MEMS Technology for Biomedical Imaging Applications

Biomedical imaging is the key technique and process to create informative images of the human body or other organic structures for clinical purposes or medical science. Micro-electro-mechanical systems (MEMS) technology has demonstrated enormous potential in biomedical imaging applications due to its outstanding advantages of, for instance, miniaturization, high speed, higher resolution, and convenience of batch fabrication. There are many advancements and breakthroughs developing in the academic community, and there are a few challenges raised accordingly upon the designs, structures, fabrication, integration, and applications of MEMS for all kinds of biomedical imaging. This Special Issue aims to collate and showcase research papers, short commutations, perspectives, and insightful review articles from esteemed colleagues that demonstrate: (1) original works on the topic of MEMS components or devices based on various kinds of mechanisms for biomedical imaging; and (2) new developments and potentials of applying MEMS technology of any kind in biomedical imaging. The objective of this special session is to provide insightful information regarding the technological advancements for the researchers in the community

Development of a XYZ scanner for home-made atomic force microscope based on FPAA control

Atomic force microscopy (AFM) is one of the useful tools in the fields of nanoscale measurement and manipulation. High speed scanning is one of the crucial requirements for live cell imaging and soft matter characterization. The scanning speed is limited by the bandwidth of the AFM’s detection and actuation components. Generally, the bandwidth of a traditional scanner is too low to conduct the live cell imaging. This paper presents a simple and integrated compact home-made AFM for high speed imaging. To improve the bandwidth of the scanner, a parallel kinematics mechanism driven by piezoelectric actuators (PZTs) is proposed for the fast positioning in the X, Y and Z directions. The mechanical design optimization, modeling and analysis, and experimental testing have been conducted to validate the performance of the proposed scanner. A number of experimental results showed that the developed scanner has the capability for broad bandwidth with low coupling errors in the actuation directions. A hybrid control strategy including feedforward and feedback loops has been designed to significantly improve the dynamic tracking performance of the scanner and a field programmable analog array (FPAA) system is utilized to implement the control algorithm for excellent and stable tracking capability. Further, a number of high speed measurements have been conducted to verify the performance of the developed AFM

MEMS devices for the control of trapped atomic particles

This thesis presents the design and characterisation of novel MEMS scanners, for use in systems involving trapped atomic particles. The scanners are manufactured using multiuser silicon-on-insulator MEMS fabrication processes and use resonant piezoelectric actuation based on aluminium nitride thin films to produce one dimensional scanning at high frequencies, with resonance tuning capabilities of up to 5 kHz. Frequencies of ~100kHz and higher are required to enable for example resonant addressing of trapped atomic particles. This work demonstrates how the 200 μm and 400 μm diameter scanners can produce optical deflection angles upwards of 2° at frequencies from 80 kHz to 400 kHz. It proposes an addressing scheme based on Lissajous scanning to steer laser pulses onto 2D grids at a scale compatible with experiments involving single trapped atoms. It also examines frequency tuning capabilities of the scanners using localized on-chip Joule heating and active cooling ; frequency tuning and synchronization are shown to be critical to the implementation of 2-dimensional scanning with multiple scanners. These features are then demonstrated in a prototype implementation using fluorescing samples as a mock target to evaluate the optical performance of the scanning system. Finally, the thesis describes a proof-of-concept for integration of the scanners in a trapped atoms experiment, in which rubidium atoms trapped inside a magneto-optical trap are selectively pumped into a fluorescing state using a beam steered by the MEMS scanners.This thesis presents the design and characterisation of novel MEMS scanners, for use in systems involving trapped atomic particles. The scanners are manufactured using multiuser silicon-on-insulator MEMS fabrication processes and use resonant piezoelectric actuation based on aluminium nitride thin films to produce one dimensional scanning at high frequencies, with resonance tuning capabilities of up to 5 kHz. Frequencies of ~100kHz and higher are required to enable for example resonant addressing of trapped atomic particles. This work demonstrates how the 200 μm and 400 μm diameter scanners can produce optical deflection angles upwards of 2° at frequencies from 80 kHz to 400 kHz. It proposes an addressing scheme based on Lissajous scanning to steer laser pulses onto 2D grids at a scale compatible with experiments involving single trapped atoms. It also examines frequency tuning capabilities of the scanners using localized on-chip Joule heating and active cooling ; frequency tuning and synchronization are shown to be critical to the implementation of 2-dimensional scanning with multiple scanners. These features are then demonstrated in a prototype implementation using fluorescing samples as a mock target to evaluate the optical performance of the scanning system. Finally, the thesis describes a proof-of-concept for integration of the scanners in a trapped atoms experiment, in which rubidium atoms trapped inside a magneto-optical trap are selectively pumped into a fluorescing state using a beam steered by the MEMS scanners

