biopoets p o e t s biomedical innovations by biopoets* · eunice s. lee, gang liu, franklin kim,...

1

Luke P. LeeBiomolecular Nanotechnology Center Berkeley Sensor & Actuator Center

Department of Bioengineering

Biomedical Innovations by BioPOETS*

*BioPOETS: Biologically-inspired Photonics-Optofluidics-Electronics Technology & Science

UC BerkeleyThe BioPOETS

Acknowledgments• Graduate & Post-doctoral Researchers :

Dino Di Carlo (Harvard) Jeonggi Seo (PARC) Teawook Kang Gang LiuPaul Hung Yeonho Choi Jay Kim (Iowa State) Philip LeeMichelle Khine (UCM) Christy Trinkle (UK) Cristian Ionescu-Zanetti Adrian LauSunghoon Kwon (SNU) Nikolas Chronis (UM) Franklin Kim (NU) J. Tanner NevillPoorya Sabounchi Kihun Jeong (KAIST) Yangku Choi (KAIST) Robert Szema Yitao Long (SWU) Megan Dueck Dukhyun Choi Yu Lu (Intel)David Breslauer Hansang Cho Eunice Lee Liz Wu Mimi Zhang Yolanda Zhang Ben Ross

• Undergraduate ResearchersRyan Cooper Tao-yang Chen Brian Lee Selena WongTodd Fong Andrea Fils Shalini Indrakanti Irene Sinn Angelee Kumar Albert Mach

• Collaborators: Erin O’Shea @ Harvard Precision Biology @ Intel Wilhelm Krek @ ETH ZurichLily Jan @ UCSF Yang Dan @ UCB Matthias Peter @ ETH ZurichGabor Somorjai @ UCB Paul Alivisatos @ UCB Markus Stoffel @ ETH Zurich

• Research Funding:NSF, DARPA, NASA, Intel Inc., Samsung Electronics, and CNMT(KMST)

2


• Motivations• Biophotonics inspired by Nature• Biologically-inspired Optics• Biologically-inspired Fluidics• Biologically-inspired Electronics• Summary

http://biopoets.berkeley.edu

Outline

UC BerkeleyThe BioPOETSQuantitative Biomedicine by BioPOETS*

*Biomolecular Photonics-Optofluidics-Electronics Technology & Science

Biologically Inspired Optical Systems

Nanoplasmonic SERS for In-vitro Diagnostics

Nanocrescent for In-vivo Molecular Probes

Optofluidics for Biophotonic Controls Cellular BASICs: Biologic Application Specific Integrated Circuits

3


Quantitative Biomedical Science

[ ][ ] [ ]

[ ]Kzxkty

zxkyxktx

⋅=∂∂

⋅−=∂∂

3

22

1

Tissue Sample Empirical Analysis

Kinetic Model Fitting

Personalized Medicine

Fundamental Concepts:• Rapid collection of large experimental data sets

• Intelligent consolidation of quantitative values


Nano-BiophotonicsInspired by Naturefor Cellular Galaxy Biophysics

and Imaging

4


Motivation:

Molecular ImagingTime to Study the Inner Life: Cellular Galaxy!!


From Telescope to Satellite Telescope

Galileo published Sidereus Nuncius in March 1610

5


Nanoring

NanotipsLaser

Excitation

Surface-enhanced

Raman scatterin

g

Sharp edge (scattering “hot site”)

Nanocrescents:NanosatellitesNanoscale Biophotonic Receivers & Transmitters

Y. Lu, G. L. Liu, J. Kim, Y. Mejia, & L. P. Lee, Nano Letters, 5(1), 119-124 (2005).

Local Electromagnetic Field Enhancement Effect


In-vivo Cellular Nanoscopy

Optical detection of electron transfer: in vivo for high spatial resolution nanoscopy.

