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Virtual Biopsies with Handheld Dual-Axis Confocal Microscope
Abstract
We demonstrate a novel microelectromechanical system (MEMS) based Dual-Axes confocal (DAC) microscope in a 10-mm diameter handheld package. Miniaturization is achieved by using a barbell-shaped, gimbaled, two-dimensional (2-D) MEMS scanner that is actuated by self-aligned vertical comb actuators. The maximum DC optical scan angles are ±4.25° on the inner axis and ±1.5° on the outer axis, and the corresponding resonance frequencies are 3.4 and 1.2 kHz. The maximum imaging rate is 5 frames/s. The miniature DAC microscope operating at 785-nm-wavelength achieves full-width-half-maximum (FWHM) transverse and axial resolutions of 4.5 μm and 5 μm, respectively.
Laser confocal tomography faces severe challenges in weak signal detection such as biological tissue imaging and low-reflection interfaces measurement. An ultra-high sensitive optical confocal tomography based on laser frequency-shifted feedback imaging technology is presented, whose theoretical magnification can reach 10⁶ notably without using high-gain detectors. In addition, this achievement possesses the same tomographic resolution as conventional laser confocal tomography without the need for spatial filtering devices. In this work, supported by theories and experiments, the lateral and vertical resolution, optical sensitivity, and system repeatability of LFCT and traditional LCT are investigated and analyzed quantificationally. Finally, comparison on the results of measuring the microfluidic device and biological tissue sections is conducted.
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.
We describe a novel confocal microscope that uses separate low-numerical-aperture objectives with the illumination and collection axes crossed at angle θ from the midline. This architecture collects images in scattering media with high transverse and axial resolution, long working distance, large field of view, and reduced noise from scattered light. We measured transverse and axial (FWHM) resolution of 1.3 and 2.1 µ m , respectively, in free space, and confirm subcellular resolution in excised esophageal mucosa. The optics may be scaled to millimeter dimensions and fiber coupled for collection of high-resolution images in vivo.
We present a dual-axes confocal microscope that employs postobjective scanning and low-coherence heterodyne detection to collect vertical cross-sectional images from biological tissue with high axial resolution, reduced noise from scattered light, deep tissue penetration, and a large dynamic range. This architecture can be scaled down to millimeter dimensions with microelectromechanical systems technology for performance of in vivo optical biopsy.
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.
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.
Progress toward early diagnosis of cancer would have significant clinical benefits in reducing mortality or prolonging life in cancer patients; thus, there is an important unmet clinical need to image cellular features of cancer in vivo and in real time to correlate pathological symptoms and underlying cells responsible for such symptoms. In this paper, we describe a review of microelectromechanical systems scanners-based endoscopic optical coherence tomography, confocal, two-photon, and photoacoustic microscopy imaging. These advanced optical imaging modalities can provide subcellular (micron-scale) resolution and deep tissue penetration to reveal both cells and molecular features for early cancer diagnosis, cancer staging, and surgical guidance.
This paper presents a dual-axes confocal fluorescence imaging system based on a two-dimensional (2-D) microelectromechanical systems (MEMS) scanner. The gimbaled scanner is fabricated on a double silicon-on-insulator (SOI) wafer and is actuated by self-aligned, vertical, electrostatic comb actuators. The device is aluminum coated by blanket evaporation to increase efficiency. Fluorescence imaging is successfully demonstrated by a table-top microscope system. Images with a field of view (FOV) of 211 mumtimes210 mum are acquired at 8 frames per second. The transverse resolution is 5.63 mum and 6.92 mum for the vertical and horizontal dimensions, respectively
We demonstrate a dual-axes confocal reflectance microscope in a 10-mm diameter handheld package. Miniaturization is achieved by using a barbell-shaped, gimbaled, two-dimensional MEMS scanner that is actuated by self-aligned vertical comb actuators. The maximum DC optical scan angles are plusmn3.3deg on the inner axis and plusmn1.0deg on the outer axis, and the corresponding resonance frequencies are 3.54 kHz and 1.1 kHz. The imaging rate is 30 frames/second, and the microscope achieves full-width-half-maximum (FWHM) transverse and axial resolutions of 8 mum and 10 mum, respectively
This paper presents a two-dimensional (2-D) MicroElectroMechanical system (MEMS) scanner that enables dual-axes confocal microscopy. Dual-axes confocal microscopy provides high resolution in both transverse and axial directions, and is also well-suited for miniaturization and integration into endoscopes for in vivo imaging. A 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. The imaging capability of the MEMS mirror is successfully demonstrated in a breadboard setup. Reflectance images with a field of view (FOV) of 344 μm × 417 μm are achieved at 8 frames per second. The transverse resolution is 3.94 μm and 6.68 μm for the horizontal and vertical dimensions, respectively.