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Microcavity lasers for cancer cell detection Aaron Gin Katie Mayes Will McBride Ryan McClintock ME 381 Final Project December 12, 2002 Presentation outline Introduction and motivation Theoretical considerations Fabrication process Alternatives and future work Microcavity lasers for cancer cell detection 2 Motivation and applications What is Cancer? Who is at risk? How is cancer traditionally detected? The need for instantaneous classification of cells The Bio-Cavity laser concept Microcavity lasers for cancer cell detection 3 What is cancer? Microcavity lasers for cancer cell detection Occasionally cells die or wear out, new cells then grow to replace them. Sometimes when cells reproduce, mistakes are made in the code than controls cell reproduction. This causes cell growth to proceed out of control, forming a tumor. www.cancer.ie 4 Who is at risk? Microcavity lasers for cancer cell detection Slightly less than 50% of men and more than 33% of women will experience some form of cancer during their lives. American Cancer Society. Facts and Figures 2002 5 How is cancer traditionally detected? Normal prostate Prostate with cancerous growth Biopsy needle inserted into a suspicious lump on wall of colon Microcavity lasers for cancer cell detection Biopsy: requires a large sample of cells be surgically removed Count cancer cells Flow Cytometry Biological markers: look for signs (typically antigens) produced by the body in response to a specific cancer. www.cancer.med.umich.edu www.rsna.org 6 How is cancer traditionally detected? Flow-Cytometry Bench top flow-cytometer Schematic diagram of flow-cytometer Microcavity lasers for cancer cell detection Powerful research tool capable of detection cancer. Uses florescence, scattering, and transmission to analyze cells suspended in a laminar fluid flow. http://www.cancer.umn.edu/page/docs/fcintro.pdf NASA, Cancer Detection Device, SpinOff (1998) 7 Need for instantaneous classification of cells Knowing how much to cut is especially important when removing delicate brain material. Microcavity lasers for cancer cell detection No instantaneous method for determining if a cell is cancerous currently exist. Surgeons can only guess how much material must be removed Samples of removed material must be sent to a lab; the patient is already recovering by the time the results are returned www.msnbc.com 8 The Bio-Cavity Laser concept Microcavity lasers for cancer cell detection Incorporates cells directly into the lasing process. A micropump pushed cells through tiny channels in the active region of the device. The active region is pumped by an external laser source Data is collected and processed by a minispectrometer and computer. www.sandia.gov. News Releases. March 23, 2000 9 The Bio-Cavity Laser concept Microcavity lasers for cancer cell detection Cancer cells contain more protein, and larger nucleuses. Their additional density changes (by refractive index) the speed of the laser light passing through them. This modulates the effective cavity length. Creates a small difference in lasing wavelength www.sandia.gov. News Releases. March 23, 2000 10 Why MEMS? Convenience User Patient Cost Effective Integration with surgical tools Laser cavity needs to be on the order of cell size Microcavity lasers for cancer cell detection 11 Optically-pumped VCSEL Vertical Cavity Surface Emitting Laser (VCSEL) Input from pump laser VCSEL output Glass or semiconductor substrate Theory overview Active layer Upper and lower mirrors Channel or cavity Upper mirror AIR Channel region Active layer Lower mirror Substrate material Microcavity lasers for cancer cell detection 12 Optical pumping Frequency of emitted photon E h • ν is frequency • ΔE is energy gap • h is Planck’s constant Population Inversion More electrons in E2 than E1 Necessary for lasing Microcavity lasers for cancer cell detection a b E3 E3 E2 E2 E1 c E1 d E3 E3 E2 E1 E2 E1 Adapted from Kasap 13 Quantum wells Active layer can be bulk GaAs or InGaAs, a single quantum well (SQW), or multiple quantum wells (MQW) MQW increases efficiency Active Layer Barrier Layer E(conduction band) E E(valence band) Adapted from Kasap Microcavity lasers for cancer cell detection 14 Top and bottom mirrors Bragg Reflectors Alternating layers of high and low index of refraction materials n1 d1 n2 d 2 2 • n1,n2 are index of refractions of material 1&2 • d1,d2 are thicknesses of material 1&2 • λ is the wavelength of the emitted photons Top: must be transparent to pump wavelength Bottom: must be lattice-matched to active layer for good epitaxial growth Microcavity lasers for cancer cell detection 15 Cavity length Distance between top and bottom mirrors L = ½nλ Includes thickness of active layer and cavity L is cavity length n is an integer λ is the output wavelength of the laser Necessary for lasing, also alludes to output dependence on the body in the cavity Microcavity lasers for cancer cell detection 16 Dependence on cell shape Dielectric Sphere Case 2 4 n x10 x00 L p d • Δλ is wavelength shift • ξ geometrical factor of the • • • • • sphere, ≤1 