Innovative Detection of Biomarkers Based on Chemiluminescent Nanoparticles and a Lensless Optical Sensor.

The identification and quantification of biomarkers with innovative technologies is an urgent need for the precise diagnosis and follow up of human diseases. Body fluids offer a variety of informative biomarkers, which are traditionally measured with time-consuming and expensive methods. In this context, lateral flow tests (LFTs) represent a rapid and low-cost technology with a sensitivity that is potentially improvable by chemiluminescence biosensing. Here, an LFT based on gold nanoparticles functionalized with antibodies labeled with the enzyme horseradish peroxidase is combined with a lensless biosensor. This biosensor comprises four Silicon Photomultipliers (SiPM) coupled in close proximity to the LFT strip. Microfluidics for liquid handling complete the system. The development and the setup of the biosensor is carefully described and characterized. C-reactive protein was selected as a proof-of-concept biomarker to define the limit of detection, which resulted in about 0.8 pM when gold nanoparticles were used. The rapid readout (less than 5 min) and the absence of sample preparation make this biosensor promising for the direct and fast detection of human biomarkers.

Preliminary Characterization of an Active CMOS Pad Detector for Tracking and Dosimetry in HDR Brachytherapy.

We assessed the accuracy of a prototype radiation detector with a built in CMOS amplifier for use in dosimetry for high dose rate brachytherapy. The detectors were fabricated on two substrates of epitaxial high resistivity silicon. The radiation detection performance of prototypes has been tested by ion beam induced charge (IBIC) microscopy using a 5.5 MeV alpha particle microbeam. We also carried out the HDR Ir-192 radiation source tracking at different depths and angular dose dependence in a water equivalent phantom. The detectors show sensitivities spanning from (5.8 ± 0.021) × 10-8 to (3.6 ± 0.14) × 10-8 nC Gy-1 mCi-1 mm-2. The depth variation of the dose is within 5% with that calculated by TG-43. Higher discrepancies are recorded for 2 mm and 7 mm depths due to the scattering of secondary particles and the perturbation of the radiation field induced in the ceramic/golden package. Dwell positions and dwell time are reconstructed within ±1 mm and 20 ms, respectively. The prototype detectors provide an unprecedented sensitivity thanks to its monolithic amplification stage. Future investigation of this technology will include the optimisation of the packaging technique.

Time-Resolved Fluorescence Spectroscopy of Molecularly Imprinted Nanoprobes as an Ultralow Detection Nanosensing Tool for Protein Contaminants.

Currently, optical sensors based on molecularly imprinted polymers (MIPs) have been attracting significant interest. MIP sensing relies on the combination of the MIP's selective capability, which is conveyed to the polymeric material by a template-assisted synthesis, with optical techniques that offer exquisite sensitivity. In this work, we devised an MIP nanoparticle optical sensor for the ultralow detection of serum albumin through time-resolved fluorescence spectroscopy. The Fluo-nanoMIPs (∅~120 nm) were synthetized using fluorescein-O-methacrylate (0.1×, 1×, 10× mol:mol versus template) as an organic fluorescent reporter. The ability of 0.1× and 1×Fluo-nanoMIPs to bind albumin (15 fM-150 nM) was confirmed by fluorescence intensity analyses and isothermal titration calorimetry. The apparent dissociation constant (Kapp) was 30 pM. Conversely, the 10× fluorophore content did not enable monitoring binding. Then, the time-resolved fluorescence spectroscopy of the nanosensors was studied. The 1×Fluo-nanoMIPs showed a decrease in fluorescence lifetime upon binding to albumin (100 fM-150 nM), Kapp = 28 pM, linear dynamic range 3.0-83.5 pM, limit of detection (LOD) 1.26 pM. Selectivity was confirmed testing 1×Fluo-nanoMIPs against competitor proteins. Finally, as a proof of concept, the nanosensors demonstrated detection of the albumin (1.5 nM) spiked in wine samples, suggesting a possible scaling up of the method in monitoring allergens in wines.

Design and Characterization of Backside Termination Structures for Thick Fully-Depleted MAPS.

Fully Depleted Monolithic Active Pixel Sensors (FD-MAPS) represent an appealing alternative to hybrid detectors for radiation imaging applications. We have recently demonstrated the feasibility of FD-MAPS based on a commercial 110 nm CMOS technology, adapted using high-resistivity substrates and backside post-processing. A p/n junction diode, fabricated on the detector backside using low-temperature processing steps after the completion of the front-side Back End of Line (BEOL), is reverse-biased to achieve the full depletion of the substrate and thus fast charge collection by drift. Test diodes including termination structures with different numbers of floating guard rings and different pitches were fabricated together with other Process Control Monitor structures. In this paper, we present the design of the backside diodes, together with results from the electrical characterization of the test devices, aiming to improve understanding of the strengths and limitations of the proposed approach. Characterization results obtained on several wafers demonstrate the effectiveness of the termination rings in increasing the breakdown voltage of the backside diodes and in coping with the variability of the passivation layer characteristics. A breakdown voltage exceeding 400 V in the worst case was demonstrated in devices with 30 guard rings with 6 µm pitch, thus enabling the full depletion of high-resistivity substrates with a thickness larger than or equal to 300 µm. Additionally, we show the first direct comparison for this technology of measured pixel characteristics with 3D TCAD simulations, proving a good agreement in the extracted operating voltages.

