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Microfluidic Biochips: Design,
Programming, and Optimization
Bill Thies
Joint work with Vaishnavi Ananthanarayanan, J.P. Urbanski,
Nada Amin, David Craig, Jeremy Gunawardena,
Todd Thorsen, and Saman Amarasinghe
Indian Statistical Institute
March 2, 2011
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Microfluidic Chips
• Idea: a whole biology lab on a single chip
– Input/output
– Sensors: pH, glucose, temperature, etc.
– Actuators: mixing, PCR, electrophoresis, cell lysis, etc.
• Benefits:
– Small sample volumes
– High throughput
– Geometrical manipulation
– Portability
• Applications:
– Biochemistry - Cell biology
– Biological computing
1 mm 10x real-time
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Application to Rural Diagnostics
Disposable
Enteric Card
PATH,
Washington U.
Micronics, Inc.,
U. Washington
Targets:
- E. coli, Shigella,
Salmonella,
C. jejuni
DxBox
U. Washington,
Micronics, Inc.,
Nanogen, Inc.
Targets:
- malaria (done)
- dengue, influenza,
Rickettsial diseases,
typhoid, measles
(under development)
CARD
Rheonix, Inc.
Targets:
- HPV diagnosis
- Detection of
specific gene
sequences
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Moore’s Law of Microfluidics:
Valve Density Doubles Every 4 Months
Source: Fluidigm Corporation (http://www.fluidigm.com/images/mlaw_lg.jpg)
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Moore’s Law of Microfluidics:
Valve Density Doubles Every 4 Months
Source: Fluidigm Corporation (http://www.fluidigm.com/didIFC.htm)
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Current Practice: Manage Gate-Level
Details from Design to Operation
• For every change in the experiment or the chip design:
1. Manually draw in AutoCAD 2. Operate each gate from LabView
fabricate
chip
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Abstraction Layers for Microfluidics
C
x86
Pentium III,
Pentium IV
Silicon Analog
transistors,
registers, …
Fluidic Instruction Set Architecture (ISA)- primitives for I/O, storage, transport, mixing
Protocol Description Language - architecture-independent protocol description
Fluidic Hardware Primitives- valves, multiplexers, mixers, latches
chip 1 chip 2 chip 3
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Abstraction Layers for Microfluidics
Fluidic Instruction Set Architecture (ISA)- primitives for I/O, storage, transport, mixing
Protocol Description Language - architecture-independent protocol description
Fluidic Hardware Primitives- valves, multiplexers, mixers, latches
chip 1 chip 2 chip 3
BioCoder Language[J.Bio.Eng. 2010]
Contributions
Optimized Compilation[Natural Computing 2007]
Demonstrate Portability[DNA 2006]
Micado AutoCAD Plugin[MIT 2008, ICCD 2009]
Digital Sample Control
Using Soft Lithography[Lab on a Chip ‗06]
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• Continuous flow of fluids (or
droplets) through fixed channels [Whitesides, Quake, Thorsen, …]
• Pro:– Smaller, more precise sample sizes
– Made-to-order availability [Stanford]
– More traction in biology community
Droplets vs. Continuous Flow
• Digital manipulation of droplets
on an electrode array [Chakrabarty, Fair, Gascoyne, Kim, …]
• Pro:– Reconfigurable routing
– Electrical control
– More traction in CAD communitySource: Chakrabarty et al, Duke University
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Primitive 1: A Valve (Quake et al.)
Control
Layer
Flow
Layer
0. Start with mask of channels
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Primitive 1: A Valve (Quake et al.)
Control
Layer
Flow
Layer
1. Deposit pattern on silicon wafer
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Primitive 1: A Valve (Quake et al.)
Control
Layer
Flow
Layer
2. Pour PDMS over mold- polydimexylsiloxane: “soft lithography”
Thick layer (poured)
Thin layer (spin-coated)
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Primitive 1: A Valve (Quake et al.)
Control
Layer
Flow
Layer
3. Bake at 80° C (primary cure),
then release PDMS from mold
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Primitive 1: A Valve (Quake et al.)
Control
Layer
Flow
Layer
4a. Punch hole in control channel
4b. Attach flow layer to glass slide
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Primitive 1: A Valve (Quake et al.)
Control
Layer
Flow
Layer
5. Align flow layer over control layer
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Primitive 1: A Valve (Quake et al.)
Control
Layer
Flow
Layer
6. Bake at 80° C (secondary cure)
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Primitive 1: A Valve (Quake et al.)
Control
Layer
Flow
Layer
pressure
actuator
7. When pressure is high, control
channel pinches flow channel to
form a valve
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Primitive 2: A Multiplexer (Thorsen et al.)
flow layer
control layerBit 2 Bit 1 Bit 0
0 1 0 1 0 1
Input
Output 0
Output 7
Output 6
Output 5
Output 4
Output 3
Output 2
Output 1
• Control lines can cross
flow lines- Only thick parts make valves
• Logic is not
complimentary
• To control n flow lines,
need 2 log2 n control lines
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Primitive 2: A Multiplexer (Thorsen et al.)
