Mixed-Transducer Micro-Origami for Efficient Motion and Decoupled Sensing.

This work introduces a mixed-transducer micro-origami to achieve efficient vibration, controllable motion, and decoupled sensing. Existing micro-origami systems tend to have only one type of transducer (actuator/sensor), which limits their versatility and functionality because any given transducer system has a narrow range of advantageous working conditions. However, it is possible to harness the benefit of different micro-transducer systems to enhance the performance of functional micro-origami. More specifically, this work introduces a micro-origami system that can integrate the advantages of three transducer systems: strained morph (SM) systems, polymer based electro-thermal (ET) systems, and thin-film lead zirconate titanate (PZT) systems. A versatile photolithography fabrication process is introduced to build this mixed-transducer micro-origami system, and their performance is investigated through experiments and simulation models. This work shows that mixed-transducer micro-origami can achieve power efficient vibration with high frequency, large vibration ranges, and little degradation; can produce decoupled folding motion with good controllability; and can accomplish simultaneous sensing and actuation to detect and interact with external environments and small-scale samples. The superior performance of mixed-transducer micro-origami systems makes them promising tools for micro-manipulation, micro-assembly, biomedical probes, self-sensing metamaterials, and more.

Scaling down the dimensions of a Fabry-Perot polymer film acoustic sensor for photoacoustic endoscopy.

Significance: A Fabry-Perot (FP) polymer film sensor can be used to detect acoustic waves in a photoacoustic endoscope (PAE) if the dimensions can be adequately scaled down in size. Current FP sensors have limitations in size, sensitivity, and array configurability. Aim: We aim to characterize and demonstrate the imaging performance of a miniature FP sensor to evaluate the effects of reduced size and finite dimensions. Approach: A transfer matrix model was developed to characterize the frequency response of a multilayer miniature FP sensor. An analytical model was derived to describe the effects of a substrate with finite thickness. Finite-element analysis was performed to characterize the temporal response of a sensor with finite dimensions. Miniature 2×2 mm2 FP sensors were designed and fabricated using gold films as reflective mirrors on either side of a parylene C film deposited on a glass wafer. A single-wavelength laser was used to interrogate the sensor using illumination delivered by fiber subprobes. Imaging phantoms were used to verify FP sensor performance, and in vivo images of blood vessels were collected from a live mouse. Results: The finite thickness substrate of the FP sensor resulted in echoes in the time domain signal that could be removed by back filtering. The substrate acted as a filter in the frequency domain. The finite lateral sensor dimensions produced side waves that could be eliminated by surface averaging using an interrogation beam with adequate diameter. The fabricated FP sensor produced a noise-equivalent pressure = 0.76 kPa, bandwidth of 16.6 MHz, a spectral full-width at-half-maximum = 0.2886 nm, and quality factor Q=2694. Photoacoustic images were collected from phantoms and blood vessels in a live mouse. Conclusions: A miniature wafer-based FP sensor design has been demonstrated with scaled down form factor for future use in PAE.

Wide-field endoscope accessory for multiplexed fluorescence imaging.

A wide-field endoscope that is sensitive to fluorescence can be used as an adjunct to conventional white light endoscopy by detecting multiple molecular targets concurrently. We aim to demonstrate a flexible fiber-coupled accessory that can pass forward through the instrument channel of standard medical endoscopes for clinical use to collect fluorescence images. A miniature scan mirror with reflector dimensions of 1.30 × 0.45  mm2 was designed, fabricated, and placed distal to collimated excitation beams at λex = 488, 660, and 785 nm. The mirror was driven at resonance for wide angular deflections in the X and Y-axes. A large image field-of-view (FOV) was generated in real time. The optomechanical components were packaged in a rigid distal tip with dimensions of 2.6 mm diameter and 12 mm length. The scan mirror was driven at 27.6 and 9.04 kHz in the fast (X) and slow (Y) axes, respectively, using a square wave with 50% duty cycle at 60 Vpp to collect fluorescence images at 10 frames per sec. Maximum total divergence angles of ± 27.4° and ± 22.8° were generated to achieve a FOV of 10.4 and 8.4 mm, respectively, at a working distance of 10 mm. Multiplexed fluorescence images were collected in vivo from the rectum of live mice using 3 fluorescently-labeled peptides that bind to unique cell surface targets. The fluorescence images collected were separated into 3 channels. Target-to-background ratios of 2.6, 3.1, and 3.9 were measured. This instrument demonstrates potential for broad clinical use to detect heterogeneous diseases in hollow organs.

