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A novel means of applying radiotherapy in cancer treatment is the application of a radiation dose at a very high intensity for a very short time in FLASH radiotherapy (FLASH-RT). This technique involves the exposure of tumors to >40 Gy/s, usually for less than one second. Studies conducted in cell and preclinical models suggest that FLASH-RT seems less damaging to normal tissues from adverse effects relative to the same overall dose of radiation administered in conventional therapy (CONV-RT), which involves the administration of lower levels of radiation repeated intermittently over a protracted period. In contrast, the susceptibility of tumor tissues to FLASH-RT is not diminished relative to CONV-RT. Within solid tumors, both modes of dispensation of radiation produce an equivalent degree of cell damage. The differential treatment between normal and malignant material has been found in isolated tissues, animal studies and, more recently, in clinical trials. However, the classic radiation concept is that high-energy linear transfer radiation (LET) is more damaging than the equivalent total dose of low LET. Thus, the susceptibility of cells should be greater after short-term exposure to high LET. This article discusses the potential reasons that may account for this discrepancy. While the relative protection given to untransformed tissues by FLASH-RT relative to tumor tissue is a major step forward in radiation therapy for cancer, the processes that lie behind this phenomenon are incompletely understood and are considered here. [ABSTRACT FROM AUTHOR]

Introduction: The scapholunate interosseous ligament is pivotal for wrist stability, and its impairment can result in instability and joint degeneration. This study explores the application of real-time MRI for dynamic assessment of the scapholunate joint during wrist motion with the objective of determining its diagnostic value in efficacy in contrast to static imaging modalities. Materials and Methods: Ten healthy participants underwent real-time MRI scans during wrist ab/adduction and fist-clenching maneuvers. Measurements were obtained at proximal, medial, and distal landmarks on both dynamic and static images with statistical analyses conducted to evaluate the reliability of measurements at each landmark and the concordance between dynamic measurements and established static images. Additionally, inter- and intraobserver variabilities were evaluated. Results: Measurements of the medial landmarks demonstrated the closest agreement with static images and exhibited the least scatter. Distal landmark measurements showed a similar level of agreement but with increased scatter. Proximal landmark measurements displayed substantial deviation, which was accompanied by an even greater degree of scatter. Although no significant differences were observed between the ab/adduction and fist-clenching maneuvers, both inter- and intraobserver variabilities were significant across all measurements. Conclusions: This study highlights the potential of real-time MRI in the dynamic assessment of the scapholunate joint particularly at the medial landmark. Despite promising results, challenges such as measurement variability need to be addressed. Standardization and integration with advanced image processing methods could significantly enhance the accuracy and reliability of real-time MRI, paving the way for its clinical implementation in dynamic wrist imaging studies. [ABSTRACT FROM AUTHOR]

The advent of FLASH radiotherapy (FLASH-RT) has brought forth a paradigm shift in cancer treatment, showcasing remarkable normal cell sparing effects with ultra-high dose rates (>40 Gy/s). This review delves into the multifaceted mechanisms underpinning the efficacy of FLASH effect, examining both physicochemical and biological hypotheses in cell biophysics. The physicochemical process encompasses oxygen depletion, reactive oxygen species, and free radical recombination. In parallel, the biological process explores the FLASH effect on the immune system and on blood vessels in treatment sites such as the brain, lung, gastrointestinal tract, skin, and subcutaneous tissue. This review investigated the selective targeting of cancer cells and the modulation of the tumor microenvironment through FLASH-RT. Examining these mechanisms, we explore the implications and challenges of integrating FLASH-RT into cancer treatment. The potential to spare normal cells, boost the immune response, and modify the tumor vasculature offers new therapeutic strategies. Despite progress in understanding FLASH-RT, this review highlights knowledge gaps, emphasizing the need for further research to optimize its clinical applications. The synthesis of physicochemical and biological insights serves as a comprehensive resource for cell biology, molecular biology, and biophysics researchers and clinicians navigating the evolution of FLASH-RT in cancer therapy. [ABSTRACT FROM AUTHOR]

Featured Application: A beam-expanding method that can achieve uniform proton beams for FLASH therapy is provided. FLASH proton therapy is widely considered in many labs. However, achieving a dose rate sufficient for FLASH is challenging, especially when using the scanning method. A beam uniformization process using a nonlinear magnet is employed to reduce the scanning time, supplemented by multi-energy extraction to enhance the dose rate. The impact of octupole fields, multipole field components, and step field on the transport line are tested. The nonlinear effect of the magnetic fields on the transverse motion of the particle beam is used to establish a uniform dose distribution at the target. Different schemes are investigated and the octupole approach was finally selected. [ABSTRACT FROM AUTHOR]