Bit 2 Bit 1 Bit 0
0 1 0 1 0 1
Input
Output 0
Output 7
Output 6
Output 5
Output 4
Output 3
Output 2
Output 1
Example: select 3 = 011
flow layer
control layer
• Control lines can cross
flow lines- Only thick parts make valves
• Logic is not
complimentary
• To control n flow lines,
need 2 log2 n control lines
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Primitive 2: A Multiplexer (Thorsen et al.)
Bit 2 Bit 1 Bit 0
0 1 0 1 0 1
Input
Output 0
Output 7
Output 6
Output 5
Output 4
Output 3
Output 2
Output 1
Example: select 3 = 011
flow layer
control layer
• Control lines can cross
flow lines- Only thick parts make valves
• Logic is not
complimentary
• To control n flow lines,
need 2 log2 n control lines
![Page 21: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/21.jpg)
Primitive 2: A Multiplexer (Thorsen et al.)
Bit 2 Bit 1 Bit 0
0 1 0 1 0 1
Input
Output 0
Output 7
Output 6
Output 5
Output 4
Output 3
Output 2
Output 1
Example: select 3 = 011
flow layer
control layer
• Control lines can cross
flow lines- Only thick parts make valves
• Logic is not
complimentary
• To control n flow lines,
need 2 log2 n control lines
![Page 22: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/22.jpg)
Primitive 3: A Mixer (Quake et al.)
1. Load sample on bottom
2. Load sample on top
3. Peristaltic pumping
Rotary Mixing
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Primitive 4: A Latch (Our contribution)
• Purpose: align sample with specific location on device
– Examples: end of storage cell, end of mixer, middle of sensor
• Latches are implemented as a partially closed valve
– Background flow passes freely
– Aqueous samples are caught
Sample Latch
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Primitive 4: A Latch (Our contribution)
• Purpose: align sample with specific location on device
– Examples: end of storage cell, end of mixer, middle of sensor
• Latches are implemented as a partially closed valve
– Background flow passes freely
– Aqueous samples are caught
Sample Latch
![Page 25: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/25.jpg)
Primitive 5: Cell Trap
• Several methods for confining cells in microfluidic chips
– U-shaped weirs - C-shaped rings / microseives
– Holographic optical traps - Dialectrophoresis
• In our chips: U-Shaped Microseives in PDMS Chambers
Source: Wang, Kim, Marquez, and Thorsen, Lab on a Chip 2007
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Primitive 6: Imaging and Detection
• As PDMS chips are translucent,
contents can be imaged directly
– Fluorescence, color, opacity, etc.
• Feedback can be used to
drive the experiment
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Abstraction Layers for Microfluidics
Fluidic Instruction Set Architecture (ISA)- primitives for I/O, storage, transport, mixing
Protocol Description Language - architecture-independent protocol description
Fluidic Hardware Primitives- valves, multiplexers, mixers, latches
chip 1 chip 2 chip 3
![Page 28: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/28.jpg)
Driving Applications
1. What are the best indicators for oocyte viability?
- With Mark Johnson‘s and
Todd Thorsen‘s groups
- During in-vitro fertilization,
monitor cell metabolites and
select healthiest embryo for implantation
2. How do mammalian signal transduction pathways
respond to complex inputs?
- With Jeremy Gunawardena‘s
and Todd Thorsen‘s groups
- Isolate cells and stimulate with
square wave, sine wave, etc.
![Page 29: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/29.jpg)
Driving Applications
1. What are the best indicators for oocyte viability?
- With Mark Johnson‘s and
Todd Thorsen‘s groups
- During in-vitro fertilization,
monitor cell metabolites and
select healthiest embryo for implantation
2. How do mammalian signal transduction pathways
respond to complex inputs?
- With Jeremy Gunawardena‘s
and Todd Thorsen‘s groups
- Isolate cells and stimulate with
square wave, sine wave, etc.
Video courtesy David Craig
![Page 30: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/30.jpg)
CAD Tools for Microfluidic Chips
• Goal: automate placement, routing, control of
microfluidic features
• Why is this different than electronic CAD?
![Page 31: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/31.jpg)
CAD Tools for Microfluidic Chips
• Goal: automate placement, routing, control of
microfluidic features
• Why is this different than electronic CAD?
