Publications (18)49.79 Total impact
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Article: In vivo near-infrared dual-axis confocal microendoscopy in the human lower gastrointestinal tract.
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ABSTRACT: Near-infrared confocal microendoscopy is a promising technique for deep in vivo imaging of tissues and can generate high-resolution cross-sectional images at the micron-scale. We demonstrate the use of a dual-axis confocal (DAC) near-infrared fluorescence microendoscope with a 5.5-mm outer diameter for obtaining clinical images of human colorectal mucosa. High-speed two-dimensional en face scanning was achieved through a microelectromechanical systems (MEMS) scanner while a micromotor was used for adjusting the axial focus. In vivo images of human patients are collected at 5 frames/sec with a field of view of 362×212 μm(2) and a maximum imaging depth of 140 μm. During routine endoscopy, indocyanine green (ICG) was topically applied a nonspecific optical contrasting agent to regions of the human colon. The DAC microendoscope was then used to obtain microanatomic images of the mucosa by detecting near-infrared fluorescence from ICG. These results suggest that DAC microendoscopy may have utility for visualizing the anatomical and, perhaps, functional changes associated with colorectal pathology for the early detection of colorectal cancer.Journal of Biomedical Optics 02/2012; 17(2):021102. · 3.16 Impact Factor -
Article: Optical design and imaging performance testing of a 9.6-mm diameter femtosecond laser microsurgery probe.
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ABSTRACT: We present the optical design of a 9.6-mm diameter fiber-coupled probe for combined femtosecond laser microsurgery and nonlinear optical imaging. Towards enabling clinical use, we successfully reduced the dimensions of our earlier 18-mm microsurgery probe by half, while improving optical performance. We use analytical and computational models to optimize the miniaturized lens system for off-axis scanning aberrations. The optimization reveals that the optical system can be aberration-corrected using simple aspheric relay lenses to achieve diffraction-limited imaging resolution over a large field of view. Before moving forward with custom lenses, we have constructed the 9.6-mm probe using off-the-shelf spherical relay lenses and a 0.55 NA aspheric objective lens. In addition to reducing the diameter by nearly 50% and the total volume by 5 times, we also demonstrate improved lateral and axial resolutions of 1.27 µm and 13.5 µm, respectively, compared to 1.64 µm and 16.4 µm in our previous work. Using this probe, we can successfully image various tissue samples, such as rat tail tendon that required 2-3 × lower laser power than the current state-of-the-art. With further development, image-guided, femtosecond laser microsurgical probes such as this one can enable physicians to achieve the highest level of surgical precision anywhere inside the body.Optics Express 05/2011; 19(11):10536-52. · 3.59 Impact Factor -
Article: In vivo imaging of human and mouse skin with a handheld dual-axis confocal fluorescence microscope.
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ABSTRACT: Advancing molecular therapies for the treatment of skin diseases will require the development of new tools that can reveal spatiotemporal changes in the microanatomy of the skin and associate these changes with the presence of the therapeutic agent. For this purpose, we evaluated a handheld dual-axis confocal (DAC) microscope that is capable of in vivo fluorescence imaging of skin, using both mouse models and human skin. Individual keratinocytes in the epidermis were observed in three-dimensional image stacks after topical administration of near-infrared (NIR) dyes as contrast agents. This suggested that the DAC microscope may have utility in assessing the clinical effects of a small interfering RNA (siRNA)-based therapeutic (TD101) that targets the causative mutation in pachyonychia congenita (PC) patients. The data indicated that (1) formulated indocyanine green (ICG) readily penetrated hyperkeratotic PC skin and normal callused regions compared with nonaffected areas, and (2) TD101-treated PC skin revealed changes in tissue morphology, consistent with reversion to nonaffected skin compared with vehicle-treated skin. In addition, siRNA was conjugated to NIR dye and shown to penetrate through the stratum corneum barrier when topically applied to mouse skin. These results suggest that in vivo confocal microscopy may provide an informative clinical end point to evaluate the efficacy of experimental molecular therapeutics.Journal of Investigative Dermatology 12/2010; 131(5):1061-6. · 6.31 Impact Factor -
Article: 3-D Near-Infrared Fluorescence Imaging Using an MEMS-Based Miniature Dual-Axis Confocal Microscope
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ABSTRACT: We demonstrate a fast miniature microelectro-mechanical-system-based near-infrared fluorescence dual-axis confocal microscope in a 10-mm-diameter package for 3-D imaging in both ex vivo and in vivo samples. The miniature microscope, while in contact with the targeted tissue, can reveal subsurface structure or anatomy as deep as 300 mum. The lateral and axial resolutions are 5 and 7 mum, respectively. Real-time en face mosaicing image of in vivo human skin is demonstrated to enlarge the overall FOV to be over 3 mm at acquisition frame rate of 5 frames/s.IEEE Journal of Selected Topics in Quantum Electronics 11/2009; · 3.78 Impact Factor -
Article: In vivo brain imaging using a portable 2.9 g two-photon microscope based on a microelectromechanical systems scanning mirror.