MEMS-Based Endomicroscopes for High Resolution in vivo Imaging

Intravital microscopy is an emerging methodology for performing real time imaging in live animals. This technology is playing a greater role in the study of cellular and molecular biology because in vitro systems cannot adequately recapitulate the microenvironment of living tissues and systems. Conventional intravital microscopes use large, bulky objectives that require wide surgical exposure to image internal organs and result in terminal experiments. If these instruments can be reduced sufficiently in size, biological phenomena can be observed in a longitudinal fashion without animal sacrifice. The epithelium is a thin layer of tissue in hollow organs, and is the origin of many types of human diseases. In vivo assessment of biomarkers expressed in the epithelium in animal models can provide valuable information of disease development and drug efficacy. The overall goal of this work is to develop miniature imaging instruments capable of visualizing the epithelium in live animals with subcellular resolution. The dissertation is divided into four projects, where each contains an imaging system developed for small animal imaging. These systems are all designed using laser beam scanning technology with tiny mirrors developed with microelectromechanical systems (MEMS) technology. By using these miniature scanners, we are able to develop endomicroscopes small enough for hollow organs in small animals. The performance of these systems has been demonstrated by imaging either excised tissue or colon of live mice. The final version of the instrument can collect horizontal/oblique plane images in the mouse colon in real time (>10 frames/sec) with sub-micron resolution (<1 um), deep tissue penetration (~200 um) and large field of view (700 x 500 um). A novel side-viewing architecture with distal MEMS scanning was developed to create clear and stable image in the mouse colon. With the use of the instrument, it is convenient to pinpoint location of interest and create a map of the colon using image mosaicking. Multispectral fluorescence images can by collected at excitation wavelength ranging from 445 nm to 780 nm. The instruments have been used to 1) validate specific binding of a cancer targeting agent in the mouse colon and 2) study the tumor development in a mouse model with endogenous fluorescence protein expression. We use these studies to show that we have developed an enabling technology which will allow biologist to perform longitudinal imaging in animal models with subcellular resolution.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/136954/2/dxy_1.pd

DEVELOPMENT OF A VERSATILE HIGH SPEED NANOMETER LEVEL SCANNING MULTI-PROBE MICROSCOPE

The motivation for development of a multi-probe scanning microscope, presented in this dissertation, is to provide a versatile measurement tool mainly targeted for biological studies, especially on the mechanical and structural properties of an intracellular system. This instrument provides a real-time, three-dimensional (3D) scanning capability. It is capable of operating on feedback from multiple probes, and has an interface for confocal photo-detection of fluorescence-based and single molecule imaging sensitivity. The instrument platform is called a Scanning Multi-Probe Microscope (SMPM) and enables 45 microm by 45 microm by 10 microm navigation of specimen with simultaneous optical and mechanical probing with each probe location being adjustable for collocation or for probing with known probe separations. The 3D positioning stage where the specimen locates was designed to have nanometer resolution and repeatability at 10 Hz scan speed with either open loop or closed loop operating modes. The fine motion of the stage is comprises three orthogonal flexures driven by piezoelectric actuators via a lever linkage. The flexures design is able to scan in larger range especially in z axis and serial connection of the stages helps to minimize the coupling between x, y and z axes. Closed-loop control was realized by the capacitance gauges attached to a rectangular block mounted to the underside of the fine stage upon which the specimen is mounted. The stage's performance was studied theoretically and verified by experimental test. In a step response test and using a simple proportional and integral (PI) controller, standard deviations of 1.9 nm 1.8 nm and 0.41 nm in the x, y and z axes were observed after settling times of 5 ms and 20 ms for the x and y axes. Scanning and imaging of biological specimen and artifact grating are presented to demonstrate the system operation. For faster, short range scanning, novel ultra-fast fiber scanning system was integrated into the xyz fine stage to achieve a super precision dual scanning system. The initial design enables nanometer positioning resolution and runs at 100 Hz scan speed. Both scanning systems are capable of characterization using dimensional metrology tools. Additionally, because the high-bandwidth, ultra-fast scanning system operates through a novel optical attenuating lever, it is physically separate from the longer range scanner and thereby does not introduce additional positioning noise. The dual scanner provides a fine scanning mechanism at relatively low speed and large imaging area using the xyz stage, and focus on a smaller area of interested in a high speed by the ultra-fast scanner easily. Such functionality is beneficial for researchers to study intracellular dynamic motion which requires high speed imaging. Finally, two high end displacement sensor systems, a knife edge sensor and fiber interferometer, were demonstrated as sensing solutions for potential feedback tools to boost the precision and resolution performance of the SMPM