1. Control ports (I/O pins) are bottleneck to scalability
– Pressurized control signals cannot yet be generated on-chip
– Thus, each logical set of valves requires its own I/O port
2. Control signals correlated due to continuous flows
Demand & opportunity for minimizing control logic
pipelined flow continuous flow
![Page 32: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/32.jpg)
Our Technique:
Automatic Generation of Control Layer
![Page 33: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/33.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
![Page 34: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/34.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
![Page 35: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/35.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
![Page 36: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/36.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
2. Infer control valves
![Page 37: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/37.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
2. Infer control valves
![Page 38: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/38.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
2. Infer control valves
3. Infer control sharing
![Page 39: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/39.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
2. Infer control valves
3. Infer control sharing
![Page 40: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/40.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
2. Infer control valves
3. Infer control sharing
4. Route valves to control ports
![Page 41: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/41.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
2. Infer control valves
3. Infer control sharing
4. Route valves to control ports
![Page 42: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/42.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
2. Infer control valves
3. Infer control sharing
4. Route valves to control ports
![Page 43: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/43.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
2. Infer control valves
3. Infer control sharing
4. Route valves to control ports
5. Generate an interactive GUI
![Page 44: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/44.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
2. Infer control valves
3. Infer control sharing
4. Route valves to control ports
5. Generate an interactive GUI
![Page 45: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/45.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
2. Infer control valves
3. Infer control sharing
4. Route valves to control ports
5. Generate an interactive GUI
![Page 46: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/46.jpg)
Our Technique:
Automatic Generation of Control Layer
1. Describe Fluidic ISA
2. Infer control valves
3. Infer control sharing
4. Route valves to control ports
5. Generate an interactive GUI
![Page 47: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/47.jpg)
1. Describe a Fluidic ISA
• Hierarchical and composable flow declarations
Sequential flow P1 P2
AND-flow F1 Λ F2
OR-flow F1 \/ F2
Mixing mix(F)
Pumped flow pump(F)
P1 P2
F1
F2
F1
F2or
F
F
F1
F2
![Page 48: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/48.jpg)
1. Describe a Fluidic ISA
![Page 49: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/49.jpg)
1. Describe a Fluidic ISA
mix-and-store (S1, S2, D) {
1. in1 top out
2. in2 bot out
3. mix(top bot-left
bot-right top)
4. wash bot-right
top bot-left store
}
50x real-time
![Page 50: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/50.jpg)
2. Infer Control Valves
![Page 51: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/51.jpg)
2. Infer Control Valves
![Page 52: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/52.jpg)
2. Infer Control Valves
![Page 53: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/53.jpg)
3. Infer Control Sharing
![Page 54: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/54.jpg)
3. Infer Control Sharing
![Page 55: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/55.jpg)
3. Infer Control Sharing
![Page 56: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/56.jpg)
3. Infer Control Sharing
![Page 57: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/57.jpg)
3. Infer Control Sharing
![Page 58: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/58.jpg)
3. Infer Control Sharing
![Page 59: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/59.jpg)
3. Infer Control Sharing
![Page 60: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/60.jpg)
3. Infer Control Sharing
![Page 61: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/61.jpg)
3. Infer Control Sharing
Column Compatibility Problem
- NP-hard
- Reducible to graph coloring
![Page 62: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/62.jpg)
3. Infer Control Sharing
Column Compatibility Problem
- NP-hard
- Reducible to graph coloring
![Page 63: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/63.jpg)
3. Infer Control Sharing
Column Compatibility Problem
- NP-hard
- Reducible to graph coloring
![Page 64: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/64.jpg)
3. Infer Control Sharing
Column Compatibility Problem
- NP-hard
- Reducible to graph coloring
![Page 65: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/65.jpg)
4. Route Valves to Control Ports
• Build on recent algorithm
for simultaneous pin
assignment & routing [Xiang et al., 2001]
• Idea: min cost - max flow
from valves to ports
• Our contribution: extend algorithm to allow sharing
– Previous capacity constraint on each edge:
– Modified capacity constraint on each edge:
Solve with linear programming, allowing sharing where beneficial
f1 + f2 + f3 + f4 + f5 + f6 ≤ 1
max(f1, f4) + max(f2 , f3) + f5 + f6 ≤ 1
![Page 66: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/66.jpg)
4. Route Valves to Control Ports
• Build on recent algorithm
for simultaneous pin
assignment & routing [Xiang et al., 2001]
• Idea: min cost - max flow
from valves to ports
• Our contribution: extend algorithm to allow sharing
– Previous capacity constraint on each edge:
– Modified capacity constraint on each edge:
Solve with linear programming, allowing sharing where beneficial
f1 + f2 + f3 + f4 + f5 + f6 ≤ 1
max(f1, f4) + max(f2 , f3) + f5 + f6 ≤ 1
![Page 67: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/67.jpg)
Micado: An AutoCAD Plugin
• Implements ISA, control inference, routing, GUI export
– Using slightly older algorithms
than presented here [Amin ‗08]
– Parameterized design rules
– Incremental construction of chips
• Realistic use by at least 3
microfluidic researchers
• Freely available at:
http://groups.csail.mit.edu/cag/micado/
![Page 68: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/68.jpg)
Cell Culture with Waveform Generator
Courtesy David Craig
![Page 69: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/69.jpg)
Cell Culture with Waveform Generator
Courtesy David Craig
![Page 70: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/70.jpg)
Embryonic Cell Culture
Courtesy J.P. Urbanski
![Page 71: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/71.jpg)
Embryonic Cell Culture
Courtesy J.P. Urbanski
![Page 72: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/72.jpg)
Metabolite Detector
Courtesy J.P. Urbanski
![Page 73: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/73.jpg)
Metabolite Detector
Courtesy J.P. Urbanski
![Page 74: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/74.jpg)
Open Problems
• Automate the design of the flow layer
– Hardware description language for microfluidics
– Define parameterized and reusable modules
• Replicate and pack a primitive as densely as possible
– How many cell cultures can you fit on a chip?
