Carl Jackson

Development of a microfluidic device for fluorescence activated cell sorting

This paper describes the development towards a miniaturized analytical system that can perform the major key functions of a flow cytometer. The development aims at diagnostic applications for cell counting and sorting with the ultimate goal of a low-cost portable instrument for point of care diagnosis. The present systems configuration consists of a disposable microfluidic device, that enables injection, single file cell flow through a miniaturized laser induced fluorescence detection system as well as sorting of identified samples. The microfluidic devices were fabricated by means of rapid prototyping technologies based on thick film photo-polymers. This paper reports various approaches on cell sorting and demonstrates sorting of single cells by means of an off-chip valve switching technique. The miniaturized fluorescence detection system employs active and passive micro-optical components, including semiconductor laser and ultra bright LED sources, highly sensitive avalanche photodiodes as well as micro-prism, holographic diffraction gratings and fibre optics for transmission and collection of light. Furthermore we demonstrate the feasibility of integrating solid-state components as part of an on-chip detection system.

High-volume silicon photomultiplier production, performance, and reliability

This publication details CMOS foundry fabrication, reliability stress assessment, and packaged sen- sor test results obtained during qualification of the SensL B-Series silicon photomultiplier (SiPM). SiPM sensors with active-area dimensions of 1, 3, and 6 mm were fabricated and tested to provide a comprehensive review of SiPM performance highlighted by fast output rise times of 300 ps and photon detection efficiency of greater than 41%, combined with low afterpulsing and crosstalk. Measurements important for medical imaging positron emis- sion tomography systems that rely on time-of-flight detectors were completed. Results with LSYO:Ce scintillation crystals of 3 × 3 × 20 mm 3 demonstrated a 225 � 2-ps coincidence resolving time (CRT), and the fast output is shown to allow for simultaneous acquisition of CRT and energy resolution. The wafer level test results from ∼150 k 3-mm SiPM are shown to demonstrate a mean breakdown voltage value of 24.69 V with a standard deviation of 0.073 V. The SiPM output optical uniformity is shown to be � 10% at a single supply voltage of 29.5 V. Finally, reliability stress assessment to Joint Electron Device Engineering Council (JEDEC) industry standards is detailed and shown to have been completed with all SiPM passing. This is the first qualification and reliability stress assessment program run to industry standards that has been reported on SiPM.©2014 Society

Fast Timing Silicon Photomultipliers for Scintillation Detectors

A new silicon photomultiplier is fabricated for fast timing applications by SensL Technologies Ltd. This new family of silicon photomultiplier, herein referred to as fast SPM devices, is fabricated with a third terminal that has a low output capacitance to improve timing performance. Two fast SPMs (an N-on-P type and a prototype P-on-N type) are assessed for energy and timing performances in scintillation detectors. When coupled with L(Y)SO:Ce crystals, the optimal energy resolutions for the 511 keV photon peak are 13.7% and 13.1%, whereas coincidence resolving times (CRTs) of 184±5 and 157±3 ps are attained with 2 × 2 × 3 mm3 crystals for the N-on-P and P-on-N devices, respectively. For longer crystals (3 × 3 × 20 mm3) , more relevant for positron emission tomography, the CRTs are 298±9 and 234±6 ps for the two SPM types, respectively, a significant improvement from standard SPM devices.