Dynamical control of one- and two-dimensional optical fibre scanning

This thesis investigates the dynamical control of one- and two-dimensional optical fibre scanning. One dimensional scanning is performed with a mechanically biaxial polarisation-preserving fibre mounted on a piezoelectric transducer with one of its principal mechanical axes aligned parallel to the excitation direction. The addition of an apertured reflector in front of the imaging lens allows a position sensing mechanism based on intermittent optical feedback to be integrated into the scanner. Over-scanning the lens generates timing pulses interlaced with back-scattered signals from the target. The timing information can be used for closed loop control of the phase and amplitude of vibration. Suitable control algorithms are developed and their convergence and stability is studied. This thesis also investigates the construction of fibres with enhanced mechanically asymmetry and their dynamical properties during two-dimensional imaging based on Lissajous scan patterns. Dip-coating is proposed as a method of forming two-cored waveguide cantilevers from two separate, parallel fibres that are encapsulated in a plastic coating. The frequency ratio between the two orthogonal bending mode resonances can be controlled with number of coatings. An exact image reconstruction algorithm based on Lissajous scanning is proposed. Latency, transient response and steady-state phase errors are all shown to cause dramatic deterioration of the reconstructed image. Solutions are provided by ensuring the correct starting time for data acquisition and introducing a drive phase correction to one of the axes. Two methods of resolution enhancement are demonstrated. The first is based on combining data sets obtained during separate scans carried out with deliberately applied phase offsets. The second operates by combining data sets from separate imaging operations carried out using the two different fibre cores. Finally, this thesis demonstrates potential applications in optogenetics by combining the two operations of imaging and writing, using different light sources that may also have different wavelengths.Open Acces

Improvement of accuracy and speed of a commercial AFM using Positive Position Feedback control

The atomic force microscope (AFM) is a device capable of generating topographic images of sample surfaces with extremely high resolutions down to the atomic level. It is also being used in applications that involve manipulation of matter at a nanoscale. Early AFMs were operated in open loop. As a result, they were susceptible to piezoelectric creep, thermal drift, hysteresis nonlinearity and scan-induced vibration. These effects tend to distort the generated image. The distortions are often minimized by limiting the scanning speed and range of the AFMs. Recently a new generation of AFMs has emerged that utilizes position sensors to measure displacements of the scanner in three dimensions. These AFMs are equipped with feedback loops that work to minimize the adverse effects of hysteresis, piezoelectric creep and thermal drift on the obtained image using standard PI controllers. These feedback controllers are often not designed to deal with the highly resonant nature of an AFM's scanner, nor with the cross-coupling between various axes. In this paper we illustrate the drastic improvement in accuracy and imaging speed that can be obtained by proper design of a feedback controller. Such controllers can be incorporated into most modern AFMs with minimal effort since they can be implemented in software with the existing hardware

Multi-beam miniaturized volumetric scanning microscopy with a single 1-dimensional actuation

Miniaturized optical imaging systems often use a 2-dimensional (2-D) actuator such as a piezoelectric tube or microelectromechanical system actuator for the acquisition of 2-D and higher dimensional images over an areal field of view (FOV). Piezoelectric tubes are the most compact, but usually produce impractical sub-millimetre FOVs and are difficult to fabricate at scale, leading to high costs. Planar piezoelectric bending actuators ('benders') are substantially lower cost and capable of much larger actuations, albeit 1-dimensional (1-D) and traditionally inadequate for 2-D steering tasks. We present a piezoelectric bender imaging system that exploits mechanical motion coupling to produce multi-millimetre scale 2-D scan coverage. Leveraging optical coherence tomography with a long coherence length laser, we further extend the FOV using three depth-multiplexed imaging beams from optical fibres resonating in synchronicity across the width of the bender. Each fibre had a FOV of ~2.1 x 1.5 mm, contributing to a stitched field of ~2.1 x 2.9 mm with a beam resolution of 12.6 um full-width at half-maximum. Imaging of biological samples including stomach tissue, an ant and cell spheroids was performed. This multi-fold improvement in imaging coverage and cost-effectiveness promises to accelerate the advent of piezoelectric scanning in compact devices such as endoscopes for biomedicine, and headsets for augmented/virtual reality and neuroscience