• Support additional primitives and functionality
– Metering volumes
– Sieve valves
– Alternate mixers
– Separation primitives
– …
![Page 75: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/75.jpg)
Conclusions: Microfludics CAD
• Microfluidics represents a rich newplayground for CAD researchers
• Two immediate goals:
– Enable designs to scale
– Enable non-experts to design own chips
• Micado is a first step towards these goals
– Hierarchical ISA for microfluidics
– Inference and minimization of control logic
– Routing shared channels to control ports
– Generation of an interactive GUI
http://groups.csail.mit.edu/cag/micado/
Courtesy J.P. Urbanski
![Page 76: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/76.jpg)
Abstraction Layers for Microfluidics
Fluidic Instruction Set Architecture (ISA)- primitives for I/O, storage, transport, mixing
Protocol Description Language - architecture-independent protocol description
Fluidic Hardware Primitives- valves, multiplexers, mixers, latches
chip 1 chip 2 chip 3
![Page 77: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/77.jpg)
Toward “General Purpose”
Microfluidic Chips
Inputs
Outp
uts
Fluidic
Storage
(RAM)
In
Out
Mixing
Chambers
Inputs
Outp
uts
Fluidic
Storage
(RAM)
In
Out
Mixing
Chambers
Sensors
and
Actuators
Inputs
Outp
uts
Fluidic
Storage
(RAM)
In
Out
Mixing
Chambers
Inputs
Outp
uts
Fluidic
Storage
(RAM)
In
Out
Mixing
Chambers
Sensors
and
Actuators
![Page 78: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/78.jpg)
A Digital Architecture
• Recent techniques can control independent samples
– Droplet-based samples
– Continuous-flow samples
– Microfluidic latches
• In abstract machine, all
samples have unit volume
– Input/output a sample
– Store a sample
– Operate on a sample
• Challenge for a digital architecture: fluid loss
– No chip is perfect – will lose some volume over time
– Causes: imprecise valves, adhesion to channels, evaporation, ...
– How to maintain digital abstraction?
[Fair et al.]
[Our contribution]
[Our contribution]
Inputs
Outp
uts
Fluidic
Storage
(RAM)
In
Out
Mixing
Chambers
Inputs
Outp
uts
Fluidic
Storage
(RAM)
In
Out
Mixing
Chambers
Sensors
and
Actuators
Inputs
Outp
uts
Fluidic
Storage
(RAM)
In
Out
Mixing
Chambers
Inputs
Outp
uts
Fluidic
Storage
(RAM)
In
Out
Mixing
Chambers
Sensors
and
Actuators
![Page 79: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/79.jpg)
Maintaining a Digital Abstraction
![Page 80: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/80.jpg)
Maintaining a Digital Abstraction
Instruction Set
Architecture (ISA)
High-Level
Language
Hardware
Electronics Microfluidics
Replenish charge
(GAIN)
Loss of charge
Randomized
Gates [Palem]
Soft error
Handling?
Replenish fluids?- Maybe (e.g., with water)
- But may affect chemistry
Loss of fluids
? ? ?
? ? ?
Expose loss in ISA- Compiler deals with it
Expose loss in language- User deals with it
![Page 81: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/81.jpg)
Towards a Fluidic ISA
• Microfluidic chips have various mixing technologies
– Electrokinetic mixing
– Droplet mixing
– Rotary mixing
• Common attributes:
– Ability to mix two samples in equal proportions, store result
• Fluidic ISA: mix (int src1, int src2, int dst)
– Ex: mix(1, 2, 3)
– To allow for lossy transport, only 1 unit of mixture retained
[Quake et al.]
[Fair et al.]
[Levitan et al.]
