Michela Esposito

DynAMITe: a wafer scale sensor for biomedical applications

In many biomedical imaging applications Flat Panel Imagers (FPIs) are currently the most common option. However, FPIs possess several key drawbacks such as large pixels, high noise, low frame rates, and excessive image artefacts. Recently Active Pixel Sensors (APS) have gained popularity overcoming such issues and are now scalable up to wafer size by appropriate reticule stitching. Detectors for biomedical imaging applications require high spatial resolution, low noise and high dynamic range. These figures of merit are related to pixel size and as the pixel size is fixed at the time of the design, spatial resolution, noise and dynamic range cannot be further optimized. The authors report on a new rad-hard monolithic APS, named DynAMITe (Dynamic range Adjustable for Medical Imaging Technology), developed by the UK MI-3 Plus consortium. This large area detector (12.8 cm × 12.8 cm) is based on the use of two different diode geometries within the same pixel array with different size pixels (50 μm and 100 μm). Hence the resulting device can possess two inherently different resolutions each with different noise and saturation performance. The small and the large pixel cameras can be reset at different voltages, resulting in different depletion widths. The larger depletion width for the small pixels allows the initial generated photo-charge to be promptly collected, which ensures an intrinsically lower noise and higher spatial resolution. After these pixels reach near saturation, the larger pixels start collecting so offering a higher dynamic range whereas the higher noise floor is not important as at higher signal levels performance is governed by the Poisson noise of the incident radiation beam. The overall architecture and detailed characterization of DynAMITe will be presented in this paper.

Proton-counting radiography for proton therapy: a proof of principle using CMOS APS technology.

Despite the early recognition of the potential of proton imaging to assist proton therapy (Cormack 1963 J. Appl. Phys. 34 2722), the modality is still removed from clinical practice, with various approaches in development. For proton-counting radiography applications such as computed tomography (CT), the water-equivalent-path-length that each proton has travelled through an imaged object must be inferred. Typically, scintillator-based technology has been used in various energy/range telescope designs. Here we propose a very different alternative of using radiation-hard CMOS active pixel sensor technology. The ability of such a sensor to resolve the passage of individual protons in a therapy beam has not been previously shown. Here, such capability is demonstrated using a 36 MeV cyclotron beam (University of Birmingham Cyclotron, Birmingham, UK) and a 200 MeV clinical radiotherapy beam (iThemba LABS, Cape Town, SA). The feasibility of tracking individual protons through multiple CMOS layers is also demonstrated using a two-layer stack of sensors. The chief advantages of this solution are the spatial discrimination of events intrinsic to pixelated sensors, combined with the potential provision of information on both the range and residual energy of a proton. The challenges in developing a practical system are discussed.

14C autoradiography with an energy-sensitive silicon pixel detector

The first performance tests are presented of a carbon-14 ((14)C) beta-particle digital autoradiography system with an energy-sensitive hybrid silicon pixel detector based on the Timepix readout circuit. Timepix was developed by the Medipix2 Collaboration and it is similar to the photon-counting Medipix2 circuit, except for an added time-based synchronization logic which allows derivation of energy information from the time-over-threshold signal. This feature permits direct energy measurements in each pixel of the detector array. Timepix is bump-bonded to a 300 µm thick silicon detector with 256 × 256 pixels of 55 µm pitch. Since an energetic beta-particle could release its kinetic energy in more than one detector pixel as it slows down in the semiconductor detector, an off-line image analysis procedure was adopted in which the single-particle cluster of hit pixels is recognized; its total energy is calculated and the position of interaction on the detector surface is attributed to the centre of the charge cluster. Measurements reported are detector sensitivity, (4.11 ± 0.03) × 10(-3) cps mm(-2) kBq(-1) g, background level, (3.59 ± 0.01) × 10(-5) cps mm(-2), and minimum detectable activity, 0.0077 Bq. The spatial resolution is 76.9 µm full-width at half-maximum. These figures are compared with several digital imaging detectors for (14)C beta-particle digital autoradiography.

Proton tracking for medical imaging and dosimetry

For many years, silicon micro-strip detectors have been successfully used as tracking detectors for particle and nuclear physics experiments. A new application of this technology is to the field of particle therapy, where radiotherapy is carried out by use of charged particles such as protons or carbon ions. Such a treatment has been shown to have advantages over standard x-ray radiotherapy and as a result of this, many new centres offering particle therapy are currently under construction - including two in the U.K.. The characteristics of a new silicon micro-strip detector based system for this application will be presented. The array uses specifically designed large area sensors in several stations in an x-u-v co-ordinate configuration suitable for very fast proton tracking with minimal ambiguities. The sensors will form a tracker capable of giving information on the path of high energy protons entering and exiting a patient. This will allow proton computed tomography (pCT) to aid the accurate delivery of treatment dose with tuned beam profile and energy. The tracker will also be capable of proton counting and position measurement at the higher fluences and full range of energies used during treatment allowing monitoring of the beam profile and total dose. Results and initial characterisation of sensors will be presented along with details of the proposed readout electronics. Radiation tests and studies with different electronics at the Clatterbridge Cancer Centre and the higher energy proton therapy facility of iThemba LABS in South Africa will also be shown.

Expected proton signal sizes in the PRaVDA Range Telescope for proton Computed Tomography

Proton radiotherapy has demonstrated benefits in the treatment of certain cancers. Accurate measurements of the proton stopping powers in body tissues are required in order to fully optimise the delivery of such treaments. The PRaVDA Consortium is developing a novel, fully solid state device to measure these stopping powers. The PRaVDA Range Telescope (RT), uses a stack of 24 CMOS Active Pixel Sensors (APS) to measure the residual proton energy after the patient. We present here the ability of the CMOS sensors to detect changes in the signal sizes as the proton traverses the RT, compare the results with theory, and discuss the implications of these results on the reconstruction of proton tracks.

