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

Photonic tools for advanced sensing and imaging at the nanoscale.

This dissertation reports a novel bio-sensing strategy based on single-mode, electro-active, integrated optical waveguide (SM-EA-IOW) platforms. It also reports the development of a super-resolved far-field optical imaging tool to enable optical, electronic, and spectroelectrochemical investigations at the nanoscale. SM-EA-IOW platforms with its outstanding sensitivity for spectroelectrochemical interrogation was combined with a sandwich bioassay for the development of a novel immunosensing based strategy for label-free detection of infectious pathogens. The strategy begins with the functionalization of the electroactive waveguide surface with a capturing antibody aimed at a specific target analyte. Once the target analyte is bound to the photonic interface, it promotes the binding of a secondary antibody that has been labeled with a redox active reporter. This labeled antibody reporter forms the analytical signal, which is linked uniquely to both the spectral and electrochemical properties of the redox probe designed to specifically recognize a target analyte. Based on this novel detection strategy experimental results in the interrogation of influenza A (H5N1) HA protein have reached an outstanding level of detection in the picomolar range. In addition, the novel label-free SM-EA-IOW bio-sensing strategy was successfully demonstrated for detection of gram-negative bacteria in present authentic clinical eye samples. Such demonstration has also shown the flexibility and ability of the new strategy to probe samples in in the microliter volume range, without any prior processing or pre-enrichment steps. As the groundwork towards the optimal operation of the novel sensing strategy, the effects of the adsorption process and the rate of electron transfer of redox bound species to the electrode surface were thoroughly studied. For each interface of a multilayer immunoassay assembly the surface density, the adsorption kinetic, and the electron-transfer rate of bound species of a redox-active protein were investigated using an optical impedance spectroscopy (OIS) technique based on measurements obtained with the SM-EA-IOW platform. Such methodology and acquired knowledge are crucial for the rational development of novel and advanced immuno-biosensors. Electrochemically modulated fluorescent molecules to be conjugated with relevant antibodies for creating an electroactive probe at the nanoscale was also investigated. Such capability has the potential to enable the development of an arrayed immunosensing technology. Fluorescence emission at the nanoscale suffers from two main restrictions, diffraction limit and photobleaching effects. To address these hinders, a modulated stimulated emission depletion microscope (STED) that is capable of achieving far-field super-resolved images was developed and used to reduce the power of the applied excitation and depletion laser beams diminish photobleaching effects in single-molecule sub-diffraction STED imaging. These two photonic devices provide new approaches for bio-sensing from ensemble range to single molecule detection studies and sensing, where new detection limits can be reached that is expected to establish novel bio-sensing devices with higher sensitivity, specificity and easier ways of sample handling

Blood-coated sensor for high-throughput ptychographic cytometry on a Blu-ray disc

Blu-ray drive is an engineering masterpiece that integrates disc rotation, pickup head translation, and three lasers in a compact and portable format. Here we integrate a blood-coated image sensor with a modified Blu-ray drive for high-throughput cytometric analysis of various bio-specimens. In this device, samples are mounted on the rotating Blu-ray disc and illuminated by the built-in lasers from the pickup head. The resulting coherent diffraction patterns are then recorded by the blood-coated image sensor. The rich spatial features of the blood-cell monolayer help down-modulate the object information for sensor detection, thus forming a high-resolution computational bio-lens with a theoretically unlimited field of view. With the acquired data, we develop a lensless coherent diffraction imaging modality termed rotational ptychography for image reconstruction. We show that our device can resolve the 435 nm linewidth on the resolution target and has a field of view only limited by the size of the Blu-ray disc. To demonstrate its applications, we perform high-throughput urinalysis by locating disease-related calcium oxalate crystals over the entire microscope slide. We also quantify different types of cells on a blood smear with an acquisition speed of ~10,000 cells per second. For in vitro experiment, we monitor live bacterial cultures over the entire Petri dish with single-cell resolution. Using biological cells as a computational lens could enable new intriguing imaging devices for point-of-care diagnostics. Modifying a Blu-ray drive with the blood-coated sensor further allows the spread of high-throughput optical microscopy from well-equipped laboratories to citizen scientists worldwide

Laser Scanning Microscopy with SPAD Array Detector: Towards a New Class of Fluorescence Microscopy Techniques

Laser scanning microscopy is one of the most common architectures in fluorescence microscopy. In a nutshell: the objective lens focuses the laser beam(s) and generates an effective excitation spot which is scanned on the sample; for each pixel, the fluorescent image is projected into a single-element detector, which \u2013 typically \u2013 spatially and temporally integrates the fluorescent light along its sensitive area and the pixel dwell-time, thus providing a single-intensity value per pixel. Notably, the integration performed by the single-element detector hinders any additional information potentially encoded in the dynamic and image of the fluorescent spot. To address this limitation, we recently upgraded the detection unit of a laser scanning microscope, replacing the single-element detector with a novel SPAD (single photon avalanche diode) array detector. We have shown at first that the additional spatial information allows to overcome the trade-off between resolution and signal-to-noise ratio proper of confocal microscopy: indeed, this architecture represents the natural implementation of image scanning microscopy (ISM). We then exploited the single-photon-timing ability of the SPAD array detector elements to combine ISM with fluorescence lifetime imaging: the results show higher resolution and better lifetime accuracy with respect to the confocal counterpart. Moreover, we explored the combination of our ISM platform with stimulated emission depletion (STED) microscopy, to mitigate the non-negligible chance of photo-damaging a sample. Lastly, we showed how the SPAD array-based microscope can be used in the context of single-molecule/particle tracking (SMT or SPT) and spectroscopy. Indeed, we implemented a real-time, feedback based SMT architecture which can potentially correlate the dynamics of a bio-molecule with its structural changes and micro-environment, taking advantage of the time-resolved spectroscopy ability of the novel detector. We believe that this novel laser scanning microscopy architecture has everything in its favour to substitute current single-element detector approaches; it will enable for a new class of fluorescence microscopy techniques capable of investigating complex living biological samples with unprecedented spatial and temporal characteristics and augmented information content