microcavity lasers for cancer cell detection aaron gin katie mayes will mcbride ryan mcclintock me...

Microcavity lasers for cancer cell detection

Aaron GinKatie MayesWill McBrideRyan McClintock

ME 381

Final Project

December 12, 2002

Microcavity lasers for cancer cell detection 2

Presentation outline

Introduction and motivation Theoretical considerations Fabrication process Alternatives and future work


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


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.

www.cancer.ie


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.

American Cancer Society. Facts and Figures 2002


How is cancer traditionally detected?

Normal prostate Prostate with cancerous growth

Biopsy needle inserted into a suspicious lump on wall of colon

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.eduwww.rsna.org


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.

http://www.cancer.umn.edu/page/docs/fcintro.pdfNASA, Cancer Detection Device, SpinOff (1998)

Bench top flow-cytometer

Schematic diagram of flow-cytometer


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

www.msnbc.com

Knowing how much to cut is especially important when removing delicate brain material.


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.

www.sandia.gov. News Releases. March 23, 2000


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

www.sandia.gov. News Releases. March 23, 2000


Why MEMS?

Convenience User Patient

Cost Effective Integration with surgical tools Laser cavity needs to be on the

order of cell size


Optically-pumped VCSEL

Vertical Cavity Surface Emitting Laser (VCSEL)

Theory overview Active layer Upper and lower

mirrors Channel or cavity

Upper mirror

Active layer

Lower mirror

AIR

Glass or semiconductor substrate

Channel region

Substrate material

VCSEL output

AIR

Input from pump laser


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

a b

dc

E1

E2

E3

E1

E2

E3

E1

E2

E3

E1

E2

E3

a b

dc

E1

E2

E3

E1

E2

E3

E1

E2

E3

E1

E2

E3

Adapted from Kasap

h

E


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 LayerE(conduction band)

E(valence band)

Active Layer Barrier LayerE(conduction band)

E(valence band)

E

Adapted from Kasap


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

22211

dndn


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


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 From Meissner, et al.

d=6 μm (bottom), 10 μm (middle) and 22 μm (top)

d

pLxxn

2

00104


Pump Laser

Photodetector Display

Spectrometer

Beam Splitter #1

Mirrors

Focusing Lens

Cavity

Analysis Region

System overview

Adapted from P.L. Gourley, U.S. Pat. #5793485

Beam Splitter #2


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.


Fabrication process

GaAs or InP Substrate

Paul L. Gourley, U.S. Patent No. 5793485 (1998).


Fabrication process

Lower distributed Bragg mirror

AlAs/Al0.2Ga0.8As (28.5 periods)

Grown by MBE or MOCVD

Molecular beam epitaxy system


Fabrication process

Laser Gain region

GaAs/InGaAs multiple quantum wells

Grown by MBE or MOCVD

Metal-organic chemical vapor deposition system


Fabrication process

Insulating material deposition by PECVD

Typically SiO2 or Si3N4

Will serve as laser cavity and microchannels

Plasma-enhanced chemical vapor deposition system


Fabrication process

Photolithography step to define cavity and microchannels

BOE or CH4 to remove SiO2

SF6 dry etch to remove Si3N4Electron cyclotron resonance reactive ion

etcher


Fabrication process

Wafer bond semiconductor or Pyrex with deposited Bragg mirror to VCSEL base

Semiconductor or Pyrex

Fusion Bonder

www.nanotech.ucsb.edu


Microcavity laser including microfluidic channels

Analysis Region

Flush Channel Processing Reservoir

Outlet Channel

Staging Area

Valves

Inlet Channel

Reagent Reservoir

Processing Reservoir

1 1

2 2

Adapted from P.L. Gourley, U.S. Pat. #5793485

Laser excitation pulse


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

C. P. Tigges, et. al., IEEE Journal of Quantum Electronics 38, 2 (2002).


Miniaturized Optical Table (MOT)

Note the silicon spring V-shaped channel Spring displacement Stress in normal direction 150m thick optical

element


Miniaturized Microscope Objective

Schematic Microscope Objective MOT micromachined

substrate Note: lenses in slots


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


Patterning of Optics: Greyscale Photomasks

Greyscale photomask Decreased

polymerization Lenslet array


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


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


Thank you!

Any questions?

microcavity lasers for cancer cell detection aaron gin katie mayes will mcbride ryan mcclintock me...

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