series
of genetic evolutions based on PRSA. It generates an optimized
schedule of bioassay operations, the binding of assay operations
to resources, and a layout of the microfluidic biochip.
Efficient reconfiguration techniques have been developed to
bypass faulty unit cells in the microfluidic array [55]. A mi-
crofluidic module containing a faulty unit cell can easily be re-
located to another part of the microfluidic array by changing the
control voltages applied to the corresponding electrodes [49].
Defect tolerance can also be achieved by including redundant
elements in the system; these elements can be used to replace
faulty elements through reconfiguration techniques [48]. An-
other method is based on graceful degradation, in which all el-
ements in the system are treated in a uniform manner, and no
element is designated as a spare [50]. In the presence of defects,
a subsystem with no faulty element is first determined from the
faulty system. This subsystem provides the desired function-
ality, but with a gracefully degraded level of performance (e.g.,
longer execution times). Due to the dynamic reconfigurability of
digital microfluidics-based biochips, microfluidic components
(e.g., mixers) can be viewed as reconfigurable virtual devices.
For example, a 2
4array mixer (implemented using a rectan-
gular array of control electrodes—two in the X-direction and
four in Y-direction) can easily be reconfigured to a 2
3 array
mixer or a 2
2 array mixer.
Fig. 3(a) shows the module placement results and the mi-
crofluidic array design for a representative protein assay [47].
The XY-plane refers to the placement of modules on the chip
real estate. The Z-axis refers to time. As shown in Fig. 3(b), we
can further integrate optical detectors as well as on-chip reser-
voirs/dispensing ports into the microfluidic array to form a com-
plete digital microfluidic biochip for the protein assay. Fig. 3(c)
shows the corresponding results when some of the unit cells
in the array are faulty, and reconfiguration is used in a unified
manner with synthesis. The solution obtained for the fault-free
array yields a biochip design with a 9
9 microfluidic array and
the completion time for the protein assay is 363 s. The design
for the faulty array allows the protein assay to operate with an
increase of only 6% in the completion time, i.e., the completion
time is now 385 seconds.
Note that there are clear similarities between the programma-
bility of dynamically reconfigurable field-programmable
gate-arrays (DR-FPGAs) and digital microfluidics. However,
there are also some key differences. The programmability of
DR-FPGAs is limited by the well-defined roles of interconnect
and logic blocks. Interconnect cannot be used for storing
information, and logic blocks cannot be used for routing. In
contrast, digital microfluidics-based biochips offer significantly
more programmability. The cells in the microfluidic array
can be used for storage and functional operations, as well as
for transporting fluid droplets. Moreover, “virtual devices” in
digital microfluidics can be easily moved without incurring
overhead. Non-reconfigurable devices such as reservoirs and
detectors also have to be considered.
The top-down synthesis flow described above unifies ar-
chitecture level design with physical-level module placement.
However, it suffers from two drawbacks. For operation sched-
uling, it is assumed that the time cost for droplet routing is
negligible, which implies that droplet routing has no influence
on the operation completion time. While generating physical
layouts, the synthesis tool in [47] provides only the layouts of
the modules and it leaves droplet routing pathways unspecified.
The assumption of negligible droplet transportation times is
valid for small microfluidic arrays. However, for large arrays
and for biochemical protocols that require several concurrent
fluidic operations on-chip, the droplet transportation time is
significant and routing complexity is non-trivial. This problem
is addressed in the next subsection.
B. Droplet Routing
A key problem in biochip physical design is droplet routing
between modules, and between modules and I/O ports (i.e.,
on-chip reservoirs). The dynamic reconfigurability inherent in
digital microfluidics allows different droplet routes to share
cells on the microfluidic array during different time intervals.
In this sense, the routes in microfluidic biochips can be viewed
as virtual routes, which make droplet routing different from
Authorized licensed use limited to: DUKE UNIVERSITY. Downloaded on January 24, 2010 at 10:38 from IEEE Xplore. Restrictions apply.

