age of the photon: the billion dollar legacy of britton chance
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Age of the Photon: The Billion Dollar Legacy of Britton Chance. David Benaron, MD Founding (and Former) Director Stanford Biophotonics Program Prof | Stanford School of Medicine and Chief Executive Officer | Spectros. BC Memorial June 2011. Where is the Need? Optics “State of the Art” - PowerPoint PPT PresentationTRANSCRIPT
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Age of the Photon:Age of the Photon:
The Billion Dollar Legacy of Britton ChanceThe Billion Dollar Legacy of Britton Chance
David Benaron, MD
Founding (and Former) DirectorStanford Biophotonics Program
Prof | Stanford School of Medicineand
Chief Executive Officer | Spectros
David Benaron, MD
Founding (and Former) DirectorStanford Biophotonics Program
Prof | Stanford School of Medicineand
Chief Executive Officer | Spectros
BC MemorialJune 2011
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1.1. Where is the Need?Where is the Need?
2.2. Optics “State of the Art”Optics “State of the Art”
3.3. Clinical Applications in Tissue Clinical Applications in Tissue OximetryOximetry
4.4. Where is this going?Where is this going?
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Which subject is dead?Which subject is dead?
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1.1. Where is the Need?Where is the Need?
2.2. Optics “State of the Art”Optics “State of the Art”
3.3. Clinical Applications in Tissue Clinical Applications in Tissue OximetryOximetry
4.4. Where is this going?Where is this going?
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Cells can be labeled and optically scanned Cells can be labeled and optically scanned ex vivo ex vivo using Flow Cytometryusing Flow Cytometry
Scanning of cells by Flow cytometry
(Benaron et al, 1982)
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Wanted to Reduce C-Section Rates, Wanted to Reduce C-Section Rates, Improve Delivery MonitoringImprove Delivery Monitoring
““There’s someone you need to meet””There’s someone you need to meet””
Maria Delivoria-PapadopoulosMaria Delivoria-Papadopoulos
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Fiber Headband on head of infant
Benaron, Cheong, et al. (1992)
Optical Tomography: The Early YearsOptical Tomography: The Early Years
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Not Your Parents’ Optics:Not Your Parents’ Optics:Optic Monitoring Includes Images, ReportersOptic Monitoring Includes Images, Reporters
Optical sensors and markers can be tested in vitro then the same model Optical sensors and markers can be tested in vitro then the same model is transferred to in vivo real time testingis transferred to in vivo real time testing
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PneumoniaPeritonitis
Lesions as small as 100 m tagged with optical emitters can be seen from outside the body in real time.
(Data: Xenogen and C. Contag, Stanford).
Bioluminescent Emitters Image In VivoBioluminescent Emitters Image In Vivo
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MethodMethodMinimum Minimum
DetectableDetectableSize (Size ())
MinimuMinimum m
Detected Detected Cells (n)Cells (n)
MRIMRI 2 mm2 mm 400,000400,000
(MRSI)(MRSI) 7 mm7 mm 1,000,001,000,0000
CTCT 2 mm2 mm 400,000400,000
RadionucliRadionuclidede 3 mm3 mm 600,000600,000
PETPET 2 mm2 mm 400,000400,000
HFUSHFUS <1 mm<1 mm 100,000100,000
Optics Shows Highest SensitivityOptics Shows Highest Sensitivity
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Method Sensitivity
Minimum
Detected Cells
MRI 2 mm 400,000
(MRSI) 7 mm1,000,00
0
CT 2 mm 400,000
Radionuclide
3 mm 600,000
PET 2 mm 400,000
HFUS 1 mm 100,000
OpticsOptics 0.05 mm0.05 mm 1-1001-100
Optics Shows Highest SensitivityOptics Shows Highest Sensitivity
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Hematopoesis from a single stem cell.
Cao et al. Shifting foci of hematopoiesis during reconstitution from single stem cells. Proc Nat Acad Sci USA. 2004;101(1):221-226.
Optical Imaging Detects Single Stem Optical Imaging Detects Single Stem EngraftmentEngraftment
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Optically labeled stem cells can be seen singly in vivo Optically labeled stem cells can be seen singly in vivo in bone marrow.in bone marrow.
Proc Natl Acad Sci 2009 from University of Tsukuba, Proc Natl Acad Sci 2009 from University of Tsukuba, Japan and Univ. of Michigan Medical School.Japan and Univ. of Michigan Medical School.
