Design and Characterization of 64K Pixels Chips Working in Single Photon Processing Mode

Progress in CMOS technology and in fine pitch bump bonding has made possible the development of high granularity single photon counting detectors for X-ray imaging. This thesis studies the design and characterization of three pulse processing chips with 65536 square pixels of 55 µm x 55 µm designed in a commercial 0.25 µm 6-metal CMOS technology. The 3 chips share the same architecture and dimensions and are named Medipix2, Mpix2MXR20 and Timepix. The Medipix2 chip is a pixel detector readout chip consisting of 256 x 256 identical elements, each working in single photon counting mode for positive or negative input charge signals. The preamplifier feedback provides compensation for detector leakage current on a pixel by pixel basis. Two identical pulse height discriminators are used to define an energy window. Every event falling inside the energy window is counted with a 13 bit pseudo-random counter. The counter logic, based in a shift register, also behaves as the input/output register for the pixel. Each cell also has an 8-bit configuration register which allows masking, test-enabling and 3-bit individual threshold adjust for each discriminator. The chip can be configured in serial mode and readout either serially or in parallel. Measurements show an electronic noise ~160 e- rms with a gain of ~9 mV/ke-. The threshold spread after equalization of ~120 e- rms brings the full chip minimum detectable charge to ~1100 e-. The analog static power consumption is ~8 µW per pixel with Vdda=2.2 V. The Mpix2MXR20 is an upgraded version of the Medipix2. The main changes in the pixel consist of: an improved tolerance to radiation, improved pixel to pixel threshold uniformity, and a 14-bit counter with overflow control. The chip periphery includes new threshold DACs with smaller step size, improved linearity, and better temperature dependence. Timepix is an evolution of the Mpix2MXR20 which provides independently in each pixel information of arrival time, time-over-threshold or event counting. Timepix uses as a time reference an external clock (Ref_Clk) up to 100 MHz which is distributed all over the pixel matrix during acquisition mode. The preamplifier is improved and there is a single discriminator with 4-bit threshold adjustment in order to reduce the minimum detectable charge limit. Measurements show an electrical noise ~100 e- rms and a gain of ~16.5 mV/ke-. The threshold spread after equalization of ~35 e- rms brings the full chip minimum detectable charge either to ~650 e- with a naked chip (i.e. gas detectors) or ~750 e- when bump-bonded to a detector. The pixel static power consumption is ~13.5 µW per pixel with Vdda=2.2 V and Ref_Clk=80 MHz. This family of chips have been used for a wide variety of applications. During these studies a number of limitations have come to light. Among those are limited energy resolution and surface area. Future developments, such as Medipix3, will aim to address those limitations by carefully exploiting developments in microelectronics

Investigation of timepix radiation detector for autoradiography and microdosimetry in targeted alpha therapy