Radiation hardness of a large area CMOS active pixel sensor for bio-medical applications

A wafer scale CMOS Active Pixel Sensor has been designed employing design techniques of transistor enclosed geometry and P+ doped guard rings to offer ionizing radiation tolerance. The detector was irradiated with 160 kVp X-rays up to a total dose of 94 kGy(Si) and remained functional. The radiation damage produced in the device has been studied, resulting in a dark current density increase per decade of 96±S pA/cm2/decade and a damage threshold of 204 Gy(Si). The damage produced in the detector has been compared with a commercially available CMOS APS, showing a radiation tolerance about 100 times higher. Moreover Monte Carlo simulations have been performed to evaluate primary and secondary energy deposition in each of the detector stages.

CMOS Active Pixel Sensors as energy-range detectors for proton Computed Tomography

Since the first proof of concept in the early 70s, a number of technologies has been proposed to perform proton CT (pCT), as a means of mapping tissue stopping power for accurate treatment planning in proton therapy. Previous prototypes of energy-range detectors for pCT have been mainly based on the use of scintillator-based calorimeters, to measure proton residual energy after passing through the patient. However, such an approach is limited by the need for only a single proton passing through the energy-range detector in a read-out cycle. A novel approach to this problem could be the use of pixelated detectors, where the independent read-out of each pixel allows to measure simultaneously the residual energy of a number of protons in the same read-out cycle, facilitating a faster and more efficient pCT scan. This paper investigates the suitability of CMOS Active Pixel Sensors (APSs) to track individual protons as they go through a number of CMOS layers, forming an energy-range telescope. Measurements performed at the iThemba Laboratories will be presented and analysed in terms of correlation, to confirm capability of proton tracking for CMOS APSs.

Using a large area CMOS APS for direct chemiluminescence detection in Western blotting electrophoresis

Western blotting electrophoretic sequencing is an analytical technique widely used in Functional Proteomics to detect, recognize and quantify specific labelled proteins in biological samples. A commonly used label for western blotting is Enhanced ChemiLuminescence (ECL) reagents based on fluorescent light emission of Luminol at 425nm. Film emulsion is the conventional detection medium, but is characterized by non-linear response and limited dynamic range. Several western blotting digital imaging systems have being developed, mainly based on the use of cooled Charge Coupled Devices (CCDs) and single avalanche diodes that address these issues. Even so these systems present key drawbacks, such as a low frame rate and require operation at low temperature. Direct optical detection using Complementary Metal Oxide Semiconductor (CMOS) Active Pixel Sensors (APS)could represent a suitable digital alternative for this application. In this paper the authors demonstrate the viability of direct chemiluminescent light detection in western blotting electrophoresis using a CMOS APS at room temperature. Furthermore, in recent years, improvements in fabrication techniques have made available reliable processes for very large imagers, which can be now scaled up to wafer size, allowing direct contact imaging of full size western blotting samples. We propose using a novel wafer scale APS (12.8 cm×13.2 cm), with an array architecture using two different pixel geometries that can deliver an inherently low noise and high dynamic range image at the same time representing a dramatic improvement with respect to the current western blotting imaging systems.

DynAMITe: a prototype large area CMOS APS for breast cancer diagnosis using x-ray diffraction measurements

X-ray diffraction studies are used to identify specific materials. Several laboratory-based x-ray diffraction studies were made for breast cancer diagnosis. Ideally a large area, low noise, linear and wide dynamic range digital x-ray detector is required to perform x-ray diffraction measurements. Recently, digital detectors based on Complementary Metal-Oxide- Semiconductor (CMOS) Active Pixel Sensor (APS) technology have been used in x-ray diffraction studies. Two APS detectors, namely Vanilla and Large Area Sensor (LAS), were developed by the Multidimensional Integrated Intelligent Imaging (MI-3) consortium to cover a range of scientific applications including x-ray diffraction. The MI-3 Plus consortium developed a novel large area APS, named as Dynamically Adjustable Medical Imaging Technology (DynAMITe), to combine the key characteristics of Vanilla and LAS with a number of extra features. The active area (12.8 × 13.1 cm2) of DynaMITe offers the ability of angle dispersive x-ray diffraction (ADXRD). The current study demonstrates the feasibility of using DynaMITe for breast cancer diagnosis by identifying six breast-equivalent plastics. Further work will be done to optimize the system in order to perform ADXRD for identification of suspicious areas of breast tissue following a conventional mammogram taken with the same sensor.

14C Autoradiography with a novel wafer scale CMOS Active Pixel Sensor

14C autoradiography is a well established technique for structural and metabolic analysis of cells and tissues. The most common detection medium for this application is film emulsion, which offers unbeatable spatial resolution due to its fine granularity but at the same time has some limiting drawbacks such as poor linearity and rapid saturation. In recent years several digital detectors have been developed, following the technological transition from analog to digital-based detection systems in the medical and biological field. Even so such digital systems have been greatly limited by the size of their active area (a few square centimeters), which have made them unsuitable for routine use in many biological applications where sample areas are typically ~ 10?100 cm2. The Multidimensional Integrated Intelligent Imaging (MI3-Plus) consortium has recently developed a new large area CMOS Active Pixel Sensor (12.8?cm ? 13.1 cm). This detector, based on the use of two different pixel resolutions, is capable of providing simultaneously low noise and high dynamic range on a wafer scale. In this paper we will demonstrate the suitability of this detector for routine beta autoradiography in a comparative approach with widely used film emulsion.