Integrated Lasers for Biophotonics
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Transcript of Integrated Lasers for Biophotonics
Integrated Lasers for Biophotonics
Peking University Summer SchoolBeijing, ChinaJuly 19, 2013
James S. HarrisStanford University
Peking University Summer School, July 19, 2013
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Outline
Motivation and background Implantable sensor design and fabrication In vivo monitoring of a molecular probe in
a tumor Blood Coagulation Sensor Neural Activity Sensor Summary
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The NANO-BIO-TECH Revolution
Integrated Circuit-1961 STM-1981 AFM-1986
Vo-Dinh, Nanobiotech 1, 3 (2005)
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Medical imaging
MRI
From structural/anatomical……to functional imaging
PETPET
MRI
Bioluminescence
Fluorescence
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Multimodality Imaging Strategies
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Light-tissue interactions
Incident Light
DiffuseReflectance
SpecularReflectance
Chromophore in ground state
Photon at incident wavelength
Chromophore in excited state
Fluorescent photon
Raman-shifted photon
TissueAbsorption
Multiple elasticScattering
Single Backscattering
Fluorescence
RamanScattering
Fluorescence
Raman Scattered
Provides molecular functional information
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Advantages of near IR Window of operation: 650–900 nm
Integrated semiconductor sensors
Low intrinsic absorption & scattering
Shah. Et al, NeuroRx Review 2, 215 (2005)Day vs night star viewing
mabs = 0.04 cm-1 mscattering = 10 cm-
1No tissue autofluorescence
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• Integration of laser-induced fluorescence (LIF) detection
Example Integrated Sensor
Photonic systems integration
LIF Detection System
– Expensive, bulky and non-portable
• Discrete components • Integrated system– Cheap, portable and
parallel
1 meter 1 mm – 100 m
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Vertical Cavity Surface Emitting Lasers: Miniature + can be integrated Low-cost manufacturing/packaging Arrayable
Images: Logitech, M-ComImages: Molec. Devices ,D. Armani et al, Nature 2003;
B. Cunningham et al, Sens Act B 2002; Biacore
Bulky, expensive external light sources and delicate alignment
not realistic for point-of-care/ bedside
2 ft long, 30 lbs
VCSELs are key for low-cost, compact biosensors
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Materials challenges for biosensors
InAs
AlSb
GaSbGeBULKSLE
(Ge)
a-SiC
GaSbInSb
AlSb CdTe
InAs
InN
GaN
AlN
ZnS MgSe
CdSAlP
CdSe
ZnTe
ZnSe
GaAs
GaPAlAs
InPSi
Lattice Constant (Å)
(.41 mm)
(.62 mm)
6.0
4.0
3.0
2.0
1.0
3.0 3.2 3.4 5.4 5.6 5.8 6.0 6.4
Ban
dgap
ene
rgy
(eV
)
(1.24 mm)
Visible Spectrum
(.31 mm)
(.21 mm)
.31
.41
.62
1.2
Wavelength (µ
m)
Telecom & IT Revolution
Fluorescent Proteins
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Outline
Motivation and background Implantable sensor design and fabrication In vivo monitoring of a molecular probe in a
tumor Blood Coagulation Sensor Neural Activity Sensor Summary
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n-DBR
Laser Cavity
675nm VCSEL Detector
Absorption region (i-GaAs)
p-DBR
GaAs Substrate
Fluorescent Molecules
Excitation
EmissionBack-scattered excitation light
Emission Filter
Detector
VCSEL
Detector
VCSEL
Detector
VCSEL
Top view
Side view
Integrated sensing geometry
Sponta
neo
us
em
issi
on
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Implantable Fluorescence Sensor
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Detector
Laser (VCSEL)High quality optical filter blocks fluorescence
excitation from reaching detector (Desire >OD6 99.9999% isolation)Requires combination of spatial and spectral
isolation
Optical Filter (above detector)
Gallium Arsenide (GaAs)-based Integrated Optical Sensor
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What are we sensing?
• Cyanine 5.5 (Cy5.5) dye – Many existing preclinical probes in use
• Near-Infrared (NIR) imaging– Favorable optical properties in
tissue – Low tissue autofluorescence– Increased availability of near-
IR molecular probes – Emerging NIR fluorescent
proteins*
*X. Shu, et al, Science 324, 804 (2009)
650 700 750 800 850 900 950 10000.0
0.2
0.4
0.6
0.8
1.0
Abs
orpt
ion
(mm
-1m
M-1)
Wavelength(nm)
Tissue NIR absorbers
HHb
O2Hb
BULK LIPID
H2O
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What are we sensing?