Optical Imaging Detects Single Stem CellsOptical Imaging Detects Single Stem Cells
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This prize was rightly BC’sThis prize was rightly BC’s
-- Optical contrast-- Optical contrast-- In vivo imaging-- In vivo imaging-- Spectroscopy-- Spectroscopy-- Metabolism-based-- Metabolism-based
2008 Nobel in Chemistry Awarded for2008 Nobel in Chemistry Awarded for“in vivo Optical Contrast Agent”“in vivo Optical Contrast Agent”
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"optical molecular imaging" OR "biophotonics“:> 1 million hits on Google
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• 4 billion cells per cc of blood
• Large volume cell imaging
• 1 min collection, 5 sec imaging time
• Useful for:
− Circulating rare cell detection
− Early sepsis detection
Cells can be detected in whole blood with Cells can be detected in whole blood with ordinary pathology labelsordinary pathology labels
Real-time imaging of labeled probes in 1-10 cc whole blood
(Benaron et al, 2011 Project with Stanford Stem Cell Center, Sloan-Kettering Cancer Center)
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Out with the Old ApproachOut with the Old Approach::Blind, Watchful waitingBlind, Watchful waitingEscalate care and monitoring Escalate care and monitoring whenever the patient gets ill whenever the patient gets ill
New Monitoring ApproachNew Monitoring Approach::More continuous,More continuous, Less Invasive monitoring. . .Less Invasive monitoring. . .
Time to Change the ParadigmTime to Change the Paradigm
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1.1. Where is the Need?Where is the Need?
2.2. Optics “State of the Art”Optics “State of the Art”
3.3. Clinical Applications in Tissue Clinical Applications in Tissue OximetryOximetry
4.4. Where is this going?Where is this going?
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1990s: multi-spectral pulse oximetry1990s: multi-spectral pulse oximetry (N wavelengths = N unknowns)(N wavelengths = N unknowns)
• More accurate: Hemoglobins, Hct, Bilirubin…More accurate: Hemoglobins, Hct, Bilirubin…• Developed at StanfordDeveloped at Stanford• Introduced by MasimoIntroduced by Masimo• Public for $2B in late ‘00sPublic for $2B in late ‘00s
Multispectral Pulse OximetryMultispectral Pulse Oximetry
1980s: 2-wavelength pulse oximetry1980s: 2-wavelength pulse oximetry (2 wavelengths = 2 unknowns)(2 wavelengths = 2 unknowns)
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650 700 750 800 850 900 950 10000.24
0.26
0.28
0.3
0.32
0.34
0.36
0.38
0.4
0.42 Spectral Fit
Wavelength (nm)
Opt
ical
De
nsity
Original Data
Oxy-Hb
Deoxy-Hb
Water
Fit to Data
Calculation of Oxygenation (NIRS)Calculation of Oxygenation (NIRS)
• n Wavelengths = n unknownsn Wavelengths = n unknowns
• Hemoglobin, fat, water allHemoglobin, fat, water all affect light in tissue affect light in tissue
• More wavelengths =More wavelengths = more accuracy more accuracy
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VLS
VLS, UV and NIRS Measure VLS, UV and NIRS Measure Different Regions of TissueDifferent Regions of Tissue
NIRS
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T-Stat Monitor* Invos Monitor
CAS Fore-Site* Hutchinson InSpectra
Noninvasive Tissue OximetryNoninvasive Tissue OximetryThe single most The single most common cause of common cause of death in the hospital death in the hospital remains inability to remains inability to supply sufficient supply sufficient oxygen to meet a oxygen to meet a tissues’ needs.tissues’ needs. * = multispectral * = multispectral
Nonin
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Multispectral Tissue Oximetry Multispectral Tissue Oximetry Correlates with SvoCorrelates with Svo22
Background: This study compared multispectral VLS tissue Sto2 as measured by T-Stat to venous Svo2 as measured by Swan-Ganz (PAC) catheter at the Stanford University Medical Center, Palo Alto, CA. Methods:Subjects undergoing cardiac surgery on cardiopulmonary bypass were monitored using non-invasive VLS monitoring, sensitive to ischemia. Results:Swan values were measured and compared to Sto2 values (r2 = 0.94).
