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

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?

Which subject is dead?Which subject is dead?

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?

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)

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

Fiber Headband on head of infant

Benaron, Cheong, et al. (1992)

Optical Tomography: The Early YearsOptical Tomography: The Early Years

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

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

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

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

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

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

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”

"optical molecular imaging" OR "biophotonics“:> 1 million hits on Google

• 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)

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

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?

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)

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

VLS

VLS, UV and NIRS Measure VLS, UV and NIRS Measure Different Regions of TissueDifferent Regions of Tissue

NIRS

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

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

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

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.

Imaging Necrotizing EnterocolitisImaging Necrotizing Enterocolitis

68±4%

68±3%

13±12%

67±4%

22±8%

NIH Grants EB008355, CA126441 (Wong, Stanford, 2009)

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

Monitoring with Monitoring with Contrast AgentsContrast Agents

Frangioni slide

Dye in LymphDye in Lymph

Subcutaneous injection of fluorescent dye allows real time lymphatic tracing

Frangioni et al (2007)

(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

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

BC: Born July 24, 1913BC: Born July 24, 1913

Britton and BrittonBritton and Britton

BB: Born July 24, 1999BB: Born July 24, 1999

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?

►► 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