• Cyanine 5.5 (Cy5.5) dye – Many existing preclinical probes in use
600 650 700 750
0
20
40
60
80
100
Inte
nsi
ty (
a.u
.)
Wavelength (nm)
Excitation Emission
Cy5.5 Absorption/Emission
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Sensor components: Laser
• VCSEL Characteristics– Optical output power (12µm oxide aperture)– 1-2mW at room temperature– Lasing up to 50°C– Wavelength: 675nm (+/- 1nm)– Multimode linewidth: <0.2nm (FWHM)
673.5 674.0 674.5 675.0 675.5 676.0
0.0
0.2
0.4
0.6
0.8
1.0
Integrated VCSEL Spectra
Inte
nsi
ty (
a.u
.)
Wavelength (nm)
5.0mA 6.0mA 7.0mA 8.0mA 9.0mA 10.0mA 11.0mA 12.0mA
0 1 2 3 4 5 6 7
0.0
0.5
1.0
1.5
2.0
1
2
3
4
Vo
ltag
e (V
)
Lig
ht
Ou
tpu
t (m
W)
Current (mA)
20C 25C 30C 35C 40C 45C 50C
Integrated VCSEL IV Characteristics
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Sensor components: Detector
Detector characteristics– Area: 0.75mm2
– Internal quantum efficiency: >75%– Dark current: <5pA/mm2 (0.1V)
0.0 0.2 0.4 0.6 0.8 1.01E-14
1E-12
1E-10
1E-8
1E-6
Da
rk C
urr
en
t (A
)
Reverse Bias (V)
No Passivation SiNx Passivation without wet etch SiNx Passivation with wet etch
Reduction of Dark Current
-1.0 -0.5 0.0 0.5 1.0 1.5
0
1
3
4
Fo
rwa
rd C
urr
en
t (m
A/m
m2)
Detector Bias (V)
Integrated Detector Dark Current
-0.4 -0.2 0.0 0.2-30
-20
-10
0
10
20
pa
/mm
2
V
T. O’Sullivan et al, Proc. SPIE 7173, (2009)
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Sensor specifications:emission filtering
600 650 700 750 800
0.0
0.2
0.4
0.6
0.8
1.0In
ten
sity
(a
.u.)
Wavelength (nm)
Cy5.5 Excitation Cy5.5 Emission Detector Response VCSEL Excitation
Overlap betweendetector response and Cy5.5 emission
VCSEL Excitation
• Consists of thin-film interference filter and thick hybrid (absorption) filter element
• 15-20% overlap with fluorescence emission
Emission Filter Spectral Response
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Summary: Sensor design
• Designed for Cy5.5 sensing• Vertical-cavity surface-emitting laser
(VCSEL), emitting at 675nm • Large-area, low dark current, uncooled
GaAs photodiode • Integrated excitation blocking elements
– Thin-film fluorescence emission combined with miniature optical filter
– Metal blocking layers
Packaged sensor with collimation lens
5x10 array of sensors Excitation blocking elements
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Outline
Motivation and background Implantable sensor design and fabrication In vivo monitoring of a molecular probe
in a tumor Blood Coagulation Sensor Neural Activity Sensor Summary
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How to monitor a cancerous tumor
Molecule of interest
Cy5.5 dye
Cancer
● Tumors start as a single cell, and divide/grow to a mass of cells
● At some point their growth is limited because of a lack of nutrients/oxygen recruits new blood vessels (angiogenesis)
● New blood vessels (neovasculature) have an up-regulated integrin receptor (αVβ3)
Fluorescent probe
?
