Heavy Ion Microbeam Research Articles

The Fate of a Normal Human Cell Traversed by a Single Charged Particle

The long-term “fate” of normal human cells after single hits of charged particles is one of the oldest unsolved issues in radiation protection and cellular radiobiology. Using a high-precision heavy-ion microbeam we could target normal human fibroblasts with exactly one or five carbon ions and measured the early cytogenetic damage and the late behaviour using single-cell cloning. Around 70% of the first cycle cells presented visible aberrations in mFISH after a single ion traversal, and about 5% of the cells were still able to form colonies. In one third of selected high-proliferative colonies we observed clonal (radiation-induced) aberrations. Terminal differentiation and markers of senescence (PCNA, p16) in the descendants of cells traversed by one carbon ion occurred earlier than in controls, but no evidence of radiation-induced chromosomal instability was found. We conclude that cells surviving single-ion traversal, often carrying clonal chromosome aberrations, undergo accelerated senescence but maintain chromosomal stability.

1G1510 重イオンマイクロビーム照射によるバイスタンダー応答で誘導されるシグナル伝達機構の解明(細胞生物的課題I,口頭発表,日本生物物理学会第50回年会(2012年度))

1G1510 重イオンマイクロビーム照射によるバイスタンダー応答で誘導されるシグナル伝達機構の解明(細胞生物的課題I,口頭発表,日本生物物理学会第50回年会(2012年度))

Involvement of bystander effect in suppression of the cytokine production induced by heavy-ion broad beams

Purpose: Immune cells accumulate in and around cancers and cooperate with each other using specific cytokines to attack the cancer cells. The heavy-ion beams for cancer therapy may stimulate immune cells and affect on the immune system. However, it is still poorly understood how the immune cells are stimulated by ion-beams. Here, we irradiated immune cells using heavy-ion beams and analyzed changes in production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) that are important cytokine for the cancer treatment.Materials and methods: The human THP-1 monocytes were differentiated into macrophages and then irradiated using carbon-ion broad-beams (108 keV μm−1). To examine the bystander response after heavy-ion irradiation, a very small fraction (approx. 0.45%) of the cell population was irradiated using heavy-ion microbeams. After irradiation, we examined the cytokine productions.Results: When cells were irradiated with 5 Gy, cytokine levels were reduced after both microbeam irradiation and broad-beam irradiation. TNF-α production of macrophages with the nitric oxide (NO) inhibitor-treatment increased after carbon-ion broad-beam. NO was involved in the radiation-induced suppression of TNF-α production.Conclusions: The suppression of cytokine production arose after irradiation with heavy-ions, and may also be induced in the surrounding non-irradiated cells via the bystander effect.

The new Sandia light ion microbeam

The Ion Beam Laboratory of Sandia National Laboratories (SNL) was recently relocated into a brand new building. The 6 MV High Voltage Engineering (HVE) tandem accelerator (hosting the heavy ion microbeam and several analytical beam lines) and the 350 kV HVE implanter with a nanobeam were moved to the new building. There were several new pieces of equipment acquired associated with the move, among them a new high brightness 3 MV Pelletron accelerator, a high resolution light ion microbeam, a nanoimplanter, and a transmission electron microscope (TEM) connected to the tandem accelerator. In this paper this new facility will be described, and initial results of the new microbeam will be presented.

Heavy-ion microbeam system for cell irradiation at Kyoto University

We have developed a heavy-ion microbeam system for cell irradiation that uses an 8-MV tandem Van de Graaff accelerator at Kyoto University. Using a pair of apertures as the final collimator, microbeams of carbon, fluorine, and silicon were extracted to the atmosphere with few background particles. We used a thin transmission scintillator and a photomultiplier detector to accurately measure the number of extracted particles. To examine beam spreading, the beam profile was measured by observing tracks of an irradiated CR-39 track detector. The two disks with holes which were added to the collimating apertures reduced background radiation due to secondary X-rays and electrons from the apertures.

