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Blank. ENDOSCOPIC APPROACHES IN SURGERY Watt W. Webb, Applied Physics, Cornell University, Ithaca NY, USA A prototype for Cornell Collaboration of CU-Ithaca.

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Presentation on theme: "Blank. ENDOSCOPIC APPROACHES IN SURGERY Watt W. Webb, Applied Physics, Cornell University, Ithaca NY, USA A prototype for Cornell Collaboration of CU-Ithaca."— Presentation transcript:

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2 ENDOSCOPIC APPROACHES IN SURGERY Watt W. Webb, Applied Physics, Cornell University, Ithaca NY, USA A prototype for Cornell Collaboration of CU-Ithaca with CU-Weill. A model for ‘Academic Incubator’ to Technology Transfer Opportunities. How does it work: Multiphoton Microscopy (MPM) images fluoresce and SHG with submicroscopic three- dimensional resolution. WE FLUORESCE by MPM and Generate Second Harmonic (SHG), which micro-image tissue interior in real time. MPM images appear to be equivalent to pathologists’ subsequent H&E stained images of fixed tissue biopsies.

3 Single-photon excitation (488 nm) Two-photon excitation (900 nm) Because simultaneous absorption of two photons is required for excitation, the emission depends on the square of the intensity, rather than being linearly proportional. Significant excitation occurs only in the focal volume (at “normal” imaging intensities - mW range). F IxIx Femtosecond pulse train at 80 MHz Two Photon Excitation Is Spatially Localized

4 WE FLUORESCE - Non-linearly Intrinsic tissue (MPE) fluorescence (ITF) and Second Harmonic Generation (SHG) Which components emit and where? Spectroscopy & Image, here in pseudocolor. Information comes with these signals, including tissue environment, aggregation state, molecular orientation, etc. that is useful for medical diagnostics. How these signals can be detected most efficiently and least obtrusively is our research. There are appropriate biophysical and biomedical applications we are developing. Arteriole Heart Choroid Plexus / Pineal Gland Elastin Retinoids NADH Collagen SHG Indoleamines Collagen SHG

5 In Vivo Imaging of Surface Epithelia in Ovary of Conditional P53/rb Knockouts (Mice) Images: Rebecca M. Williams, Andrea Flesken-Nikitin, Alexander Nikitin, Watt W. Webb and Warren R. Zipfel, Cornell University. epithelium breathing artifact corpus luteum 20  m Blue autofluorescence (retinoids in hormone producing cells) in transformed ovary.

6 Ovarian Cancer Detection MPM Images (A, C, E) compared with conventional hemotoxylin- eosin stained histological pathology (B, D, F). Normal ovary A vs. B Early Dysplastic Changes C vs. D Invasive Tumor E vs. F Note monomorphous polygonal tumor cells at arrow. Calibration bar: (B -E), 50  m. Multiphoton Image Pathology Image

7 Images by Rebecca M. Williams, Douglas Scherr*, Warren R. Zipfel and Watt W. Webb, Cornell University and *Weill Medical College, Human Bladder Tumor Biopsy (ex vivo) Blue autofluorescent cells of low-grade transitional cell carcinoma stage TA, grade 1, showing rounded homogeneous cell array of low nuclear/cytoplasmic ratio and some disorganization of cell layer structure. Some longer wavelength punctate autofluorescent spots not yet identified. Color contrast somewhat degraded by 24 hr delay during shipping after biopsy. Images comparable to Hematoxylin & Eosin pathologist’s stained images. (All scale bars, 20  m)

8 (A) 20 microns deep. Blue pseudocolor is collagen second harmonic signal; yellow/white pseudocolor represents epithelial tissue of the bladder wall. (B) 120 microns deep. Epithelial cells can be clearly seen in the upper left-hand side. (C) Higher zoom image showing the epithelia and umbrella cells (large yellow cells on the lower edge). Multiphoton Images of a Mouse Urinary Bladder (ex vivo) ABC Images by Rebecca M. Williams, Warren R. Zipfel and Watt W. Webb, Cornell University, Scale bar, 10  m Scale bar, 40  m

9 CA3 Dentate gyrus Mossy fibers (red) Zinc (TSQ) in green SHG in red SHG and zinc in the rat hippocampus Karl Kasischke, Harsh Vishwasrao and Dan Dombeck Dombeck, D. A., K. A. Kasischke, H. D. Vishwasrao, M. Ingelsson, B. T. Hyman and W. W. Webb, "Second Harmonic Generation Microscopy of Uniformly Oriented Microtubules in Native Brain Tissue," PNAS 100, , 2003.