Simple Summary: Ultra-high dose rate (UHDR) irradiation in proton therapy has mostly been performed using a cyclotron system so far. In this study, we present our approach to achieve an ultra-high dose rate for a clinical synchrotron proton therapy system and its dosimetric specifications. We demonstrated that it is feasible to adapt an existing clinical synchrotron-based proton therapy system and reach ~100 nA nozzle beam. UHDR dose rate (>40 Gy/s) was reached with the tested spot scanning patterns. The maximum dose per spill depends on the field size and is limited by the maximum charge extraction per spill. A beam monitoring ion chamber is currently being incorporated into the beam control system to improve system reproducibility and expand the irradiation area. Background: This study aims to present the feasibility of developing a synchrotron-based proton ultra-high dose rate (UHDR) pencil beam scanning (PBS) system. Methods: The RF extraction power in the synchrotron system was increased to generate 142.4 MeV pulsed proton beams for UHDR irradiation at ~100 nA beam current. The charge per spill was measured using a Faraday cup. The spill length and microscopic time structure of each spill was measured with a 2D strip transmission ion chamber. The measured UHDR beam fluence was used to derive the spot dwell time for pencil beam scanning. Absolute dose distributions at various depths and spot spacings were measured using Gafchromic films in a solid-water phantom. Results: For proton UHDR beams at 142.4 MeV, the maximum charge per spill is 4.96 ± 0.10 nC with a maximum spill length of 50 ms. This translates to an average beam current of approximately 100 nA during each spill. Using a 2 × 2 spot delivery pattern, the delivered dose per spill at 5 cm and 13.5 cm depth is 36.3 Gy (726.3 Gy/s) and 56.2 Gy (1124.0 Gy/s), respectively. Conclusions: The synchrotron-based proton therapy system has the capability to deliver pulsed proton UHDR PBS beams. The maximum deliverable dose and field size per pulse are limited by the spill length and extraction charge. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite ongoing medical advancements, glioblastoma remains a nearly uniformly fatal disease with a median survival of less than two years. This is largely attributable to its aggressive infiltration of surrounding brain parenchyma, which leads to a high risk of locoregional recurrence after the first line of therapy. Many strategies have been explored in an attempt to improve locoregional control, including hypofractionation. Here, we review a range of preclinical and clinical research on hypofractionation in the neoadjuvant, adjuvant, and recurrent or palliative setting. Additionally, we discuss novel hypofractionation strategies currently under investigation, such as FLASH radiotherapy. Glioblastoma (GBM) is the most common primary brain malignancy in adults, and its incidence is increasing worldwide. Its prognosis remains limited despite recent imaging and therapeutic advances. The current standard of care is maximal safe resection followed by conventionally fractionated radiotherapy with concurrent and adjuvant temozolomide (TMZ), with or without tumor-treating fields (TTF). However, hypofractionated radiotherapy (HFRT) has also been utilized for a variety of reasons. It is an established treatment option in the palliative setting, where shortened treatment duration can positively impact the overall quality of life for older patients or those with additional health or socioeconomic considerations. HFRT, and in particular stereotactic radiosurgery (SRS), has also been explored in both the pre- and post-operative setting for newly diagnosed and recurrent diseases. In this review, we summarize the ways in which HFRT has been utilized in the GBM patient population and its evolving role in the experimental space. We also provide commentary on scenarios in which HFRT may be indicated, as well as guidance on dose and fractionation regimens informed by our institutional experience. [ABSTRACT FROM AUTHOR]

The current tools for validating dose delivery and optimizing new radiotherapy technologies in radiation therapy do not account for important dose modifying factors (DMFs), such as variations in cellular repair capability, tumor oxygenation, ultra-high dose rates and the type of ionizing radiation used. These factors play a crucial role in tumor control and normal tissue complications. To address this need, we explored the feasibility of developing a transportable cell culture platform (TCCP) to assess the relative biological effectiveness (RBE) of ionizing radiation. We measured cell recovery, clonogenic viability and metabolic viability of MDA-MB-231 cells over several days at room temperature in a range of concentrations of fetal bovine serum (FBS) in medium-supplemented gelatin, under both normoxic and hypoxic oxygen environments. Additionally, we measured the clonogenic viability of the cells to characterize how the duration of the TCCP at room temperature affected their radiosensitivity at doses up to 16 Gy. We found that (78 ± 2) % of MDA-MB-231 cells were successfully recovered after being kept at room temperature for three days in 50% FBS in medium-supplemented gelatin at hypoxia ( 0.4 ± 0.1) % pO2, while metabolic and clonogenic viabilities as measured by ATP luminescence and colony formation were found to be (58 ± 5) % and (57 ± 4) %, respectively. Additionally, irradiating a TCCP under normoxic and hypoxic conditions yielded a clonogenic oxygen enhancement ratio (OER) of 1.4 ± 0.6 and a metabolic OER of 1.9 ± 0.4 . Our results demonstrate that the TCCP can be used to assess the RBE of a DMF and provides a feasible platform for assessing DMFs in radiation therapy applications. [ABSTRACT FROM AUTHOR]

Although research into ultrahigh dose-rate (UHDR) radiation therapy is ongoing, there is a significant lack of experimental measurements for two-dimensional (2D) dose-rate distributions. Additionally, conventional pixel-type detectors result in significant beam loss. In this study, we developed a pixel array-type detector with adjustable gaps and a data acquisition system to evaluate its effectiveness in measuring UHDR proton beams in real time. We measured a UHDR beam at the Korea Institute of Radiological and Medical Sciences using an MC-50 cyclotron, which produced a 45-MeV energy beam with a current range of 10–70 nA, to confirm the UHDR beam conditions. To minimize beam loss during measurement, we adjusted the gap and high voltage on the detector and determined the collection efficiency of the developed detector through Monte Carlo simulation and experimental measurements of the 2D dose-rate distribution. We also verified the accuracy of the real-time position measurement using the developed detector with a 226.29-MeV PBS beam at the National Cancer Center of the Republic of Korea. Our results indicate that, for a current of 70 nA with an energy beam of 45 MeV generated using the MC-50 cyclotron, the dose rate exceeded 300 Gy/s at the center of the beam, indicating UHDR conditions. Simulation and experimental measurements show that fixing the gap at 2 mm and the high voltage at 1000 V resulted in a less than 1% loss of collection efficiency when measuring UHDR beams. Furthermore, we achieved real-time measurements of the beam position with an accuracy of within 2% at five reference points. In conclusion, our study developed a beam monitoring system that can measure UHDR proton beams and confirmed the accuracy of the beam position and profile through real-time data transmission. [ABSTRACT FROM AUTHOR]

