The Implementation of Optofluidic Microscopy on a Chip Scale and Its Potential Applications in Biology

This thesis presents an effort to miniaturize conventional optical microscopy to a chip level using microfluidic technology. Modern compound microscopes use a set of bulk glass lenses to form magnified images from biological objects. This limits the possibility of shrinking the size of a microscope system. The invention of micro/nanofabrication technology gives hope to engineers who want to rethink the way we build optical microscopes. This advancement can fundamentally reform the way clinicians and biologists conduct microscopy. Optofluidic microscopy (OFM) is a miniaturized optical imaging method which utilizes a microfluidic flow to deliver biological samples across a 1-D or 2-D array of sampling points defined in a microfluidic channel for optical scanning. The optical information of these sampling points is collected by a CMOS imaging sensor on the bottom of the microfluidic channel. Although the size of the OFM device is as small as a US dime, it can render high resolution images of less than 1 μm with quality comparable to that of a bulky, standard optical microscope. OFM has a good potential in various biological applications. For example, the integration of an OFM system with high-speed hydrodynamic focusing technology will allow very large scale imaging-based analysis of cells or microorganisms; the compactness and low cost nature of OFM systems can enable portable or even disposable biomedical diagnostic tools for future telemedicine and personalized health care.

[1]  G. Whitesides,et al.  Complex Optical Surfaces Formed by Replica Molding Against Elastomeric Masters , 1996, Science.

[2]  D. Sinton,et al.  Ionic dispersion in nanofluidics , 2006, Electrophoresis.

[3]  Changhuei Yang,et al.  Focus grid generation by in-line holography. , 2010, Optics express.

[4]  Luke P. Lee,et al.  Micromachined transmissive scanning confocal microscope. , 2004, Optics letters.

[5]  Guoan Zheng,et al.  Focal plane tuning in wide-field-of-view microscope with Talbot pattern illumination. , 2011, Optics letters.

[6]  Derek K. Tseng,et al.  Compact and light-weight automated semen analysis platform using lensfree on-chip microscopy. , 2010, Analytical chemistry.

[7]  Gregory T. A. Kovacs,et al.  A microfluidic shadow imaging system for the study of the nematode Caenorhabditis elegans in space , 2005 .

[8]  P A Singer,et al.  Grand Challenges in Global Health , 2003, Science.

[9]  A. K. Agarwal,et al.  Adaptive liquid microlenses activated by stimuli-responsive hydrogels , 2006, Nature.

[10]  S. Takayama,et al.  Gravity-driven microfluidic particle sorting device with hydrodynamic separation amplification. , 2007, Analytical chemistry.

[11]  Demetri Psaltis,et al.  Optofluidics can create small, cheap biophotonic devices , 2006 .

[12]  G. Whitesides,et al.  Rapid Prototyping of Microfluidic Systems in Poly(dimethylsiloxane). , 1998, Analytical chemistry.

[13]  G. Whitesides,et al.  Rapid prototyping of microfluidic switches in poly(dimethyl siloxane) and their actuation by electro-osmotic flow , 1999 .

[14]  Mehmet Toner,et al.  Blood-on-a-chip. , 2005, Annual review of biomedical engineering.

[15]  Paul K. Hansma,et al.  Biological applications of the AFM: From single molecules to organs , 1997 .

[16]  Demetri Psaltis,et al.  Lensless high-resolution on-chip optofluidic microscopes for Caenorhabditis elegans and cell imaging , 2008, Proceedings of the National Academy of Sciences.

[17]  Feng Xu,et al.  Miniaturized lensless imaging systems for cell and microorganism visualization in point‐of‐care testing , 2011, Biotechnology journal.

[18]  C. Y. Teo,et al.  Enhanced microfiltration devices configured with hydrodynamic trapping and a rain drop bypass filtering architecture for microbial cells detection. , 2008, Lab on a chip.

[19]  Ali Khademhosseini,et al.  A cell-based biosensor for real-time detection of cardiotoxicity using lensfree imaging. , 2011, Lab on a chip.

[20]  Paul C. H. Li,et al.  Transport, manipulation, and reaction of biological cells on-chip using electrokinetic effects. , 1997, Analytical chemistry.

[21]  M. Young Zone Plates and Their Aberrations , 1972 .

[22]  David J Beebe,et al.  A passive pumping method for microfluidic devices. , 2002, Lab on a chip.

[23]  Changhuei Yang,et al.  The application of on-chip optofluidic microscopy for imaging Giardia lamblia trophozoites and cysts , 2009, Biomedical microdevices.

[24]  R. Lal,et al.  Biological applications of atomic force microscopy. , 1994, The American journal of physiology.

[25]  Michael J Rust,et al.  Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM) , 2006, Nature Methods.

[26]  P. Yager,et al.  Point-of-care diagnostics for global health. , 2008, Annual review of biomedical engineering.

[27]  J. Michael Ramsey,et al.  Electrokinetic Focusing in Microfabricated Channel Structures , 1997 .

[28]  Changhuei Yang,et al.  Fluorescence microscopy imaging with a Fresnel zone plate array based optofluidic microscope. , 2011, Lab on a chip.

[29]  Samuel K Sia,et al.  Lab-on-a-chip devices for global health: past studies and future opportunities. , 2007, Lab on a chip.