Miniature side-view dual axes confocal endomicroscope for repetitive in vivo imaging.

A side-view dual axes confocal endomicroscope is demonstrated that can be inserted repetitively in hollow organs of genetically engineered mice for in vivo real-time imaging in horizontal and vertical planes. Near infrared (NIR) excitation at λex = 785 nm was used. A monolithic 3-axis parametric resonance scan mirror was fabricated using micro-electro-mechanical systems (MEMS) technology to perform post-objective scanning in the distal end of a 4.19 mm diameter instrument. Torsional and serpentine springs were designed to "switch" the mode of imaging between vertical and horizontal planes by tuning the actuation frequency. This system demonstrated real-time in-vivo images in horizontal and vertical planes with 310 µm depth and 1.75 and 7.5 µm lateral and axial resolution. Individual cells and discrete mucosal structures could be identified.

Confocal laser endomicroscope with distal MEMS scanner for real-time histopathology.

Confocal laser endomicroscopy is an emerging methodology to perform real time optical biopsy. Fluorescence images with histology-like quality can be collected instantaneously from the epithelium of hollow organs. Currently, scanning is performed at the proximal end of probe-based instruments used routinely in the clinic, and flexibility to control the focus is limited. We demonstrate use of a parametric resonance scanner packaged in the distal end of the endomicroscope to perform high speed lateral deflections. An aperture was etched in the center of the reflector to fold the optical path. This design reduced the dimensions of the instrument to 2.4 mm diameter and 10 mm length, allowing for forward passage through the working channel of a standard medical endoscope. A compact lens assembly provides lateral and axial resolution of 1.1 and 13.6 µm, respectively. A working distance of 0 µm and field-of-view of 250 µm × 250 µm was achieved at frame rates up to 20 Hz. Excitation at 488 nm was delivered to excite fluorescein, an FDA-approved dye, to generate high tissue contrast. The endomicroscope was reprocessed using a clinically-approved sterilization method for 18 cycles without failure. Fluorescence images were collected during routine colonoscopy from normal colonic mucosa, tubular adenomas, hyperplastic polyps, ulcerative colitis, and Crohn's colitis. Individual cells, including colonocytes, goblet cells, and inflammatory cells, could be identified. Mucosal features, such as crypt structures, crypt lumens, and lamina propria, could be distinguished. This instrument has potential to be used as an accessory during routine medical endoscopy.

Tracking Peripheral Artery Motion and Vascular Resistance With a Multimodal Wearable Sensor Under Pressure Perturbations.

The status of peripheral arteries is known to be a key physiological indicator of the body's response to both acute and chronic medical conditions. In this paper, peripheral artery deformation is tracked by wearable photoplethysmograph (PPG) and piezo-electric (polyvinylidene difluoride, PVDF) sensors, under pressure-varying cuff. A simple mechanical model for the local artery and intervening tissue captures broad features present in the PPG and PVDF signals on multiple swine subjects, with respect to varying cuff pressure. These behaviors provide insight into the robustness of cardiovascular property identification by noninvasive wearable sensing. This is found to help refine noninvasive blood pressure measurements and estimation of systemic vascular resistance (SVR) using selected features of sensor amplitude versus applied pressure.

Capacitive Sensing for 2-D Electrostatic MEMS Scanner in a Clinical Endomicroscope.

