On-chip light sheet illumination enables diagnostic size and concentration measurements of membrane vesicles in biofluids

Cell-derived membrane vesicles that are released in biofluids, like blood or saliva, are emerging as potential non-invasive biomarkers for diseases, such as cancer. Techniques capable of measuring the size and concentration of membrane vesicles directly in biofluids are urgently needed. Fluorescence single particle tracking microscopy has the potential of doing exactly that by labelling the membrane vesicles with a fluorescent label and analysing their Brownian motion in the biofluid. However, an unbound dye in the biofluid can cause high background intensity that strongly biases the fluorescence single particle tracking size and concentration measurements. While such background intensity can be avoided with light sheet illumination, current set-ups require specialty sample holders that are not compatible with high-throughput diagnostics. Here, a microfluidic chip with integrated light sheet illumination is reported, and accurate fluorescence single particle tracking size and concentration measurements of membrane vesicles in cell culture medium and in interstitial fluid collected from primary human breast tumours are demonstrated

Microfluidic Scintillation Detectors for High Energy Physics

This thesis deals with the development and study of microfluidic scintillation detectors, a technology of recent introduction for the detection of high energy particles. Most of the interest for such devices comes from the use of a liquid scintillator, which entails the possibility of changing the active material in the detector, leading to increased radiation resistance. A first part of the thesis focuses on the work performed in terms of design and modelling studies of novel prototype devices, hinting to new possibilities and applications. In this framework, the simulations performed to validate selected designs and the main technological choices made in view of their fabrication are addressed. The second part of this thesis deals with the microfabrication of several prototype devices. Two different materials were studied for the manufacturing of microfluidic scintillation detectors, namely the SU-8 photosensitive epoxy and monocrystalline silicon. For what concerns the former, an original fabrication approach based on successive bonding and selective release steps of resin layers patterned over sacrificial metal films is detailed. This approach was used to fabricate monolithic, free-standing devices embedding one or two layers of microfluidic channels, with a material budget corresponding to only 0.03% and 0.06% of the radiation length of SU-8. A first experimental validation of these devices is presented as well. Concerning silicon devices, studies on the fabrication of microchannel arrays by both dry and wet etching are reported. Adaptations of these standard techniques to the specific needs of microfluidic scintillation detectors are addressed, specifically the smoothing of scalloped sidewalls resulting from deep reactive ion etching as well as the mask design methodology applied to KOH etching in order to yield microchannels with smooth vertical sidewalls on wafers with the standard crystalline orientation. The anisotropic characteristics of wet etching were also exploited to demonstrate the fabrication of arrays of microfluidic channels having slanted reflective facets at their extremities, which can act as micromirrors that deviate the scintillation light in the out of plane direction, thus introducing new possibilities for the planar integration of the devices. Experimental results on the characterization of the light yield and attenuation length of silicon prototype devices performed using electrons from a radioactive source are presented. A brief study on the accelerated ageing of the detector in which the liquid scintillator was damaged by intense UV irradiation is reported. Such study provides encouraging results on how the capability of recirculating the active material in microfluidic scintillation detectors can be used to extend their lifetime or increase the stability of their performance in time

Metal-Coated SU-8 Structures for High-Density 3-D Microelectrode Arrays

Electric fields can be effectively used to sense, manipulate, and move particles in lab-on-a-chip devices. Nevertheless, the throughput of such devices is a critical issue, which can be effectively improved by increasing the height of the microchannels. For this purpose, vertical electrodes are needed in order to apply electrical stimuli homogeneously over the full height of the channel. In this paper, we propose different fabrication processes based on a conformal coating of 3-D SU-8 structures with metal layers, defining vertical electrodes in microfluidic channels with high aspect ratio and uniform coating of the vertical sidewalls. We describe two different strategies to achieve the patterning of connection lines inside the gaps of the pillar electrodes--one based on liftoff and the other based on dry film resist. We show how the liftoff approach allows for high connection densities and high resolution of the patterning inside the 3-D electrode arrays. Moreover, we highlight how the dry film process provides an efficient and low-cost alternative when neither high-density patterning nor high resolution is needed. Standard resistive and impedance measurements show high conductivity of the structures whose fabrication process grants standard photolithographic resolution in the definition of the electrode features

SU-8 as a Material for Microfabricated Particle Physics Detectors

Several recent detector technologies developed for particle physics applications are based on microfabricated structures. Detectors built with this approach generally exhibit the overall best performance in terms of spatial and time resolution. Many properties of the SU-8 photoepoxy make it suitable for the manufacturing of microstructured particle detectors. This article aims to review some emerging detector technologies making use of SU-8 microstructuring, namely micropattern gaseous detectors and microfluidic scintillation detectors. The general working principle and main process steps for the fabrication of each device are reported, with a focus on the advantages brought to the device functionality by the use of SU-8. A novel process based on multiple bonding steps for the fabrication of thin multilayer microfluidic scintillation detectors developed by the authors is presented. Finally, a brief overview of the applications for the discussed devices is given

Scintillation detectors based on silicon microfluidic channels

Microfluidic channels obtained by SU-8 photolithography and filled with liquid scintillators were recently demonstrated to be an interesting technology for the implementation of novel particle detectors.The main advantages of this approach are the intrinsic radiationresistance resulting from the simple microfluidic circulation of theactive medium and the possibility to manufacture devices with highspatial resolution and low material budget using microfabricationtechniques.Here we explore a different technological implementation of thisconcept, reporting on scintillating detectors based on siliconmicrofluidic channels. A process for manufacturing microfluidicdevices on silicon substrates, featuring microchannel arrays suitablefor light guiding, was developed. Such process can be in principlecombined with standard CMOS processing and lead to a tight integrationwith the readout photodetectors and electronics in the future.Several devices were manufactured, featuring microchannel geometriesdiffering in depth, width and pitch. A preliminary characterizationof the prototypes was performed by means of a photomultiplier tubecoupled to the microchannel ends, in order to detect the scintillationlight produced upon irradiation with beta particles from a90Sr source. The photoelectron spectra thusobtained were fitted with the expected output function in order toextract the light yield

Correlation between a Force-Sensing Oral Appliance and Electromyography in the Detection of Tooth Contact Bruxism Events

Background: Oral appliances embedding sensors can be interesting tools for monitoring tooth contact bruxism in a home environment, as they address some of the usability limitations of portable electromyography (EMG) systems. In this study, an oral appliance for sleep bruxism monitoring was compared to an electromyograph. Methods: Simulated bruxism events with tooth contact, specifically clenching and grinding, and other occlusal activities unrelated to bruxism, were measured in 23 subjects with the two instruments simultaneously. The recordings were analyzed automatically by a computer program in order to compare the two techniques. Results: The two instruments were found to be strongly correlated in terms of detecting events (r = 0.89), and estimating their duration (r = 0.88) and their intensity (r = 0.83). Conclusions: The two techniques were in agreement in measuring event frequency, duration and intensity in the studied group, suggesting that force-sensing oral appliances have the potential to be easy-to-use tools for home monitoring of bruxism, alone or as complements to portable EMGs