Bionano Receivers & Transmitters

100 nm

6


SERS-based Nanocrescent’s LFE

600 800 1000 1200 1400 16000

100

200

300

400

500

1nM R6G

1μM R6G

10μM R6G

100μM R6G

1mM R6G

Inte

nsity

[arb

. uni

t]

Raman Shift [cm-1]

615

7881151

1347 1508154515831659

1698

600 800 1000 1200 1400 1600

0

100

200100nmO.D. Au nanobowl

60nm Au nanosphere

169816591583

15451508

1347

1151788

615

Raman Shift [cm-1]

Inte

nsity

[arb

. uni

t]

SERS spectra of different concentrations of R6G

Comparison of SERS spectra from Au nano-crescent & nanospheres

Estimated LFE factor: ~ 3Estimated LFE factor: ~ 3××101022

Rhodamine 6G- High photostability- High quantum yield- Low costExcitation Excitation

(785 nm)(785 nm)

1mM R6G

cf. Nanorings: LFE < 102


Nanocrescent SERS Probes

Fe

Ag

Au

Laser Excitation Surface

-enhan

ced

Raman

Scatte

ring

MultilayeredNanocrescent

SERSHot Spots

Multiple particleswith dispersed SERS hot spots

Multiple SERSHot Spots

Single nanocrescent with multiple SERS hot spots

SERSWeak Spots

vs.

TEM image of nanocrescent

(c)

7


1 μm 1 μm 1 μm

0 50 100 150 200 250 3000

100

200

300

400

500

600

Pixel

Inte

nsity

[a.u

.]

0 50 100 150 200 250 3000

100

200

300

400

500

600

Pixel

Inte

nsity

[a.u

.]

0 50 100 150 200 250 3000

100

200

300

400

500

600

Pixel

Inte

nsity

[a.u

.]

1 μm1 μm 1 μm1 μm 1 μm1 μm

0 50 100 150 200 250 3000

100

200

300

400

500

600

Pixel

Inte

nsity

[a.u

.]

0 50 100 150 200 250 3000

100

200

300

400

500

600

Pixel

Inte

nsity

[a.u

.]

0 50 100 150 200 250 3000

100

200

300

400

500

600

Pixel

Inte

nsity

[a.u

.]

(b)

400 600 800 1000 1200

0

50

100

150

In

tens

ity [a

.u.]

Raman Shift [cm-1]

backgroundoblique excitationperpendicular excitation

Au

MTMO

400 600 800 1000 1200

0

50

100

150

In

tens

ity [a

.u.]

Raman Shift [cm-1]

backgroundoblique excitationperpendicular excitation

AuAu

MTMO

(c)

(d)

500 600 700 800 900 1000 1100 1200 1300

150

200

250

300

350

Inte

nsity

[a.u

.]

Raman Shift [cm-1]

864

1030637

N SN SN SN S

500 600 700 800 900 1000 1100 1200 1300

150

200

250

300

350

Inte

nsity

[a.u

.]

Raman Shift [cm-1]

864

1030637

N SN SN SN S

0 50 100 150 200 250 300 3500

5

10

15

20

25

30

35

40

45

Ram

an P

eak

Inte

nsity

at 6

37 c

m-1

Rotation angle [degree]

N S

N

S

NS

N

S

N S

0 50 100 150 200 250 300 3500

5

10

15

20

25

30

35

40

45

Ram

an P

eak

Inte

nsity

at 6

37 c

m-1

Rotation angle [degree]

N SN S

N

SN

S

NS NS

N

SN

S

N SN S

(e)

(f)

(a)

Magnetic Nano-

Crescent SERS

G. L. Liu, Y. Lu, J. Kim, J. C. Doll,

and L. P. Lee

Advanced Materials

(2005)


Plasmonic Resonance Energy Transfer

(PRET)

G. Liu, Y. Long, Y. Choi, T. Kang, and L. P. Lee (Nature Methods, 2007)

Nanospectroscopic Imaging

8


Time Resolved Dip Spectroscopy

Quantized Nanoplasmonic Dip Spectroscopy by PRET

Cyt C

Cyt C


9


Molecular Dynamics of Cyt c10 μm Time resolved dip change

2μm


Multiplexed PRET for Functional

Cellular Imaging

10


Spatially Resolved in-vivo Cellular Imaging

Internalized GNPs

Cytochrome c

Mitochodrium

Nucleus

ER

0

0.5

1.0Cyt c [c]