[30]  U. Schnars,et al.  Direct recording of holograms by a CCD target and numerical reconstruction. , 1994, Applied optics.

[31]  Chih-Ming Ho,et al.  MICRO-ELECTRO-MECHANICAL-SYSTEMS (MEMS) AND FLUID FLOWS , 1998 .

[32]  David N Breslauer,et al.  Mobile Phone Based Clinical Microscopy for Global Health Applications , 2009, PloS one.

[33]  George M. Whitesides,et al.  Control of the shape of liquid lenses on a modified gold surface using an applied electrical potential across a self-assembled monolayer , 1995 .

[34]  Derek K. Tseng,et al.  Detection of waterborne parasites using field-portable and cost-effective lensfree microscopy. , 2010, Lab on a chip.

[35]  D. Psaltis,et al.  Developing optofluidic technology through the fusion of microfluidics and optics , 2006, Nature.

[36]  Chih-Ming Ho,et al.  REVIEW: MEMS and Its Applications for Flow Control , 1996 .

[37]  A. Ozcan,et al.  Lensfree holographic imaging of antibody microarrays for high-throughput detection of leukocyte numbers and function. , 2010, Analytical chemistry.

[38]  I-Kao Chiang,et al.  Three-dimensional continuous particle focusing in a microfluidic channel via standing surface acoustic waves (SSAW). , 2011, Lab on a chip.

[39]  D. M. Shotton,et al.  Confocal scanning optical microscopy and its applications for biological specimens , 1989 .

[40]  Ali Khademhosseini,et al.  Integrating microfluidics and lensless imaging for point-of-care testing , 2009, 2009 IEEE 35th Annual Northeast Bioengineering Conference.

[41]  Ethan Schonbrun,et al.  Scanning microscopy using a short-focal-length Fresnel zone plate. , 2009, Optics letters.

[42]  Guoan Zheng,et al.  Characterization of acceptance angles of small circular apertures. , 2009, Optics express.

[43]  J. Lippincott-Schwartz,et al.  Imaging Intracellular Fluorescent Proteins at Nanometer Resolution , 2006, Science.

[44]  Changhuei Yang,et al.  The application of Fresnel zone plate based projection in optofluidic microscopy. , 2008, Optics express.

[45]  Guoan Zheng,et al.  Wide field-of-view microscope based on holographic focus grid illumination. , 2010, Optics letters.

[46]  E. Ash,et al.  Super-resolution Aperture Scanning Microscope , 1972, Nature.

[47]  Derek Tseng,et al.  Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications. , 2010, Lab on a chip.

[48]  Aydogan Ozcan,et al.  On-chip differential interference contrast microscopy using lensless digital holography , 2010, Optics express.

[49]  George M. Whitesides,et al.  Reconfigurable diffraction gratings based on elastomeric microfluidic devices , 1999 .

[50]  J. Lichtman,et al.  Optical sectioning microscopy , 2005, Nature Methods.

[51]  H. Verheijen,et al.  REVERSIBLE ELECTROWETTING AND TRAPPING OF CHARGE : MODEL AND EXPERIMENTS , 1999, cond-mat/9908328.

[52]  Michael D. Mason,et al.  Ultra-high resolution imaging by fluorescence photoactivation localization microscopy. , 2006, Biophysical journal.

[53]  M. Hutley,et al.  The manufacture of microlenses by melting photoresist , 1990 .

[54]  Changhuei Yang,et al.  Quantitative differential interference contrast microscopy based on structured-aperture interference , 2008 .

[55]  E. Schonbrun,et al.  A microfluidic fluorescence measurement system using an astigmatic diffractive microlens array. , 2011, Optics express.

[56]  Alain M. Jonas,et al.  Ultrathin polymer coatings by complexation of polyelectrolytes at interfaces: suitable materials, structure and properties , 2000 .

[57]  Yukako Yagi,et al.  Use of whole slide imaging in surgical pathology quality assurance: design and pilot validation studies. , 2006, Human pathology.

[58]  R. Tompkins,et al.  Continuous inertial focusing, ordering, and separation of particles in microchannels , 2007, Proceedings of the National Academy of Sciences.

[59]  S. Kuiper,et al.  Variable-focus liquid lens for miniature cameras , 2004 .

[60]  Nam-Trung Nguyen,et al.  Micro-optofluidic Lenses: A review. , 2010, Biomicrofluidics.

[61]  Nikos Chronis,et al.  A high numerical aperture, polymer-based, planar microlens array. , 2009, Optics express.

[62]  Luke P. Lee,et al.  Heterogeneous integration of CdS filters with GaN LEDs for fluorescence detection microsystems , 2004 .

[63]  S. Quake,et al.  Monolithic microfabricated valves and pumps by multilayer soft lithography. , 2000, Science.

[64]  Fook Siong Chau,et al.  Filter-based microfluidic device as a platform for immunofluorescent assay of microbial cells. , 2004, Lab on a chip.

[65]  M. Oheim High‐throughput microscopy must re‐invent the microscope rather than speed up its functions , 2007, British journal of pharmacology.

[66]  Ethan Schonbrun,et al.  High-throughput fluorescence detection using an integrated zone-plate array. , 2010, Lab on a chip.