Personalized radioiodine therapy for thyroid cancer patients with known disease.

Radioactive iodine (RAI) 131I is a targeted therapy for patients with RAI-avid follicular cell-derived thyroid cancer. However, the responsiveness to 131I therapy varies among thyroid cancer patients mainly owing to differential RAI uptake and RAI radiosensitivity among patients' lesions. A personalized approach to maximize 131I therapeutic efficacy is proposed based on recent scientific advances and future opportunities.

Active damping and disturbance rejection control of a six-axis magnetic levitation stage.

This paper presents the design and application of a novel active damping and disturbance rejection controller for a magnetic levitation stage. Feedback linearization, based on the rigid-body dynamics of the levitated stage, and force distribution, based on a time-varying force distribution matrix that takes six-axis motion of a floater into account, are adopted to establish a decoupled and linearized dynamics between the six inputs and the six-axis motion. By integrating an augmented state estimator that provides full state and disturbance estimation, a linear controller that provides active damping for each axis is designed, providing the whole controller with active damping and disturbance rejection capability. In addition, the parameters of the designed controller can be easily selected based on the desired damping and natural frequency, while the parameters of the augmented estimator can be determined according to the desired estimator bandwidth and first system resonance, which make the parameter tuning have a clear physical meaning. Finally, the designed controller was implemented in a field programmable gate array-based control system. Experimental results of the proposed controller and comparison with the previously designed controller are provided to illustrate the feasibility and effectiveness of the designed control algorithm.

Automated MicroSPECT/MicroCT Image Analysis of the Mouse Thyroid Gland.

BACKGROUND: The ability of thyroid follicular cells to take up iodine enables the use of radioactive iodine (RAI) for imaging and targeted killing of RAI-avid thyroid cancer following thyroidectomy. To facilitate identifying novel strategies to improve 131I therapeutic efficacy for patients with RAI refractory disease, it is desired to optimize image acquisition and analysis for preclinical mouse models of thyroid cancer. METHODS: A customized mouse cradle was designed and used for microSPECT/CT image acquisition at 1 hour (t1) and 24 hours (t24) post injection of 123I, which mainly reflect RAI influx/efflux equilibrium and RAI retention in the thyroid, respectively. FVB/N mice with normal thyroid glands and TgBRAFV600E mice with thyroid tumors were imaged. In-house CTViewer software was developed to streamline image analysis with new capabilities, along with display of 3D voxel-based 123I gamma photon intensity in MATLAB. RESULTS: The customized mouse cradle facilitates consistent tissue configuration among image acquisitions such that rigid body registration can be applied to align serial images of the same mouse via the in-house CTViewer software. CTViewer is designed specifically to streamline SPECT/CT image analysis with functions tailored to quantify thyroid radioiodine uptake. Automatic segmentation of thyroid volumes of interest (VOI) from adjacent salivary glands in t1 images is enabled by superimposing the thyroid VOI from the t24 image onto the corresponding aligned t1 image. The extent of heterogeneity in 123I accumulation within thyroid VOIs can be visualized by 3D display of voxel-based 123I gamma photon intensity. CONCLUSIONS: MicroSPECT/CT image acquisition and analysis for thyroidal RAI uptake is greatly improved by the cradle and the CTViewer software, respectively. Furthermore, the approach of superimposing thyroid VOIs from t24 images to select thyroid VOIs on corresponding aligned t1 images can be applied to studies in which the target tissue has differential radiotracer retention from surrounding tissues.

Modeling and calibrating nonlinearity and crosstalk in back focal plane interferometry for three-dimensional position detection.

Back focal plane (BFP) interferometry is frequently used to detect the motion of a single laser trapped bead in a photonic force microscope (PFM) system. Whereas this method enables high-speed and high-resolution position measurement, its measurement range is limited by nonlinearity coupled with crosstalk in three-dimensional (3-D) measurement, and validation of its measurement accuracy is not trivial. This Letter presents an automated calibration system in conjunction with a 3-D quadratic model to render rapid and accurate calibration of the laser measurement system. An actively controlled three-axis laser steering system and a high-speed vision-based 3-D particle tracking system are integrated to the PFM system to enable rapid calibration. The 3-D quadratic model is utilized to correct for nonlinearity and crosstalk and, thus, extend the 3-D position detection volume of BFP interferometry. We experimentally demonstrated a 12-fold increase in detection volume when applying the method to track the motion of a 2.0 µm laser trapped polystyrene bead.