Simple Summary: Ultra-high dose-rate (UHDR) irradiation can lead to a FLASH-effect which reduces the biological effect on healthy tissue without affecting the dose to the tumor. UHDRs can currently be achieved using 250 MeV (transmission) proton beams. Up until now, suggested treatment sites potentially benefiting from a FLASH effect include, e.g., small lung, skin, and brain tumors. We suggest the use of FLASH for breast tumors because almost the entire target consists of healthy tissue and hypofractionated dose schedules are common. In this study, we demonstrate that whole breast irradiation (WBI) can be performed using a single transmission proton beam. We evaluated the necessary proton beam parameters in order to achieve the maximum FLASH-effect according to our current knowledge. Although currently not clinically applicable, we hypothesize that a potential FLASH-effect can even allow for further hypofractionation of WBI. Healthy tissue-sparing effects of FLASH (≥40 Gy/s, ≥4–8 Gy/fraction) radiotherapy (RT) make it potentially useful for whole breast irradiation (WBI), since there is often a lot of normal tissue within the planning target volume (PTV). We investigated WBI plan quality and determined FLASH-dose for various machine settings using ultra-high dose rate (UHDR) proton transmission beams (TBs). While five-fraction WBI is commonplace, a potential FLASH-effect might facilitate shorter treatments, so hypothetical 2- and 1-fraction schedules were also analyzed. Using one tangential 250 MeV TB delivering 5 × 5.7 Gy, 2 × 9.74 Gy or 1 × 14.32 Gy, we evaluated: (1) spots with equal monitor units (MUs) in a uniform square grid with variable spacing; (2) spot MUs optimized with a minimum MU-threshold; and (3) splitting the optimized TB into two sub-beams: one delivering spots above an MU-threshold, i.e., at UHDRs; the other delivering the remaining spots necessary to improve plan quality. Scenarios 1–3 were planned for a test case, and scenario 3 was also planned for three other patients. Dose rates were calculated using the pencil beam scanning dose rate and the sliding-window dose rate. Various machine parameters were considered: minimum spot irradiation time (minST): 2 ms/1 ms/0.5 ms; maximum nozzle current (maxN): 200 nA/400 nA/800 nA; two gantry-current (GC) techniques: energy-layer and spot-based. For the test case (PTV = 819 cc) we found: (1) a 7 mm grid achieved the best balance between plan quality and FLASH-dose for equal-MU spots; (2) near the target boundary, lower-MU spots are necessary for homogeneity but decrease FLASH-dose; (3) the non-split beam achieved >95% FLASH for favorable (not clinically available) machine parameters (SB GC, low minST, high maxN), but <5% for clinically available settings (EB GC, minST = 2 ms, maxN = 200 nA); and (4) splitting gave better plan quality and higher FLASH-dose (~50%) for available settings. The clinical cases achieved ~50% (PTV = 1047 cc) or >95% (PTV = 477/677 cc) FLASH after splitting. A single UHDR-TB for WBI can achieve acceptable plan quality. Current machine parameters limit FLASH-dose, which can be partially overcome using beam-splitting. WBI FLASH-RT is technically feasible. [ABSTRACT FROM AUTHOR]

Simple Summary: In proton therapy, there is a sharp peak in the delivered dose followed by a rapid falloff, known as the Bragg peak, which is not present in photons. This allows for treatment plans that deliver lower doses to normal tissue than can be performed with photons. This requires a high degree of accuracy and precision of delivery due to the short distance between an area of high and low doses. Image guidance allows for better visualization of the target and more accurate delivery of proton (and photon) radiation. The equipment used to deliver proton therapy differs in several ways from that of photon radiation, which impacts the methods used for image guidance in proton therapy. This paper aims to summarize the various methods of image guidance in current proton therapy and their relative advantages and disadvantages, as well as areas for future improvements. Image guidance for radiation therapy can improve the accuracy of the delivery of radiation, leading to an improved therapeutic ratio. Proton radiation is able to deliver a highly conformal dose to a target due to its advantageous dosimetric properties, including the Bragg peak. Proton therapy established the standard for daily image guidance as a means of minimizing uncertainties associated with proton treatment. With the increasing adoption of the use of proton therapy over time, image guidance systems for this modality have been changing. The unique properties of proton radiation present a number of differences in image guidance from photon therapy. This paper describes CT and MRI-based simulation and methods of daily image guidance. Developments in dose-guided radiation, upright treatment, and FLASH RT are discussed as well. [ABSTRACT FROM AUTHOR]

Numerous studies have demonstrated the normal tissue-sparing effects of ultra-high dose rate 'FLASH' irradiation in vivo, with an associated reduction in damage burden being reported in vitro. Towards this, two key radiochemical mechanisms have been proposed: radical–radical recombination (RRR) and transient oxygen depletion (TOD), with both being proposed to lead to reduced levels of induced damage. Previously, we reported that FLASH induces lower levels of DNA strand break damage in whole-blood peripheral blood lymphocytes (WB-PBL) ex vivo, but our study failed to distinguish the mechanism(s) involved. A potential outcome of RRR is the formation of crosslink damage (particularly, if any organic radicals recombine), whilst a possible outcome of TOD is a more anoxic profile of induced damage resulting from FLASH. Therefore, the aim of the current study was to profile FLASH-induced damage via the Comet assay, assessing any DNA crosslink formation as a putative marker of RRR and/or anoxic DNA damage formation as an indicative marker of TOD, to determine the extent to which either mechanism contributes to the "FLASH effect". Following FLASH irradiation, we see no evidence of any crosslink formation; however, FLASH irradiation induces a more anoxic profile of induced damage, supporting the TOD mechanism. Furthermore, treatment of WB-PBLs pre-irradiation with BSO abrogates the reduced strand break damage burden mediated by FLASH exposures. In summary, we do not see any experimental evidence to support the RRR mechanism contributing to the reduced damage burden induced by FLASH. However, the observation of a greater anoxic profile of damage following FLASH irradiation, together with the BSO abrogation of the reduced strand break damage burden mediated by FLASH, lends further support to TOD being a driver of the reduced damage burden plus a change in the damage profile mediated by FLASH. [ABSTRACT FROM AUTHOR]