Performance evaluation of SensL SiPM arrays for high-resolution PET

Silicon photomultipliers (SiPMs) have high gain, excellent timing performance, and are well suited to PET/MRI applications due, in part, to their MR-compatibility and small form factor. Within the constraints of a resistor-based multiplexing circuit, it is useful to evaluate the four generations of SiPM arrays manufactured by SensL: the SPMArray4, ArraySL-4, ArraySM-4, and ArraySB-4. Breakdown voltage and dark current were measured as a function of temperature in two each of the four generations of SensL SiPM arrays. Flood histograms were created with a 68Ge-irradiated 9×9 LYSO crystal array at temperatures of 5 °C to 45 °C in 5 °C increments and overvoltages of 2 to 4 V in 0.5 V increments. Measurements of dark current vs. bias voltage increased as temperature increased, with a corresponding increase in the breakdown voltage, Vb. The temperature dependence of Vb is similar between all four generations of SiPM arrays with slopes ranging from 17.0 to 23.8 mV/°C. Notably, the ArraySB-4 has lower values for the breakdown voltage, with Vb = 24 V at 0 °C. Mean energy resolution for individual LYSO crystals showed improvements in each successive generation. The average energy resolution of the ArraySB-4 was 11.9% after correcting for non-linearity in the SiPM pixels. The linearity of the SensL SiPM arrays as a function of temperature and breakdown voltage makes them a suitable choice for a high-resolution, small animal PET/MRI system. Based on its improved resolvability and energy resolution, lower sensitivity to temperature and higher PDE, the ArraySB-4 will be used in our PET system.

Geiger mode avalanche photodiodes for microarray systems

New Geiger Mode Avalanche Photodiodes (GM-APD) have been designed and characterized specifically for use in microarray systems. Critical parameters such as excess reverse bias voltage, hold-off time and optimum operating temperature have been experimentally determined for these photon-counting devices. The photon detection probability, dark count rate and afterpulsing probability have been measured under different operating conditions. An active- quench circuit (AQC) is presented for operating these GM- APDs. This circuit is relatively simple, robust and has such benefits as reducing average power dissipation and afterpulsing. Arrays of these GM-APDs have already been designed and together with AQCs open up the possibility of having a solid-state microarray detector that enables parallel analysis on a single chip. Another advantage of these GM-APDs over current technology is their low voltage CMOS compatibility which could allow for the fabrication of an AQC on the same device. Small are detectors have already been employed in the time-resolved detection of fluorescence from labeled proteins. It is envisaged that operating these new GM-APDs with this active-quench circuit will have numerous applications for the detection of fluorescence in microarray systems.

A novel brain PET insert for the MINDView project

The Multimodal Imaging of Neurological Disorders (MINDview) project aims to develop a high resolution and sensitivity dedicated brain Positron Emission Tomography (PET) system capable of visualizing neurotransmitter pathways and their disruptions for mental disorders for diagnosis and treatment follow-up. Moreover, this compact PET system should be fully compatible with a Magnetic Resonance Imaging (MRI) system in order to allow its operation as a brain insert in a hybrid imaging setup with most MRI scanners. The proposed design will enable current installed MRI base to be easily upgraded to PET/MRI systems. The current design for the PET insert consists of a 3 rings configuration, 20 modules per ring, with an axial field of view of ~15 cm and a geometrical aperture of ~33 cm in diameter. When coupled to the new head Radio Frequency (RF) coil, the inner diameter of the complete PET-RF coil insert is reduced to 26 cm. Main features of the PET detector insert for the MINDView project in terms of its overall design, electronic readout, and MRI compatibility will be presented. In addition, the main parameters of the PET detector insert, such as expected spatial and energy resolution, depth of interaction (DOI) capabilities and sensitivity will be discussed in terms of the different approaches considered so far for the construction of the first MINDView prototype. Laboratory tests results associated with the current MINDView PET module concept in terms of key parameters optimisation such as scintillator crystal, photosensor configuration and signal readout will be also presented.

Real time processing enables fast 3D imaging at single photon level

3D LIDAR imaging is a key enabling technology for automatic navigation of future spacecraft, including landing, rendezvous and docking and rover navigation. Landing is typically the most demanding task because of the range of operation, speed of movement, field of view (FOV) and the spatial resolution required. When these parameters are combined with limited mass and power budget, required for interplanetary operations, the technological challenge becomes significant and innovative solutions must be found. Single Photon Avalanche Photodiodes (SPADs) can reduce the laser power by orders of magnitude, array detector format can speed up the data acquisition while some limited scanning may extend the FOV without pressure on the mechanics. In the same time, SPADs have long dead times that complicate their use for rangefinding. Optimization and balance between the instrument subsystems are required. We discuss how the implementation of real-time control as an integral part of the LIDAR allows the use of SPAD array detectors in conditions of high dynamics. The result is a projected performance of more than 1 million 3D pixels/s at a distance of several kilometers within a small mass/power package. The work is related to ESA technology development for future planetary landing missions.