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ABSTRACT: We present a two-photon microscope that is approximately 2.9 g in mass and 2.0 x 1.9 x 1.1 cm(3) in size and based on a microelectromechanical systems (MEMS) laser-scanning mirror. The microscope has a focusing motor and a micro-optical assembly composed of four gradient refractive index lenses and a dichroic microprism. Fluorescence is captured without the detected emissions reflecting off the MEMS mirror, by use of separate optical fibers for fluorescence collection and delivery of ultrashort excitation pulses. Using this microscope we imaged neocortical microvasculature and tracked the flow of erythrocytes in live mice.Optics Letters 09/2009; 34(15):2309-11. · 3.40 Impact Factor -
Article: Miniaturized probe for femtosecond laser microsurgery and two-photon imaging.
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ABSTRACT: Combined two-photon fluorescence microscopy and femtosecond laser microsurgery has many potential biomedical applications as a powerful "seek-and-treat" tool. Towards developing such a tool, we demonstrate a miniaturized probe which combines these techniques in a compact housing. The device is 10 x 15 x 40 mm(3) in size and uses an aircore photonic crystal fiber to deliver femtosecond laser pulses at 80 MHz repetition rate for imaging and 1 kHz for microsurgery. A fast two-axis microelectromechanical system scanning mirror is driven at resonance to produce Lissajous beam scanning at 10 frames per second. Field of view is 310 microm in diameter and the lateral and axial resolutions are 1.64 microm and 16.4 microm, respectively. Combined imaging and microsurgery is demonstrated using live cancer cells.Optics Express 07/2008; 16(13):9996-10005. · 3.59 Impact Factor -
Article: Three-dimensional in vivo imaging by a handheld dual-axes confocal microscope.
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ABSTRACT: We present a handheld dual-axes confocal microscope that is based on a two-dimensional microelectromechanical systems (MEMS) scanner. It performs reflectance and fluorescence imaging at 488 nm wavelength, with three-dimensional imaging capability. The fully packaged microscope has a diameter of 10 mm and acquires images at 4 Hz frame rate with a maximum field of view of 400 microm x 260 microm. The transverse and axial resolutions of the handheld probe are 1.7 microm and 5.8 microm, respectively. Capability to perform real time small animal imaging is demonstrated in vivo in transgenic mice.Optics Express 06/2008; 16(10):7224-32. · 3.59 Impact Factor -
Article: Two-Dimensional MEMS Scanner for Dual-Axes Confocal Microscopy
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ABSTRACT: In this paper, we present a novel 2-D microelectromechanical systems (MEMS) scanner that enables dual-axes confocal microscopy. Dual-axes confocal microscopy provides high resolution and long working distance, while also being well suited for miniaturization and integration into endoscopes for in vivo imaging. The gimbaled MEMS scanner is fabricated on a double silicon-on-insulator (SOI) wafer (a silicon wafer bonded on a SOI wafer) and is actuated by self-aligned vertical electrostatic combdrives. Maximum optical deflections of plusmn4.8deg and plusmn5.5deg are achieved in static mode for the outer and inner axes, respectively. Torsional resonant frequencies are at 500 Hz and 2.9 kHz for the outer and inner axes, respectively. The imaging capability of the MEMS scanner is successfully demonstrated in a breadboard setup. Reflectance images with a field of view of are achieved at 8 frames/s. The transverse resolutions are 3.94 mum and 6.68 mum for the horizontal and vertical dimensions, respectively.Journal of Microelectromechanical Systems 09/2007; · 2.10 Impact Factor -
Article: Fiber-optic confocal microscope using a MEMS scanner and miniature objective lens.
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ABSTRACT: We designed and constructed a single-fiber-optic confocal microscope (SFCM) with a microelectromechanical system (MEMS) scanner and a miniature objective lens. Axial and lateral resolution values for the system were experimentally measured to be 9.55 mum and 0.83 mum respectively, in good agreement with theoretical predictions. Reflectance images were acquired at a rate of 8 frames per second, over a 140 mum x 70 mum field-of-view. In anticipation of future applications in oral cancer detection, we imaged ex vivo and in vivo human oral tissue with the SFCM, demonstrating the ability of the system to resolve cellular detail.Optics Express 08/2007; 15(15):9113-22. · 3.59 Impact Factor -
Article: Miniature near-infrared dual-axes confocal microscope utilizing a two-dimensional microelectromechanical systems scanner.