10 We could see Amyloid deposits with 2P-excited intrinsic fluorescence and polarized microtubules with SHG 1. No obvious alteration in the density and intensity of polarized MTs. 2. At least 6 examples of polarized MTs going through the peripheral regions of deposit. 3. Plaques do not generate SHG. 100  m

11 Inappropriately Cross-linked Molecules (often associated with disease states) Oxidized monoamines (5HT) SHG?? Arteriosclerotic plaque Advanced glycation products Crystalline and prion deposits Autofluorescence (In collaboration with Brad Hyman’s Lab, Harvard Medical School) NFT lipofuscin Lipofuscin, Neurofibrillary tangles (NFT’s) PHF-tau Ab

12 US Patent 6,839,586 Multiphoton Fiber Optic Based Endoscopic Microscope

13 B) GRIN Lenses for Deep Brain Imaging Levene, M. J., D. A. Dombeck, R. P. Molloy, K. A. Kasischke, R. M. Williams, W. R. Zipfel and W. W. Webb, "In vivo multiphoton microscopy of deep brain tissue," Journal of Neurophysiology (Online), /jn , (December 10, 2003) Levene, M. J., D. A. Dombeck, R. M. Williams, J. Skoch, G. A. Hickey, K. A. Kasischke, R. P. Molloy, M. Ingelsson, E. A. Stern, J. Klucken, B. J. Backskai, W. R. Zipfel, B. T. Hyman and W. W. Webb. "In vivo multiphoton microscopy of deep tissue with gradient index lenses," Photonics West 2004, San Jose, CA, Proceedings of SPIE, 2004

14 Cornell Ithaca: Technology Developments Watt WebbMPM and Biophysics Harold CraigheadNanobiotechnology Chris XuUltrafast Optics Developments, Biophysics Alex Gaeta Non-linear Optics – Fibers for Mode-locked Lasers Rebecca WilliamsMPM Imaging of Tissue and Cancer Warren ZipfelMPM Resource Director – Instrumentation, Imaging Weill Medical: Medical MPM Endoscopic Methods (partial list) Doug Sherr, MDDirector of Urological Surgery, Coordinator Fred MaxfieldChairman Biochemistry, Microscopic Facility Coordinator, Coordinator of MPM imaging, Coordination with Pathology Caputo, Thomas A.OB/GYN oncology Fahey, Thomas J.Diagnosis and Differentiation of Thyroid Nodules Jacobson, Ira M.Gastroenterology and Hepatology Kaner, Robert J.Lung Surgery and Biopsies Milsom, Jeffrey W.Minimal Access Colon and Rectal Surgery Pochapin, Mark B.Colon Cancer Rodeo, Scott A.Orthopedic Surgery Schwartz, Theodore H.Optical imaging of epilepsy Tewari, Ashutosh K.Robotic, Nerve-sparing Prostate Surgery Yankelevitz, David F.Lung Biopsy and Nodule Diagnosis Initial Collaborators in Developing MPM Endoscopy

15 Development Stages: Ithaca Femtosecond lasers OK, plus advancing developments Optical Fibers for fs lasers [OK, our discovery] plus narrow band, smaller fibers Laser scanning tools OK for Colonoscope; develop smaller MPM imaging of cancer in animal models: Williams, Nikitin, Zipfel Analyze excitation and emission spectral responses of tissues for optical fiber biopsy analyses: Ithaca and Weill Applicability of MPM Endo in Medical Specialties: Webb with Weill, Plus Prototype Instrument Developments: Ithaca Translation to Clinical Setting Stages Testing in Human Applications: Weill Med MD’s Development of Proof Test Atlas of Images: Pathology and Maxfield, Weill Endoscopy Product Developments: All Collaborating Technology Transfer and Business Strategy: CCTEC +? Some Technological Background Issues

16 “Lasers Set Cells Aglow for a Biopsy Without the Knife” Article by Anne Eisenberg NY Times, June 26, 2003, Illustration by Bob Scott, copyright  NY Times, Lasers set Cells AglowLasers set Cells Aglow Zipfel, W.R., R.M. Williams, R.H. Christie, A.Y. Nikitin, B.T. Hyman and W W. Webb, PNAS 100(12), , 2003 Dombeck, D.A., K.A. Kasischke, H.D. Vishwasrao, M. Ingelsson, B.T. Hyman and W.W. Webb, PNAS 100(12), , 2003

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