n is refractive index xln nth 0 of the lth Hankel function L is effective cavity length p is longitudinal mode index d is diameter of sphere Microcavity lasers for cancer cell detection d=6 μm (bottom), 10 μm (middle) and 22 μm (top) From Meissner, et al. 17 System overview Photodetector Beam Splitter #2 Display Spectrometer Beam Splitter #1 Mirrors Focusing Lens Pump Laser Analysis Region Cavity Adapted from P.L. Gourley, U.S. Pat. #5793485 Microcavity lasers for cancer cell detection 18 Fabrication summary MBE or MOCVD growth of laser gain medium (VCSEL). Machining of substrate to obtain fluidic channels and laser microcavity. Wafer bonding to glass and top Bragg reflector. Microcavity lasers for cancer cell detection 19 Fabrication process GaAs or InP Substrate Microcavity lasers for cancer cell detection Paul L. Gourley, U.S. Patent No. 5793485 (1998). 20 Fabrication process Lower distributed Bragg mirror AlAs/Al0.2Ga0.8As (28.5 periods) Grown by MBE or MOCVD Molecular beam epitaxy system Microcavity lasers for cancer cell detection 21 Fabrication process Laser Gain region GaAs/InGaAs multiple quantum wells Grown by MBE or MOCVD Metal-organic chemical vapor deposition system Microcavity lasers for cancer cell detection 22 Fabrication process Insulating material deposition by PECVD Typically SiO2 or Si3N4 Will serve as laser cavity and microchannels Plasma-enhanced chemical vapor deposition system Microcavity lasers for cancer cell detection 23 Fabrication process Photolithography step to define cavity and microchannels BOE or CH4 to remove SiO2 SF6 dry etch to remove Si3N4 Electron cyclotron resonance reactive ion etcher Microcavity lasers for cancer cell detection 24 Fabrication process Wafer bond semiconductor or Pyrex with deposited Bragg mirror to VCSEL base Fusion Bonder www.nanotech.ucsb.edu Semiconductor or Pyrex Microcavity lasers for cancer cell detection 25 Microcavity laser including microfluidic channels Laser excitation pulse Flush Channel 1 Processing Reservoir Inlet Channel Outlet Channel Analysis Region 1 Staging Area Valves Processing Reservoir 2 2 Reagent Reservoir Adapted from P.L. Gourley, U.S. Pat. #5793485 Microcavity lasers for cancer cell detection 26 Miniaturized Optics for Imaging Pre-cancer Miniaturized Optic Table (MOT) Image sensor Collector mirror Light source Scanning grating Folding-flat mirror Dichroic beam-splitter Lithographically printed refractive lenses “Lean-to” folding flat mirror Objective lens Microcavity lasers for cancer cell detection C. P. Tigges, et. al., IEEE Journal of Quantum Electronics 38, 2 (2002). 27 Miniaturized Optical Table (MOT) Microcavity lasers for cancer cell detection Note the silicon spring V-shaped channel Spring displacement Stress in normal direction 150m thick optical element 28 Miniaturized Microscope Objective Schematic Microscope Objective MOT micromachined substrate Note: lenses in slots Microcavity lasers for cancer cell detection 29 Patterning of Optics: Binary Photomask Lithographically patterned Binary photomask Black White Hybrid glass material 150 m thick glass substrate Older element: 17.8m thick hybrid material Recent element: 34m thick hybrid material Microcavity lasers for cancer cell detection 30 Patterning of Optics: Greyscale Photomasks Microcavity lasers for cancer cell detection Greyscale photomask Decreased polymerization Lenslet array 31 Future work Need reliable methods of transporting fluids into and out of the semiconductor wafer. Biocompatibility of MEMS and optical devices needs to be addressed. Need to collaborate with real surgeons to demonstrate feasibility in real operating environment Microcavity lasers for cancer cell detection 32 Bibliography P.L. Gourley, J.D. Cox, J.K. Hendricks, A.E. McDonald G.C. Copeland, D.Y. Sasaki, M. Curry, and S.L. Skirboll, “Semiconductor Microcavity Laser Spectroscopy of Intracellular Protein in Human Cancer Cells” Proc. SPIE, 4265, 113-124 (2001). T. French, P.L. Gourley, and A.E. McDonald, “Optical properties of fluids in microfabricated channels” Proc. SPIE, 2978, 123-128 (1997). P.L. Gourley and A.E. McDonald, “Semiconductor microlasers with intracavity microfluidics for biomedical applications” Proc. SPIE, 2978, 186-196 (1997). M.F. Gourley and P.L. Gourley, “Integration of Electro-Optical Mechanical Systems and Medicine: Where are we and Where can we go?” Proc. SPIE, 2978, 197-204 (1997). Paul L. Gourley, “Resonant-cavity apparatus for cytometry or particle analysis” U.S. Patent No. 5793485, 36 pp. (1998). American Cancer Society. Facts and Figures 2002 NASA, Cancer Detection Device, SpinOff (1998) (http://www.sti.nasa.gov/tto/index.html) S.O. Kasap, Optoelectronics and Photonics: Principles and Practices, Prentice Hall, Upper Saddle River, NJ, 2001 K. E. Meissner, P. L. Gourley, T. M. Brennan, B. E. Hammons, and A. E. McDonald, “Intracavity spectroscopy in vertical cavity surface-emitting lasers for micro-optical-mechanical systems,” Applied Physics Letters, vol 69 (11), 9 Sept. 1996 Microcavity lasers for cancer cell detection 33 Thank you! Any questions? Microcavity lasers for cancer cell detection 34