Conclusions:VLS oximetry is correlated to measures of central venous oxygen. The relationship in of Svo2 to Sto2 in normoxia to hyperoxia appears to be linear
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Multispectral Tissue OximetryMultispectral Tissue OximetryCorrelates w/SvoCorrelates w/Svo2 2 to very low satsto very low sats
Background: This study compared multispectral VLS tissue Sto2 as measured by T-Stat to venous Svo2 as measured by Swan-Ganz (PAC) catheter at the Stanford University Medical Center, Palo Alto, CA. Methods:Neonates were monitored using a VLS buccal probe for a period of 48-h post congenital open-heart procedures. Buccal readings were correlated to central SvO2 obtained from blood draws during this period. Results:25 neonates monitored post op. Age 5 +/- 26 mo.; weight 6.4 +/- 4.3 kg).
Conclusions:VLS multispectral tissue oximetry linearly correlated with SvO2.
y = 0.9881x - 3
R2 = 0.5153
20
30
40
50
60
70
80
20 30 40 50 60 70 80
SvO2
Bucc
al
20 30 40 50 60 70 80 Svo2
80
70
60
50
40
30
20
To be presented in the Am. Cardiology Congress 2011, Phoenix AZ
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Correlates with Aortic FlowCorrelates with Aortic Flow
r 2 = 0.98
0
10
20
30
40
50
60
0 2 4 6 8 10
Doppler Flow (a.u.)
Col
on T
issu
e S
atur
atio
n (S
tO2)
Ramp Down
Ramp Up
StO2
Linear (RampDown)
Blood flow in the Abdominal Aorta is highly correlated with serosal intestinal saturation during stepwise reductions and reestablishment of Aortic blood flow.
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Imaging Necrotizing EnterocolitisImaging Necrotizing Enterocolitis
68±4%
68±3%
13±12%
67±4%
22±8%
NIH Grants EB008355, CA126441 (Wong, Stanford, 2009)
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0
20
40
60
80
100
0 2 4 6 8 10
Time in ICU (h)
Sa
tura
tio
n (
%)
Flap VLS Oxygenation
Normal Range (95% C.I.)
Take Back
Falls BelowNormal
Background: This study describes the normal post-operative recovery of perfusion to DIEP flaps.
Methods:41 DIEP flaps were monitored post-operatively using a VLS surface probe placed on the flap for a period of 60 h. No flaps required takeback, or experienced complete or partial flap loss. The mean and 95% CI was compared to a subsequent flap that was taken back for revision approximately 9 hours post surgery.
Results:VLS provides a repeatable baseline for flap recovery, and may be able to detect reduced flap perfusion earlier than existing methods.
Tissue Oximetry in SurgeryTissue Oximetry in Surgery
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Monitoring with Monitoring with Contrast AgentsContrast Agents
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Frangioni slide
Dye in LymphDye in Lymph
Subcutaneous injection of fluorescent dye allows real time lymphatic tracing
Frangioni et al (2007)
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(A) A post-CABG intraoperative image shows no flow in graft (arrow)(B) Revised, and graft working prior to closure
(from Novadaq, 2008)
ICG Intraoperative Coronary Imaging SystemICG Intraoperative Coronary Imaging System
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Implantable fluorescent microspheres made of polyethylene glycol that have an assay chemistry specific to glucose that changes the fluorescence work in conjunction with an external optical biosensor (LED light source) to enable noninvasive glucose monitoring.
(Courtesy Texas A&M, 2008)
Microsphere reporters can be monitoredMicrosphere reporters can be monitored
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BC: Born July 24, 1913BC: Born July 24, 1913
Britton and BrittonBritton and Britton
BB: Born July 24, 1999BB: Born July 24, 1999
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1.1. Where is the Need?Where is the Need?
2.2. Optics “State of the Art”Optics “State of the Art”
3.3. Clinical Applications in Tissue Clinical Applications in Tissue OximetryOximetry
4.4. Where is this going?Where is this going?
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►► The 21st Century is the Age of the Photon. In biology, The 21st Century is the Age of the Photon. In biology, biochemistry, and medicine, it was BC who led the way.biochemistry, and medicine, it was BC who led the way.
►► Nanotechnology allows for sensors only tens of atoms acrossNanotechnology allows for sensors only tens of atoms across
− Sensors will be too small to even see − Sensors will be too small to even see− − Small sensors diffuse everywhere, report from anywhereSmall sensors diffuse everywhere, report from anywhere− − Enable massively-parallel multi-parametric monitoringEnable massively-parallel multi-parametric monitoring− − Nanobots will enable self-guiding sensor/treatmentsNanobots will enable self-guiding sensor/treatments
““Nano” will change everything we doNano” will change everything we do