Mapping of Cellular Processing: Apoptosis Dynamics

PRET Nanospectroscopic Imaging


Dynamic Molecular Rulerfor Measuring Nuclease Activity

& DNA FootprintingG. L. Liu et al. (Nature Nanotechnology, 2006)

11


Mechanism of Plasmon Resonance Wavelength Shift by Nucleolytic Reactions

1. Effective size change after DNA digestion.

2. Dielectric constant of dsDNAis dependent on its length (Langevin model).

3. Ionic condensation condition change due to the DNA length change

DNA length negative charges PR Shift

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DNA Footprinting of the Binding Position of EcoRI Mutant

Nature Nanotechnology (2006)

12


Plasmon Resonance Detection of EcoRI Mutant Position on the dsDNA

500 520 540 560 580 600 620 640 660 680 7000

200

400

600

800

1000

1200

1400

1600

1800

Inte

nsity

[a.u

.]

Wavelength [nm]

1 min 3 min 5 min 7 min 9 min 11 min 13 min 15 min 17 min 19 min 21 min

520 540 560 580 600 620 640 660 680 7000

200

400

600

800

1000

1200

1400

1600

1800

Inte

nsity

[a.u

.]

Wavelength [nm]

1 min 2 min 3 min 4 min 5 min 6 min 7 min 8 min 9 min 10 min 15 min 20 min

+ DNase I + EcoRI Mutant + DNase I

0 5 10 15 20 25 30

+DNase I +EcoRI Mutant +DNase I

Dig

este

d ba

se p

air n

umbe

r

Time [min]

3034384248

27242017141180

60555045403530252015105 W

avelength Change [nm

]

0


Oligonucleotides on a Nanoplasmonic Carrier

Optical Switch (ONCOS)

Eunice S. Lee, Gang Liu, Franklin Kim, Yitao Long, and Luke P. Lee(unpublished)

Precise Temporal and Spatial Controls of Localized Gene Regulation and Protein Translation

13


Conjugated GNP

AntisenseOligonucleotidereleased

NIR light

localized activation

– 50

nm

– 15

nm

– r

– T

On Demand Localized Gene Regulation

Precise Temporal

Spatial &Temperature

Controls


ONCOS

b

mRNA

nucleus

a

old protein

RNaseH digestionprotein translation halted

old protein

protein folding

shuttling of new protein

nucleus

mRNAribosome

conjugated GNPs

NIR light

Fig. 2

ONCOS Gene Regulation and Protein Translation

14



Time to Study the Inner Life

via Quantum Nanoplasmonics: Nanospectroscopic Imaging

15


Biologically-inspired

Optical Systemsfor Biological microprocesor controls,

automations, and imaging


Learn from Nature: Watch out carefully

16


Biologically Inspired Optical System for Advanced

Photonic Systems(Science, Nov. 2005)


Artificial Compound Eye

Jeong et al, “Biologically Inspired Artificial Compound Eyes,” Science, 312, 557-561 (2006)

17


Biologically Inspired Optical System

Ki-Hun Jeong, “Biologically Inspired Artificial Compound Eyes,” Science, vol. 312, p. 557-561 (2006)


Omni-directional Imaging SystemHoneycomb-Packed Polymer Microlens

Arrays on a Curvilinear Surface

CMOS Image Sensor Array

Microlens-waveguides

waveguides coupled with ISA

Eyel

et: u

p to

5m

m

Potential applications: Handheld miniaturized Imaging System for wide field-of-view, Endoscopic imaging system, Omni-directional sensor array for surveillance detection.