Simple Summary: The ability of ultra-high dose rate FLASH radiation therapy (RT) to reduce normal tissue toxicity without affecting tumor response relative to conventional dose rate radiation therapy could fundamentally change the way we treat cancer. However, this field is still in its early stages, and the magnitude of the sparing effect between treatment centers differs greatly for reasons as yet unknown, which has put the robustness of the effect into question. In this study, we show that when similar irradiation beam parameter settings are used, the induced sparing effect is robust and reproducible across institutions. These settings should serve as a reference for further optimization of the FLASH effect. FLASH radiation therapy (RT) is a promising new paradigm in radiation oncology. However, a major question that remains is the robustness and reproducibility of the FLASH effect when different irradiators are used on animals or patients with different genetic backgrounds, diets, and microbiomes, all of which can influence the effects of radiation on normal tissues. To address questions of rigor and reproducibility across different centers, we analyzed independent data sets from The University of Texas MD Anderson Cancer Center and from Lausanne University (CHUV). Both centers investigated acute effects after total abdominal irradiation to C57BL/6 animals delivered by the FLASH Mobetron system. The two centers used similar beam parameters but otherwise conducted the studies independently. The FLASH-enabled animal survival and intestinal crypt regeneration after irradiation were comparable between the two centers. These findings, together with previously published data using a converted linear accelerator, show that a robust and reproducible FLASH effect can be induced as long as the same set of irradiation parameters are used. [ABSTRACT FROM AUTHOR]

Reports of concurrent sparing of normal tissue and iso-effective treatment of tumors at ultra-high dose-rates (uHDR) have fueled the growing field of FLASH radiotherapy. However, iso-effectiveness in tumors is often deduced from the absence of a significant difference in their growth kinetics. In a model-based analysis, we investigate the meaningfulness of these indications for the clinical treatment outcome. The predictions of a previously benchmarked model of uHDR sparing in the "UNIfied and VERSatile bio response Engine" (UNIVERSE) are combined with existing models of tumor volume kinetics as well as tumor control probability (TCP) and compared to experimental data. The potential TCP of FLASH radiotherapy is investigated by varying the assumed dose-rate, fractionation schemes and oxygen concentration in the target. The developed framework describes the reported tumor growth kinetics appropriately, indicating that sparing effects could be present in the tumor but might be too small to be detected with the number of animals used. The TCP predictions show the possibility of substantial loss of treatment efficacy for FLASH radiotherapy depending on several variables, including the fractionation scheme, oxygen level, and DNA repair kinetics. The possible loss of TCP should be seriously considered when assessing the clinical viability of FLASH treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Information about light exposure patterns is integrated across time and space in retinal circuits before being passed to downstream hypothalamic targets, including the circadian pacemaker in the suprachiasmatic nuclei. In multiple mammalian species, these circuits can integrate brief flashes of light such that the effective impact on the circadian pacemaker is greater than that of continuous light of similar intensity. Using a series of 16-d studies combining outpatient behavioral manipulation and in-laboratory intensive physiologic monitoring, we examined the impact of different durations of light flash sequences on the timing of the human circadian pacemaker. We find that 15 min of light flashes engenders a similar effect on the timing of the human circadian pacemaker as light flashes given for 3.5 h. Our study indicates that the impact of a sequence of light flashes occurs within the first 15 min of exposure, and the retinohypothalamic circuit responsible for shifting the timing of the circadian pacemaker is refractory to further stimulation. These data are important for both the understanding of retinohypothalamic circuitry and the design of robust light interventions meant to change circadian timing during sleep, as would be used in the treatment of circadian rhythm sleep disorders. Unlike light input for forming images, non-image-forming retinal pathways are optimized to convey information about the total light environment, integrating this information over time and space. In a variety of species, discontinuous light sequences (flashes) can be effective stimuli, notably impacting circadian entrainment. In this study, we examined the extent to which this temporal integration can occur. A group of healthy, young (n = 20) individuals took part in a series of 16-day protocols in which we examined the impact of different lengths of light flash sequences on circadian timing. We find a significant phase change of −0.70 h in response to flashes that did not differ by duration; a 15-min sequence could engender as much change in circadian timing as 3.5-h sequences. Acute suppression of melatonin was also observed during short (15-min) exposures, but not in exposures over one hour in length. Our data are consistent with the theory that responses to light flashes are mediated by the extrinsic, rod/cone pathway, and saturate the response of this pathway within 15 min. Further excitation leads to no greater change in circadian timing and an inability to acutely suppress melatonin, indicating that this pathway may be in a refractory state following this brief light stimulation. [ABSTRACT FROM AUTHOR]