A flexible fiber-coupled confocal laser endomicroscope has been developed using an electrostatic micro-electromechanical system (MEMS) scanner located in at distal optics to collect in vivo images in human subjects. Long transmission lines are required that deliver drive and sense signals with limited bandwidth. Phase shifts have been observed between orthogonal X and Y scanner axes from environmental perturbations, which impede image reconstruction. Image processing algorithms used for correction depend on image content and quality, while scanner calibration in the clinic can be limited by potential patient exposure to lasers. We demonstrate a capacitive sensing method to track the motion of the electrostatically driven two-dimensional MEMS scanner and to extract phase information needed for image reconstruction. This circuit uses an amplitude modulation envelope detection method on shared drive and sensing electrodes of the scanner. Circuit parameters were optimized for performance given high scan frequencies, transmission line effects, and substantial parasitic coupling of drive signal to circuit output. Extraction of phase information further leverages nonlinear dynamics of the MEMS scanner. The sensing circuit was verified by comparing with data from a position sensing detector measurement. The phase estimation showed an accuracy of 2.18° and 0.79° in X and Y axes for motion sensing, respectively. The results indicate that the sensing circuit can be implemented with feedback control for pre-calibration of the scanner in clinical MEMS-based imaging systems.

Detection of Low Cardiac Index using a Polyvinylidene Fluoride-Based Wearable Ring and Convolutional Neural Networks.

This study investigated the use of a wearable ring made of polyvinylidene fluoride film to identify a low cardiac index (≤2 L/min). The waveform generated by the ring contains patterns that may be indicative of low blood pressure and/or high vascular resistance, both of which are markers of a low cardiac index. In particular, the waveform contains reflection waves whose timing and amplitude are correlated with pulse travel time and vascular resistance, respectively. Hence, the pattern of the waveform is expected to vary in response to changes in blood pressure and vascular resistance. By analyzing the morphology of the waveform, our aim was to create a tool to identify patients with low cardiac index. This was done using a convolutional neural network which was trained on data from animal models. The model was then tested on waveforms that were collected from patients undergoing pulmonary artery catheterization. The results indicate high accuracy in classifying patients with a low cardiac index, achieving an area under the receiver operating characteristics and precision-recall curves of 0.88 and 0.71, respectively.

Ultra-Compact Microsystems-Based Confocal Endomicroscope.

Point-of-care medical diagnosis demands immediate feedback on tissue pathology. Confocal endomicroscopy can provide real-time in vivo images with histology-like features. The working channel in medical endoscopes are becoming smaller in dimension. Microsystems methods can produce tiny mechanical scanners. We demonstrate a flexible fiber instrument for in vivo imaging as an endoscope accessory. The optical path is folded on-axis to reduce length while allowing the beam to expand and achieve a numerical aperture of 0.41. A high-speed parametric resonance mirror produces large deflection angles > 13°, and is mounted on a 2 mm diameter chip designed with clamp structures for reduced space. A compact lens assembly provides diffraction-limited lateral and axial resolution of 1.5 and [Formula: see text], respectively. A working distance of [Formula: see text] and field-of-view of [Formula: see text] m are achieved. Miniature apparatus is fabricated to assemble and align the scanhead components. The optics and scanner are packaged in a distal tip with 2.4 mm diameter and 10 mm rigid length. These dimensions allow the endomicroscope to pass forward easily through the 2.8 mm diameter working channel in medical endoscopes commonly used in clinical practice. Fluorescence images are collected in vivo at 10 frames per second in the colon of genetically-engineered mice that spontaneously develop adenomas. A FITC-labeled peptide heterodimer is administered intravenously to provide specific contrast. Sub-cellular structures are visualized to distinguish pre-malignant from normal mucosa. These results demonstrate use of microsystems methods to produce an ultra-compact instrument with sufficiently small dimensions for broad use.

Improved Extended Kalman Filter Estimation using Threshold Signal Detection with a MEMS Electrostatic Microscanner.

A threshold signal detector is proposed to improve the state estimation accuracy of an extended Kalman filter (EKF) and is validated experimentally with a MEMS electrostatic micro-scanner. A first order derivative of Gaussian (DOG) filter is used to detect and locate rapid changes in voltage signal caused by crossing of a threshold angle determined by maximum overlap of capacitive electrodes. The event-triggered measurement is used in the update step of the EKF to provide intermittent but more accurate angle measurements than those of the capacitive sensor's continuous output. Experiments on the electrostatic micro-scanner show that with the threshold signal detector incorporated, the average position estimation accuracy of the EKF is improved by 15.1%, with largest improvement (30.3%) seen in low signal-to-noise ratio (SNR) conditions. A parametric study is conducted to examine sampling frequency and capacitance profile, among other factors that may affect detection error and EKF accuracy.