Quantitative characterization of cell behaviors through cell cycle progression via automated cell tracking.

Cell behaviors are reflections of intracellular tension dynamics and play important roles in many cellular processes. In this study, temporal variations in cell geometry and cell motion through cell cycle progression were quantitatively characterized via automated cell tracking for MCF-10A non-transformed breast cells, MCF-7 non-invasive breast cancer cells, and MDA-MB-231 highly metastatic breast cancer cells. A new cell segmentation method, which combines the threshold method and our modified edge based active contour method, was applied to optimize cell boundary detection for all cells in the field-of-view. An automated cell-tracking program was implemented to conduct live cell tracking over 40 hours for the three cell lines. The cell boundary and location information was measured and aligned with cell cycle progression with constructed cell lineage trees. Cell behaviors were studied in terms of cell geometry and cell motion. For cell geometry, cell area and cell axis ratio were investigated. For cell motion, instantaneous migration speed, cell motion type, as well as cell motion range were analyzed. We applied a cell-based approach that allows us to examine and compare temporal variations of cell behavior along with cell cycle progression at a single cell level. Cell body geometry along with distribution of peripheral protrusion structures appears to be associated with cell motion features. Migration speed together with motion type and motion ranges are required to distinguish the three cell-lines examined. We found that cells dividing or overlapping vertically are unique features of cell malignancy for both MCF-7 and MDA-MB-231 cells, whereas abrupt changes in cell body geometry and cell motion during mitosis are unique to highly metastatic MDA-MB-231 cells. Taken together, our live cell tracking system serves as an invaluable tool to identify cell behaviors that are unique to malignant and/or highly metastatic breast cancer cells.

Real-time visual sensing system achieving high-speed 3D particle tracking with nanometer resolution.

This paper presents a real-time visual sensing system, which is created to achieve high-speed three-dimensional (3D) motion tracking of microscopic spherical particles in aqueous solutions with nanometer resolution. The system comprises a complementary metal-oxide-semiconductor (CMOS) camera, a field programmable gate array (FPGA), and real-time image processing programs. The CMOS camera has high photosensitivity and superior SNR. It acquires images of 128×120 pixels at a frame rate of up to 10,000 frames per second (fps) under the white light illumination from a standard 100 W halogen lamp. The real-time image stream is downloaded from the camera directly to the FPGA, wherein a 3D particle-tracking algorithm is implemented to calculate the 3D positions of the target particle in real time. Two important objectives, i.e., real-time estimation of the 3D position matches the maximum frame rate of the camera and the timing of the output data stream of the system is precisely controlled, are achieved. Two sets of experiments were conducted to demonstrate the performance of the system. First, the visual sensing system was used to track the motion of a 2 µm polystyrene bead, whose motion was controlled by a three-axis piezo motion stage. The ability to track long-range motion with nanometer resolution in all three axes is demonstrated. Second, it was used to measure the Brownian motion of the 2 µm polystyrene bead, which was stabilized in aqueous solution by a laser trapping system.

Calibration of measurement sensitivities of multiple micro-cantilever dynamic modes in atomic force microscopy using a contact detection method.

An accurate experimental method is proposed for on-spot calibration of the measurement sensitivities of multiple micro-cantilever dynamic modes in atomic force microscopy. One of the key techniques devised for this method is a reliable contact detection mechanism that detects the tip-surface contact instantly. At the contact instant, the oscillation amplitude of the tip deflection, converted to that of the deflection signal in laser reading through the measurement sensitivity, exactly equals to the distance between the sample surface and the cantilever base position. Therefore, the proposed method utilizes the recorded oscillation amplitude of the deflection signal and the base position of the cantilever at the contact instant for the measurement sensitivity calibration. Experimental apparatus along with various signal processing and control modules was realized to enable automatic and rapid acquisition of multiple sets of data, with which the calibration of a single dynamic mode could be completed in less than 1 s to suppress the effect of thermal drift and measurement noise. Calibration of the measurement sensitivities of the first and second dynamic modes of three micro-cantilevers having distinct geometries was successfully demonstrated. The dependence of the measurement sensitivity on laser spot location was also experimentally investigated. Finally, an experiment was performed to validate the calibrated measurement sensitivity of the second dynamic mode of a micro-cantilever.