8 IEEE TRANSACTIONS ON CIRCUITS AND SYSTEMS—I: REGULAR PAPERS, VOL. 57, NO. 1, JANUARY 2010
Fig. 3. (a) A 3-D model illustrating the synthesis results. (b) A digital microflu-
idic biochip for a protein assay. (c) A defective array and module placement for
the protein assay on this array.
the classical wire VLSI routing problem. Systematic routing
method for digital microfluidic biochips have therefore been
developed to minimize the number of cells used for droplet
routing, while satisfying constraints imposed by performance
goals and fluidic properties.
One of the first methods for droplet routing in biochips was
published in [51]. The main objective in routing is to find
droplet routes with minimum lengths, where route length is
measured by the number of cells in the path from the starting
point to the destination. For a microfluidic array of fixed size,
minimum-length droplet routes lead to the minimization of the
total number of cells used in droplet routing, thus freeing up
more spare cells for fault tolerance. As in the case of electronic
circuits, the fluidic ports on the boundary of microfluidic mod-
ules are referred to as pins. Similarly, we refer to the droplet
routes between pins of different modules or on-chip reservoirs
as nets. Thus, a fluidic route on which a single droplet is trans-
ported between two terminals can easily be modeled as a 2-pin
net. We also need to move two droplets from different terminals
to one common microfluidic module (e.g., mixer) for mixing.
To allow droplet mixing simultaneously during their transport,
we need to model such fluidic routes using 3-pin nets.
During droplet routing, a minimum spacing between droplets
must be maintained to prevent accidental mixing, except for the
case when droplet merging is desired (e.g., in 3-pin nets). Flu-
idic constraint rules in [51] need to be satisfied in order to avoid
undesirable mixing. We view the microfluidic modules placed
on the array as obstacles in droplet routing. In order to avoid
conflicts between droplet routes and assay operations, a seg-
regation region is added to wrap around the functional region
of microfluidic modules. Another constraint in droplet routing
is given by an upper limit on droplet transportation time. The
delay for each droplet route should not exceed some maximum,
e.g., 10% of a time-slot used in scheduling, in order that the
droplet-routing time can be ignored for scheduling assay oper-
ations [51].
Since a digital microfluidic array can be reconfigured dy-
namically at run-time, a series of 2-D placement configurations
of modules in different time spans are obtained in the module
placement phase [48]. Therefore, the droplet routing is de-
composed into a series of sub-problems. We obtain a complete
droplet-routing solution by solving these sub-problems sequen-
tially.
Based on this problem formulation, a two-stage routing
method has been proposed in [51]. In the first stage,
alter-
native routes for each net are generated. In the second stage,
a single route from the
alternatives for each net is selected
independent of the routing order of nets. This method also
exploits the features of dynamic reconfigurability and indepen-
dent controllability of electrodes to modify droplet pathways to
override potential violation of fluidic constraints.
Droplet routing should be considered in the synthesis flow
for digital microfluidics, in order to generate a routable synthe-
sized design for the availability of routing paths. [59] proposed
a method to incorporate droplet-routability in the PRSA-based
synthesis flow. This method estimates the droplet-routability
using two metrics. It adopts the average module distance (over
all interdependent modules) as the first design metric to guar-
antee the routability of modules in the synthesized biochip. It
also adopts the maximum module distance as the second de-
sign metric to approximate the maximum length of droplet ma-
nipulation. Since synthesis results with high routability values
are more likely to lead to simple and efficient droplet path-
ways, this method incorporates the above two metrics into the
fitness function by a factor that can be fine-tuned according to
different design specifications to control the PRSA-based pro-
cedure. For each chromosome considered in the PRSA-based
synthesis flow, this method calculates both the average and max-
imum module distance. Candidate designs with low routability
are discarded during evolution. Thus, the synthesis procedure
guarantees that the routing complexity is reduced for the syn-
thesized biochip, while meeting constraints on array size and
bioassay processing time.
Authorized licensed use limited to: DUKE UNIVERSITY. Downloaded on January 24, 2010 at 10:38 from IEEE Xplore. Restrictions apply.

Citations
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Journal ArticleDOI
27 May 2011-Sensors
TL;DR: A broad overview of the need for devices that are easy to operate, sensitive, fast, portable and sufficiently reliable to be used as complementary tools for the control of pathogenic agents that damage the environment is provided.
Abstract: Microfluidics-based lab-on-chip (LOC) systems are an active research area that is revolutionising high-throughput sequencing for the fast, sensitive and accurate detection of a variety of pathogens. LOCs also serve as portable diagnostic tools. The devices provide optimum control of nanolitre volumes of fluids and integrate various bioassay operations that allow the devices to rapidly sense pathogenic threat agents for environmental monitoring. LOC systems, such as microfluidic biochips, offer advantages compared to conventional identification procedures that are tedious, expensive and time consuming. This paper aims to provide a broad overview of the need for devices that are easy to operate, sensitive, fast, portable and sufficiently reliable to be used as complementary tools for the control of pathogenic agents that damage the environment.

96 citations


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]....

    [...]