Storage Cells
1
2
3
4
Mixer
![Page 82: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/82.jpg)
Implementation: Oil-Driven Chip
Inputs Storage Cells Background Phase Wash Phase Mixing
Chip 1 2 8 Oil — Rotary
![Page 83: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/83.jpg)
Implementation: Oil-Driven Chip
Inputs Storage Cells Background Phase Wash Phase Mixing
Chip 1 2 8 Oil — Rotary
mix (S1, S2, D) {
1. Load S1
2. Load S2
3. Rotary mixing
4. Store into D
}
50x real-time
![Page 84: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/84.jpg)
Implementation 2: Air-Driven Chip
Inputs Storage Cells Background Phase Wash Phase Mixing
Chip 1 2 8 Oil — Rotary
Chip 2 4 32 Air Water In channels
![Page 85: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/85.jpg)
Implementation 2: Air-Driven Chip
mix (S1, S2, D) {
1. Load S1
2. Load S2
3. Mix / Store into D
4. Wash S1
5. Wash S2
}
Inputs Storage Cells Background Phase Wash Phase Mixing
Chip 1 2 8 Oil — Rotary
Chip 2 4 32 Air Water In channels
50x real-time
![Page 86: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/86.jpg)
“Write Once, Run Anywhere”
• Example: Gradient generation
• Hidden from programmer:
– Location of fluids
– Details of mixing, I/O
– Logic of valve control
– Timing of chip operations450 Valve Operations
Fluid yellow = input (0);
Fluid blue = input(1);
for (int i=0; i<=4; i++) {
mix(yellow, 1-i/4, blue, i/4);
}
![Page 87: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/87.jpg)
450 Valve Operations
• Example: Gradient generation
• Hidden from programmer:
– Location of fluids
– Details of mixing, I/O
– Logic of valve control
– Timing of chip operations
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
Fluid yellow = input (0);
Fluid blue = input(1);
for (int i=0; i<=4; i++) {
mix(yellow, 1-i/4, blue, i/4);
}
“Write Once, Run Anywhere”
![Page 88: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/88.jpg)
• Example: Gradient generation
• Hidden from programmer:
– Location of fluids
– Details of mixing, I/O
– Logic of valve control
– Timing of chip operations
Fluid yellow = input (0);
Fluid blue = input(1);
for (int i=0; i<=4; i++) {
mix(yellow, 1-i/4, blue, i/4);
}
“Write Once, Run Anywhere”
450 Valve Operations
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
![Page 89: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/89.jpg)
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
“Write Once, Run Anywhere”
Direct Control- 450 valve actuations
- only works on 1 chip
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
![Page 90: Microfluidic Biochips: Design, Programming, and Optimizationbillthies.net/microfluidics-kolkata-web.pdf · 2011-03-14 · Microfluidic Biochips: Design, Programming, and Optimization](https://reader030.vdocuments.us/reader030/viewer/2022040819/5e66b885ddaa0040f06853d9/html5/thumbnails/90.jpg)
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
Gradient Generation in Fluidic ISA
input(0, 0);
input(1, 1);
input(0, 2);
mix(1, 2, 3);
input(0, 2);
mix(2, 3, 1);
input(1, 3);
input(0, 4);
mix(3, 4, 2);
input(1, 3);
input(0, 4);
mix(3, 4, 5);
input(1, 4);
mix(4, 5, 3);
mix(0, 4);
Direct Control- 450 valve actuations
- only works on 1 chip
Fluidic ISA- 15 instructions
- portable across chips
abstraction
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
setValve(0, HIGH); setValve(1, HIGH);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, LOW);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, LOW); setValve(11, HIGH);
setValve(12, LOW); setValve(13, HIGH);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, LOW); setValve(17, LOW);
setValve(18, LOW); setValve(19, LOW);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
wait(2000);
setValve(14, HIGH); setValve(2, LOW);
wait(1000);
setValve(4, HIGH); setValve(12, LOW);
setValve(16, HIGH); setValve(18, HIGH);
setValve(19, LOW);
wait(2000);
setValve(0, LOW); setValve(1, LOW);
setValve(2, LOW); setValve(3, HIGH);
setValve(4, LOW); setValve(5, HIGH);
setValve(6, HIGH); setValve(7, LOW);
setValve(8, LOW); setValve(9, HIGH);
setValve(10, HIGH); setValve(11, LOW);
setValve(12, LOW); setValve(13, LOW);
setValve(14, LOW); setValve(15, HIGH);
setValve(16, HIGH); setValve(17, LOW);
setValve(18, HIGH); setValve(19, LOW);
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Fluid[] out = new Fluid[8];
Fluid yellow, blue, green;
out[0] = input(0);
yellow = input(0);
blue = input(1);
green = mix(yellow, blue);
yellow = input(0);
out[1] = mix(yellow, green);
yellow = input(0);
blue = input(1);
out[2] = mix(yellow, blue);
yellow = input(0);
blue = input(1);
green = mix(yellow, blue);
blue = input(1);
out[3] = mix(blue, green);
out[4] = input(1);
Abstraction 1: Managing Fluidic Storage
• Programmer uses location-independent Fluid variables
– Runtime system assigns & tracks location of each Fluid
– Comparable to automatic memory management (e.g., Java)
Fluidic
ISA
1. Storage
Management
input(0, 0);
input(1, 1);
input(0, 2);
mix(1, 2, 3);
input(0, 2);
mix(2, 3, 1);
input(1, 3);
input(0, 4);