Photon counting imaging: the DigitalAPD

Geiger Mode avalanche photodiodes offer single photon detection, however, conventional biasing and processing circuitry make arrays impractical to implement. A novel photon counting concept is proposed which greatly simplifies the circuitry required for each device, giving the potential for large, single photon sensitive, imaging arrays. This is known as the DigitalAPD. The DigitalAPD treats each device as a capacitor. During a write, the capacitor is periodically charged to photon counting mode and then left open circuit. The arrival of photons causes the charge to be lost and this is later detected during a read phase. Arrays of these devices have been successfully fabricated and a read out architecture, employing well known memory addressing and scanning techniques to achieve fast frame rates with a minimum of circuitry, has been developed. A discrete prototype has been built to demonstrate the DigitalAPD with a 4x4 array. Line rates of up to 5MHz have been observed using discrete electronics. The frame burst can be transferred to a computer where the arrival of single photons at any of the 16 locations can be examined, frame by frame. The DigitalAPD concept is highly scalable and is soon to be extended to a fully integrated implementation for use with larger 32x32 and 100x100 APD arrays.

3-carbamyl-N-allylquinuclidinium bromide: Effects on cholinergic activity and protection against soman

3-Carbamyl-N-allylquinuclidinium bromide (CAB) was synthesized and evaluated for its pharmacological effects on cholinergic activity and for protection in vivo against soman toxicity in guinea pigs. This carbamylated derivative of N-allyl-3-quinuclidinol (NAQ), a potent inhibitor of high-affinity choline uptake, demonstrated stereospecific alterations of cholinergic function as well as protection against soman. The R-isomer, but not the S-isomer, of CAB inhibited erythrocyte acetylcholinesterase (AChE) and plasma pseudocholinesterase (pChE) in a concentration-response manner (IC50 = 25 and 29 microM, respectively). The R-isomer of CAB was also a more potent inhibitor of high-affinity choline uptake (IC50 = 4.8 microM) than S-CAB (IC50 = 63 microM). When R-CAB (10 mumol/kg, i.m.) was administered to guinea pigs 30 min prior to soman in conjunction with atropine (16 mg/kg, i.m.) given 1 min post-soman, the compound significantly reduced lethality up to 5 LD50S. This represents enhanced protection when compared to NAQ (up to 100 mumol/kg); the S-isomer of CAB failed to protect against soman intoxication. The results demonstrate that reversible inhibition of AChE with suppression of acetylcholine synthesis into a single compound, CAB, enhances the protection against organophosphates.

Through silicon via developments for silicon photomultiplier sensors

Packaging can have a significant impact on the performance characteristics of Silicon Photomultipliers (SiPM) sensors as well as having an impact on reliability and yield. To provide the highest performance possible, SensL have recently developed and tested a surface mount, through silicon via (TSV) package that provides high array fill factor, high photon detection efficiency (PDE) and magnetic resonance imaging (MRI) system compatibility. The PDE of TSV packaged sensors will be shown to be the highest when compared to traditional SiPM package types. In addition the PDE in the UV and blue region will be shown to approach that of unprotected bare die. Additionally, the TSV package has minimal deadspace outside of the active area which will be shown to allow close packing when used in a sensor array. It will be shown that arrays of TSV sensors have the highest fill factor currently possible when creating arrays from singulated die. Additionally, it will be shown that TSV parts are non-magnetic and results of images taken with the TSV SiPM in a 3 Tesla magnetic resonance imaging (MRI) system will be shown to have no impact on the MRI system.