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ABSTRACT: The first, to our knowledge, miniature dual-axes confocal microscope has been developed, with an outer diameter of 10 mm, for subsurface imaging of biological tissues with 5-7 microm resolution. Depth-resolved en face images are obtained at 30 frames per second, with a field of view of 800 x 100 microm, by employing a two-dimensional scanning microelectromechanical systems mirror. Reflectance and fluorescence images are obtained with a laser source at 785 nm, demonstrating the ability to perform real-time optical biopsy.Optics Letters 03/2007; 32(3):256-8. · 3.40 Impact Factor -
Article: Single fiber confocal microscope with a two-axis gimbaled MEMS scanner for cellular imaging.
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ABSTRACT: We present a single fiber reflectance confocal microscope with a two dimensional MEMS gimbaled scanner. Achieved lateral and axial resolutions are 0.82 mum and 13 mum, respectively. The field of view is 140 x 100 mum at 8 frames/second. Images and videos of cell phantoms and tissue are presented with sub-cellular resolution.Optics Express 10/2006; 14(19):8604-12. · 3.59 Impact Factor -
Article: Fast-scanning two-photon fluorescence imaging based on a microelectromechanical systems two- dimensional scanning mirror.
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ABSTRACT: Towards overcoming the size limitations of conventional two-photon fluorescence microscopy, we introduce two-photon imaging based on microelectromechanical systems (MEMS) scanners. Single crystalline silicon scanning mirrors that are 0.75 mm x 0.75 mm in size and driven in two dimensions by microfabricated vertical comb electrostatic actuators can provide optical deflection angles through a range of approximately16 degrees . Using such scanners we demonstrated two-photon microscopy and microendoscopy with fast-axis acquisition rates up to 3.52 kHz.Optics Letters 08/2006; 31(13):2018-20. · 3.40 Impact Factor -
Article: Optical design and imaging performance testing of a 9.6-mm diameter femtosecond laser microsurgery probe
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ABSTRACT: We present the optical design of a 9.6-mm diameter fiber-coupled probe for combined femtosecond laser microsurgery and nonlinear optical imaging. Towards enabling clinical use, we successfully reduced the dimensions of our earlier 18-mm microsurgery probe by half, while improving optical performance. We use analytical and computational models to optimize the miniaturized lens system for off-axis scanning aberrations. The optimization reveals that the optical system can be aberration-corrected using simple aspheric relay lenses to achieve diffraction-limited imaging resolution over a large field of view. Before moving forward with custom lenses, we have constructed the 9.6-mm probe using off-the-shelf spherical relay lenses and a 0.55 NA aspheric objective lens. In addition to reducing the diameter by nearly 50% and the total volume by 5 times, we also demonstrate improved lateral and axial resolutions of 1.27 µm and 13.5 µm, respectively, compared to 1.64 µm and 16.4 µm in our previous work. Using this probe, we can successfully image various tissue samples, such as rat tail tendon that required 2-3 × lower laser power than the current state-of-the-art. With further development, image-guided, femtosecond laser microsurgical probes such as this one can enable physicians to achieve the highest level of surgical precision anywhere inside the body.Appl. Phys. B Am. J. Ophthalmol. J. Appl. Phys. Appl. Phys. B Lasers Surg. Med. J. Biomed. Opt. J. Biomed. Opt. Opt. Express Nano Lett. Appl. Opt. Opt. Express J. Microsc. Optik (Stuttg.) J. Biomed. Opt. J. Biomed. Opt. C. L. Hoy, N. J. Durr, and A. Ben-Yakar Appl. Opt. in press. Opt. Lett. Opt. Lett. Opt. Express J Biophotonics J. Biomed. Opt. 01/2005; 8125(12):1015-1047. -
Article: Two-Photon Luminescence Imaging Using a MEMS-Based Miniaturized Probe
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ABSTRACT: We present two-photon luminescence (TPL) imaging of cancer cells through a 10 × 15 × 40 mm 3 miniaturized probe employing a two-axis MEMS scanning mirror and an air-core photonic crystal fiber. The combination of TPL imaging with a small probe represents a potential method of distinguishing cancerous cells in tissue for diagnosis.5403. -
Article: High-resolution microelectromechanical scanners for miniaturized dual-axes confocal microscopes
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ABSTRACT: In this paper we present scanning micromirrors, actuated by self-aligned, bidirectional, vertical electrostatic combdrives, for dual-axes confocal microscopy. The fabrication process, which is based on Deep Reactive Ion Etching (DRIE) of Silicon-on-insulator (SOI) wafers with two silicon device layers, requires only three lithography steps for one-dimensional scanners, while an additional two lithography steps must be performed to create two-dimensional scanners. Only front side processing is required and the two oxide layers of the double SOI wafers provide efficient and reliable etch stops. These features combined with the fact that the combs are self aligned, enable high-speed, high-resolution microscanners with stable and reliable operation as required for endoscopic implementations of confocal microscopes. -
