components for generic and programmable microﬂuidic...

Components for Generic and Programmable Microfluidic Devices

William GroverManalis Group, Biological Engineering Division

Massachusetts Institute of Technology

Lessons from the history of computing

Vannevar Bush and Differential Analyzer, MIT, 1931

- Single-purpose machines- New application requires new machine- No standard components

- General-purpose machines- New application requires only a new program- Made from standard components

Lessons from the history of computing

Vannevar Bush and Differential Analyzer, MIT, 1931

- Single-purpose machines- New application requires new machine- No standard components

- General-purpose machines- New application requires only a new program- Made from standard components

Standard toolkit of components (control, readout, etc.) that can be assembled into any useful circuit according to logical rules

Processors that can run many different programs using the same generic hardware

Two components for microfluidic processors

Transistor Readout

Valve-based pneumatic logic circuits for device control and operation

(Mathies Group,University of California, Berkeley)

Suspended Microchannel Resonators as generic mass/density sensors

(Manalis Group,Massachusetts Institute of Technology)

Generic microfluidic processorAutosampler chip(Manalis Group)

Valve-based pneumatic logic

Pneumatic input

Fluid input

Fluid output


Pneumatic input

Fluid input

Fluid output

Pneumatic input

Pneumatic input

Pneumatic output


Pneumatic input

Fluid input

Fluid output

Pneumatic input

Pneumatic input

Pneumatic output

Pneumatic input

Pneumatic input

Pneumatic input

Fluid input

Fluid output

Ultimate goal:All logic of device operation

integrated on-chip in pneumatic logic

Off-chip controllers for on-chip pneumatic valves and pumps cost

more $ and consume more power and space than the chip itself.

The next thing to go on-chip is the logic of device operation

The pretty picture The reality

Monolithic membrane valves

W.H. Grover, A.M. Skelley, C.N. Liu, E.T. Lagally and R.A. Mathies, Sensors and Actuators B 89, 315 (2003).

Etched fluidic features

Etched pneumatic features

Featureless PDMS sheet


Pneumatic wafer(etched displacement chamber)

PDMS (polydimethylsiloxane) membrane

Fluidic wafer(etched discontinuity or valve seat)


4-layer monolithic membrane valves

Pneumatic wafer

PDMS membrane

Hybrid glass-PDMS fluidic wafer

All-glass fluidic wafer


Fluidic wafer

Pneumatic wafer

Fluidic wafer

Pneumatic wafer

Valve operation

Fluidic wafer

Pneumatic wafer

Fluidic wafer

Pneumatic wafer

Pressure oratmospheric

Vacuum

Valve closed Valve open

Fluidic wafer(channel discontinuity)

Pneumatic wafer(displacement chamber)

Assembled monolithicmembrane valve

+ =Input Output

Control


Integrated portable genetic analysis microsystem for

pathogen/infectious disease detection. E.T. Lagally et al.,

Analytical Chemistry 76, 3162 (2004).

Multichannel PCR-CE Microdevice for Genetic Analysis. C.N. Liu, N.M.

Toriello, and R.A. Mathies, Analytical Chemistry 78, 5474 (2006).

Microfabricated bioprocessor for integrated nanoliter-scale Sanger DNA sequencing. R.G. Blazej et al., Proceedings of the National Academy of Sciences of the USA 103, 7240 (2006).

Integrated microsystem for dielectrophoretic cell

concentration and genetic detection. E.T. Lagally, S.H. Lee, and H.T. Soh, Lab on a Chip 5, 2005.

Pressure injection on a valved microdevice for electrophoretic

analysis of submicroliter samples. J.M. Karlinsey et al.,


On-chip pressure injection for integration of infrared-mediated DNA amplification with electrophoretic separation. C.J. Easley, J.M. Karlinsey, and J.P. Landers, Lab on a Chip 6, 601 (2006).

Development and evaluation of a microdevice for amino acid biomarker

detection and analysis on Mars.A.M. Skelley et al., Proceedings of the National

Academy of Sciences of the USA 102, 1041 (2005).

Microfluidic serial transfer circuit: Automated evolution of RNA catalysts

B.M. Paegel et al., Analytical Chemistry, in press.