18


Biologically-inspired

Fluidic ICsfor Quantitative Cell Biology and

Quantitative Medicine on Chip


Cellular BASICs*BASIC #1 Integrated Microfluidic Patch-clamp Array Chip BASIC #2 Single Cell Electroporation ChipBASIC #3 High-density Single Cell Analysis ChipBASIC #4 Dynamic Cell Culture Chip for Systems BiologyBASIC #5 Cell-cell Communication ChipBASIC #6 Cell Lysing Devices for Sample PreparationBASIC #7 Biomimetic Cell Sorting Microfluidic DevicesBASIC #8 Micro PALM for Cell ManipulationsBASIC #9 Integrated Cell Culture & Lysing & HarvestingBASIC #10 Biomimetic Artificial Livers on a ChipBASIC #11 Biofluidic Self-assembly of Spheroids on a Chip

http://biopoets.berkeley.edu

*Biological Application Specific Integrated Circuits

19


Basics of BASICs: Fluidic Resistance

( )( ) vPvvvdt2∇+−∇=∇•+ ηρ

vP 2∇=∇ η

( )ρη ,,,,,, Pwhzyfv Δ=

( )RPPwhLfQ Δ

=Δ= ρη,,,,,

( ) whwhLRrect 3

1/63.01

12−

≅η

yx

z

wL

h

Time, translation invarience at low Re

Pressure Driven Navier-Stokes

7.5*101450x50 μm

4.0*10202x5 μm

R/L(Pa s/m3)

Cross Section

R1/R2 = 5.4*105

UC BerkeleyThe BioPOETSMammalian Electrophysiology on

Microfluidic BASICs* Platform

BASICs:Biological

Application Specific

Integrated Circuits

C. Ionescu-Zanetti, R. M. Shaw, J. Seo, Y. Jan, L. Y. Jan, and L. P. Lee (PNAS, 2005)

20


BASIC #3

High-density Single Cell Analysis Chip

http://biopoems.berkeley.edu


BASIC#3: High density Single Cell Array via Hydrodynamic Single Cell Tweezers

21



Carboxylesterase Kinetics • Probed with Calcein

AM – fluorogenic substrate

• Two different cell types: – Human cervical

carcinoma vs. human kidney cells

• Key result:– Statistically larger

esterase activity in kidney cell line.

– Means: 50 nM vs. 125 nM

22


NDGA InhibitionKey results:• IC50 of 233 nM for

carboxylesterase and isozyme inhibition

• 20 nM of 50 nM total activity is not inhibited by NDGA.

• Future: Various fluorogenic substrates having different enzyme specificity.


23


Long-term Cytotoxic Drug Assay via Single-Cell Microfluidic Array

Media Input Drug Input

Waste Output

Single Cell Culture Chamber

log-gradientgenerator

= 9:1Media : Drug


Apoptosis Mechanism is Concentration Dependent

100nM Taxol,1μL min-1 perfusion

Suppression of MT dynamics

low conc. of Taxol (<200nm)

Mitotic spindlecheckpoint

Mitotic arrest

Apoptosis

Cdc2 activationBcl-2 phosphorylC-Mos up regulation

LT narrow distributedT Wang, et al., CANCER (88), 2000

24


Apoptosis Mechanism is Concentration Dependent

10μM Taxol 20mins,1μL min-1

Massive MT damage

High conc. of Taxol (0.2-30μm)

Cdc2, Cdks

Apoptosis

LT dispersedT Wang, et al., CANCER (88), 2000

JNK activation

Caspase activation


Cultural Revolutionsfor Physiologically Relevant

Cell Culture ArrayCreating Dynamic Cell

Culture Systems

25


Biomimetic Physiological Microenvironment

Tissue

ComplexExtracellular Matrix0.1 μm/sInterstitial Flow (i)700 μm/sCirculatory Flow (c)

100-300 μmSize (D)

D

c

i Cell Growth and “Interstitial”

Space

Cell Loading

“Blood” Flow

Surface Coating0.08-4 μm/s

80-4,000 μm/s50-1000 μm

Microfluidic


Cell Culture Biotechnology

40-80%<10%5%Cell Density (v/v)

64-102411-384Throughput

2-120 sec0.5-3 days3 daysMedium Turnover

3 nl2 L50 μlVolume

Microfluidic Bioreactor

CSTR Bioreactor

Microtiter Plate

26


Nanoliter Scale Microbioreactor Array for Quantitative Cell Biology

Lee et al., Biotechnology & Bioengineering, 94 (1), 5-14 (2006)


Design for Uniform Fluid Velocity Profile

With different flow rates applied from the perfusion inlet, shear stresses inside the chamber can be adjusted. This would potentially be beneficial for study the responses of cells

under various shear conditions.