mix(3, 4, 2);
input(1, 3);
input(0, 4);
mix(3, 4, 5);
input(1, 4);
mix(4, 5, 3);
mix(0, 4);
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Fluid[] out = new Fluid[8];
Fluid yellow = input(0);
Fluid blue = input(1);
Fluid green = mix(yellow, blue);
out[0] = yellow;
out[1] = mix(yellow, green);
out[2] = green;
out[3] = mix(blue, green);
out[4] = blue;
Fluid[] out = new Fluid[8];
Fluid yellow, blue, green;
out[0] = input(0);
yellow = input(0);
blue = input(1);
green = mix(yellow, blue);
yellow = input(0);
out[1] = mix(yellow, green);
yellow = input(0);
blue = input(1);
out[2] = mix(yellow, blue);
yellow = input(0);
blue = input(1);
green = mix(yellow, blue);
blue = input(1);
out[3] = mix(blue, green);
out[4] = input(1);
Abstraction 2: Fluid Re-Generation
2. Fluid Re-Generation
• Programmer may use a Fluid variable multiple times
– Each time, a physical Fluid is consumed on-chip
– Runtime system re-generates Fluids from computation history
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Abstraction 3: Arbitrary Mixing
• Allows mixing fluids in any proportion, not just 50/50
– Fluid mix (Fluid F1, float p1, Fluid f2, float F2)
Returns Fluid that is p1 parts F1 and p2 parts F2
– Runtime system translates to 50/50 mixes in Fluidic ISA
– Note: some mixtures only reachable within error tolerance
Fluid[] out = new Fluid[8];
Fluid yellow = input (0);
Fluid blue = input (1);
out[0] = yellow;
out[1] = mix(yellow, 3/4, blue, 1/4);
out[2] = mix(yellow, 1/2, blue, 1/2);
out[3] = mix(yellow, 1/4, blue, 3/4);
out[4] = blue;
3. Arbitrary Mixing
Fluid[] out = new Fluid[8];
Fluid yellow = input(0);
Fluid blue = input(1);
Fluid green = mix(yellow, blue);
out[0] = yellow;
out[1] = mix(yellow, green);
out[2] = green;
out[3] = mix(blue, green);
out[4] = blue;
2. Fluid Re-Generation
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Abstraction 3: Arbitrary Mixing
Fluid[] out = new Fluid[8];
Fluid yellow = input (0);
Fluid blue = input (1);
for (int i=0; i<=4; i++) {
out[i] = mix(yellow, 1-i/4, blue, i/4);
}
• Allows mixing fluids in any proportion, not just 50/50
– Fluid mix (Fluid F1, float p1, Fluid f2, float F2)
Returns Fluid that is p1 parts F1 and p2 parts F2
– Runtime system translates to 50/50 mixes in Fluidic ISA
– Note: some mixtures only reachable within error tolerance
4. Parameterized Mixing
Fluid[] out = new Fluid[8];
Fluid yellow = input (0);
Fluid blue = input (1);
out[0] = yellow;
out[1] = mix(yellow, 3/4, blue, 1/4);
out[2] = mix(yellow, 1/2, blue, 1/2);
out[3] = mix(yellow, 1/4, blue, 3/4);
out[4] = blue;
3. Arbitrary Mixing
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Algorithms for Efficient Mixing
• Mixing is fundamental operation of microfluidics
– Prepare samples for analysis
– Dilute concentrated substances
– Control reagant volumes
• How to synthesize complex mixture using simple steps?
– Many systems support only 50/50 mixers
– Should minimize number of mixes, reagent usage
– Note: some mixtures only reachable within error tolerance
• N
Analogous to ALU operations on microprocessors
Interesting scheduling and optimization problem
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Why Not Binary Search?
0 13/8
1/41/2
1/23/8 5 inputs, 4 mixes
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Why Not Binary Search?
0 13/8
3/41/2
3/8
4 inputs, 3 mixes
1/41/2
1/23/8 5 inputs, 4 mixes
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Min-Mix Algorithm
• Simple algorithm yields minimal number of mixes
– For any number of reagents, to any reachable concentration
– Also minimizes reagent usage on certain chips
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1. The mixing process can be represented by a tree.
Min-Mix Algorithm: Key Insights
BA
B
A
5/8 A, 3/8 B
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1. The mixing process can be represented by a tree.
2. The contribution of an input sample to the overall mixture
is 2-d, where d is the depth of the sample in the tree
Min-Mix Algorithm: Key Insights
BA
B
A
5/8 A, 3/8 B
d
3
2
1
2-d
1/8
1/4
1/2
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1. The mixing process can be represented by a tree.
2. The contribution of an input sample to the overall mixture
is 2-d, where d is the depth of the sample in the tree
3. In the optimal mixing tree, a reagent appears at depths
corresponding to the binary representation of its overall
concentration.
Min-Mix Algorithm: Key Insights
BA
B
A
5/8 A, 3/8 B
d
3
2
1
2-d
1/8
1/4
1/2
3 = 011
0
1
1
5 = 101
1
0
1
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Min-Mix Algorithm
• Example: mix 5/16 A, 7/16 B, 4/16 C
• To mix k fluids with precision 1/n:
– Min-mix algorithm: O(k log n) mixes
– Binary search: O(k n) mixes
4
3
2
1
B CA
B
A B
A
A
B
B
B
C
1/16
1/8
1/4
1/2
2-dd
A=5 B=7 C=4
=0101 =0111 =0100
[Natural Computing 2007]
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Related Work
• Algorithms for microfluidic sample preparation [Sudip Roy et al.]
• Aquacore – builds on our work, ISA + architecture [Amin et al.]