Real-time continuous image registration enabling ultraprecise 2-D motion tracking.

In this paper, we present a novel continuous image registration method (CIRM), which yields near-zero bias and has high computational efficiency. It can be realized for real-time position estimation to enable ultraprecise 2-D motion tracking and motion control over a large motion range. As the two variables of the method are continuous in spatial domain, pixel-level image registration is unnecessary, thus the CIRM can continuously track the moving target according to the incoming target image. When applied to a specific target object, measurement resolution of the method is predicted according to the reference image model of the object along with the variance of the camera's overall image noise. The maximum permissible target speed is proportional to the permissible frame rate, which is limited by the required computational time. The precision, measurement resolution, and computational efficiency of the method are verified through computer simulations and experiments. Specifically, the CIRM is implemented and integrated with a visual sensing system. Near-zero bias, measurement resolution of 0.1 nm (0.0008 pixels), and measurement of one nanometer stepping are demonstrated.

Design and Modeling of a 3-D Magnetic Actuator for Magnetic Microbead Manipulation.

This paper presents the design, implementation, modeling, and analyses of a hexapole magnetic actuator that is capable of 3-D manipulation of a magnetic microbead. The magnetic actuator employs six sharp-tipped magnetic poles placed in hexapole configuration, six actuating coils, and a magnetic yoke. The magnetic poles concentrate the magnetic flux generated by the coils to the workspace, resulting in a high magnetic field with a large field gradient for magnetic force generation on the magnetic microbead. A lumped-parameter magnetic force model is then established to characterize nonlinearity of the magnetic force exerting on the magnetic microbead with respect to the applied currents to the coils and the position dependence of the magnetic force in the workspace. The force generation capability of the designed system is then explored using the force model. Moreover, an inverse force model is derived and its effect on the magnetic actuation capability is investigated. The inverse force model facilitates the implementation of a feedback control law to stabilize and control the motion of a magnetic microbead. Experimental results in terms of the magnetic force in relation to stable motion control of a magnetic microbead are used to validate the force model.

Dynamic Force Sensing Using an Optically Trapped Probing System.

This paper presents the design of an adaptive observer that is implemented to enable real-time dynamic force sensing and parameter estimation in an optically trapped probing system. According to the principle of separation of estimation and control, the design of this observer is independent of that of the feedback controller when operating within the linear range of the optical trap. Dynamic force sensing, probe steering/clamping, and Brownian motion control can, therefore, be developed separately and activated simultaneously. The adaptive observer utilizes the measured motion of the trapped probe and input control effort to recursively estimate the probe-sample interaction force in real time, along with the estimation of the probing system's trapping bandwidth. This capability is very important to achieving accurate dynamic force sensing in a time-varying process, wherein the trapping dynamics is nonstationary due to local variations of the surrounding medium. The adaptive estimator utilizes the Kalman filter algorithm to compute the time-varying gain in real time and minimize the estimation error for force probing. A series of experiments are conducted to validate the design of and assess the performance of the adaptive observer.

Minimum-variance Brownian motion control of an optically trapped probe.

This paper presents a theoretical and experimental investigation of the Brownian motion control of an optically trapped probe. The Langevin equation is employed to describe the motion of the probe experiencing random thermal force and optical trapping force. Since active feedback control is applied to suppress the probe's Brownian motion, actuator dynamics and measurement delay are included in the equation. The equation of motion is simplified to a first-order linear differential equation and transformed to a discrete model for the purpose of controller design and data analysis. The derived model is experimentally verified by comparing the model prediction to the measured response of a 1.87 microm trapped probe subject to proportional control. It is then employed to design the optimal controller that minimizes the variance of the probe's Brownian motion. Theoretical analysis is derived to evaluate the control performance of a specific optical trap. Both experiment and simulation are used to validate the design as well as theoretical analysis, and to illustrate the performance envelope of the active control. Moreover, adaptive minimum variance control is implemented to maintain the optimal performance in the case in which the system is time varying when operating the actively controlled optical trap in a complex environment.