An integrated microfluidic processor for single nucleotide polymorphism-based DNA computing.W.H. Grover and R.A. Mathies, Lab on a Chip 5, 1033 (2005).

Integrated portable genetic analysis microsystem for

pathogen/infectious disease detection. E.T. Lagally et al.,


Multichannel PCR-CE Microdevice for Genetic Analysis. C.N. Liu, N.M.

Toriello, and R.A. Mathies, Analytical Chemistry 78, 5474 (2006).

Microfabricated bioprocessor for integrated nanoliter-scale Sanger DNA sequencing. R.G. Blazej et al., Proceedings of the National Academy of Sciences of the USA 103, 7240 (2006).

Integrated microsystem for dielectrophoretic cell

concentration and genetic detection. E.T. Lagally, S.H. Lee, and H.T. Soh, Lab on a Chip 5, 2005.

Pressure injection on a valved microdevice for electrophoretic

analysis of submicroliter samples. J.M. Karlinsey et al.,


On-chip pressure injection for integration of infrared-mediated DNA amplification with electrophoretic separation. C.J. Easley, J.M. Karlinsey, and J.P. Landers, Lab on a Chip 6, 601 (2006).

Development and evaluation of a microdevice for amino acid biomarker

detection and analysis on Mars.A.M. Skelley et al., Proceedings of the National

Academy of Sciences of the USA 102, 1041 (2005).

Microfluidic serial transfer circuit: Automated evolution of RNA catalysts

B.M. Paegel et al., Analytical Chemistry, in press.

An integrated microfluidic processor for single nucleotide polymorphism-based DNA computing.W.H. Grover and R.A. Mathies, Lab on a Chip 5, 1033 (2005).

If we want more independent valves on-chip or reduced cost, size, or power consumption, the logic

of device operation must be integrated on-chip.

Pressure Pressure

Vacuum Vacuum

No connection No connection

Vacuum

Vacuum

Vacuum

Pressure

Pressure

Pressure

Pneumatic Valve “Truth Table”

Pressure Pressure

Vacuum Vacuum


Vacuum

Vacuum

Vacuum

Pressure

Pressure

Pressure

No vacuum

Vacuum

No vacuum

No pressure

Pressure

Pressure

CLOSED CLOSED

OPEN, thenCLOSED

OPEN

CLOSED OPEN


Pressure Pressure

Vacuum Vacuum


Vacuum

Vacuum

Vacuum

Pressure

Pressure

Pressure

No vacuum

Vacuum

No vacuum

No pressure

Pressure

Pressure

CLOSED CLOSED

OPEN, thenCLOSED

OPEN

CLOSED OPEN


These rules are the building blocks for an infinite variety of valve-based

pneumatic logical “circuits.”

Latching valve operation

NC

1

Closed

Closed

Closed

Set pulse input

V valve

P valve

Latching valve

Vacuum

2

Open

Closed

Open

Vacuum

3

Closed

Closed

Open

NC

4

Closed

Closed

Latchedopen

Pressure

5

Closed

Closed

Open

Pressure

6

Closed

Open

Closed

NC

7

Closed

Closed

Closed

Vent

A. Latching open

NC NC

1 3 4

Latchingvalve

Vacuumvalve

Pressurevalve

Vacuum Vacuum

2

Open

B. Latching closed

NC NCPressure

1 2 3

Open Open Open

Open Closed Closed

Closed Closed

Closed Closed

Closed

Closed Closed Closed ClosedOpen

Closed Closed Closed

Set input

Closed

Vent

A. Latching open

NC NC

1 3 4

Latchingvalve

Vacuumvalve

Pressurevalve

Vacuum Vacuum

2

Open

B. Latching closed

NC NCPressure

1 2 3

Open Open Open

Open Closed Closed

Closed Closed

Closed Closed

Closed

Closed Closed Closed ClosedOpen

Closed Closed Closed

Set input

Closed

Vent

NC

1

Closed

Closed

Closed

Set pulse input

V valve

P valve

Latching valve

Vacuum

2

Open

Closed

Open

Vacuum

3

Closed

Closed

Open

NC

4

Closed

Closed

Latchedopen

Pressure

5

Closed

Closed

Open

Pressure

6

Closed

Open

Closed

NC

7

Closed

Closed

Closed

Vent

W.H. Grover, R.H.C. Ivester, E.C. Jensen and R.A. Mathies, Lab on a Chip 6, 623 (2006)