Rapidly growing interest in smartphone cameras as the basis of point-of-need diagnostic and bioanalytical technologies increases the importance of quantitative characterization of phone optical performance under real-world operating conditions. In the context of our development of lateral-flow immunoassays based on phosphorescent nanoparticles, we have developed a suite of tools for characterizing the temporal and spectral profiles of smartphone torch and flash emissions, and their dependence on phone power state. In this work, these tools are described and documented to make them easily available to others, and demonstrated by application to characterization of Apple iPhone 5s, iPhone 6s, iPhone 8, iPhone XR, and Samsung Note8 flash performance as a function of time and wavelength, at a variety of power settings. Flash and torch intensity and duration vary with phone state and among phone models. Flash has high variability when the battery charge is below 10%, thus, smartphone-based Point-of-Care (POC) tests should only be performed at a battery level of at least 15%. Some output variations could substantially affect the results of assays that rely on the smartphone flash. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of any kind of external radiation therapy is to control a tumor with the highest possible probability of the lowest possible side effects. Here, we study further opportunities of reducing the side effects of proton therapy by applying longitudinally heterogeneous dose distributions in the tumor respecting the delivery of a minimum prescribed dose. In our simulations, the longitudinally heterogeneous dose distributions show a reduced dose in the healthy tissue already in the case of proton broadbeam irradiations, but a much higher (calculated) mean cell survival in the case of proton minibeam irradiation. This demonstrates its potential to substantially reduce side effects at a simultaneously higher tumor control probability, opening new opportunities of easier application when striving for high dose-rate applications of proton beams (>~10 Gy/s), in order to additionally profit from the so-called FLASH effects. The prerequisite of any radiation therapy modality (X-ray, electron, proton, and heavy ion) is meant to meet at least a minimum prescribed dose at any location in the tumor for the best tumor control. In addition, there is also an upper dose limit within the tumor according to the International Commission on Radiation Units (ICRU) recommendations in order to spare healthy tissue as well as possible. However, healthy tissue may profit from the lower side effects when waving this upper dose limit and allowing a larger heterogeneous dose deposition in the tumor, but maintaining the prescribed minimum dose level, particularly in proton minibeam therapy. Methods: Three different longitudinally heterogeneous proton irradiation modes and a standard spread-out Bragg peak (SOBP) irradiation mode are simulated for their depth-dose curves under the constraint of maintaining a minimum prescribed dose anywhere in the tumor region. Symmetric dose distributions of two opposing directions are overlaid in a 25 cm-thick water phantom containing a 5 cm-thick tumor region. Interlaced planar minibeam dose distributions are compared to those of a broadbeam using the same longitudinal dose profiles. Results and Conclusion: All longitudinally heterogeneous proton irradiation modes show a dose reduction in the healthy tissue compared to the common SOBP mode in the case of broad proton beams. The proton minibeam cases show eventually a much larger mean cell survival and thus a further reduced equivalent uniform dose (EUD) in the healthy tissue than any broadbeam case. In fact, the irradiation mode using only one proton energy from each side shows better sparing capabilities in the healthy tissue than the common spread-out Bragg peak irradiation mode with the option of a better dose fall-off at the tumor edges and an easier technical realization, particularly in view of proton minibeam irradiation at ultra-high dose rates larger than ~10 Gy/s (so-called FLASH irradiation modes). [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) is one of the primary treatment modalities for cancer patients. The clinical use of RT requires a balance to be struck between tumor effect and the risk of toxicity. Sparing normal tissue is the cornerstone of reducing toxicity. Advances in physical targeting and dose-shaping technology have helped to achieve this. FLASH RT is a promising, novel treatment technique that seeks to exploit a potential normal tissue-sparing effect of ultra-high dose rate irradiation. A significant body of in vitro and in vivo data has highlighted a decrease in acute and late radiation toxicities, while preserving the radiation effect in tumor cells. The underlying biological mechanisms of FLASH RT, however, remain unclear. Three main mechanisms have been hypothesized to account for this differential FLASH RT effect between the tumor and healthy tissue: the oxygen depletion, the DNA damage, and the immune-mediated hypothesis. These hypotheses and molecular mechanisms have been evaluated both in vitro and in vivo. Furthermore, the effect of ultra-high dose rate radiation with extremely short delivery times on the dynamic tumor microenvironment involving circulating blood cells and immune cells in humans is essentially unknown. Therefore, while there is great interest in FLASH RT as a means of targeting tumors with the promise of an increased therapeutic ratio, evidence of a generalized FLASH effect in humans and data to show that FLASH in humans is safe and at least effective against tumors as standard photon RT is currently lacking. FLASH RT needs further preclinical investigation and well-designed in-human studies before it can be introduced into clinical practice. [ABSTRACT FROM AUTHOR]

A Fault Attack (FA) is performed mainly under the data corruption model and poses a threat to security chips. Instruction corruption can enact the same purpose at the behavioral level, which is produced by interfering with the instruction system. Laser Fault Injection (LFI) on program memory during the instruction-fetching process, which we refer to as an instruction-fetching attack, is studied in this paper. This process bears the ability to produce a controllable instruction-fetching fault. Our work shows the implementation of the attack and its specific application case on an 8-bit microcontroller. The main contributions of this paper include: (1) We have mapped the sensitive areas precisely to the faulted instructions via laser injection and implemented controllable instruction tampering. (2) A Collision Fault Attack (CFA) scheme based on instruction-fetching fault is proposed. (3) The impacts of the faulted instructions are fully explored, including the influence on subsequent operations and key recovery. (4) The fault mechanism of the on-chip Flash is further investigated. Instruction-fetching fault means that the controller fetches a tampered instruction from the program memory under external interference, which likely gives rise to an invalid or incorrect operation. The experiment confirms that this specific fault can induce particular types of faults that are different to realize, e.g., the byte-fault model in CFA. The realization, application and mechanism of instruction-fetching fault are discussed in detail. [ABSTRACT FROM AUTHOR]

A 6-bit 20 GS/s 16-channel time-interleaved (TI) analog-to-digital converter (ADC) using a two-step flash ADC with a sample-and-hold (S/H) sharing technique and a gain-boosted voltage-to-time converter (VTC) is presented for high-speed wireline communication systems. By sharing one S/H between coarse and fine stages in the two-step flash ADC, the input bandwidth as well as area and power efficiency can be improved without a gain error between coarse and fine ADCs. Thanks to an eight-time interpolation using the gain-boosted VTC, the fine ADC has a small gate capacitance without a speed penalty, even in a small input voltage range. A prototype ADC implemented in a 40 nm CMOS process occupies a 0.1 mm2 active area. The measured differential non-linearity (DNL) and integral non-linearity (INL) after offset and gain calibrations were 0.45 and 0.39 least significant bit (LSB), respectively. With a 9.042 GHz input, the measured signal-to-noise and distortion ratio (SNDR) and the spurious-free dynamic range (SFDR) were 30.12 and 40.23 dB, respectively. The small input capacitance of the sub-ADC enables a power-efficient track-and-hold amplifier (THA), resulting in a power consumption of 56.2 mW under a supply voltage of 0.9 V. The prototype ADC achieves a figure of merit (FoM) of 107.4 fJ/conversion-step at 20 GS/s. [ABSTRACT FROM AUTHOR]