• Automatic scheduling of biology protocols
– EDNAC computer for automatically solving 3-SAT [Johnson]
– Compile SAT to microfluidic chips [Landweber et al.] [van Noort]
– Mapping sequence graphs to grid-based chips [Su/Chakrabarty]
• Custom microfluidic chips for biological computation
– DNA computing [Grover & Mathies] [van Noort et al.] [McCaskill] [Livstone,
Weiss, & Landweber] [Gehani & Reif] [Farfel & Stefanovic]
– Self-assembly [Somei, Kaneda, Fujii, & Murata] [Whitesides et al.]
• General-purpose microfluidic chips
– Using electrowetting, with flexible mixing [Fair et al.]
– Using dialectrophoresis, with retargettable GUI [Gascoyne et al.]
– Using Braille displays as programmable actuators [Gu et al.]
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Conclusions: Fluidic ISA
• Fluidic ISA gives flexibility to evolve underlying
hardware
– Including various device technologies
• It remains to be seen to what degree the functionality of
chips can be standardized
– May need to reconsider abstractions for analog machines
• Opportunities for future work
– Rich extensions to mixing algorithms
– Schedule separate protocols onto shared hardware,
maximizing utilization of shared resource (e.g., thermocycler)
– Parallelize single protocol across people or chips
– Dynamic optimization of slow co-processors (lazy vectorization)?
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Abstraction Layers for Microfluidics
Fluidic Instruction Set Architecture (ISA)- primitives for I/O, storage, transport, mixing
Protocol Description Language - architecture-independent protocol description
Fluidic Hardware Primitives- valves, multiplexers, mixers, latches
chip 1 chip 2 chip 3
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―Immunological detection ... was carried out as
described in the Boehringer digoxigenin-nucleic
acid detection kit with some modifications.‖
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- Main paper
- Ref. papers
- References
Papers from Nature, Spring 2010
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Problems with Existing
Descriptions of Protocols
• Incomplete
– Cascading references several levels deep
– Some information missing completely
• Ambiguous
– One word can refer to many things
– E.g., ―inoculate‖ a culture
• Non-uniform
– Different words can refer to the same thing
– E.g., ―harvest‖, ―pellet down‖, ―centrifuge‖ are equivalent
• Not suitable for automation
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BioCoder: A High-Level Programming
Language for Biology Protocols
1. Enable automation
via microfluidic chips
2. Improve reproducibility
of manual experiments
In biology publications, can we replace the textual
description of the methods used with a computer program?
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Related Work
• EXACT: EXperimental ACTions ontology as a formal
representation for biology protocols [Soldatova et al., 2009]
• Robot Scientist: functional genomics driven by
macroscopic laboratory automation [King et al., 2004]
• PoBol: RDF-based data exchange standard for BioBricks
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The BioCoder Language
• BioCoder is a protocol language for reuse & automation
– Independent of chip or laboratory setup
– Initial focus: molecular biology
• Implemented as a C library
– Used to express 65 protocols, 5800 lines of code
– Restricted backend: automatic execution on microfluidic chips
– General backend: emit readable instructions for human
• Validation
– Used to direct actions of scientists in the lab (IISc)
– Used to control microfluidic chips (MIT)
– Standardizing online Wiki; interest from Berkeley, UW, UMN…
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• Declaration / measurement / disposal- declare_fluid
- declare_column
- measure_sample
- measure_fluid
- volume
- discard
- transfer
- transfer_column
- declare_tissue
• Combination / mixing- combine
- mix
- combine_and_mix
- addto_column
- mixing_table
• Centrifugation- centrifuge_pellet
- centrifuge_phases
- centrifuge_column
• Temperature- set_temp
- use_or_store
- autoclave
• Timing- wait
- time_constraint
- store_until
- inoculation
- invert_dry
• Detection- ce_detect
- gas_chromatography
- nanodrop
- electrophoresis
- mount_observe_slide
- sequencing
BioCoder Language Primitives
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FluidSample f1 = measure_and_add(f0, lysis_buffer, 100*uL);
FluidSample f2 = mix(f1, INVERT, 4, 6);
time_constraint(f1, 2*MINUTES, next_step);
Example: Plasmid DNA Extraction
I. Original protocol (Source: Klavins Lab)
II. BioCoder code
III. Auto-generated text output
Add 100 ul of 7X Lysis Buffer (Blue) and mix by inverting the tube
4-6 times. Proceed to step 3 within 2 minutes.
Add 100 ul of 7X Lysis Buffer (Blue).
Invert the tube 4-6 times.
NOTE: Proceed to the next step within 2 mins.
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Example: Plasmid DNA Extraction
Auto-Generated
Dependence Graph
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1. Data Types
Sample
FluidSample SolidSample
Stock
Fluid Solid
conceptually infinite volume finite volume
measure instruction
Can measure symbolic volume
which is resolved by compiler /
runtime system depending on
eventual uses
declare_fluid
instruction
other instructions
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2. Standardizing Ad-Hoc Language
• Need to convert qualitative words to quantitative scale
• Example: a common scale for mixing
– When a protocol says ―mix‖, it could mean many things
– Level 1: tap
– Level 2: stir
– Level 3: invert
– Level 4: vortex / resuspend / dissolve
• Similar issues with temperature, timing, opacity, …
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3. Separating Instructions from Hints
• How to translate abstract directions?