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Sensor performance:In vivo sensitivity
• Injected live anesthetized mouse subcutaneously on dorsum with 50µL dilutions Cy5.5
• Sensed Cy5.5 concentration down to 50nM• Correlates with CCD-based fluorescence imager
10 100 1000
1E9
1E10
N=2 mice each concentration
Correlation of Sensor and CCD Imager
CC
D M
ax R
adia
nce
(p/s
ec/c
m2 /s
r)
Sensor Photocurrent (pA)
50nM
100nM
250nM
500nM
2.5M
5M
10M
100 1000 10000
10
100
1000
Variation due to background
Subcutaneous in vivo Sensitivity
Se
nso
r P
ho
tocu
rre
nt (
pA
)
Cy5.5 Concentration (nM)
Live Nude(Nu/Nu) Anesthetized Mouse
Dye
Control
50nM in vivo sensitivity
T. O’Sullivan et al, Opt. Express 18, (2010)
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Cy5.5-RGD accumulates at tumor sites
RGDCy5.5 dye
Cancerous cell / angiogenesis
Cy5.5
Cheng et al. Bioconjugate Chem., Vol. 16 No. 6 2005
Cy5.5-RGD binds to neovasculature associated with
cancer
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Application: Study binding kinetics of molecular probe in cancer tumors
• Continuously monitored the RGD-Cy5.5 and RAD-Cy5.5 probe in live anesthetized animals for 2-4 hours post-injection
• We are able to study binding kinetics with higher temporal resolution
0 1 2 3 40
10
20
30
40
50
60
AC
Ph
oto
curr
en
t (R
MS
-pA
)
Time (hr)
Tumor Control
0 1 20
10
20
30
40
50
60
AC
Ph
oto
curr
en
t (R
MS
-pA
)
Time (hr)
Tumor Control
Tumor-specific probe (RGD-Cy5.5) Not tumor-specific (RAD-Cy5.5)
T. O’Sullivan et al, in preparation (2010)
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Application: Study binding kinetics of molecular probe in cancer tumors
• Continuously monitored the RGD-Cy5.5 and RAD-Cy5.5 probe in live anesthetized animals for 2-4 hours post-injection
• We are able to study binding kinetics with higher temporal resolution• Device is also sensitive to changes in anesthesia (blood
oxygenation)
0 1 2 3 40
10
20
30
40
50
60
AC
Ph
oto
curr
en
t (R
MS
-pA
)
Time (hr)
Tumor Control
Tumor-specific probe (RGD-Cy5.5)
650 700 750 800 850 900 950 10000.0
0.2
0.4
0.6
0.8
1.0
Abs
orpt
ion
(mm
-1m
M-1)
Wavelength(nm)
Tissue NIR absorbers
HHb
O2Hb
BULK LIPID
H2O
T. O’Sullivan et al, in preparation (2010)
Changes in anesthesia
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Transitioning to theimplanted sensor
• The cable is a significant source of noise for analog readout
• Packaged the sensor with a low-noise readout circuit (collaboration with Roxana Heitz / Prof. Bruce Wooley Group)
• Represents first step towards realizing wireless operation
0 50 100 150 200 2501.0
2.0
3.0
4.0
5.0
Pho
tocu
rren
t (nA
)
Time (s)
Detector with analog readout Detector with digital readout
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Miniaturization for Implantation
• Fabricated small (10mm x 10mm custom PCB, 0.031’’ thick) for bonding chips directly
• Ability to sample continuously at 5kHz / 5pA resolution / up to 20nA
• Device encapsulated in insulating biocompatible epoxy for direct implantation in rodents
• Weight: <1g, Size: 10x10x8mm
1cm
Suture holes
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Miniaturization for implantation
Implanted sensor
Implanted sensor
Freely-moving animal subject
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Outline
Motivation and background Implantable sensor design and fabrication In vivo monitoring of a molecular probe in
a tumor Blood Coagulation Sensor Neural Activity Sensor Summary
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Compact thrombin sensors integrated ‘in-line’ could greatly improve survival:real-time hemostasis management during surgeries, hemodialysis
Beckman Coulter
Medscape.org, Rockwell Medical
Existing techniques measure clotting time or assess viscoelasticity
only provide ‘snapshots’ bulky, expensive instrumentation trained personnel
Thrombin indicates activation of the coagulation cascade, and plays an active role in hemostasis
controlledhemostasis
thrombosishemorrhage
Regulation of coagulation is crucial:
Real-time, continuous blood monitoring
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Optical fiber whole blood prothrombin assay
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vascular injury (blood exposed to tissue factor)
TFVIIa
Prothrombin
IXa Xa
VIIIaVa
Thrombin
Fibrinogen Fibrin Clot
XIaXIa
Coagulation cascade: thrombin molecular probes
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vascular injury (blood exposed to tissue factor)
TFVIIa
Prothrombin
IXa Xa
VIIIaVa
Cys-Gly-D-Phe-Pip-Arg - Ser-Gly-Gly-Gly-G-LysThrombin
CY5.5 quencher
Fibrinogen Fibrin Clot
XIaXIa
vascular injury (blood exposed to tissue factor)