Motion Estimation for a Compact Electrostatic Microscanner via Shared Driving and Sensing Electrodes in Endomicroscopy.

We present a method to estimate high frequency rotary motion of a highly compact electrostatic micro-scanner using the same electrodes for both actuation and sensing. The accuracy of estimated rotary motion is critical for reducing blur and distortion in image reconstruction applications with the micro-scanner given its changing dynamics due to perturbations such as temperature. To overcome the limitation that no dedicated sensing electrodes are available in the proposed applications due to size constraints, the method adopts electromechanical amplitude modulation (EAM) to separate motion signal from parasitic capacitance feedthrough, and a novel non-linear measurement model is derived to characterize the relationship between large out-of-plane angular motion and circuit output. To estimate motion, an extended Kalman filter (EKF) and an unscented Kalman filter (UKF) are implemented, incorporating a process model based on the micro-scanner's parametric resonant dynamics and the measurement model. Experimental results show that compared to estimation without using the measurement model, our method is able to improve the rotary motion estimation accuracy of the micro-scanner significantly, with a reduction of root-mean-square error (RMSE) in phase shift of 86.1%, and a reduction of RMSE in angular position error of 78.5 %.

3 degree-of-freedom resonant scanner with full-circumferential range and large out-of-plane displacement.

Microsystems-based scanning technologies can achieve deflection angles of several tens of degrees and translational displacements of a couple hundred microns. Emerging applications need performance with multi-fold greater torsional and translational motion. A compliant lever-based mechanism is introduced into the comb-drive actuators of a MEMS resonant scanner to achieve full-circumferential range and large out-of-plane displacement at ambient pressures. A 1.5 mm diameter mirror is demonstrated that generates 494° total deflection angle and 561 µm translational displacement at either 853 or 956 Hz and either 100 or 90V, respectively. At 40V, an optical scan angle of ~200° and translational displacement of ~310 µm are achieved.

Visualizing Epithelial Expression in Vertical and Horizontal Planes With Dual Axes Confocal Endomicroscope Using Compact Distal Scanner.

The epithelium is a thin layer of tissue that lines hollow organs, such as colon. Visualizing in vertical cross sections with sub-cellular resolution is essential to understanding early disease mechanisms that progress naturally in the plane perpendicular to the tissue surface. The dual axes confocal architecture collects optical sections in tissue by directing light at an angle incident to the surface using separate illumination and collection beams to reduce effects of scattering, enhance dynamic range, and increase imaging depth. This configuration allows for images to be collected in the vertical as well as horizontal planes. We designed a fast, compact monolithic scanner based on the principle of parametric resonance. The mirrors were fabricated using microelectromechanical systems (MEMS) technology and were coated with aluminum to maximize near-infrared reflectivity. We achieved large axial displacements [Formula: see text] and wide lateral deflections >20°. The MEMS chip has a 3.2×2.9 mm2 form factor that allows for efficient packaging in the distal end of an endomicroscope. Imaging can be performed in either the vertical or horizontal planes with [Formula: see text] depth or 1 ×1 mm2 area, respectively, at 5 frames/s. We systemically administered a Cy5.5-labeled peptide that is specific for EGFR, and collected near-infrared fluorescence images ex vivo from pre-malignant mouse colonic epithelium to reveal the spatial distribution of this molecular target. Here, we demonstrate a novel scanning mechanism in a dual axes confocal endomicroscope that collects optical sections of near-infrared fluorescence in either vertical or horizontal planes to visualize molecular expression in the epithelium.

Axial beam scanning in multiphoton microscopy with MEMS-based actuator.

We demonstrate a remotely located microelectromechanical systems (MEMS) actuator that can translate >400 µm to perform axial beam scanning in a multiphoton microscope. We use a 2-dimensional MEMS mirror for lateral scanning, and collected multiphoton excited fluorescence images in either the horizontal or vertical plane with a field-of-view of either 270 × 270 or 270 × 200 µm2, respectively, at 5 frames per second. Axial resolution varied from 4.5 to 7 µm over the scan range. The compact size of the actuator and scanner allows for use in an endomicroscope to collect images in the vertical plane with >200 µm depth.

Three-dimensional side-view endomicroscope for tracking individual cells in vivo.