Real-time in situ calibration of an optically trapped probing system.

We present real-time in situ calibration of an optically trapped probing system. In the probing system, a micro/nanobead is stably trapped around the minimum of the field potential to serve as the measurement probe, whereas the random thermal force tends to destabilize it and causes Brownian motion around the equilibrium. The weighted recursive least-squares algorithm is applied to recursively update the system's parameters, such as the state transition coefficient, and to estimate specific system response and the unknown variance of the Gaussian white noise in real time according to the probe's motion. The real-time recursive algorithm was first applied to real-time calibration of measurement sensitivity and trapping stiffness for the case that the local temperature and the damping coefficient of the probe are known. It was then applied to estimate the probe's local temperature in real time. Two experiments were designed to illustrate the applicability of the real-time calibration method. The experimental results show that the recursive algorithm is able to real-time calibrate the trapping stiffness of the probing system and the measurement sensitivity of the back-focal-plane interferometry employed for position measurement. The experimental results also show that the method can estimate the probe's local temperature in real time.

Three-axis rapid steering of optically propelled micro/nanoparticles.

This paper presents the design and implementation of a three-axis steering system, wherein a micro/nanoparticle is optically trapped and propelled to serve as a measurement probe. The actuators in the system consist of a deformable mirror enabling axial steering and a two-axis acousto-optic deflector for lateral steering. The actuation range is designed and calibrated to be over 20 microm along the two lateral axes and over 10 microm along the axial direction. The actuation bandwidth of the two lateral axes is over 50 kHz and the associated resolution is 0.016 nm (1sigma). The axial resolution is 0.16 nm, while the bandwidth is enhanced to over 3 kHz by model cancellation method. The performance of the three-axis steering system is illustrated by three sets of experiments. First, active Brownian motion control of the trapped probe is utilized to enhance trapping stability. Second, a large range three-dimensional (3D) steering of a 1.87 microm probe, contouring a complex 3D trajectory in a 6 x 6 x 4 microm3 volume, is demonstrated. Third, a closed-loop steering is implemented to achieve improved precision.

Best linear unbiased axial localization in three-dimensional fluorescent bead tracking with subnanometer resolution using off-focus images.

A three-dimensional particle tracking technique, based on microscope off-focus images, was introduced in Z. Zhang and C.-H. Menq, Appl. Opt.47, 2361 (2008) and applied to bright-field imaging. This paper presents two major improvements to the axial localization algorithm of the 3D particle tracking technique. First, it extends the algorithm to measure fluorescent particles in the presence of photobleaching and excitation variation. Second, it enhances the measurement resolution by achieving the best linear unbiased estimation of the particle's axial position. Similarly to the original algorithm, a radius vector is first converted from the off-focus 2D image of the particle, and the axial position is estimated by comparing the radius vector with an object-specific model, calibrated automatically prior to each experiment. Although it was an intensity-based method, by normalizing the radius vectors the improved algorithm becomes a shape-based method, thus invariant to image intensity change and robust to photobleaching. Moreover, when considering the noise variance of each point in the radius vector and their correlations, the best linear unbiased estimation based on a linearized model is achieved. It is shown that variance equalization and correlation-weighted optimization greatly reduce the estimation variance and lead to near-uniform localization resolution over the entire measurement range. Estimation resolution is theoretically analyzed and validated by experiments. Theoretical analysis enables the prediction of measurement resolution based on calibration data. Finally, experimental results are presented to illustrate the performance of the measurement method in terms of measurement precision and range, as well as its robustness to intensity variation.

Three-dimensional particle tracking with subnanometer resolution using off-focus images.

A three-dimensional (3D) particle tracking algorithm based on microscope off-focus images is presented in this paper. Subnanometer resolution in all three axes at 400 Hz sampling rate is achieved using a complementary metal-oxide-semiconductor (CMOS) camera. At each sampling, the lateral position of the spherical particle is first estimated by the centroid method. The axial position is then estimated by comparing the radius vector, which is converted from the off-focus two-dimensional image of the particle with no information loss, with an object-specific model, calibrated automatically prior to each experiment. Estimation bias and variance of the 3D tracking algorithm are characterized through analytical analysis. It leads to an analytical model, enabling prediction of the measurement performance based on calibration data. Finally, experimental results are presented to illustrate the performance of the measurement method in terms of precision and range. The validity of the theoretical analysis is also experimentally confirmed.