TFVIIa
Prothrombin
IXa Xa
VIIIaVa
Thrombin
Fibrinogen Fibrin Clot
XIaXIa
First probe modeled after C.H. Tung et al., modified with quencher dyes Probe synthesized and characterized
for IRQC-1, IRQC-2, BHQ3, QSY21, QXL680
Coagulation cascade: thrombin molecular probes
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vascular injury (blood exposed to tissue factor)
TFVIIa
Prothrombin
IXa Xa
VIIIaVa
Cys-Gly-D-Phe-Pip-Arg - Ser-Gly-Gly-Gly-G-LysThrombin
CY5.5 quencher
Fibrinogen Fibrin Clot
XIaXIa
vascular injury (blood exposed to tissue factor)
TFVIIa
Prothrombin
IXa Xa
VIIIaVa
Thrombin
Fibrinogen Fibrin Clot
XIaXIa
In the absence of thrombin, Cy5.5 fluorescence is quenched
Coagulation cascade: thrombin molecular probes
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peptide cleavage
vascular injury (blood exposed to tissue factor)
TFVIIa
Prothrombin
IXa Xa
VIIIaVa
Cys-Gly-D-Phe-Pip-Arg - Ser-Gly-Gly-Gly-G-LysThrombin
CY5.5 quencher
Fibrinogen Fibrin Clot
XIaXIa
vascular injury (blood exposed to tissue factor)
TFVIIa
Prothrombin
IXa Xa
VIIIaVa
Thrombin
Fibrinogen Fibrin Clot
XIaXIa
In the presence of thrombin, Cy5.5 and quencher separate fluorescence emission increases
Ser-Gly-Gly-Gly-G-Lys
quencher
CY5.5
Cys-Gly-D-Phe-Pip-Arg
Ser-Gly-Gly-Gly-G-Lys
quencher
CY5.5
Cys-Gly-D-Phe-Pip-Arg
Coagulation cascade: thrombin molecular probes
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peptide cleavage
vascular injury (blood exposed to tissue factor)
TFVIIa
Prothrombin
IXa Xa
VIIIaVa
Cys-Gly-D-Phe-Pip-Arg - Ser-Gly-Gly-Gly-G-LysThrombin
CY5.5 quencher
Fibrinogen Fibrin Clot
XIaXIa
vascular injury (blood exposed to tissue factor)
TFVIIa
Prothrombin
IXa Xa
VIIIaVa
Thrombin
Fibrinogen Fibrin Clot
XIaXIa
Confirmed up to up to ~4x increases so far in 15 min incubation time, not 24 hrs
Optimizations for speed, contrast underway
Ser-Gly-Gly-Gly-G-Lys
quencher
CY5.5
Cys-Gly-D-Phe-Pip-Arg
Ser-Gly-Gly-Gly-G-Lys
quencher
CY5.5
Cys-Gly-D-Phe-Pip-Arg
Coagulation cascade: thrombin molecular probes
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Outline
Motivation and background Implantable sensor design and fabrication In vivo monitoring of a molecular probe in
a tumor Blood Coagulation Sensor Neural Activity Sensor Summary
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Need for an Alternate TPM Source
Microscope with MML laser
Replace current LARGE and COSTLY mode locked lasers
More mobility for animals Continuous real-time monitoring Highly parallel animal studiesSchnitzer group, Stanford
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Two Photon Microscopy
Non-linear deep tissue imaging Neuroscience and bio-imaging Fluorescence is excited by absorbing
two photons simultaneously (~10-16 s) 890nm < λ < 940nm
Excitation (Intensity)2
~125pJ per pulse Sub-picosecond pulse length
Advantages of TPM Localized excitation Better noise immunity Image 100s um deep 3 dimensional maps
a) One Photon b) Two-PhotonNonlinear magic: multiphoton microscopy in the biosciences,
Nature Biotechnology 2003,Warren R Zipfel, Rebecca M Williams & Watt W Webb
∆
E2
E1
E1
∆
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Mark Schnitzer Lab Stanford
Two photon neural imaging
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Mode-Locking Repetition Rate
• Pulse Energy = PAVG/Repetition Rate– Lower R More energy per pulse for a given power– 1GHz, 125pJ/pulse 125mW Average power
• 1GHz repetition rate requires a 42mm GaAs cavity -- impractical– Use external cavity– Increase ng to shrink cavity
f
fT 1
nL
cfR
2
Adapted from R. I. Aldaz thesis, Stanford University
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Mode-Locked Repetition Rate (2)
• Longer effective cavity lower rep rate and more energy/pulse
Adapted from R. I. Aldaz thesis, Stanford University
nL
cfR
2
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Monolithic Mode Locked Lasers (MMLL)
Design Challenges Passive Mode Locking for an integrated device Small and light MMLL R=2xL/c, 100Mhz requires 1.5m air or 40cm GaAs cavity 100 pJ/pulse or Average Power ~10 mW Pulse widths 1~50 ps in integrated MLL
Mode-locked quantum-dot lasers,E. U. Rafailov, M. A. Cataluna & W. Sibbett,Nature Photonics 1, 395 - 401 (2007)
QW
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Optically Pumped PCW MLL Design
• Two section photonic crystal slow light waveguide cavity– Optically pumped gain section– Electrically reverse bias saturable absorber (SA) – Sweeps out photo-generated carriers quickly– p-contact made to selectively etch p+ GaAs cap layer; n-
backside contact – Photonic crystal mirrors, one partially transmitting, form cavity.