Application of heavy-ion microbeam system at Kyoto University: Energy response for imaging plate by single ion irradiation

A heavy-ion microbeam system for cell irradiation has been developed using an accelerator at Kyoto University. We have successfully developed proton-, carbon-, fluorine- and silicon-beams in order to irradiate a micro-meter sized area with ion counting, especially single ion irradiation. In the heavy-ion microbeam system, an imaging plate (IP) was utilized for beam diagnostics on the irradiation. The IP is widely used for radiography studies in biology. However, there are a few studies on the low linear energy transfer (LET) by single ions, i.e., low-intensity exposure. Thus we have investigated the energy response for the IP, which can be utilized for microbeam diagnostics.

High energy heavy ion microbeam irradiation facility at IMP

A high energy heavy ion microbeam irradiation facility was designed and installed in the Institute of Modern Physics (IMP) of Chinese Academy of Sciences (CAS). It can deliver well-focused ions into the targets at exact locations. With the advantage of allowing vertical irradiation as well as focusing ions from Carbon to Uranium with high energies in a broad energy range (7MeV/u to 100MeV/u for Carbon ions), this setup is able to deliver a preset number of ions into pre-selected target positions. Material specimens in vacuum and living cells in air can also be irradiated by this facility. Detailed description of this microbeam facility as well as its beam optics is presented in this paper. Some preliminary test results are also given.

Beam Profile Rapid-evaluation of Heavy-ion Microbeam in The Atmosphere Using Improved Etching Method for CR-39 and Semi-automatic Image Analysis

集束式重イオンマイクロビームの大気中でのビームサイズの迅速評価を目的として，固体飛跡検出器CR-39のエッチング時間の短縮，ImageJを用いたエッチピットの半自動画像処理，及びSRIMによるビームサイズの予測方法について検討した。その結果，従来の作業時間に対してエッチング時間，大気中ビームサイズの評価をそれぞれ1/12，1/30まで短縮化することができた。更に，ビームサイズの予測に成功した。本方法は将来の集束式重イオンマイクロビーム運用において十分な実用性を持つ優れた方法であることを確認した。

The Effect of Layout Topology on Single-Event Transient Pulse Quenching in a 65 nm Bulk CMOS Process

Heavy-ion microbeam and broadbeam data are presented for a 65 nm bulk CMOS process showing the existence of pulse quenching at normal and angular incidence for designs where the pMOS transistors are in common n-wells or isolated in separate n-wells. Experimental data and simulations show that pulse quenching is more prevalent in the common n-well design than the separate n-well design, leading to significantly reduced SET pulsewidths and SET cross-section in the common n-well design.

Single Event Transient Hardness of a New Complementary (npn <formula formulatype="inline"><tex Notation="TeX">$+$</tex></formula> pnp) SiGe HBT Technology on Thick-Film SOI

We report heavy-ion microbeam and total dose data for a new complementary (npn + pnp) SiGe on thick-film SOI technology. Measured transient waveforms from heavy-ion strikes indicate a significantly shortened single-event-induced transient current, while maintaining the total dose robustness associated with SiGe devices. Heavy-ion broad-beam data confirm a reduced single event upset (SEU) cross-section in a high-speed shift register circuit.

Radiation Biology of Caenorhabditis elegans: Germ Cell Response, Aging and Behavior

The study of radiation effect in Caenorhabditis (C.) elegans has been carried out over three decades and now allow for understanding at the molecular, cellular and individual levels. This review describes the current knowledge of the biological effects of ionizing irradiation with a scope of the germ line, aging and behavior. In germ cells, ionizing radiation induces apoptosis, cell cycle arrest and DNA repair. Lots of molecules involved in these responses and functions have been identified in C. elegans, which are highly conserved throughout eukaryotes. Radiosensitivity and the effect of heavy-ion microbeam irradiation on germ cells with relationship between initiation of meiotic recombination and DNA lesions are discussed. In addition to DNA damage, ionizing radiation produces free radicals, and the free radical theory is the most popular aging theory. A first signal transduction pathway of aging has been discovered in C. elegans, and radiation-induced metabolic oxidative stress is recently noted for an inducible factor of hormetic response and genetic instability. The hormetic response in C. elegans exposed to oxidative stress is discussed with genetic pathways of aging. Moreover, C. elegans is well known as a model organism for behavior. The recent work reported the radiation effects via specific neurons on learning behavior, and radiation and hydrogen peroxide affect the locomotory rate similarly. These findings are discussed in relation to the evidence obtained with other organisms. Altogether, C. elegans may be a good "in vivo" model system in the field of radiation biology.