Characterizing a single latching valve

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080450 5 s single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080451 1 s single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080452 3 s single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080453 500 ms single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080454 250 ms single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080455 170 ms single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080456 120 ms single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080457 80 ms single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0

200 400 600 800 1000

flow rate [m

L/s]

time [s]

05080470 hold.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080450 5 s single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080451 1 s single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080452 3 s single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080453 500 ms single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080454 250 ms single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080455 170 ms single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080456 120 ms single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080457 80 ms single.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flow

rate

[m

L/s

]

time [s]

05080470 hold.15.15.txt

open

open

clos

e

clos

e

clos

e

clos

e

clos

e

open

open

open

open

time [min]

0 2 4 6 8 10

flo

w r

ate

[!

L/s

]

0

1.0

0

1.0

0

1.0

0

1.0

0

1.0

0

1.0

0

1.0

0

1.0

0

1.0

se

t time

[ms]

5000

3000

1000

500

250

170

120

80

60 000

120 ms V/P pulse holds valve open or closed for 2 minutes.

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flo

w r

ate

[m

L/s

]

time [s]

05080460 120 ms latch closed.15.15.txt

0

0.0005

0.001

0.0015

0.002

0 200 400 600 800 1000

flo

w r

ate

[m

L/s

]

time [s]

05080461 120 ms latch open.15.15.txt

flo

w r

ate

[!

L/s

]

0

1.0

time [min]

0 2 4 6 8 10

open

clos

e

open

clos

e

0

1.0

set time: 120 ms

10% decrease after 2 min

Time for 1000 valves to be actuated in 2 min.

How to actuate 1000 on-chip valves without 1000 off-chip solenoids?


Latch valve/demultiplexer test chip

Set input

Sixteen latching valves

Via holes

through PDMSVacuum and

pressure valves

Four-bit demultiplexer


n off-chip controllers: 2n-1 independent on-chip valves

Latch valve/demultiplexer test chip


190 ms P/V pulses

Set all 16 latching valves according to any pattern every 3 seconds


190 ms pulses,inverted Valve 3

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1

123456789

101112131415161718192021222324252627282930313233

0

1

2

3

4

5

6

Latching valve number

Cycle

nu

mb

er T

ime

(s)

All errors consist of a valve changing too early, with its “Least Significant Bit” neighbor.

Need a software solution, a different program...

- Open valves

- Incorrect valves


120 ms P/V pulses, Gray code addressing

Set all 16 latching valves according to any pattern every 2 seconds


120 ms P/V pulses, inverted Valve 3

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1

123456789

101112131415161718192021222324252627282930313233

0

1.0

2.0

3.0

0.5

1.5

2.5

3.5

Latching valve number

Ste

p n

um

ber

Tim

e (s

)

No errors


60 ms P/V pulses

Set all 16 latching valves according to any pattern every 1 second


120 ms P/V pulses, static pattern

Valve open/closed patterns can be maintained indefinitely


Input A Input B

Output

Vacuum = 1 or TRUEPressure = 0 or FALSE E.C. Jensen, W.H. Grover and R.A. Mathies, submitted

Eight-bit valve-based pneumatic adder

1111111100000001+

Eight binary adders linked in series to form an eight-bit ripple carry adder

E.C. Jensen, W.H. Grover and R.A. Mathies, submitted


1 + 1

1111111100000001+

1 + 0

1 + 0

1 + 0

1 + 0

1 + 0

1 + 0

1 + 0




1 + 1

1111111100000001

0+

1 + 0

1 + 0

1 + 0

1 + 0

1 + 0

1 + 0

1 + 0

carrythe 1

0




1 + 1

1111111100000001

0+

1 + 0

1 + 0

1 + 0

1 + 0

1 + 0

1 + 0

1 + 0

carrythe 1

carrythe 1

0

0

0




1 + 1

1111111100000001

0+

1 + 0

1 + 0

1 + 0

1 + 0

1 + 0

1 + 0

1 + 0

carrythe 1

carrythe 1

carry the 1

carrythe 1

carrythe 1

carrythe 1

carrythe 1

carrythe 1

0

0

0

0

0

0

0

0

1 00000001

Carry info must propagate

counterclockwise through all eight

adders




1111111100000001+



1111111100000001

100000000+


100 sums

+

0110+0100

0110+1101

0110+0101

0110+0110

0110+0111

0110+1000

0110+1001

0110+1010

0110+1011

0110+1100

Fig. 7a

11111111

01111111

00111111

01000001

00000001

11001010

11000010

01010101

10111100

11100011

11111110

10111011

00011010

11100110

01000101

11010101

00000101

10110011

00111110

00100011

11111111 00000001 00000000 10101010 01010101

Fig. 7b


What do you want in a microfluidic readout component?