Journal ArticleDOI
TL;DR: The droplet-based “digital” microfluidic technology platform and emerging applications are described, and computer-aided design tools for simulation, synthesis and chip optimization are presented.
Abstract: Microfluidics-based biochips enable the precise control of nanoliter volumes of biochemical samples and reagents. They combine electronics with biology, and they integrate various bioassay operations, such as sample preparation, analysis, separation, and detection. Compared to conventional laboratory procedures, which are cumbersome and expensive, miniaturized biochips offer the advantages of higher sensitivity, lower cost due to smaller sample and reagent volumes, system integration, and less likelihood of human error. This paper first describes the droplet-based “digital” microfluidic technology platform and emerging applications. The physical principles underlying droplet actuation are next described. Finally, the paper presents computer-aided design tools for simulation, synthesis and chip optimization. These tools target modeling and simulation, scheduling, module placement, droplet routing, pin-constrained chip design, and testing.

84 citations

Book ChapterDOI
31 Jan 1994

82 citations

Journal ArticleDOI
TL;DR: This paper proposes the first reagent-saving mixing algorithm for biochemical samples of multiple target concentrations, which not only minimizes the consumption of reagents, but it also reduces the number of waste droplets and the sample preparation time by preparing the target concentrations concurrently.
Abstract: Recent advances in digital microfluidics have led to the promise of miniaturized laboratories, with the associated advantages of high sensitivity and less human-induced errors. Front-end operations such as sample preparation play a pivotal role in biochemical laboratories, and in applications in biomedical engineering and life science. For fast and high-throughput biochemical applications, preparing samples of multiple target concentrations sequentially is inefficient and time-consuming. Therefore, it is critical to concurrently prepare samples of multiple target concentrations. In addition, since reagents used in biochemical reactions are expensive, reagent-saving has become an important consideration in sample preparation. Prior work in this area does not address the problem of reagent-saving and concurrent sample preparation for multiple target concentrations. In this paper, we propose the first reagent-saving mixing algorithm for biochemical samples of multiple target concentrations. The proposed algorithm not only minimizes the consumption of reagents, but it also reduces the number of waste droplets and the sample preparation time by preparing the target concentrations concurrently. The proposed algorithm is evaluated on both real biochemical experiments and synthetic test cases to demonstrate its effectiveness and efficiency. Compared to prior work, the proposed algorithm can achieve up to 41% reduction in the number of reagent droplets and waste droplets, and up to 50% reduction in sample preparation time.

76 citations

Proceedings ArticleDOI
09 Oct 2011
TL;DR: An overview of DMFBs is provided and emerging CAD tools for the automated synthesis and optimization ofDMFB designs are described, from fluidic-level synthesis and chip-level design to testing.
Abstract: Microfluidic biochips are replacing the conventional biochemical analyzers, and are able to integrate on-chip all the basic functions for biochemical analysis. The “digital” microfluidic biochips (DM-FBs) are manipulating liquids not as a continuous flow, but as discrete droplets on a two-dimensional array of electrodes. Basic mi-crofluidic operations, such as mixing and dilution, are performed on the array, by routing the corresponding droplets on a series of electrodes. The challenges facing biochips are similar to those faced by microelectronics some decades ago. To meet the challenges of increasing design complexity, computer-aided-design (CAD) tools are being developed for DMFBs. This paper provides an overview of DMFBs and describes emerging CAD tools for the automated synthesis and optimization of DMFB designs, from fluidic-level synthesis and chip-level design to testing. Design automations are expected to alleviate the burden of manual optimization of bioassays, time-consuming chip designs, and costly testing and maintenance procedures. With the assistance of CAD tools, users can concentrate on the development and abstraction of nanoscale bioassays while leaving chip optimization and implementation details to CAD tools.

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]....

    [...]

  • ...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
More filters
Book
01 May 1997
TL;DR: Gaph Teory Fourth Edition is standard textbook of modern graph theory which covers the core material of the subject with concise yet reliably complete proofs, while offering glimpses of more advanced methods in each chapter by one or two deeper results.
Abstract: Gaph Teory Fourth Edition Th is standard textbook of modern graph theory, now in its fourth edition, combines the authority of a classic with the engaging freshness of style that is the hallmark of active mathematics. It covers the core material of the subject with concise yet reliably complete proofs, while offering glimpses of more advanced methods in each fi eld by one or two deeper results, again with proofs given in full detail.

6,255 citations

Book
01 Jan 1994
TL;DR: This book covers techniques for synthesis and optimization of digital circuits at the architectural and logic levels, i.e., the generation of performance-and-or area-optimal circuits representations from models in hardware description languages.
Abstract: From the Publisher: Synthesis and Optimization of Digital Circuits offers a modern, up-to-date look at computer-aided design (CAD) of very large-scale integration (VLSI) circuits. In particular, this book covers techniques for synthesis and optimization of digital circuits at the architectural and logic levels, i.e., the generation of performance-and/or area-optimal circuits representations from models in hardware description languages. The book provides a thorough explanation of synthesis and optimization algorithms accompanied by a sound mathematical formulation and a unified notation. The text covers the following topics: modern hardware description languages (e.g., VHDL, Verilog); architectural-level synthesis of data flow and control units, including algorithms for scheduling and resource binding; combinational logic optimization algorithms for two-level and multiple-level circuits; sequential logic optimization methods; and library binding techniques, including those applicable to FPGAs.