Heavy Ion Microbeam- and Broadbeam-Induced Transients in SiGe HBTs

Silicon-germanium heterojunction bipolar transistor (SiGe HBT) heavy ion-induced current transients are measured using Sandia National Laboratories' microbeam and high- and low-energy broadbeam sources at the Grand Acce?le?rateur National d'Ions Lourds, Caen, France, and the University of Jyva?skyla?, Finland. The data were captured using a custom broadband IC package and real-time digital phosphor oscilloscopes with at least 16 GHz of analog bandwidth. These data provide detailed insight into the effects of ion strike location, range, and LET.

Single Event Transient Response of SiGe Voltage References and Its Impact on the Performance of Analog and Mixed-Signal Circuits

We investigate the single-event transient (SET) response of bandgap voltage references (BGRs) implemented in SiGe BiCMOS technology through heavy ion microbeam experiments. The SiGe BGR circuit is used to provide the input reference voltage to a voltage regulator. SiGe HBTs in the BGR circuit are struck with 36-MeV oxygen ions, and the subsequent transient responses are captured at the output of the regulator. Sensitive devices responsible for generating transients with large peak magnitudes (more than 5% of the dc output voltage) are identified. To determine the effectiveness of a transistor-layout-based radiation hardened by design (RHBD) technique with respect to immunity to SETs at the circuit level, the BGR circuit implemented with HBTs surrounded by an alternate reverse-biased <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">pn</i> junction (n-ring RHBD) is also bombarded with oxygen ions, and subsequent SETs are captured. Experimental results indicate that the number of events causing transients with peak magnitude more than 5% above the dc level have been reduced in the RHBD version; however, with the inclusion of the n-ring RHBD, new locations for the occurrence of transients (albeit with smaller peak magnitude) are created. Transients at the transistor-level are also independently captured and are presented. It is demonstrated that while the transients are short at the transistor level (ns duration), relatively long transients are obtained at the circuit level (hundreds of nanoseconds). In addition, the impact of the SET response of the BGR on the performance of an ultra-high-speed 3-bit SiGe analog-to-digital converter (ADC) is investigated through simulation. It is shown that ion-induced transients in the reference voltage could eventually lead to data corruption at the output of the ADC.

Study of the aberrations of the IMP heavy ion microbeam irradiation system

A high energy heavy ion microbeam irradiation system is constructed at the Institute of Modern Physics (IMP) of the Chinese Academy of Sciences (CAS). A quadrupole focusing system, in combination with a series of slits, has been designed here. The IMP microbeam system is described in detail. The intrinsic and parasitic aberrations associated with the magnets are simulated. The ion beam optics of this microbeam system is investigated systematically. Then the optimized initial beam parameters are given for high spatial resolution and high hitting rates.

Design of the IMP microbeam irradiation system for 100 MeV/u heavy ions

A state-of-the-art high energy heavy ion microbeam irradiation system is constructed at the Institute of Modern Physics of the Chinese Academy of Sciences. This microbeam system operates in both full current intensity mode and single ion mode. It delivers a predefined number of ions to pre-selected targets for research in biology and material science. The characteristic of this microbeam system is high energy and vertical irradiation. A quadrupole focusing system, in combination with a series of slits, has been designed to optimize the spatial resolution. A symmetrically achromatic system leads the beam downwards and serves simultaneously as an energy analyzer. A high gradient quadrupole triplet finally focuses a C6+ ion beam to 1 μm in the vacuum chamber within the energy range from 10 MeV/u to 100 MeV/u. In this paper, the IMP microbeam system is described in detail. A systematic investigation of the ion beam optics of this microbeam system is presented together with the associated aberrations. Comparison is made between the IMP microbeam system and the other existing systems to further discuss the performance of this microbeam. Then the optimized initial beam parameters are given for high resolution and high hitting efficiency. At last, the experiment platform is briefly introduced.