With different flow rates applied With different flow rates applied from the perfusion inlet, shear from the perfusion inlet, shear stresses inside the chamber stresses inside the chamber can be adjusted. This would can be adjusted. This would potentially be beneficial for potentially be beneficial for study the responses of cells study the responses of cells

under various shear conditions.under various shear conditions.

High Aspect Ratio between the Perfusion Channels & Cell Culture Chamber

100μm

Loading

Waste

Perfusion Inlet

Perfusion Outlet

Cell Culture Chamber

100μm

Loading

Waste

Perfusion Inlet

Perfusion Outlet

Cell Culture Chamber

50μmPerfusion Channels 50μmPerfusion Channels

27


Uniform Mass Transfer

2 sec2 sec2 sec2 sec 5 sec5 sec 15 sec15 sec

Medium is introduced from the perfusion inlet at 0.2μL/min.Medium is introduced from the perfusion inlet at 0.2Medium is introduced from the perfusion inlet at 0.2μμL/min.L/min.

a


Device Fabrication

Key Features:• Biocompatible• Rapid Processing Time• 1.5-250 μm PR Available• Optically Transparent

28


Cell Growth

Cell Growth (HeLa, 30 min/frame, 38 hours)


Quantitative Data

Cell Growth RateCell Attachment Kinetics

NdtdN μ=

● Microfluidic

▲ 24 Well Plate

29

UC BerkeleyThe BioPOETSCell Types Cultured

HeLa HeLa “tumor” NIH3T3 Fibroblast

Primary BAEC HepG2 Hepatocyte SY5Y Neuroblasts


Physiologically-inspired Artificial Liver Sinusoids

Lee et al., Biotechnology and Bioengineering 97, 1340 (2007)

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Liver Micro-architecture

• Sinusoid space transports blood to hepatocytes• Lined with fenestrated endothelial barrier• Hepatocytes form extensive cell-cell contact


Microfluidic Artificial Liver Sinusoid

• Microfluidic endothelial barrier• High density hepatocyte culture• Continuous flow mass transport

1 sec 40 sec 80 sec 120 sec 240 sec

7 days

Hepatocyte Loading

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Effect of Hepatocyte Density

• Microfluidic culture without ECM coating• “Spheroid” effect previously documented

High density = happy cells Low density = dead cells


Quantitative Results

• Collagen coating required for dish based hepatocyte culture

• High density loading can rescue viability in absence of ECM coating

□ High density

▲ Low density

■ Dish (no coat)

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Microfluidic Assembly of Spheroids“Tumor factory” to Accelerate Cancer Drug Development


Effects of Flow Rate in Spheroids Assembly for Drug Screening

33


Biologically-relevant Stem Cell Research

Known Stem Cell Modulators

Shear Stress Growth FactorsNutrient Content ECM ContactSurface Material Oxygen LevelElectrical Signaling Temporal ModulationCo-Culture Genetic Manipulation

?

Renewal

Endothelial Cell

Stem Cell

Blood Cell

Nerve Cell

?

??

0 2 4 6 8 100.0

0.5

1.0

0 2 4 6 8 100.0

0.5

1.0

0 2 4 6 8 100.0

0.5

1.0

Time

Culture Parameter

High Throughput Experimentation

Data Analysis and Optimization


Innovative Personalized Medicine

Information Technology

Disposable Diagnostic

Biochip

Mobile Healthcare iMDs*

BiotechnologyNanotechnology

*iMDs: Innovative Medical Diagnostic Systems

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Summary• Biologically-inspired photonics and optical systems are

being developed for innovative healthcare systems.

• Cellular BioASICs are being developed for quantitative biology & medicine.

• Quantum nanoplasmonic molecular probes, molecular ruler, ONCOS (gene regulator & protein expression controller) are developed for molecular/cellular imaging, and quantitative in vivo biology.

• High-content Integrated Quantitative Molecular Diagnostic (iQMD) system can be created for future preventive, personalized medicine, and integrated health & environmental monitoring systems.

biopoets p o e t s biomedical innovations by biopoets* · eunice s. lee, gang liu, franklin kim,...

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