– ―Remove the medium by aspiration, leaving the bacterial pellet
as dry as possible.‖
• Hints provide tutorial or self-check information
– Can be ignored if rest of protocol is executed correctly
• Separating instructions and hints keeps language
tractable
– Small number of precise instructions
– Extensible set of hints
Centrifuge(&medium, ...);
hint(pellet_dry)
Aspirate and remove medium.
Leave the pellet as dry as possible.
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4. Generating Readable Instructions
• In typical programming languages, aim to define the
minimal set of orthogonal primitives
• However, for generating readable protocols, separating
primitives can detract from readability
Original: ―Mix the sample with 1uL restriction enzyme.‖
BioStream with orthogonal primitives:
FluidSample s1 = measure(&restriction_enzyme, 1*uL);
FluidSample s2 = combine(&sample, &s1);
mix(s2, vortex);
Measure out 1uL of restriction enzyme.
Combine the sample with the restriction enzyme.
Mix the combined sample by vortexing.
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4. Generating Readable Instructions
• In typical programming languages, aim to define the
minimal set of orthogonal primitives
• However, for generating readable protocols, separating
primitives can detract from readability
Original: ―Mix the sample with 1uL restriction enzyme.‖
BioStream with compound primitives:
combine_and_mix(&restriction_enzyme, 1*uL,
&sample, vortex);
Add 1uL restriction enzyme and mix by vortexing.
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4. Generating Readable Instructions
• In typical programming languages, aim to define the
minimal set of orthogonal primitives
• However, for generating readable protocols, separating
primitives can detract from readability
Original: ―Mix the sample with 1uL restriction enzyme.‖
BioStream with compound primitives:
combine_and_mix(&restriction_enzyme, 1*uL,
&sample, vortex);
Add 1uL restriction enzyme and mix by vortexing.
• General approaches:
– Detect combined operations with policies (peekhole optimizer)
– Define a standard library that combines primitive operations
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4. Generating Readable Instructions
mixing_table_pcr(7,20,array_pcr,initial_conc,
final_conc,vol);
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5. Timing Constraints
• Precise timing is critical for many biology protocols
– Minimum delay: cell growth, enzyme digest, denaturing, etc.
– Maximum delay: avoid precipitation, photobleaching, etc.
– Exact delay: regular measurements, synchronized steps, etc.
• May require parallel execution
– Fluid f1 = mix(…); useBetween(f1, 10, 10);
– Fluid f2 = mix(…); useBetween(f2, 10, 10);
– Fluid f3 = mix(f1, f2);
f1 f2
f3
1010
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Benchmark Suite
65 protocols
5800 LOC
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Plasmid DNA Extraction
214 lines
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PCR
73 lines
repeat
thermocycling
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Molecular Barcodes
200 lines
Preparation
+ PCR (2)
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DNA Sequencing
144 linesPreparation
PCR
Analysis
PCR PCR PCR
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Instruction Usage
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Validating the Language
• Eventual validation: automatic execution
– But BioCoder more capable than most chips today
– Need to decouple language research from microfluidics research
• Initial validation: human execution
– In collaboration with Prof. Utpal Nath‘s lab at IISc
– Target Plant DNA Isolation, common task for summer intern
Biologist is never exposed to original lab notes
• To the best of our knowledge, first execution of a real
biology protocol from a portable programming language
Original
Lab Notes
BioCoder
Code
Auto-Generated
Protocol
Execution
in Lab
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3. Add 1.5 vol. CTAB to each MCT and vortex. Incubate at 65°
C for 10-30 mins
4. Add 1 vol. Phenol:chloroform:isoamylalcohol: 48:48:4 and
vortex thoroughly
5. Centrifuge at 13000g at room temperature for 5 mins
6. Transfer aqueous (upper) layer to clean MCT and
repeat the extraction using chloroform: Isoamyalcohol: 96:4
Exposing Ambiguity in Original Protocols
?
Coding protocols in precise language removes
ambiguity and enables consistency checking
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Growing a Community
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Growing a Community
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Growing a Community
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Future Work
• Backends for BioStream
– Generate graphical protocol
– Generate a microfluidic chip to perform protocol
• Reliability and troubleshooting
– Verify that protocol is safe, correct, obeys timing constraints
– If protocol fails, automatically suggest troubleshooting routine
• Building a knowledge base
– Encode experimental results in addition to protocols
– Search for a protocol based on input/output relationship
– Revision control for biology protocols
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Conclusions
• Abstraction layers forprogrammable microfluidics
– Microfluidic CAD tools
– General-purpose chips
– Fluidic ISA
– BioCoder language
• Vision for microfluidics:everyone uses standard chip
• Vision for software:a defacto language for experimental science
– Download a colleague‘s code, run it on your chip
– Compose modules and libraries to enable complex experiments
that are impossible to perform today