Quick change of ion species of heavy-ion microbeam by cocktail beam acceleration technique with the JAEA AVF cyclotron

A heavy-ion microbeam with hundreds of MeV energy is utilized for research in biotechnology and materials science at the JAEA AVF cyclotron facility. Beam users need microbeams providing a wide range of the LET. We have to change ion species and/or energy in order to vary the LET widely. However, it takes much time to develop a new microbeam of different ion species step by step using a flat-top acceleration system. A cocktail beam acceleration technique is frequently used to change the ion species and energy quickly. The cocktail beam acceleration has been first applied to the microbeam formation for quick change of the ion species. As a result, we have succeeded to reduce considerably microbeam changing time to within 30 min between a 520 MeV 40Ar 14+ and a 260 MeV 20Ne 7+. No deterioration of the microbeam spot size has been confirmed using a SE image of a copper grid.

Heavy ion microbeam vacuum requirements

Transport of heavy ions through an ion microbeam focusing system can be affected by insufficient vacuum within the beam transport tube. Due to interactions of heavy ions with atoms of residual gas in the vacuum tube of a microbeam facility, the angular, lateral and energy spreading of an ion beam increases prior to focusing, creating a beam halo. This beam halo can produce undesirable effects in some applications of ion microbeam techniques. In order to model this effect, the ion beam angular spread in residual gas has been approximated by Sigmund’s theoretical predictions for small-angle ion multiple scattering (MS), while ion energy loss straggling distributions have been applied for studying the energy spread. The extent of the beam halo has been estimated by combining the results of these calculations with ion optics calculations. Recommendations concerning microbeam focusing due to the vacuum conditions are given for different heavy ions in the MeV energy range.

Transient current mapping obtained from silicon photodiodes using focused ion microbeams with several hundreds of MeV

Single Event Effects (SEEs) triggered by energetic heavy ions traversing a sensitive parts of electric devices have been studied using high-energy heavy ion microbeams connected with Transient Ion Beam Induced Current (TIBIC) measuring system at the Japan Atomic Energy Agency (JAEA) Takasaki Ion Accelerators for Advanced Radiation Applications (TIARA) facility. In the TIBIC system, SEE for semiconductor device, that is fast charge collection, has been observed in timescales of the order of picoseconds. In this paper, we show successful demonstration of the performance of the system, in which clear images of TIBIC map have been observed for Si pin photodiodes irradiated by 260 MeV 20Ne 7+ and also by 520 MeV 40Ar 14+ microbeams.

Insufficient Membrane Fusion in Dysferlin-Deficient Muscle Fibers after Heavy-Ion Irradiation

Recently, SJL/J mice have been used as an animal model in studies of dysferlinopathy, a spectrum of muscle diseases caused by defects in dysferlin protein. In this study we irradiated muscle fibers isolated from skeletal muscle of SJL/J mice with heavy-ion microbeam, and the ultrastructural changes were observed by electron microscopy. The plasma membrane of heavy-ion beam irradiated areas showed irregular protrusions and invaginations. Disruption of sarcomeric structures and the enhancement of autophagy were also observed. In addition, many vesicles of varying size and shape were seen to be accumulated just beneath the plasma membrane. This finding further supports the recent hypothesis that dysferlin functions as a membrane fusion protein in the wound healing system of plasma membrane, and that the defect in dysferlin causes insufficient membrane fusion resulting in accumulation of vesicles.

Targeted Heavy-Ion Microbeam Irradiation of the Embryo But Not Yolk in the Diapause-Terminated Egg of the Silkworm, Bombyx mori, Induces The Somatic Mutation

Using heavy-ion microbeam, we report target irradiation of selected compartments within the diapause-terminated egg and its mutational consequences in the silkworm, Bombyx mori. On one hand, carbon-ion exposure of embryo to 0.5-6 Gy increased the somatic mutation frequency, suggesting targeted radiation effects. On the other, such increases were not observed when yolk was targeted, suggesting a lack of nontargeted bystander effect.