We demonstrate a side-view endomicroscope using a monolithic 3-axis scanner placed in the post-objective position that performs either tilt or piston motion to achieve either optical scan angles >10° or large vertical displacements, respectively. This configuration allows for scaling down of instrument dimensions for high maneuverability and accurate positioning in vivo. Images exceeded either 700 × 600 µm2 in the horizontal plane or vertical depths of 200 µm. Resolution of 1.19 and 3.46 µm was obtained in the horizontal and oblique planes, respectively. Optical sections were collected from dysplastic colonic epithelium in vivo in mice that express tdTomato at 10 Hz to visualize individual cells.

Multi-photon vertical cross-sectional imaging with a dynamically-balanced thin-film PZT z-axis microactuator.

Use of a thin-film piezoelectric microactuator for axial scanning during multi-photon vertical cross-sectional imaging is described. The actuator uses thin-film lead-zirconate-titanate (PZT) to generate upward displacement of a central mirror platform, micro-machined from a silicon-on-insulator (SOI) wafer to dimensions compatible with endoscopic imaging instruments. Device modeling in this paper focuses on existence of frequencies near device resonance producing vertical motion with minimal off-axis tilt even in the presence of multiple vibration modes and non-uniformity in fabrication outcomes. Operation near rear resonance permits large stroke lengths at low voltages relative to other vertical microactuators. Highly uniform vertical motion of the mirror platform is a key requirement for vertical cross-sectional imaging in the remote scan architecture being used for multi-photon instrument prototyping. The stage is installed in a benchtop testbed in combination with an electrostatic mirror that performs in-plane scanning. Vertical sectional images are acquired from 15 µm diameter beads and excised mouse colon tissue.

Visualizing epithelial expression of EGFR in vivo with distal scanning side-viewing confocal endomicroscope.

Confocal endomicroscopy is an emerging imaging technology that has recently been introduced into the clinic to instantaneously collect "optical biopsies" in vivo with histology-like quality. Here, we demonstrate a fast scanner located in the distal end of a side-viewing instrument using a compact lens assembly with numerical aperture of 0.5 to achieve a working distance of 100 µm and field-of-view of 300 × 400 µm2. The microelectromechanical systems (MEMS) mirror was designed based on the principle of parametric resonance and images at 5 frames per second. The instrument has a 4.2 mm outer diameter and 3 cm rigid length, and can pass through the biopsy channel of a medical endoscope. We achieved real time optical sections of NIR fluorescence with 0.87 µm lateral resolution, and were able to visualize in vivo binding of a Cy5.5-labeled peptide specific for EGFR to the cell surface of pre-cancerous colonocytes within the epithelium of dysplastic crypts in mouse colon. By performing targeted imaging with endomicroscopy, we can visualize molecular expression patterns in vivo that provide a biological basis for disease detection.

Integrated monolithic 3D MEMS scanner for switchable real time vertical/horizontal cross-sectional imaging.

We present an integrated monolithic, electrostatic 3D MEMS scanner with a compact chip size of 3.2 × 2.9 mm(2). Use of parametric excitation near resonance frequencies produced large optical deflection angles up to ± 27° and ± 28.5° in the X- and Y-axes and displacements up to 510 µm in the Z-axis with low drive voltages at atmospheric pressure. When packaged in a dual axes confocal endomicroscope, horizontal and vertical cross-sectional images can be collected seamlessly in tissue with a large field-of-view of >1 × 1 mm(2) and 1 × 0.41 mm(2), respectively, at 5 frames/sec.

MEMS-based multiphoton endomicroscope for repetitive imaging of mouse colon.

We demonstrate a handheld multiphoton endomicroscope with 3.4 mm distal diameter that can repetitively image mouse colon in vivo. A 2D resonant MEMS mirror was developed to perform beam scanning in a Lissajous pattern. The instrument has an effective numerical aperture of 0.63, lateral and axial resolution of 2.03 and 9.02 µm, respectively, working distance of 60 µm, and image field-of-view of 300 × 300 µm(2). Hoechst was injected intravenously in mice to stain cell nuclei. We were able to collect histology-like images in vivo at 5 frames/sec, and distinguish between normal and pre-malignant colonic epithelium.