Multiphoton imaging for clinical endoscopy
Chris Xu
School of Applied and Engineering Physics Cornell University
Multiphoton endoscopy
Core Technology • Platform technology: in vivo clinical detection of
disease states
• Prototype endoscopes: cancer detection, image guided surgery and therapeutics
• Supported by an extensive portfolio of issued and pending patents: – 18 issued patents in US, Europe, China, Japan – 15 applications pending in US, EU, China, Japan – Several inventions in the pipeline
• Unique advantage: in vivo, chemically specific, high
spatial resolution, 3 dimensional imaging with or WITHOUT stain.
Current Medical Endoscopy and Biopsy
• Low resolution optical viewing • Invasive tissue removal • Delayed diagnosis
Real Time Tissue Diagnostics by Multiphoton Endoscopy
In vivo, chemically specific, high spatial resolution, 3-dimensional imaging with or WITHOUT stain.
Low magnification optical viewing
High magnification multiphoton imaging
• High spatial resolution • No tissue removal • Immediate assessment
20 µm 2 mm
One Photon Two Photon
Fluorescein solution
focal plane focal plane
Signal I∝ 2Signal I∝
Multiphoton enabling 3-dimensional, deep tissue imaging
Arteriole Heart Choroid Plexus / Pineal Gland
Retinoids
NADH Collagen SHG
Indoleamines Collagen SHG
WE FLUORESCE - Nonlinearly
Intrinsic tissue fluorescence and harmonic generation (SHG or THG) are unique to multiphoton excitation, allowing imaging live human and animal without fluorescent dye.
20 µm
Potential for clinical applications.
Intrinsic tissue fluorescence (ITF) and Second Harmonic Generation (SHG)
Sensitivity = 90.4% Specificity = 76.9% MPM Sensitivity = 73% Specificity = 43%
“Multiphoton microscopy in the evaluation of human bladder biopsies” by S. Mukherjee et al. Archives of Pathology and Laboratory Medicine, 2012
Routine cystoscopy
Human bladder
Multiphoton imaging H&E stained histology ≈
Proven in Multiphoton Microscopy (~ 2000 microscopes and 1000 papers/year)
A lab-built multiphoton microscope Titanium-Sapphire femtosecond lasers
XY scanner
Clinical Endoscopy
microscope
(2007 – present)
3 mm flexible endoscope
1 mm needle endoscope
optical zoom endoscope
Opt. Lett. 35, 2735-2737, 2010 PNAS 108, 17598-17603, 2011 Biomed. Opt. Exp. 3, 1077–1085, 2012 Opt. Lett., 37, 1349-1351, 2012 Opt. Lett., 37, 881-883, 2012 J. Biomed. Opt. 17, 040505 (2012) Patents pending
Developed Endoscope Prototypes
1 mm needle lens
Multiphoton endoscopy vs microscopy
Mouse lung autofluorescence
Mouse colon autofluorescence
“Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue”, PNAS 2011, 108, 17598-17603.
Movie: Live animal imaging
Biomed. Opt. Exp. 3, 1077–1085, 2012 J. Biomed. Opt. 17, 040505 (2012)
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Indications and Value Propositions Nerve-sparing prostate resection – avoid nerves
Better patient outcomes Quickest path to market for Newco
Tumor margin evaluation during resection Better patient outcomes Save surgeon/OR time compared to frozen sections
Optical biopsy, in indications requiring surveillance and defensive or aggressive biopsies (e.g. bladder cancer) Patients avoid unnecessary pain/morbidity and delay Insurers avoid unnecessary lab testing
first-to-market
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In a test dataset of recent biopsy submissions from cystoscopic procedures to surgical pathology over a 2-month period, our collaborators at Weill Medical College found:
• 70% of the cystoscopic biopsies were benign
>4 million cystoscopies are performed every year in Europe and North America
Assuming - a rate of benign biopsies of 70%, and - an average of 1 biopsy/cystoscopy procedure
• ~2.8 million benign biopsies each year
• cost of $1.12 billion/year (assuming an average billing rate of ~$400/biopsy).
Bladder cancer: Current clinical problem
wasted time for surgeon + patient morbidity + possibility of complications
Competitive Technologies • Fluorescence Endoscopy
– External fluorophore must be applied – Identical to simple light endoscopy – Not diagnostic, not the cellular level
• Optical Coherence Tomography
– Recognizes optical patterns (reflection/scattering) – Not chemically specific – Not comparable to “gold standard” histology
• Confocal Endoscopy
– External fluorophore must be applied in general – Poor tissue penetration
Other Medical Imaging Technologies
• MRI • CT and X-ray • Ultrasound
• All provide minimally-invasive imaging with deep penetration but low spatial resolution.
• Synergistic, and can be combined with in vivo multiphoton endoscopy. – e.g., ultrasound guided multiphoton endoscope
Envisioned product: multiphoton endoscopes Combine with existing endoscope systems
Olympus CV-160 Video colonoscopy System
• Our flexible endoscope is small enough to pass through the working channels. • Leveraging the existing platform for white-light/narrow-band illumination, wide-field imaging, liquid flushing, and mechanical manipulation
working channel
working channel7.5 fr
21 fr
15 fr
Richards and Wolf cystoscope
Envisioned product: multiphoton laparoscopes Combine with existing laparoscopy
• Laparoscopic imaging • Robotic manipulation • Stereoscopic imaging • Liquid flushing
Da VinciTM system
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Multiphoton surgical endomicroscope • Real-time tissue assessment • Contrast-free • Improve outcomes
• margin assessment • avoid sensitive structures (e.g., nerves) • minimize unnecessary biopsies
Chris Xu: [email protected]
Acknowledgments PhD students: David Rivera David Huland Post-docs: Dimitre Ouzounov Chris Brown Ina Pavlova (Former) Minghan Chen (Former)
Cornell Collaborators: Watt W. Webb Robert Weiss Teresa Southard Wendy O. Williams Weill Cornell Medical College: Sushmita Mukherjee (PhD) Doug Scherr (MD) Ashutosh K. Tewari (MD)
Supported by NIH/NCI and NIH/NIBIB
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