MoS2 Based Photodetectors: A Review.

Photodetectors based on transition metal dichalcogenides (TMDs) have been widely reported in the literature and molybdenum disulfide (MoS2) has been the most extensively explored for photodetection applications. The properties of MoS2, such as direct band gap transition in low dimensional structures, strong light-matter interaction and good carrier mobility, combined with the possibility of fabricating thin MoS2 films, have attracted interest for this material in the field of optoelectronics. In this work, MoS2-based photodetectors are reviewed in terms of their main performance metrics, namely responsivity, detectivity, response time and dark current. Although neat MoS2-based detectors already show remarkable characteristics in the visible spectral range, MoS2 can be advantageously coupled with other materials to further improve the detector performance Nanoparticles (NPs) and quantum dots (QDs) have been exploited in combination with MoS2 to boost the response of the devices in the near ultraviolet (NUV) and infrared (IR) spectral range. Moreover, heterostructures with different materials (e.g., other TMDs, Graphene) can speed up the response of the photodetectors through the creation of built-in electric fields and the faster transport of charge carriers. Finally, in order to enhance the stability of the devices, perovskites have been exploited both as passivation layers and as electron reservoirs.

Fully Depleted Monolithic Active Microstrip Sensors: TCAD Simulation Study of an Innovative Design Concept.

The paper presents the simulation studies of 10 µµm pitch microstrips on a fully depleted monolithic active CMOS technology and describes their potential to provide a new and cost-effective solution for particle tracking and timing applications. The Fully Depleted Monolithic Active Microstrip Sensors (FD-MAMS) described in this work, which are developed within the framework of the ARCADIA project, are compliant with commercial CMOS fabrication processes. A set of Technology Computer-Aided Design (TCAD) parametric simulations was performed in the perspective of an upcoming engineering production run with the aim of designing FD-MAMS, studying their electrical characteristics, and optimizing the sensor layout for enhanced performance in terms of low capacitance, fast charge collection, and low-power operation. A fine pitch of 10 µµm was chosen to provide high spatial resolution. This small pitch still allows readout electronics to be monolithically integrated in the inter-strip regions, enabling the segmentation of long strips and the implementation of distributed readout architectures. The effects of surface radiation damage expected for total ionizing doses of the order of 10 to 105 krad were also modeled in the simulations. The results of the simulations exhibit promising performance in terms of timing and low power consumption and motivate R&D efforts to further develop FD-MAMS; the results will be experimentally verified through measurements on the test structures that will be available from mid-2021.

Development of low-energy X-ray detectors using LGAD sensors.

Recent advances in segmented low-gain avalanche detectors (LGADs) make them promising for the position-sensitive detection of low-energy X-ray photons thanks to their internal gain. LGAD microstrip sensors fabricated by Fondazione Bruno Kessler have been investigated using X-rays with both charge-integrating and single-photon-counting readout chips developed at the Paul Scherrer Institut. In this work it is shown that the charge multiplication occurring in the sensor allows the detection of X-rays with improved signal-to-noise ratio in comparison with standard silicon sensors. The application in the tender X-ray energy range is demonstrated by the detection of the sulfur Kα and Kß lines (2.3 and 2.46 keV) in an energy-dispersive fluorescence spectrometer at the Swiss Light Source. Although further improvements in the segmentation and in the quantum efficiency at low energy are still necessary, this work paves the way for the development of single-photon-counting detectors in the soft X-ray energy range.

AN ONLINE, RADIATION HARD PROTON ENERGY-RESOLVING SCINTILLATOR STACK FOR LASER-DRIVEN PROTON BUNCHES.

We report on a scintillator-based online detection system for the spectral characterization of polychromatic proton bunches. Using up to nine stacked layers of radiation hard polysiloxane scintillators, coupled to and readout edge-on by a large area pixelated CMOS detector, impinging polychromatic proton bunches were characterized. The energy spectra were reconstructed using calibration data and simulated using Monte-Carlo simulations. Despite the scintillator stack showed some problems like thickness inhomogeneities and unequal layer coupling, the prototype allows to obtain a first estimate of the energy spectrum of proton beams.

Design and characterization of a p+/n-well SPAD array in 150nm CMOS process: erratum.

An erratum is presented to correct a reference mistake in Table 1 in Sect. 4 of [Opt. Express25, 12765 (2017)].