Article: Compact optical design for dual-axes confocal endoscopic microscopes
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ABSTRACT: Here we describe a simple optical design for a MEMS-based dual-axes fiber optic confocal scanning microscope that has been miniaturized for handheld imaging of tissues, and which is capable of being further scaled to smaller dimensions for endoscope compatibility while preserving it's field-of-view (FOV), working distance, and resolution. Based on the principle of parallel beams that are focused by a single parabolic mirror to a common point, the design allows the use of replicated optical components mounted and aligned within a rugged cylindrical housing that is designed for use as a handheld tissue microscope. A MEMS scanner is used for high speed scanning in the X-Y plane below the tissue surface. An additional design feature is a mechanism for controlling a variable working distance, thus producing a scan in the Z direction and allowing capture of 3-D volumetric images of tissue. The design parameters that affect the resolution, FOV, and working distance are analyzed using ASAP TM optical modeling software and verified by experimental results. Other features of this design include use of a solid immersion lens (SIL), which enhances both resolution and FOV, and also provides index matching between the optics and the tissue. -
Conference Proceeding: A Portable Two-photon Fluorescence Microendoscope Based on a Two-dimensional Scanning Mirror
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ABSTRACT: Towards overcoming the size limitations of conventional two-photon fluorescence microscopy for brain imaging in freely moving mice, we introduce a portable laser-scanning microendoscope based on a microelectromechanical systems (MEMS) two-dimensional (2-D) scanning mirror, compound gradient refractive index (GRIN) micro-lenses, and a photonic bandgap fiber (PBF). The microendoscope achieves fast line scanning acquisition rates up to 3.5 kHz and micron-scale imaging resolution.Optical MEMS and Nanophotonics, 2007 IEEE/LEOS International Conference on; -
Article: Micromirror-scanned dual-axis confocal microscope utilizing a gradient-index relay lens for image guidance during brain surgery.
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ABSTRACT: A fluorescence confocal microscope incorporating a 1.8-mm-diam gradient-index relay lens is developed for in vivo histological guidance during resection of brain tumors. The microscope utilizes a dual-axis confocal architecture to efficiently reject out-of-focus light for high-contrast optical sectioning. A biaxial microelectromechanical system (MEMS) scanning mirror is actuated at resonance along each axis to achieve a large field of view with low-voltage waveforms. The unstable Lissajous scan, which results from actuating the orthogonal axes of the MEMS mirror at highly disparate resonance frequencies, is optimized to fully sample 500x500 pixels at two frames per second. Optically sectioned fluorescence images of brain tissues are obtained in living mice to demonstrate the utility of this microscope for image-guided resections.Journal of Biomedical Optics 15(2):026029. · 3.16 Impact Factor -
Article: Assessing delivery and quantifying efficacy of small interfering ribonucleic acid therapeutics in the skin using a dual-axis confocal microscope.
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ABSTRACT: Transgenic reporter mice and advances in imaging instrumentation are enabling real-time visualization of cellular mechanisms in living subjects and accelerating the development of novel therapies. Innovative confocal microscope designs are improving their utility for microscopic imaging of fluorescent reporters in living animals. We develop dual-axis confocal (DAC) microscopes for such in vivo studies and create mouse models where fluorescent proteins are expressed in the skin for the purpose of advancing skin therapeutics and transdermal delivery tools. Three-dimensional image volumes, through the different skin compartments of the epidermis and dermis, can be acquired in several seconds with the DAC microscope in living mice, and are comparable to histologic analyses of reporter protein expression patterns in skin sections. Intravital imaging with the DAC microscope further enables visualization of green fluorescent protein (GFP) reporter gene expression in the skin over time, and quantification of transdermal delivery of small interfering RNA (siRNA) and therapeutic efficacy. Visualization of transdermal delivery of nucleic acids will play an important role in the development of innovative strategies for treating skin pathologies.Journal of Biomedical Optics 15(3):036027. · 3.16 Impact Factor
Top co-authors
Top Journals
Institutions
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2007–2012
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Stanford University
- • Department of Pediatrics
- • Department of Electrical Engineering
Stanford, CA, USA
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2008–2011
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University of Texas at Austin
- Department of Mechanical Engineering
Texas City, TX, USA
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