Simple Summary: Four decades ago, intraoperative electron radiation therapy (IOeRT) was developed to improve precision in local cancer treatment by combining real-time surgical exploration and resection with high-energy electron irradiation. The technology of ultra-high dose rate electron and other radiation beams known as FLASH irradiation sharply increases its interests, as data from preclinical experiments have proven a marked favorable effect on the therapeutic index: similar cancer control with a clearly improved tolerance of many normal tissues to high doses of irradiation. The knowledge and tools regarding technology, physics, biology, and preclinical results in heterogeneous cancers opens great opportunities towards the path of developing the first clinical applications of the emerging FLASH technology via clinical trials based on state-of-the-art medical practice with IOeRT. Introduction: The clinical practice and outcome results of intraoperative electron radiation therapy (IOeRT) in cancer patients have been extensively reported over 4 decades. Electron beams can be delivered in the promising FLASH dose rate. Methods and Materials: Several cancer models were approached by two alternative radiobiological strategies to optimize local cancer control: boost versus exclusive IOeRT. Clinical outcomes are revisited via a bibliometric search performed for the elaboration of ESTRO/ACROP IORT guidelines. Results: In the period 1982 to 2020, a total of 19,148 patients were registered in 116 publications concerning soft tissue sarcomas (9% of patients), unresected and borderline-resected pancreatic cancer (22%), locally recurrent and locally advanced rectal cancer (22%), and breast cancer (45%). Clinical outcomes following IOeRT doses in the range of 10 to 25 Gy (with or without external beam fractionated radiation therapy) show a wide range of local control from 40 to 100% depending upon cancer site, histology, stage, and treatment intensity. Constraints for normal tissue tolerance are important to maintain tumor control combined with acceptable levels of side effects. Conclusions: IOeRT represents an evidence-based approach for several tumor types. A specific risk analysis for local recurrences supports the identification of cancer models that are candidates for FLASH studies. [ABSTRACT FROM AUTHOR]

The impact of the exact temporal pulse structure on the potential cell and tissue sparing of ultra-high dose-rate irradiation applied in FLASH studies has gained increasing attention. A previous version of our biophysical mechanistic model (UNIVERSE: UNIfied and VERSatile bio response Engine), based on the oxygen depletion hypothesis, has been extended in this work by considering oxygen-dependent damage fixation dynamics on the sub-milliseconds scale and introducing an explicit implementation of the temporal pulse structure. The model successfully reproduces in vitro experimental data on the fast kinetics of the oxygen effect in irradiated mammalian cells. The implemented changes result in a reduction in the assumed amount of oxygen depletion. Furthermore, its increase towards conventional dose-rates is parameterized based on experimental data from the literature. A recalculation of previous benchmarks shows that the model retains its predictive power, while the assumed amount of depleted oxygen approaches measured values. The updated UNIVERSE could be used to investigate the impact of different combinations of pulse structure parameters (e.g., dose per pulse, pulse frequency, number of pulses, etc.), thereby aiding the optimization of potential clinical application and the development of suitable accelerators. [ABSTRACT FROM AUTHOR]

Featured Application: The characteristics of X-rays generated at the synchrotron facilities in Australia (the Australian Synchrotron) and France (the European Synchrotron Radiation Facility) share common features which provide the basis for development of new modalities for cancer radiotherapy treatment. In addition to the empirical optimization of the physical configurations of the radiation, research is now focused on the underlying radiobiological mechanisms, especially in the context of systemic "non-targeted effects". Studies have been conducted at synchrotron facilities in Europe and Australia to explore a variety of applications of synchrotron X-rays in medicine and biology. We discuss the major technical aspects of the synchrotron irradiation setups, paying specific attention to the Australian Synchrotron (AS) and the European Synchrotron Radiation Facility (ESRF) as those best configured for a wide range of biomedical research involving animals and future cancer patients. Due to ultra-high dose rates, treatment doses can be delivered within milliseconds, abiding by FLASH radiotherapy principles. In addition, a homogeneous radiation field can be spatially fractionated into a geometric pattern called microbeam radiotherapy (MRT); a coplanar array of thin beams of microscopic dimensions. Both are clinically promising radiotherapy modalities because they trigger a cascade of biological effects that improve tumor control, while increasing normal tissue tolerance compared to conventional radiation. Synchrotrons can deliver high doses to a very small volume with low beam divergence, thus facilitating the study of non-targeted effects of these novel radiation modalities in both in-vitro and in-vivo models. Non-targeted radiation effects studied at the AS and ESRF include monitoring cell–cell communication after partial irradiation of a cell population (radiation-induced bystander effect, RIBE), the response of tissues outside the irradiated field (radiation-induced abscopal effect, RIAE), and the influence of irradiated animals on non-irradiated ones in close proximity (inter-animal RIBE). Here we provide a summary of these experiments and perspectives on their implications for non-targeted effects in biomedical fields. [ABSTRACT FROM AUTHOR]

FLASH irradiations use dose-rates orders of magnitude higher than commonly used in patient treatments. Such irradiations have shown interesting normal tissue sparing in cell and animal experiments, and, as such, their potential application to clinical practice is being investigated. Clinical accelerators used in proton therapy facilities can potentially provide FLASH beams; therefore, the topic is of high interest in this field. However, a clear FLASH effect has so far been observed in presence of high dose rates (>40 Gy/s), high delivered dose (tens of Gy), and very short irradiation times (<300 ms). Fulfilling these requirements poses a serious challenge to the beam diagnostics system of clinical facilities. We will review the status and proposed solutions, from the point of view of the beam definitions for FLASH and their implications for beam diagnostics. We will devote particular attention to the topics of beam monitoring and control, as well as absolute dose measurements, since finding viable solutions in these two aspects will be of utmost importance to guarantee that the technique can be adopted quickly and safely in clinical practice. [ABSTRACT FROM AUTHOR]

The reaction microscope (REMI) endstation for atomic and molecular science at the free-electron laser FLASH2 at DESY in Hamburg is presented together with a brief overview of results recently obtained. The REMI allows coincident detection of electrons and ions that emerge from atomic or molecular fragmentation reactions in the focus of the extreme-ultraviolet (XUV) free-electron laser (FEL) beam. A large variety of target species ranging from atoms and molecules to small clusters can be injected with a supersonic gas-jet into the FEL focus. Their ionization and fragmentation dynamics can be studied either under single pulse conditions, or for double pulses as a function of their time delay by means of FEL-pump–FEL-probe schemes and also in combination with a femtosecond infrared (IR) laser. In a recent upgrade, the endstation was further extended by a light source based on high harmonic generation (HHG), which is now available for upcoming FEL/HHG pump–probe experiments. [ABSTRACT FROM AUTHOR]

