Architectural-Level Synthesis of

Digital Microfluidics-Based
Biochips

Fei Su & Krishnendu Chakrabarty

Electrical and Computer Engineering

Duke University
Motivation
„ Application to clinical diagnostics, e.g., healthcare
for premature infant
„ “Bio-smoke alarm” to counter bioterrorism
„ Massive parallel DNA analysis; automated drug
discovery
Shrink
Microfluidics-Based
Biochip

Microfluidic
Lab-on-Chip

Conventional Biochemical
Analyzer

2
Microfluidics
„ Continuous-flow biochips: Permanently etched
microchannels, micropumps and microvalves
„ Digital microfluidic biochips: Manipulation of
liquids as discrete droplets (digital microfluidics)

(University of Michigan) (Duke University)

1998 2002

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Integration of microfluidics: one of the system-
level design challenges (≤ 50nm/beyond 2009)
2003 International Technology Roadmap for
Semiconductors (ITRS)
Heterogeneous SOCs
-Mixed-signal
-Mixed-technology

Digital Analog & RF MEMS

blocks blocks components

CAD support needed for Fluidic

biochip design components

4
Outline
„ Motivation
„ Background
„ Related prior work
„ Architectural-level synthesis for digital
microfluidic biochips
„ Sequencing graph model
„ Mathematical programming model
„ Heuristics for scheduling problem
„ Simulation experiments
„ Conclusions

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Background
„ Novel microfluidic platform invented at Duke University
„ Droplet actuation is achieved through an effect called
electrowetting
 Electrical modulation of the solid-liquid interfacial tension

No Potential Applied Potential

A droplet on a hydrophobic The droplet’s surface energy
surface originally has a increases, which results in a
large contact angle. reduced contact angle. The
droplet now wets the surface.

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Background (Cont.)
„ Actuation principle of digital microfluidics
Droplet Transport
A droplet can be transported by
removing a potential on the
current electrode, and applying a
potential to an adjacent electrode.

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Background (Cont.)
„ Digital microfluidics-based biochips

TRANSPORT
TRANSPORT DISPENSING
DISPENSING MIXERS
MIXERS REACTORS
REACTORS DETECTION
DETECTION

„ Basic microfluidic functions

INTEGRATE
(transport, splitting, merging,
and mixing) have already been
demonstrated on a 2-D array
Digital Microfluidic „ Digital microfluidics-based
Biochip biochip is a high reconfigurable
system

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Background (Cont.)
„ The in-vitro measurement of glucose in human
physiological fluids
Glucose + H 2 O + O 2 Glucose
 Oxidase
→ Gluconic Acid + H 2 O 2
2H 2 O 2 + 4 - AAP + TOPS Peroxidase
 → Quinoneimi ne + 4H 2 O

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Background (Cont.)
„ Digital microfluidics-based biochip used in glucose
measurement
Length of the control electrode
L = 1.5mm
Height between two plates
H = 475nm
Thickness of insulator layer
(parylene C) = 800nm
Thickness of hydrophobic film
(Teflon AF) = 60nm
Dispensing/Transportation:
Sample droplet (glucose) and reagent
droplet (glucose oxidase, peroxidase,
4-AAP and TOPS), are dispensed into
the microfluidic system from reservoirs.
Mixing:
Sample droplet and reagent droplet are
mixed in a mixer (i.e. 2x2 array mixer).
Optical Detection:
Assay result (quinoneimine) is detected
by a green LED and a photodiode.
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Background (Cont.)
„ Detection of lactate, glutamate and pyruvate has also been
demonstrated.
„ Biochip used for multiplexed in-vitro diagnostics on human
physiological fluids

Fabricated microfluidic array used

in multiplexed biomedical assays.
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Synthesis Methodology
„ Full-custom design Æ Top-down system-level design

ƒ Scheduling of operations
ƒ Binding to functional
resources
ƒ Physical design

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Related Prior Work
„ Synthesis of integrated circuits: well-studied
problem
„ MEMS simulation & synthesis tools
„ CAD tools for microfluidic biochips
„ Physical-level simulation: CFD-ACE+, FlumeCAD
„ System-level design: CoventorWare (targeted at
continuous flow system)

„ DNA array (ICCAD’03)

„ Special session on BioMEMS CAD at DAC’04

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Architectural-Level Synthesis
„ Sequencing graph model
„ Multiplexed in-vitro diagnostics

