Microcavity lasers for cancer cell detection

1. Microcavity lasers for cancer cell detection Aaron Gin Katie Mayes Will McBride Ryan McClintock ME 381 Final Project December 12, 2002

2. Presentation outline • Introduction and motivation • Theoretical considerations • Fabrication process • Alternatives and future work Microcavity lasers for cancer cell detection

3. 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

4. What is cancer? 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. Microcavity lasers for cancer cell detection www.cancer.ie

5. Who is at risk? Slightly less than 50% of men and more than 33% of women will experience some form of cancer during their lives. Microcavity lasers for cancer cell detection American Cancer Society. Facts and Figures 2002

6. How is cancer traditionally detected? • 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. Normal prostate Prostate with cancerous growth Biopsy needle inserted into a suspicious lump on wall of colon www.cancer.med.umich.eduwww.rsna.org Microcavity lasers for cancer cell detection

7. How is cancer traditionally detected? • Flow-Cytometry • Powerful research tool capable of detection cancer. • Uses florescence, scattering, and transmission to analyze cells suspended in a laminar fluid flow. Bench top flow-cytometer Schematic diagram of flow-cytometer http://www.cancer.umn.edu/page/docs/fcintro.pdf NASA, Cancer Detection Device, SpinOff (1998) Microcavity lasers for cancer cell detection

8. Need for instantaneous classification of cells 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 Knowing how much to cut is especially important when removing delicate brain material. Microcavity lasers for cancer cell detection www.msnbc.com

9. The Bio-Cavity Laser concept 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 mini-spectrometer and computer. Microcavity lasers for cancer cell detection www.sandia.gov. News Releases. March 23, 2000

10. The Bio-Cavity Laser concept 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 Microcavity lasers for cancer cell detection www.sandia.gov. News Releases. March 23, 2000

11. 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

12. Input from pump laser VCSEL output Glass or semiconductor substrate Upper mirror Channel region AIR AIR Active layer Lower mirror Substrate material Optically-pumped VCSEL • Vertical Cavity Surface Emitting Laser (VCSEL) • Theory overview • Active layer • Upper and lower mirrors • Channel or cavity Microcavity lasers for cancer cell detection

13. Optical pumping • Frequency of emitted photon • ν is frequency • ΔE is energy gap • h is Planck’s constant • Population Inversion • More electrons in E2 than E1 • Necessary for lasing Adapted from Kasap Microcavity lasers for cancer cell detection

14. Active Layer Active Layer Barrier Layer Barrier Layer E(conduction band) E(conduction band) E E(valence band) E(valence band) Adapted from Kasap Quantum wells • Active layer can be bulk GaAs or InGaAs, a single quantum well (SQW), or multiple quantum wells (MQW) • MQW increases efficiency Microcavity lasers for cancer cell detection

15. Top and bottom mirrors • Bragg Reflectors • Alternating layers of high and low index of refraction materials • 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

16. Cavity length • Distance between top and bottom mirrors • Includes thickness of active layer and cavity • L = ½nλ • 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

17. Dependence on cell shape • Dielectric Sphere Case • 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 d=6 μm (bottom), 10 μm (middle) and 22 μm (top) From Meissner, et al. Microcavity lasers for cancer cell detection

18. System overview Photodetector Display Beam Splitter #2 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

19. 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

20. GaAs or InP Substrate Fabrication process Microcavity lasers for cancer cell detection Paul L. Gourley, U.S. Patent No. 5793485 (1998).

21. Molecular beam epitaxy system Fabrication process Lower distributed Bragg mirror AlAs/Al0.2Ga0.8As (28.5 periods) Grown by MBE or MOCVD Microcavity lasers for cancer cell detection

22. Metal-organic chemical vapor deposition system Fabrication process Laser Gain region GaAs/InGaAs multiple quantum wells Grown by MBE or MOCVD Microcavity lasers for cancer cell detection

23. Plasma-enhanced chemical vapor deposition system Fabrication process Insulating material deposition by PECVD Typically SiO2 or Si3N4 Will serve as laser cavity and microchannels Microcavity lasers for cancer cell detection

24. Electron cyclotron resonance reactive ion etcher Fabrication process Photolithography step to define cavity and microchannels BOE or CH4 to remove SiO2 SF6 dry etch to remove Si3N4 Microcavity lasers for cancer cell detection

25. Fusion Bonder www.nanotech.ucsb.edu Semiconductor or Pyrex Fabrication process Wafer bond semiconductor or Pyrex with deposited Bragg mirror to VCSEL base Microcavity lasers for cancer cell detection

26. Laser excitation pulse Flush Channel Processing Reservoir Inlet Channel Outlet Channel 1 1 Analysis Region Staging Area Valves Processing Reservoir 2 2 Reagent Reservoir Adapted from P.L. Gourley, U.S. Pat. #5793485 Microcavity laser including microfluidic channels Microcavity lasers for cancer cell detection

27. 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).

28. Miniaturized Optical Table (MOT) • Note the silicon spring • V-shaped channel • Spring displacement • Stress in normal direction • 150m thick optical element Microcavity lasers for cancer cell detection

29. Miniaturized Microscope Objective • Schematic • Microscope Objective • MOT micromachined substrate • Note: lenses in slots Microcavity lasers for cancer cell detection

30. Patterning of Optics: Binary Photomask • Lithographically patterned • Binary photomask • Black • White • Hybrid glass material • 150 m thick glass substrate • Older element: 17.8m thick hybrid material • Recent element: 34m thick hybrid material Microcavity lasers for cancer cell detection

31. Patterning of Optics: Greyscale Photomasks • Greyscale photomask • Decreased polymerization • Lenslet array Microcavity lasers for cancer cell detection

32. 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

33. 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

34. Thank you! Any questions? Microcavity lasers for cancer cell detection