Two-axis probing system for atomic force microscopy.

A novel two-axis probing system is proposed for multiaxis atomic force microscopy (AFM). It employs a compliant manipulator that is optimally designed in terms of geometries and kinematics, and is actuated by multiple magnetic actuators to simultaneously control tip position and change tip orientation to achieve greater accessibility of the sample surface when imaging surfaces having large geometric variations. It leads to the creation of a multiaxis AFM system, which is a three-dimensional surface tool rather than a two-dimensional planar surface tool. The use of the system to scan the bottom corner of a grating step is reported.

Design, implementation, and control of a six-axis compliant stage.

This paper presents the development of a new compact six-axis compliant stage employing piezoelectric actuators to achieve six-axis actuation with nanometer resolution. The integration of direct metrology in the object space, based on real-time visual feedback, enables high-precision motion control. In order to achieve greater motion range, the simple and compact decoupled mechanical structure utilizes two-tap displacement amplifiers for in-plane motion and semibridge amplifiers for out-of-plane motion. The kinematic analysis of the stage is presented. Laterally sampled white light interferometry was implemented to measure the out-of-plane motion of the stage, and a measurement model associated with the designed target patterns is developed to estimate the in-plane motion in real time. Together, they form a visual tracking system and are integrated with the six-axis compliant stage to realize precision six-axis real-time visual servo-control. Experimental results demonstrate that the six-axis compliant stage has the motion range of 77.42 microm, 67.45 microm, 24.56 microm, 0.93 mrad, 0.95 mrad, and 3.10 mrad, and the resolution of +/-5 nm, +/-8 nm, +/-10 nm, +/-10 murad, +/-10 murad, and +/-20 murad for x-axis, y-axis, and z-axis translation and rotation, respectively.

Control of tip-to-sample distance in atomic force microscopy: a dual-actuator tip-motion control scheme.

The control of tip-to-sample distance in atomic force microscopy (AFM) is achieved through controlling the vertical tip position of the AFM cantilever. In the vertical tip-position control, the required z motion is commanded by laser reading of the vertical tip position in real time and might contain high frequency components depending on the lateral scanning rate and topographical variations of the sample. This paper presents a dual-actuator tip-motion control scheme that enables the AFM tip to track abrupt topographical variations. In the dual-actuator scheme, an additional magnetic mode actuator is employed to achieve high bandwidth tip-motion control while the regular z scanner provides the necessary motion range. This added actuator serves to make the entire cantilever bandwidth available for tip positioning, and thus controls the tip-to-sample distance. A fast programmable electronics board was employed to realize the proposed dual-actuator control scheme, in which model cancellation algorithms were implemented to enlarge the bandwidth of the magnetic actuation and to compensate the lightly damped dynamics of the cantilever. Experiments were conducted to illustrate the capabilities of the proposed dual-actuator tip-motion control in terms of response speed and travel range. It was shown that while the bandwidth of the regular z scanner was merely a small fraction of the cantilever's bandwidth, the dual-actuator control scheme led to a tip-motion control system, the bandwidth of which was comparable to that of the cantilever, where the dynamics overdamped, and the motion range comparable to that of the z scanner.

Laser interferometric system for six-axis motion measurement.

This article presents the development of a precision laser interferometric system, which is designed to achieve six-axis motion measurement for real-time applications. By combining the advantage of the interferometer with a retroreflector and that of the interferometer with a plane mirror reflector, the system is capable of simultaneously measuring large transverse motions along and large rotational motions about three orthogonal axes. Based on optical path analysis along with the designed kinematics of the system, a closed form relationship between the six-axis motion parameters of the object being measured and the readings of the six laser interferometers is established. It can be employed as a real-time motion sensor for various six-axis motion control stages. A prototype is implemented and integrated with a six-axis magnetic levitation stage to illustrate its resolution and measurement range.