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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.

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Presentation on theme: "Age of the Photon: The Billion Dollar Legacy of Britton Chance David Benaron, MD Founding (and Former) Director Stanford Biophotonics Program Prof | Stanford."— Presentation transcript:

1 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 David Benaron, MD Founding (and Former) Director Stanford Biophotonics Program Prof | Stanford School of Medicine and Chief Executive Officer | Spectros BC Memorial June 2011

2 1.Where is the Need? 2.Optics “State of the Art” 3.Clinical Applications in Tissue Oximetry 4.Where is this going?

3 Which subject is dead?

4 1.Where is the Need? 2.Optics “State of the Art” 3.Clinical Applications in Tissue Oximetry 4.Where is this going?

5 Cells can be labeled and optically scanned ex vivo using Flow Cytometry Scanning of cells by Flow cytometry (Benaron et al, 1982)

6 Wanted to Reduce C-Section Rates, Improve Delivery Monitoring “There’s someone you need to meet”” Maria Delivoria-Papadopoulos Maria Delivoria-Papadopoulos

7 Fiber Headband on head of infant Benaron, Cheong, et al. (1992) Optical Tomography: The Early Years

8 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

9 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 Vivo

10 Method Minimum Detectable Size (  ) Minimum Detected Cells (n) MRI 2 mm 400,000 (MRSI) (MRSI) 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 Shows Highest Sensitivity

11 MethodSensitivity Minimum Detected Cells MRI2 mm400,000 (MRSI)7 mm1,000,000 CT2 mm400,000 Radionuclide3 mm600,000 PET2 mm400,000 HFUS1 mm100,000 Optics 0.05 mm Optics Shows Highest Sensitivity

12 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): Optical Imaging Detects Single Stem Engraftment

13 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. Optical Imaging Detects Single Stem Cells

14 This prize was rightly BC’s -- Optical contrast -- In vivo imaging -- Spectroscopy -- Metabolism-based 2008 Nobel in Chemistry Awarded for “in vivo Optical Contrast Agent”

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

16 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 ordinary 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)

17 Out with the Old Approach: Blind, Watchful waiting Escalate care and monitoring whenever the patient gets ill New Monitoring Approach: New Monitoring Approach: More continuous, Less Invasive monitoring... Less Invasive monitoring... Time to Change the Paradigm

18 1.Where is the Need? 2.Optics “State of the Art” 3.Clinical Applications in Tissue Oximetry 4.Where is this going?

19 1990s: multi-spectral pulse oximetry (N wavelengths = N unknowns) (N wavelengths = N unknowns) More accurate: Hemoglobins, Hct, Bilirubin… More accurate: Hemoglobins, Hct, Bilirubin… Developed at Stanford Developed at Stanford Introduced by Masimo Introduced by Masimo Public for $2B in late ‘00s Public for $2B in late ‘00s Multispectral Pulse Oximetry 1980s: 2-wavelength pulse oximetry (2 wavelengths = 2 unknowns) (2 wavelengths = 2 unknowns)

20 Spectral Fit Wavelength (nm) Optical Density Original Data Oxy-Hb Deoxy-Hb Water Fit to Data Calculation of Oxygenation (NIRS) n Wavelengths = n unknownsn Wavelengths = n unknowns Hemoglobin, fat, water all affect light in tissueHemoglobin, fat, water all affect light in tissue More wavelengths = more accuracyMore wavelengths = more accuracy

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

22 T-Stat Monitor*Invos Monitor CAS Fore-Site*Hutchinson InSpectra 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

23 Multispectral Oximetry in Neonates

24 Multispectral Tissue Oximetry Correlates with Svo 2 Background: This study compared multispectral VLS tissue Sto 2 as measured by T-Stat to venous Svo 2 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 Sto 2 values (r 2 = 0.94). Conclusions: VLS oximetry is correlated to measures of central venous oxygen. The relationship in of Svo 2 to Sto 2 in normoxia to hyperoxia appears to be linear

25 Multispectral Tissue Oximetry Correlates w/Svo 2 to very low sats Background: This study compared multispectral VLS tissue Sto 2 as measured by T-Stat to venous Svo 2 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 SvO Svo To be presented in the Am. Cardiology Congress 2011, Phoenix AZ

26 Correlates with Aortic Flow Blood flow in the Abdominal Aorta is highly correlated with serosal intestinal saturation during stepwise reductions and reestablishment of Aortic blood flow.

27 Imaging Necrotizing Enterocolitis 68±4% 68±3% 13±12% 67±4% 22±8% NIH Grants EB008355, CA (Wong, Stanford, 2009)

28 What are normal tissue values? In a study completed at Mills Peninsula Hospital in San Mateo, California, normal values were collected on 30 free flaps. The average value after the patient left the OR was 48% saturation, followed by a steady increase to 60% after 6 hours. After the initial 12 hours, the most critical time for the flap, the average values roughly at 65%. Soon after day one of the procedure the values stabilized just below 70% and remained for the duration of the patient stay. Tissue Oximetry in Skin Flap Surgery

29 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 Surgery

30 Monitoring with Contrast Agents

31 Frangioni slide Dye in Lymph Subcutaneous injection of fluorescent dye allows real time lymphatic tracing Frangioni et al (2007)

32 (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 System

33 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 monitored

34 BC: Born July 24, 1913 BC: Born July 24, 1913 Britton and Britton BB: Born July 24, 1999 BB: Born July 24, 1999

35 1.Where is the Need? 2.Optics “State of the Art” 3.Clinical Applications in Tissue Oximetry 4.Where is this going?

36 ► The 21st Century is the Age of the Photon. In biology, biochemistry, and medicine, it was BC who led the way. ► 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 “Nano” will change everything we do


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