The Timepix detector developed by CERN is a novel and sophisticated particle detector. It consists of a semiconductor layer divided into an array of pixels. This array of pixels is bumpbonded to an electronics integrated layer (i.e. the readout chip). Timepix can be used for a wide range of measurements of electromagnetic radiation and particles and their applications in different fields such as space physics, nuclear physics, radiotherapy physics, imaging and radiation protection. The Timepix detector used in this work was purchased from Amsterdam Scientific Instruments, the Netherlands, in order to investigate its use for microdosimetry purposes, in particular in targeted alpha therapy. The device has the following properties: 256 x 256 pixels of 55 x 55 μm2 area each, the chip is effective for positive or negative charge and can be used to detect electrons, X-rays, neutrons and heavy charge particles. It can work as an energy spectrometer, has good spatial resolution and reason1ble detection efficiency. The device can operate in three common modes: Timepix mode, Medipix mode, and Time-Over-Threshold (TOT) mode. Targeted alpha therapy (TAT) is a novel type of radionuclide therapy in which an alpha emitting radioisotope is attached to a cancer cell seeking vector (so called radioimmunoconjugate (RIC)). Once attached to a cancer cell, it causes localized damage due to traversal and energy deposition high LET a-particles. There is, however, a lack of data related to a-particle distribution in TAT. These data are required to more accurately estimate the absorbed dose on a cellular level. As a result, this work aims to develop a microdosimetry technique, using Timepix detector that will estimate, or better yet determine the absorbed dose deposited by a-particles in cells as well as will measure the biodistribution of the radioisotope in a tumour. Initially, extensive Timepix characterization and testing has been done to evaluate the detector's response, including linearity, reproducibility, and sensitivity to low doses of radiations (μGy-mGy dose region) and energy dependence. 1-125 seeds and superficial X-rays (below 70 kVp), produced by the Gulmay superficial X-ray unit, were used. The measured Timepix pixel value was correlated with the known dose (based on the irradiation time used and TLD-100 measurements) and a pixel-value-to- dose calibration curve was obtained. It was confinned that Timepix value increased linearly with the dose delivered. The dose calibration curves using the superficial X-ray beams showed that the pixel value, however, depended on the energy of the X-ray beam. The application of Timepix to measure radioisotope biodistribution (i.e. autoradiography) was investigated. Mice with Lewis lung (LL2) tumours were treated with about 18 kBq oP27Thlabelled DAB4 murine monoclonal antibody that bounds to necrotic tumour cells. The rationale is to develop a-particle-mediated bystander kill of nearby viable tumour cells. To generate more necrotic tumour cells for 227Th-DAB4 binding, some mice also received chemotherapy before being injected with Th-227-DAB4. Finally, 5 mm tumour sections were cut from treated mice for autoradiography with Timepix. Each tumour section was mounted onto a slide with front face uncovered to allow emission of a-particles from the tumour section. Simple steel collimator (I cm radius, 2 cm length) was manufactured in-house and positioned around the tumour section. The slide was placed 2 cm away from the Timepix detector. Bias voltage of 7 V was applied, and a-particle filter was selected for acquisition. Detector cover was removed, exposing the Si layer, to allow the emitted a-particles ( - 6 Me V) to reach the detector. Image acquisition took -14 h. Good resolution autoradiographs of radiolabelled tumour sections were acquired, showing a-particle, electron and X-ray tracks. Timepix measurements also showed an increased Th-227-DAB4 uptake following chemotherapy due to increase in necrotic tissue volume. Timepix was also used to measure the uptake of Cr-51 by A549 cells (lung carcinoma cell line) for different pH levels and the dependence of uptake on pH was investigated. Timepix was observed to be sensitive to detect small changes in the activity/uptake of radioactive sources depending on the environmental condition and the number of cells. The last part of this thesis deals with the development of a transmitted a-particle microdosimetry technique. First, A549 cells were grown in vitro using standard protocols and were irradiated using a 6 MY photon beam with different doses varying between 2-8 Gy and Ra-226 source was used for a-particle irradiation to evaluate A549 radiation sensitivity using clonogenic assay and MTT assay. The cell line was found radiosensitive, with 050 of~ 2 Gy for X-ray irradiation. For transmitted dosimetry, A549 cells were either unirradiated (control) or irradiated for ~2, 1, 2 or 3 hours with a-particles emitted from a Ra-223 source positioned below a monolayer of A549 cells. The HTS Transwell" 96 well system (Corning, USA), consisting of 2 compartments, was used to develop a method for tracking a-particles through a cell mono layer. This system comprises of two compartments, with liquid Ra-223 evaporated in the lower compartment to avoid a-particle self-absorption inside the liquid. The measured activity of 5 kBq was unifonnly distributed, as confirmed by Timepix detector. The second compartment consists of a flat bottom polycarbonate membrane (I 0 μm thick) where cells are plated. It is sufficiently thin to allow a-particles to penetrate through and hit the cells. Fifteen thousand A549 cells were seeded in the upper compartment that was then inserted into the lower compartment containing the evaporated Ra-223. The transwell system was positioned under the Timepix detector. Transmitted a-particles were detected for 1;2, I, 2 or 3 hour irradiation times. Additionally, DNA double strand breaks (DSBs) in the form of y-H2AX foci, were examined by fluorescence microscopy. The number of transmitted a-particles was correlated with the observed DNA DSBs and the delivered radiation dose was estimated. Additionally, the dose deposited was calculated using Monte Carlo code SRIM. Approximately 20% of a-particles were transmitted and detected by Timepix. The frequency and number of y-H2AX foci increased significantly following a-particle irradiation as compared to unirradiated controls. The RBE equivalent dose delivered to A549 cells was estimated to be approximately 0.66 Gy, 1.32 Gy, 2.53 Gy and 3. 96 Gy after Y2, I, 2 and 3 h irradiation, respectively, considering a relative biological effectiveness of a-particles of 5.5. In summary, the Timepix detector can be used effectively for autoradiography in TAT, providing high resolution images and excellent spatial resolution of detected a-particles, as well as a transmitted a-particle microdosimetry detector. If cross-calibrated using biological dosimetry, this method will give a good indication of the biological effects of a-particles without the need for repeated biological dosimetry which is costly, time consuming and not readily available.Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, School of Physical Sciences, 2017

Review of hybrid pixel detector readout ASICs for spectroscopic X-ray imaging

Semiconductor detector readout chips with pulse processing electronics have made possible spectroscopic X-ray imaging, bringing an improvement in the overall image quality and, in the case of medical imaging, a reduction in the X-ray dose delivered to the patient. In this contribution we review the state of the art in semiconductor-detector readout ASICs for spectroscopic X-ray imaging with emphasis on hybrid pixel detector technology. We discuss how some of the key challenges of the technology (such as dealing with high fluxes, maintaining spectral fidelity, power consumption density) are addressed by the various ASICs. In order to understand the fundamental limits of the technology, the physics of the interaction of radiation with the semiconductor detector and the process of signal induction in the input electrodes of the readout circuit are described. Simulations of the process of signal induction are presented that reveal the importance of making use of the small pixel effect to minimize the impact of the slow motion of holes and hole trapping in the induced signal in high-Z sensor materials. This can contribute to preserve fidelity in the measured spectrum with relatively short values of the shaper peaking time. Simulations also show, on the other hand, the distortion in the energy spectrum due to charge sharing and fluorescence photons when the pixel pitch is decreased. However, using recent measurements from the Medipix3 ASIC, we demonstrate that the spectroscopic information contained in the incoming photon beam can be recovered by the implementation in hardware of an algorithm whereby the signal from a single photon is reconstructed and allocated to the pixel with the largest deposition

Effective atomic number image determination with an energy-resolving photon-counting detector using polychromatic X-ray attenuation by correcting for the beam hardening effect and detector response

13301甲第5284号博士（保健学）金沢大学博士論文本文Full 以下に掲載：Applied Radiation and Isotopes 170 Airticle No.109617 14p. 2021. Elsevier. 共著者：Natsumi Kimoto, Hiroaki Hayashi, Takumi Asakawa, Cheonghae Lee, Takashi Asahara, Tatsuya Maeda, Sota Goto, Yuki Kanazawa, Akitoshi Katsumata, Shuichiro Yamamoto, Masahiro Okad