Fiber Optics - Window on Human Biology:  Olav Solgaard
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Fiber Optics - Window on Human Biology: Olav Solgaard

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Stanford Engineering Professor Olav Solgaard describes how optical fibers can be used to provide a crisp, three-dimensional window into human anatomy at a cellular level.

Stanford Engineering Professor Olav Solgaard describes how optical fibers can be used to provide a crisp, three-dimensional window into human anatomy at a cellular level.

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  • 1. Fiber optics: Window on human biology H. Ra, W. Piyawattanametha, E. Gonzalez-Gonzalez, J.-W. Jeung, Y.Taguchi, D. Lee, U. Krishnamoorthy, I.W. Jung, M. Mandela, J. Liu, K. Loewke, T. Wang G.S. Kino, C. Contag, O. Solgaard Stanford University Support: CIS, NIH, NSF O.Solgaard Stanford
  • 2. In-vivo Microscopy Tabletop Miniaturized Combined with image-guided, Microscope Microscope endoscopic surgery Tools for continuous observations of biological systems  Fundamental biology10 cm Optical microscopy is non-invasive with sub-cellular resolution  How do we see through tissue with a miniaturized optical microscope? O.Solgaard Stanford
  • 3. Use lasers, detectors, and lenses! O.Solgaard Stanford
  • 4. Optical Fiber cladding (n2) ~10um core (n1) 125um Optical fibers are glass cylinders  Highways of the internet Transmission band: 1,280 to 1,610 nm => 50 THz!  Transmission band of coaxial cable <10GHz O.Solgaard Stanford
  • 5. My Favorite Optical Device! O.Solgaard Stanford
  • 6. Camera Obscura – Pin Hole Cam The pinhole projects a scene on the camera screen Object at any distance are imaged with high fidelity (but upside down) The pinhole must be small to give a sharp image  => low light efficiency O.Solgaard Stanford
  • 7. The LENS enabled Telescopes and Microscopes! f a b The lens projects a scene on the camera screen Objects in focus (1/a+1/b=1/f) are imaged with high fidelity The lens can be large and still give a sharp image  => high light efficiency O.Solgaard Stanford
  • 8. Why combine a Pinhole Camera with a lens microscope? Detector Pinhole The lens projects a single volumetric pixel (voxel) on the pinhole Only light from the single voxel in focus is registered on the detector We scan the voxel around to get a 3-D image O.Solgaard Stanford
  • 9. We get 3-D AND we can see through scattering media! Detector We still see the voxel even if it is embedded in a scattering medium, e.g. tissue!  We get a less bright voxel, but it is not obscured by light from other voxels We can see into the body! (Camera not-obscura?) O.Solgaard Stanford
  • 10. Confocal Microscopy Confocal Microscopy SamplePoint SourceIllumination Beamsplitter Rejected Light Pinhole or Imag Rejected Image Reject Plane Plane SMF Accepted Accept Light Detector M. Minsky, Memoir on inventing the confocal microscope, Scanning, Vol. 10, Issue 4, 1988. O.Solgaard Stanford
  • 11. MicroElectroMechanical System (MEMS) Mirror substrate 1mm Top Device Layer Bottom Device Layer Substrate Thermal Oxide 1mm substrate O.Solgaard Stanford
  • 12. Operation of 2-D Scanner GND  Outer axis rotation = V1 and V2 V3  Inner axis rotation = V3 and V4 V2 substrate 1mmV1 GND V4 1mm substrate O.Solgaard Stanford
  • 13. 2-D Scanner Characterization V1 and V2 = Outer-axis rotation V3 and V4 = Inner-axis rotation Static mode Dynamic mode 6 V2 Outer axis 5 10 1 V1 Inner axis 4Optical deflection angle (degree) Optical deflection angle (degree) V3 3 V4 2 0 1 10 0 -1 -2 -1 10 -3 -4 -5 -6 10 -2 0 20 40 60 80 100 120 140 160 180 200 2 3 10 10 DC voltage (V) Driving frequency (Hz) − Outer axis: ±5.5° − Outer axis: ±11.8°@1.18kHz − Inner axis: ±3.8° − Inner axis: ±8.8°@2.76kHz 13 O.Solgaard Stanford
  • 14. DAC Design Schematic of the dual-axis confocal (DAC) microscope  HL: hemispherical lens  MEMS: microelectromechanical systems scanning mirror  PMT: photomultiplier tube The laser, PMT, and transimpedance amplifier setting and gains are constant within and across 3-D datasets for quantification. O.Solgaard Stanford