Design and characterization of a p+/n-well SPAD array in 150nm CMOS process.

This paper reports on characterization results of a single-photon avalanche diode (SPAD) array in standard CMOS 150nm technology. The array is composed by 25 (5 × 5) SPADs, based on p+/n-well active junction along with a retrograde deep n-well guard ring. The square-shaped SPAD has a 10µm active diameter and 15.6µm pitch size, achieving a 39.9% array fill factor. Characterization results show a good breakdown voltage uniformity (40mV max-min) within each chip and 17mV/°C temperature coefficient. The median DCR is 0.4Hz/µm2, and the afterpulsing probability is 0.85% for a dead time of 150ns at 3V excess bias voltage. The peak PDP is 31% at 450nm wavelength and a good uniformity (1.1% standard deviation) is observed for the array at 5V excess bias. The single SPADs exhibit a timing jitter of 52ps (FWHM) and 42ps (FWHM) under a 468-nm and a 831-nm laser, respectively. The crosstalk probability as a function of pixel-to-pixel distance and excess bias voltage is presented, and random telegraph signal (RTS) noise is also discussed in detail.

Compact SPAD-Based Pixel Architectures for Time-Resolved Image Sensors.

This paper reviews the state of the art of single-photon avalanche diode (SPAD) image sensors for time-resolved imaging. The focus of the paper is on pixel architectures featuring small pixel size (<25 µm) and high fill factor (>20%) as a key enabling technology for the successful implementation of high spatial resolution SPAD-based image sensors. A summary of the main CMOS SPAD implementations, their characteristics and integration challenges, is provided from the perspective of targeting large pixel arrays, where one of the key drivers is the spatial uniformity. The main analog techniques aimed at time-gated photon counting and photon timestamping suitable for compact and low-power pixels are critically discussed. The main features of these solutions are the adoption of analog counting techniques and time-to-analog conversion, in NMOS-only pixels. Reliable quantum-limited single-photon counting, self-referenced analog-to-digital conversion, time gating down to 0.75 ns and timestamping with 368 ps jitter are achieved.

Fast and simple spectral FLIM for biochemical and medical imaging.

Spectrally resolved fluorescence lifetime imaging microscopy (λFLIM) has powerful potential for biochemical and medical imaging applications. However, long acquisition times, low spectral resolution and complexity of λFLIM often narrow its use to specialized laboratories. Therefore, we demonstrate here a simple spectral FLIM based on a solid-state detector array providing in-pixel histrogramming and delivering faster acquisition, larger dynamic range, and higher spectral elements than state-of-the-art λFLIM. We successfully apply this novel microscopy system to biochemical and medical imaging demonstrating that solid-state detectors are a key strategic technology to enable complex assays in biomedical laboratories and the clinic.

SPAD aptasensor for the detection of circulating protein biomarkers.

The need for decentralized clinical tests together with the concept of time and cost saving are pushing the development of portable, miniaturized, compact biosensors with diagnostic and prognostic purpose. Here, we propose an innovative detection system based on a Single Photon Avalanche Diode (SPAD) with high sensitivity and low noise, crucial features for an efficient chemiluminescence biosensor. The SPAD detector, having 60 µm diameter, has a Photon Detection Efficiency higher than 55% at 425 nm and a Dark Count Rate lower than 100 Hz at room temperature. Our design allows a good optical coupling efficiency between sample and detector. A specific biofunctional surface was implemented taking advantage of aptamers, short DNA sequences having high selectivity and affinity toward their targets. We successfully detected physiological levels of Vascular Endothelial Growth Factor (VEGF), a circulating protein biomarker highly correlated with cancer. The SPAD aptasensor showed a Limit of Detection (LoD) in the pM range, stability (up to 42 days) and re-usability (up to seven cycles). This compact biosensor is therefore a promising step toward the actual use of portable microdevices in diagnostics.

A hybrid CMOS-imager with a solution-processable polymer as photoactive layer.

The solution-processability of organic photodetectors allows a straightforward combination with other materials, including inorganic ones, without increasing cost and process complexity significantly compared with conventional crystalline semiconductors. Although the optoelectronic performance of these organic devices does not outmatch their inorganic counterparts, there are certain applications exploiting the benefit of the solution-processability. Here we demonstrate that the small pixel fill factor of present complementary metal oxide semiconductor-imagers, decreasing the light sensitivity, can be increased up to 100% by replacing silicon photodiodes with an organic photoactive layer deposited with a simple low-cost spray-coating process. By performing a full optoelectronic characterization on this first solution-processable hybrid complementary metal oxide semiconductor-imager, including the first reported observation of different noise types in organic photodiodes, we demonstrate the suitability of this novel device for imaging. Furthermore, by integrating monolithically different organic materials to the chip, we show the cost-effective portability of the hybrid concept to different wavelength regions.