To enable the design of large capacity memory structures, novel memory technologies such as non-volatile memory (NVM) and novel fabrication approaches, e.g., 3D stacking and multi-level cell (MLC) design have been explored. The existing modeling tools, however, cover only a few memory technologies, technology nodes and fabrication approaches. We present DESTINY, a tool for modeling 2D/3D memories designed using SRAM, resistive RAM (ReRAM), spin transfer torque RAM (STT-RAM), phase change RAM (PCM) and embedded DRAM (eDRAM) and 2D memories designed using spin orbit torque RAM (SOT-RAM), domain wall memory (DWM) and Flash memory. In addition to single-level cell (SLC) designs for all of these memories, DESTINY also supports modeling MLC designs for NVMs. We have extensively validated DESTINY against commercial and research prototypes of these memories. DESTINY is very useful for performing design-space exploration across several dimensions, such as optimizing for a target (e.g., latency, area or energy-delay product) for a given memory technology, choosing the suitable memory technology or fabrication method (i.e., 2D v/s 3D) for a given optimization target, etc. We believe that DESTINY will boost studies of next-generation memory architectures used in systems ranging from mobile devices to extreme-scale supercomputers. The latest source-code of DESTINY is available from the following git repository: https://bitbucket.org/sparsh_mittal/destiny_v2. [ABSTRACT FROM AUTHOR]

This review summarizes the most widely used mechanisms in memory devices based on conjugated polymers, such as charge transfer, space charge traps, and filament conduction. In addition, recent studies of conjugated polymers for memory device applications are also reviewed, discussed, and differentiated based on the mechanisms and structural design. Moreover, the electrical conditions of conjugated polymers can be further fine-tuned by careful design and synthesis based on the switching mechanisms. The review also emphasizes and demonstrates the structure-memory properties relationship of donor-acceptor conjugated polymers for advanced memory device applications. [ABSTRACT FROM AUTHOR]

Protein microarrays represent important tools for biomedical analysis. We have recently described the use of the biarsenical-tetracysteine (TC) tag for the preparation of protein microarrays. The unique feature of this tag enables the site-specific immobilization of TC-containing proteins on biarsenical-modified surfaces, resulting in a fluorescence enhancement that allows the direct quantification of the immobilized proteins. Moreover, the reversibility of the binding upon incubation with large quantities of thiols permits the detachment of the proteins from the surface, thereby enabling recovery of the substrate to extend the life time of the slide. Herein, we describe our recent results that further extend the applicability of the CrAsH/TC tag to the fabrication of biochips. With this aim, the immobilization of proteins on surfaces has been investigated using two different spacers and two TC tags, the minimal TC sequence (CCPGCC) and an optimized motif (FLNCCPGCCMEP). While the minimal peptide motif enables a rapid recycling of the slide, the optimized TC sequence reveals an increased affinity due to its greater resistance to displacement by thiols. Moreover, the developed methodology was applied to the immobilization of proteins via on-chip ligation of recombinant protein thioesters. [ABSTRACT FROM AUTHOR]

Flash memory is the most widely used non-volatile memory device nowadays. In order to keep up with the demand for increased memory capacities, flash memory has been continuously scaled to smaller and smaller dimensions. The main benefits of down-scaling cell size and increasing integration are that they enable lower manufacturing cost as well as higher performance. Charge trapping memory is regarded as one of the most promising flash memory technologies as further down-scaling continues. In addition, more and more exploration is investigated with high-k dielectrics implemented in the charge trapping memory. The paper reviews the advanced research status concerning charge trapping memory with high-k dielectrics for the performance improvement. Application of high-k dielectric as charge trapping layer, blocking layer, and tunneling layer is comprehensively discussed accordingly. [ABSTRACT FROM AUTHOR]

The density and cost-effectiveness of flash memory chips continue to increase, driven by: (a) The continuous physical scaling of memory cells in a single layer; (b) The vertical stacking of multiple layers; and (c) Logical scaling through storing multiple bits of information in a single memory cell. The physical properties of flash memories impose disproportionate latency and energy expenditures to ensure the high integrity of the data during flash memory writes. This paper experimentally explores this disproportionality on state-of-the-art commercial 3D NAND flash memories and introduces EXPRESS—a technique for increasing the energy efficiency of flash memory writes by exploiting the premature termination of the flash write operations. An experimental evaluation shows that EXPRESS reduces energy expenditures by 20–50%, relative to the traditional flash writes, at the cost of a minimal loss in the data integrity (<1%). In addition, we evaluate the effects of the page-to-page variability, program–erase cycling, and data retention on the implementation of EXPRESS, and we propose enhancements to counter these effects. [ABSTRACT FROM AUTHOR]