  • 15. Dual Axes Confocal Microscope O.Solgaard Stanford
  • 16. 3-D MEMS Scanning Two MEMS mirrors are used to enable 3-D scanning O.Solgaard Stanford
  • 17. Dual Axis Confocal Microscope O.Solgaard Stanford
  • 18. Raytracing of 3-D Scanning Total scanning volume = 340um × 236um × 286um Z-scanning by 1-D depth scanner 27.5um 143um FOVz (z axis=+/-27.5um) = 286um X-Y scanning by 2-D lateral scanner 2.7º 170umFOVx(q=+/- 2.7deg) = 340um / FOVy (q=+/- 1.9deg) = 236um O.Solgaard Stanford
  • 19. Dual Axis Confocal microscopes 10 mm with alignment optics  Skin Miniaturized 5 mm for endoscopy  GI tract 10 mm with GRIN extender  Brain imaging Implantable DAC  …. O.Solgaard Stanford
  • 20. Multimodality Package 1Wide-Field Fluorescence + DAC Microscope O.Solgaard Stanford
  • 21. Multimodality: DAC + Wide-field 300 micron FOV (confocal) 70 deg. FOV (wide-field) O.Solgaard 21 Stanford
  • 22. Multimodality Package 2Ultrasound + DAC Microscope O.Solgaard Stanford
  • 23. DAC Applications: Cancer Screening The first in vivo imaging in the GI tract of a patient using a MEMS- based confocal microscope has been demonstrated with the 785 nm 5-mm-diamter DAC microscope  Images are taken at 5 Hz with 2 frame averaging, yielding FWHM transverse and axial resolutions of 4 um and 7 um  The DAC endomicroscope was loaded in the instrument channel of a therapeutic upper GI endoscope  Topical application of ICG (25 mg of medical grade ICG diluted in 4 ml of aqueous solvent) ICG is a chromophore as well as a fluorophore, so we identify areas where ICG is binding well with a wide-field CCD camera, and then bring the DAC into contact with the tissue of interest. O.Solgaard Stanford
  • 24. Visualizing the Vasculature Normal Tumor Mouse Ear Tumor Model Jonathan Liu O.Solgaard Stanford
  • 25. Imaging of GFP in a Reporter Mouse of Medulloblastoma Jonathan LiuIn vivo tumor: through the skull Ventral side of the brain IVIS200 B. Maestro Image C. DAC DAC Medulloblastoma Normal brain O.Solgaard Stanford
  • 26. In vivo sequential imaging: siRNA silencing Experimental methods  Silencing the GFP reporter gene in the epidermis by intradermal injection of siRNA  Intradermally inject irrelevant control siRNA and specific siRNA (targeting GFP mRNA) in each footpad for 14 days  siRNA potently and specifically inhibits GFP expression in the epidermis, control siRNA has no effect Standard fluorescence microscope Stratum corneum GranulosumEx vivo Footpad skin skin gene silencing Green – GFPsections 20 µm 20 µm Irrelevant control siRNA Specific siRNA O.Solgaard Stanford
  • 27. Clinical test Topical application of IC-GREEN cream formulation  Excess cream removed with cotton pads after 15 - 30 mins  Gel used as an optical coupling agent Volunteer PC patient  Prior treatment  Intradermal injection of TD101 siRNA (right) and vehicle control solution (left) in symmetric plantar calluses  Twice weekly for 17 weeks  Imaged 48 days after last siRNA treatment Leachman, et al., Mol Ther, 2010 O.Solgaard Stanford
  • 28. siRNA as a Therapeutic Lieberman et al., Cell (2006) Short, 19-23 nucleotides long, double stranded RNA Any gene can be theoretically be silenced  Easy to synthesize  Can target multiple genes Highly specific and efficient (in cell culture)  Delivery is the rate limiting step to translation More than $4 billion worth of deals struck since 2000. Yet, no effective delivery tools described to date. O.Solgaard Stanford
  • 29. Evolution of theDAC Microscope at Stanford O.Solgaard 29 Stanford
  • 30. System ConceptSpatial Light Multimode Fiber Focused Light in Modulator (MMF) 3D (SLM)  A cylindrical, step-index waveguide can support propagating modes  NA = 1.33, a = 50 µm, λ = 550 nm => N ~ 175,000 = 4202 O.Solgaard Stanford
  • 31. Impact Studies of mammalian gene function and regulation Models of human diseases Molecular reporters  Fluorescent markers Continuous intravital optical microscopy will lead to new understanding of fundamental biological processes  Investigations of Biological processes over extended time  Cancer progression and metastasis  Stem cell regeneration and differentiation  Neurology  Optogenetics O.Solgaard Stanford