Pump Laser
-VA
SLOW Waveguide
95% Photonic Crystal Mirror
99.99% Photonic Crystal Mirror
n-doped
p-doped
adapted from E. U. Rafailov et al, Nature Photonics, Vol. 1 (2007).
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Slow Light in Photonic Crystal Waveguides
• Two Regimes:• Steep angle of incidence
– Near Γ point– E.g. DBR mirrors– Not confined in a slab
• Nearly parallel to axis– Near band edge– TIR top & bottom mirrors• Must operate below light line
for propagating modes
– Large ng (10s-100s)
– Very sensitive to fabrication– Very large dispersion
• Up to 109 ps2/kmT. Krauss, J. Phys. D: Appl. Phys. 40 (2007)
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Saturable Absorber Biasing
• Lateral Biasing– Complex fabrication involving selective area ion implantation– InP regrown buried heterojunctions CW room temp lasing @
1.55um
• Vertical Biasing– Simple but inefficient, only need to sweep out carriers not inject
• Method of choice for prototype device
S. Matsuo et al., Optics Express, Jan (2011).B. Ellis et al., Nature Photonics, Apr (2011).
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Light Output
QW Laser in Slow Light PC
• Combine control of electronic and photonic states– Monolithic Passively Mode Locked Edge Emitting Photonic
Crystal Waveguide Laser (MPMLEEPCWL)
AlGaAs Cladding Layer
AlGaAs Cladding Layer
GaAs Substrate
Gain RegionSaturable Absorber
GaAs SQW/MQW Layer
PC Slow Light Waveguide( in active layer)
Laser Gain Electrode
Saturable Absorber Electrode
PC Air Columns
Side View of Wafer Top View of Device
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First Indication of Mode-Locking
Gain SA
p-AlGaAs Cladding
n-AlGaAs Cladding
n-GaAs Substrate
p+ GaAs Cap
1x AlInGaAs QDs
Gain Section
Saturable Absorber
Output, 920nm
22.3 GHz!!!
K. Leedle, Late News CLEO San Jose 2013
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RF Spectrum and Autocorrelation
• Assume sech2 pulse shape ~4ps pulses• 18.1 GHz rep rate
Laser RF Spectrum
4.0ps
560mA, -2.5V SA
Autocorrelation
560mA, -2.5V SA
K. Leedle, Late News CLEO San Jose 2013
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• Definite threshold hysteresis under most conditions• Nearly 10x jump at threshold typical, easy to tell by SA current
200 300 400 500 6000
2
4
6
8
10
12
14
16
18
Current [mA]
Pow
er [
mW
]
LI Curves
Saturable AbsorberFloating0.0V-1.0V-2.0V-2.5V-3.0V-3.5V-4.0V
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Integrated sensor arrays are a foundation for bio-medical diagnostics, continuous tumor monitoring, drug development and minimally invasive in-vivo imaging
Integrated bio-sensor arrays can be easily fabricated to realize high throughput, compact, cheap bio-sensor arrays
Photonic crystal-laser integration offers unique opportunity to control both electronic and photonic states to produce new systems for high sensitivity sensing
Development of a new class of engineered, near IR fluorescent proteins is an absolute game changer for in-vivo molecular imaging
Prediction: Nanotechnology will have its greatest impact in biology and medicine
Summary
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Acknowledgements
COLLABORATORS
Students Postdocs Faculty ColleaguesEvan Thrush Ofer Levi Mark SchnitzerThomas O’Sullivan Pascale El-Kallassi Sam GambhirMeredith Lee Zac Walls Jim ZehnderAltamash Janjua Ophir Vermesh Natesh ParashruamaKen Leedle Alfred ForchelElizabeth Munro
SUPPORTStanford BioX ProgramSanofiNSF
Thank You