Sample Reagent Enzymatic Assay

Plasma: S1 R1 Glucose Measurement

Serum: S2 R2 Lactate Measurement

Urine : S3 R3 Pyruvate Measurement

Saliva: S4 R4 Glutamate Measurement

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Sequencing Graph Model (Cont.)
„ Node representing the input operation
Sj Rj
Ij Ij+m

(Dispensing sample Sj, j=1,…, m) (Dispensing reagent Rj, j=1,…, n)

Assumption 1: The time

required to generate
and dispense droplets
from the reservoir is
determined mainly by
the system hardware
parameters

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Sequencing Graph Model (Cont.)
„ Node representing different types of mixing operations

S1 Ri S2 Ri Sm Ri
…...
M1 M2 Mm

(Mixing of sample S1 and (Mixing of sample S2 and (Mixing of sample Sm and

reagent Ri, i=1, …, n) reagent Ri, i=1, …, n) reagent Ri, i=1, …, n)

Assumption 2: The time required for

complete mixing mainly depends
on the viscosity of the sample

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Sequencing Graph Model (Cont.)
„ Node representing the detection operations
S i+R1 Si +R2 Si+Rn

D1 D2 …... Dn

Optical detection of Optical detection of Optical detection of

Assay 1, e.g., Assay 2, e.g., Assay n, e.g.,
glucose assay lactate assay glutamate assay

Assumption 3: The type

of enzymatic assay
determines the
optical detection time.

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Sequencing Graph Model (Cont.)
Assumption 4: In contrast to the above operations,
droplet movement on a digital microfluidic array is
very fast. We can ignore the droplet movement
time for scheduling assay operations.

Size view Top view

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Sequencing Graph Model (Cont.)
NOP Input
operations:
2mn Nodes
… …… …… …… …… …… …
S1 S1 Sm Sm R1 Rn R1 Rn

I1 …… I1 …… Im …… Im Im+1 ……… Im+n …… Im+1 …… Im+n

2mn
1
……… ……… ………
……… ………

Mixing
M1 M1 Mm Mm operations:
………… ………… …………
2mn+1 3mn mn Nodes
……… ……… ………
Detection
D1 ………… Dn ………… D1 ………… Dn operations:
3mn+1 4mn
… … …
mn Nodes

NOP Time Step

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M1
Sequencing graph model of a 25
Storage unit is
required during

multiplexed bioassays 30
this time period

D1

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Mathematical Programming Model
Objective Constraints
„ First define a binary variable „ Dependency constraints
Stj ≥ Sti + d(vi) if there is a dependency
 1 if operation vi starts at
X ij =  time slot j. between vi and vj
 0 otherwise
„ Resource constraints
„ Starting time of operation vi : „ Reservoirs/dispensing ports
T
St i = ∑ j × X ij Nr reservoirs/dispensing ports assigned to
j =1 each type of fluid (Nr = 1)

„ Completion time of operation: ∑ X ij ≤ 1, … ∑ X ij ≤ 1 : 1≤ j≤ T

i:vi ∈I1 i:vi ∈I m + n
C = max {Sti + d(vi) : vi ∈D1, …, Dn}
„ Reconfigurable mixers and
„ Objective function: storage units
minimize C Nmixer(j) + 0.25 Nmemory(j) ≤ Na 1≤ j≤T
„ Optical detectors
Nd detectors are assigned to each
bioassay (Nd = 1)
j j
∑ ∑ X ij ≤ 1, …i:v∑
∈D
∑ X ij
l = j − d ( vi )
≤ 1 1≤ j≤ T
i:vi ∈D1 l = j − d ( vi ) i n1

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Mathematical Programming Model (Cont.)
„ Evaluated for a problem of the modest size:
„ Plasma and serum are sampled and assayed for glucose,
lactate and pyruvate measurements; i.e., m = 2, n = 3
„ Assume Nr = Nd = 1, and Na = 4
Time Reservoirs Reconfigurable Optical Detectors
step for S1 for S2 for R1 for R2 for R3 Mixers for D1 for D2 for D3
1
S1 S1 S1 S2 S2 S2 R1 R2 R3 R1 R2 R3 1 6 7 12
2
3
I1 I1 I1 I2 I2 I2 I3 I4 I5 I3 I4 I5 2 8 18
4
3 9 13
1 2 3 4 5 6 7 8 9 10 11 12 5

