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
1. Where is the Need?
2. Optics “State of the Art”
3. Clinical Applications in Tissue
Oximetry
4. Where is this going?
Which subject is dead?
1. Where is the Need?
2. Optics “State of the Art”
3. Clinical Applications in Tissue
Oximetry
4. Where is this going?
Cells can be labeled and optically scanned
ex vivo using Flow Cytometry
Scanning of cells by
Flow cytometry
(Benaron et al, 1982)
Wanted to Reduce C-Section Rates,
Improve Delivery Monitoring
“There’s someone you need to meet””
Maria Delivoria-Papadopoulos
Optical Tomography: The Early Years
Fiber Headband
on head of infant
Benaron, Cheong, et al. (1992)
Not Your Parents’ Optics:
Optic Monitoring Includes Images, Reporters
Optical sensors and markers can be tested in vitro then the same model
is transferred to in vivo real time testing
Bioluminescent Emitters Image In Vivo
Peritonitis
Pneumonia
Lesions as small as 100 mm tagged with
optical emitters can be seen from outside
the body in real time.
(Data: Xenogen and C. Contag, Stanford).
Optics Shows Highest Sensitivity
Minimum
Detectable
Size (f)
Minimum
Detected
Cells (n)
2 mm
400,000
7 mm
1,000,000
CT
2 mm
400,000
Radionuclide
3 mm
600,000
PET
2 mm
400,000
HFUS
<1 mm
100,000
Method
MRI
(MRSI)
Optics Shows Highest Sensitivity
Sensitivity
Minimum
Detected
Cells
2 mm
400,000
7 mm
1,000,000
CT
2 mm
400,000
Radionuclide
3 mm
600,000
PET
2 mm
400,000
HFUS
1 mm
100,000
Optics
0.05 mm
Method
MRI
(MRSI)
1-100
Optical Imaging Detects Single Stem
Engraftment
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 Cells
Optically labeled stem cells can be seen singly in vivo
in bone marrow.
Proc Natl Acad Sci 2009 from University of Tsukuba,
Japan and Univ. of Michigan Medical School.
2008 Nobel in Chemistry Awarded for
“in vivo Optical Contrast Agent”
This prize was rightly BC’s
-- Optical contrast
-- In vivo imaging
-- Spectroscopy
-- Metabolism-based
"optical molecular imaging" OR "biophotonics“:
> 1 million hits on Google
Cells can be detected in whole blood with
ordinary pathology labels
• 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
Real-time imaging of labeled probes in
1-10 cc whole blood
(Benaron et al, 2011 Project with
Stanford Stem Cell Center, SloanKettering Cancer Center)
Time to Change the Paradigm
Out with the Old Approach:
Blind, Watchful waiting
Escalate care and monitoring
whenever the patient gets ill
New Monitoring Approach:
More continuous,
Less Invasive monitoring. . .
1. Where is the Need?
2. Optics “State of the Art”
3. Clinical Applications in Tissue
Oximetry
4. Where is this going?
Multispectral Pulse Oximetry
1980s: 2-wavelength pulse oximetry
(2 wavelengths = 2 unknowns)
1990s: multi-spectral pulse oximetry
(N wavelengths = N unknowns)
• More accurate: Hemoglobins, Hct, Bilirubin…
• Developed at Stanford
• Introduced by Masimo
• Public for $2B in late ‘00s
Calculation of Oxygenation (NIRS)
Original Data
Spectral Fit
0.42
Oxy-Hb
Deoxy-Hb
• n Wavelengths = n unknowns
Water
0.4
Fit to Data
Optical Density
0.38
• Hemoglobin, fat, water all
affect light in tissue
0.36
0.34
• More wavelengths =
more accuracy
0.32
0.3
0.28
0.26
0.24
650
700
750
800
850
900
Wavelength (nm)
950
1000
VLS, UV and NIRS Measure
Different Regions of Tissue
VLS
NIRS
Noninvasive Tissue Oximetry
The single most
common cause of
death in the hospital
remains inability to
supply sufficient
oxygen to meet a
tissues’ needs.
* = multispectral
Nonin
T-Stat Monitor*
Invos Monitor
CAS Fore-Site* Hutchinson InSpectra
Multispectral Tissue Oximetry
Correlates with Svo2
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 noninvasive 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 Oximetry
Correlates w/Svo2 to 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.
80
80
y = 0.9881x - 3
2
R = 0.5153
70
70
60
Buccal
60
Methods:
Neonates were monitored using a VLS buccal
probe for a period of 48-h post congenital openheart procedures. Buccal readings were
correlated to central SvO2 obtained from blood
draws during this period.
50
50
40
40
Results:
25 neonates monitored post op. Age 5 +/- 26
mo.; weight 6.4 +/- 4.3 kg).
30
30
20
20
20
20
30
30
40
40
50
50
Svo2
SvO2
60
60
70
70
80
80
To be presented in the Am. Cardiology Congress 2011,
Phoenix AZ
Conclusions:
VLS multispectral tissue oximetry linearly
correlated with SvO2.
Correlates with Aortic Flow
60
2
r = 0.98
Colon Tissue Saturation (StO2)
50
Blood flow in the
Abdominal Aorta is
highly correlated
with serosal
intestinal saturation
during stepwise
reductions and
reestablishment of
Aortic blood flow.
40
30
20
Ramp Down
10
Ramp Up
StO2
0
0
2
4
6
Linear8 (Ramp
Doppler Flow (a.u.) Down)
10
Imaging Necrotizing Enterocolitis
22±8%
68±4%
13±12%
68±3%
67±4%
NIH Grants EB008355, CA126441 (Wong,
Stanford, 2009)
Tissue Oximetry in Surgery
Background:
This study describes the normal
post-operative recovery of perfusion
to DIEP flaps.
80
Flap VLS Oxygenation
Normal Range (95% C.I.)
Saturation (%)
Methods:
41 DIEP flaps were monitored postoperatively 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.
100
60
Falls Below
Normal
40
Take Back
20
Results:
VLS provides a repeatable baseline
for flap recovery, and may be able to
detect reduced flap perfusion earlier
than existing methods.
0
0
2
4
6
Time in ICU (h)
8
10
Monitoring with
Contrast Agents
Dye in Lymph
Frangioni slide
Subcutaneous injection of fluorescent dye allows
real time lymphatic tracing
Frangioni et al (2007)
ICG Intraoperative Coronary Imaging System
(A) A post-CABG intraoperative image shows no flow in graft (arrow)
(B) Revised, and graft working prior to closure
(from Novadaq, 2008)
Microsphere reporters can be monitored
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)
Britton and Britton

BC: Born July 24, 1913

BB: Born July 24, 1999
1. Where is the Need?
2. Optics “State of the Art”
3. Clinical Applications in Tissue
Oximetry
4. Where is this going?
“Nano” will change everything we do
► The 21st Century is the Age of the Photon. In biology,
biochemistry, and medicine, it was BC who led the way.
► Nanotechnology allows for sensors only tens of atoms across
− Sensors will be too small to even see
− Small sensors diffuse everywhere, report from anywhere
− Enable massively-parallel multi-parametric monitoring
− Nanobots will enable self-guiding sensor/treatments