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....

    [...]

Journal ArticleDOI
TL;DR: In this paper, the authors report the completion of four fundamental fluidic operations considered essential to build digital microfluidic circuits, which can be used for lab-on-a-chip or micro total analysis system (/spl mu/TAS): 1) creating, 2) transporting, 3) cutting, and 4) merging liquid droplets, all by electrowetting.
Abstract: Reports the completion of four fundamental fluidic operations considered essential to build digital microfluidic circuits, which can be used for lab-on-a-chip or micro total analysis system (/spl mu/TAS): 1) creating, 2) transporting, 3) cutting, and 4) merging liquid droplets, all by electrowetting, i.e., controlling the wetting property of the surface through electric potential. The surface used in this report is, more specifically, an electrode covered with dielectrics, hence, called electrowetting-on-dielectric (EWOD). All the fluidic movement is confined between two plates, which we call parallel-plate channel, rather than through closed channels or on open surfaces. While transporting and merging droplets are easily verified, we discover that there exists a design criterion for a given set of materials beyond which the droplet simply cannot be cut by EWOD mechanism. The condition for successful cutting is theoretically analyzed by examining the channel gap, the droplet size and the degree of contact angle change by electrowetting on dielectric (EWOD). A series of experiments is run and verifies the criterion.

1,522 citations

Journal ArticleDOI
TL;DR: In this article, a microactuator for rapid manipulation of discrete microdroplets is presented, which is accomplished by direct electrical control of the surface tension through two sets of opposing planar electrodes fabricated on glass.
Abstract: A microactuator for rapid manipulation of discrete microdroplets is presented. Microactuation is accomplished by direct electrical control of the surface tension through two sets of opposing planar electrodes fabricated on glass. A prototype device consisting of a linear array of seven electrodes at 1.5 mm pitch was fabricated and tested. Droplets (0.7–1.0 μl) of 100 mM KCl solution were successfully transferred between adjacent electrodes at voltages of 40–80 V. Repeatable transport of droplets at electrode switching rates of up to 20 Hz and average velocities of 30 mm/s have been demonstrated. This speed represents a nearly 100-fold increase over previously demonstrated electrical methods for the transport of droplets on solid surfaces.

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]....

    [...]

Journal ArticleDOI
TL;DR: This work presents an alternative paradigm--a fully integrated and reconfigurable droplet-based "digital" microfluidic lab-on-a-chip for clinical diagnostics on human physiological fluids, and demonstrates reliable and repeatable high-speed transport of microdroplets.
Abstract: Clinical diagnostics is one of the most promising applications for microfluidic lab-on-a-chip systems, especially in a point-of-care setting. Conventional microfluidic devices are usually based on continuous-flow in microchannels, and offer little flexibility in terms of reconfigurability and scalability. Handling of real physiological samples has also been a major challenge in these devices. We present an alternative paradigm—a fully integrated and reconfigurable droplet-based “digital” microfluidic lab-on-a-chip for clinical diagnostics on human physiological fluids. The microdroplets, which act as solution-phase reaction chambers, are manipulated using the electrowetting effect. Reliable and repeatable high-speed transport of microdroplets of human whole blood, serum, plasma, urine, saliva, sweat and tear, is demonstrated to establish the basic compatibility of these physiological fluids with the electrowetting platform. We further performed a colorimetric enzymatic glucose assay on serum, plasma, urine, and saliva, to show the feasibility of performing bioassays on real samples in our system. The concentrations obtained compare well with those obtained using a reference method, except for urine, where there is a significant difference due to interference by uric acid. A lab-on-a-chip architecture, integrating previously developed digital microfluidic components, is proposed for integrated and automated analysis of multiple analytes on a monolithic device. The lab-on-a-chip integrates sample injection, on-chip reservoirs, droplet formation structures, fluidic pathways, mixing areas and optical detection sites, on the same substrate. The pipelined operation of two glucose assays is shown on a prototype digital microfluidic lab-on-chip, as a proof-of-concept.

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]....

    [...]

Frequently Asked Questions (1)
Q1. What are the contributions in "Design automation and test solutions for digital microfluidic biochips" ?

This tutorial paper provides an overview of droplet-based “ digital ” microfluidic biochips.