Readout

Doesn’t require specific chemical properties like color, fluorescence, electrochemistry...

Doesn’t change the fluid - just a passive “flow through”

Cleanable and reusable without cross-contamination

Many different modes of operation

The Suspended Microchannel Resonator (SMR)

T.P. Burg and S.R. Manalis. Physics Letters 83, 13 (2003)

10 pL channel inside a suspended silicon

cantilever

2 mm

20 μm

Resonant frequency ~200 kHz

Density of fluid contents affects

resonant frequency

One SMR, many “programs”

T.P. Burg, M. Godin, S.M. Knudsen, W. Shen, G. Carlson, J.S. Foster, K. Babcock and S.R. Manalis, Nature 446, 1066 (2007)

- Bulk solution density measurement


- Bulk solution density measurement- Surface binding measurement



- Bulk solution density measurement- Surface binding measurement- Particle counting and measurement


0 20 40 60 80 100 120 140

-400

-300

-200

-100

0

Freq

uenc

y Sh

ift (m

Hz)

Time (sec)

Conventional autosampler instrument

Internal volumes can take hundreds of microliters to

prime and rinse

Cost, size, and power consumption precludes use in third-world or

point-of-care applications

The autosampler chip

1

3

5

7

2

4

6

8

10

12

14

9

11

13

15

16

Glass-Teflon-glass valve structure for chemical inertness

Microfluidic switchboard: Fluid from any of 16 connections can be sent to any other connection

Instruction set: 240 different generic, useful operations to combine into an infinite variety of programs

Internal volume is rinsable between operations

Autosampler chip + SMR


Rapid switching of fluid through SMR

Autosampler chip alternates between flowing water and 0.5x PBS (mostly 70 mM NaCl) across cantilever.

10 pL contents of cantilever replaced every 3 seconds, requiring only 300 ms per switch.


Automated building and removal of surface-bound multilayer

Frequency shifts after polylysine-PEG-biotin and neutravidin solutions confirm binding.

Return to 0 Hz baseline after autosampler chip delivers piranha (concentrated sulfuric acid and hydrogen peroxide)

Standard toolkit of components (control, readout, etc.) that can be assembled into any useful circuit according to logical rules

Valve-based on-chip pneumatic logic - n off-chip controllers: 2n-1 independent on-chip valves - 1000 independent valves: only 11 off-chip controllers - Possible because of normally-closed nature of valves - Log2 reduction in $, power, space wasted by off-chip controllers - 8-bit adder suggests any digital logic circuit is possible

Suspended Microchannel Resonator sensor - Single component, many different modes of operation - 100 ng/cm3 fluid density resolution - 10 pg/cm2 surface mass resolution - 0.25 fg particle mass resolution

Processors that can run many different programs using the same generic hardware

Autosampler chip - Fraction of cost, size, power of conventional autosampler - Chemically generic - 240 instructions, infinite programs

Acknowledgments

Mathies Group, College of ChemistryThe University of California, Berkeley

Manalis Group, Biological Engineering DivisionMassachusetts Institute of Technology

Prof. Eric Lagally (now at University of British Columbia)Teris LiuDr. Alison Skelley (now at Massachusetts Institute of Technology)Robin IvesterErik JensenProf. Richard Mathies

Donations from Affymetrix to theBerkeley Center for Analytical Biotechnology

Yao-Chung WengDr. Scott KnudsenDr. Thomas BurgMarcio von MuhlenProf. Scott Manalis

Funding from the Institute for Collaborative Biotechnologiesthrough grant DAAD19-03-0004 from the US Army Research Office

components for generic and programmable microﬂuidic...

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