6
4 10 14
d(Ii)=1 7
5 11 15
8 24
M1 M1 M1 M2 M2 M2 d(M1)=5 16
9
13 14 15 16 17 18 d(M2)=3 17 19
10

d(D1)=5 11 20
D1 D2 D3 D1 D2 D3 d(D2)=4 12
19 20 21 22 23 24 d(D3)=6 13

14 21
22
15 23
NOP 16
17

Optimal schedule obtained by using integer linear programming

Completion time is 17 time-slots; i.e., 34 seconds.
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Heuristics for the Scheduling Problem
„ Heuristic algorithms
„ Modified List Scheduling algorithm (M-LS)
„ Extend well-known List Scheduling algorithm
„ Modified to handle the reconfigurable resources
(i.e., mixer and storage units)

„ Heuristic based on a Genetic algorithm (GA)

„ Representation of chromosome (random keys)
„ Ad-hoc schedule construction procedure
„ Evolution strategy

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Simulation Experiments
„ Lower bound (LB)
LB = m×max{d(D1),… d(Dn)}+min{d(M1),… d(Mm)}+d(Ii)+1
„ Upper bound (UB)
UB = m× max{d(D1),…d(Dn)}+k×max{d(M1),…d(Mm)}+max(m, n)×d(Ii)+ 1
Reservoirs
Mixer with Detector with
Reservoirs smallest d largest d Phase I
1
Input operations:
Max duration =
Min{d(M 1), Worst case: 2mn storage units needed
…, d(Mm)} max(m, n)

Step 1: NMix1 mixing operations scheduled

Phase II NMix1 +0.25(2mn-2NMix1 )≤Na
Æ NMix1≤2Na-mn

Mixing operations: Step 2: NMix2 mixing operations scheduled

m×Max{d(D1), Max duration
…, d(Dn)} = k×max{d(M1), NMix2 +0.25NMix1+0.25(2mn-
…, d(Mm )} 2 NMix1-2NMix2)≤Na
Æ NMix2≤2Na-mn+0.5NMix1

Step k: NMix k mixing operations scheduled

Phase III

Detection operations:
Max duration
= m×max{d(D1),
…, d(Dn)}

(a) (b) 23
Simulation Experiments (Cont.)
„ Five examples (four samples) S1: Plasma, S2: Serum, S3:
Urine, S4: Saliva, Assay1: Glucose assay, Assay2: Lactate assay,
Assay3: Pyruvate assay, Assay4: Glutamate assay

Example Description
Example 1 S1 and S2 are assayed for
(Nr=Nd=1,Na=3) m=2, n=2 Assay1 and Assay2.

Example 2 S1, and S2 are assayed for

(Nr=Nd=1,Na=4) m=2, n=3 Assay1, Assay2, and Assay3.

Example 3 S1, S2, and S3 are assayed for

(Nr=Nd=1,Na=5) m=3, n=3 Assay1, Assay2, and Assay3.

Example 4 S1, S2, and S3 are assayed for

(Nr=Nd=1,Na=7) m=3, n=4
Example 5
(Nr=Nd=1,Na=9) m=4, n=4
Assay1, Assay2, Assay3 and
Assay4.
S1, S2, S3 and S4 are assayed for
Assay1, Assay2, Assay3 and
Assay4.
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Simulation Experiments (Cont.)
„ Simulation results

Example Opt LB UB M-LS GA

Example 1 15 15 23 17 15
Example 2 17 17 25 19 17
Example 3 N/A 23 47 26 25
Example 4 N/A 23 43 27 26
Example 5 N/A 29 59 35 34
1.4

1.2
Ratio of Heuristic/Lower Boun

0.8
GA/LB
M-LS/LB
0.6

0.4

0.2

0
1 2 3 4 5
Example
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Conclusions
„ A system design methodology to apply classical
architectural-level synthesis techniques to digital
microfluidics-based biochips
„ An optimal strategy based on integer linear
programming for scheduling assay operations
under resource constraints
„ Two heuristic techniques that scale well for large
problem instances
„ M-LS: computationally more efficient
„ GA: yields lower completion times for bioassays
„ A clinical diagnostic procedure used to evaluate
the proposed methodology
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