In this paper, we report X-ray absorption and core-level electron spectra of the nucleobase derivative 2-thiouracil at the sulfur L1- and L2,3-edges. We used soft X-rays from the free-electron laser FLASH2 for the excitation of isolated molecules and dispersed the outgoing electrons with a magnetic bottle spectrometer. We identified photoelectrons from the 2p core orbital, accompanied by an electron correlation satellite, as well as resonant and non-resonant Coster–Kronig and Auger–Meitner emission at the L1- and L2,3-edges, respectively. We used the electron yield to construct X-ray absorption spectra at the two edges. The experimental data obtained are put in the context of the literature currently available on sulfur core-level and 2-thiouracil spectroscopy. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aims at using a multi-technique approach to detect and analyze the effects of high dose rate spatially fractionated radiation therapies and to compare them to seamless broad beam irradiation targeting healthy and glioblastoma-bearing rat brains and delivering three different doses per each irradiation geometry. Brains were analyzed post mortem by multi-scale X-ray phase contrast imaging–computed tomography, histology, immunohistochemistry, X-ray fluorescence, and small- and wide-angle X-ray scattering to achieve detailed visualization, characterization and classification in 3D of the radio-induced effects on brain tissues. The original results bring new insights to the understanding of the response of cerebral tissue and tumors treated with high dose rate spatially fractioned radiotherapies and put the basis for channeling studies of in-vivo applications for monitoring RT effects. The purpose of this study is to use a multi-technique approach to detect the effects of spatially fractionated X-ray Microbeam (MRT) and Minibeam Radiation Therapy (MB) and to compare them to seamless Broad Beam (BB) irradiation. Healthy- and Glioblastoma (GBM)-bearing male Fischer rats were irradiated in-vivo on the right brain hemisphere with MRT, MB and BB delivering three different doses for each irradiation geometry. Brains were analyzed post mortem by multi-scale X-ray Phase Contrast Imaging–Computed Tomography (XPCI-CT), histology, immunohistochemistry, X-ray Fluorescence (XRF), Small- and Wide-Angle X-ray Scattering (SAXS/WAXS). XPCI-CT discriminates with high sensitivity the effects of MRT, MB and BB irradiations on both healthy and GBM-bearing brains producing a first-time 3D visualization and morphological analysis of the radio-induced lesions, MRT and MB induced tissue ablations, the presence of hyperdense deposits within specific areas of the brain and tumor evolution or regression with respect to the evaluation made few days post-irradiation with an in-vivo magnetic resonance imaging session. Histology, immunohistochemistry, SAXS/WAXS and XRF allowed identification and classification of these deposits as hydroxyapatite crystals with the coexistence of Ca, P and Fe mineralization, and the multi-technique approach enabled the realization, for the first time, of the map of the differential radiosensitivity of the different brain areas treated with MRT and MB. 3D XPCI-CT datasets enabled also the quantification of tumor volumes and Ca/Fe deposits and their full-organ visualization. The multi-scale and multi-technique approach enabled a detailed visualization and classification in 3D of the radio-induced effects on brain tissues bringing new essential information towards the clinical implementation of the MRT and MB radiation therapy techniques. [ABSTRACT FROM AUTHOR]

Simple Summary: Standard intensity-modulated proton therapy (IMPT) places the Bragg-peak in the target. However, it is also possible to use high energy proton transmission beams (TBs), where the Bragg-peak is placed outside the patient, irradiating with the beam section proximal to the Bragg-peak. TBs use only one energy, increase robustness, are insensitive to density changes and have sharper penumbras. TBs can also be delivered at ultra-high dose-rates (UHDRs, e.g., ≥40 Gy/s), which is one of the requirements for the FLASH-effect. The aim of this work was twofold: (1) comparison of TB-plan quality to IMPT and photon volumetric-modulated arc therapy (VMAT) for conventionally fractionated head-and-neck cancer; (2) analysis of TB-plan UHDR-metrics. We showed that TB-plan quality was comparable to IMPT for contoured organs at risk and better than VMAT. Any potential FLASH-effect would only further improve plan quality. TB plans can also be delivered quickly, which might facilitate higher patient through-put and enhance patient comfort. Transmission beam (TB) proton therapy (PT) uses single, high energy beams with Bragg-peak behind the target, sharp penumbras and simplified planning/delivery. TB facilitates ultra-high dose-rates (UHDRs, e.g., ≥40 Gy/s), which is a requirement for the FLASH-effect. We investigated (1) plan quality for conventionally-fractionated head-and-neck cancer treatment using spot-scanning proton TBs, intensity-modulated PT (IMPT) and photon volumetric-modulated arc therapy (VMAT); (2) UHDR-metrics. VMAT, 3-field IMPT and 10-field TB-plans, delivering 70/54.25 Gy in 35 fractions to boost/elective volumes, were compared (n = 10 patients). To increase spot peak dose-rates (SPDRs), TB-plans were split into three subplans, with varying spot monitor units and different gantry currents. Average TB-plan organs-at-risk (OAR) sparing was comparable to IMPT: mean oral cavity/body dose were 4.1/2.5 Gy higher (9.3/2.0 Gy lower than VMAT); most other OAR mean doses differed by <2 Gy. Average percentage of dose delivered at UHDRs was 46%/12% for split/non-split TB-plans and mean dose-averaged dose-rate 46/21 Gy/s. Average total beam-on irradiation time was 1.9/3.8 s for split/non-split plans and overall time including scanning 8.9/7.6 s. Conventionally-fractionated proton TB-plans achieved comparable OAR-sparing to IMPT and better than VMAT, with total beam-on irradiation times <10s. If a FLASH-effect can be demonstrated at conventional dose/fraction, this would further improve plan quality and TB-protons would be a suitable delivery system. [ABSTRACT FROM AUTHOR]

Simple Summary: Dose and efficacy of radiation therapy are limited by the toxicity to normal tissue adjacent to the treated tumor region. Recently, ultra-high dose rate radiotherapy (FLASH radiotherapy) has shown beneficial reduction of normal tissue damage while preserving similar tumor efficacy with electron, photon and scattered proton beam irradiation in preclinical models. Proton therapy is increasingly delivered by pencil beam scanning (PBS) technology, and we therefore set out to test PBS FLASH radiotherapy on normal tissue toxicity and tumor control in vivo in mouse using a clinical proton delivery system. This validation of the FLASH normal tissue-sparing hypothesis with a clinical delivery system provides supporting data for PBS FLASH radiotherapy and its potential role in improving radiotherapy outcomes. Ultra-high dose rate radiation has been reported to produce a more favorable toxicity and tumor control profile compared to conventional dose rates that are used for patient treatment. So far, the so-called FLASH effect has been validated for electron, photon and scattered proton beam, but not yet for proton pencil beam scanning (PBS). Because PBS is the state-of-the-art delivery modality for proton therapy and constitutes a wide and growing installation base, we determined the benefit of FLASH PBS on skin and soft tissue toxicity. Using a pencil beam scanning nozzle and the plateau region of a 250 MeV proton beam, a uniform physical dose of 35 Gy (toxicity study) or 15 Gy (tumor control study) was delivered to the right hind leg of mice at various dose rates: Sham, Conventional (Conv, 1 Gy/s), Flash60 (57 Gy/s) and Flash115 (115 Gy/s). Acute radiation effects were quantified by measurements of plasma and skin levels of TGF-β1 and skin toxicity scoring. Delayed irradiation response was defined by hind leg contracture as a surrogate of irradiation-induced skin and soft tissue toxicity and by plasma levels of 13 different cytokines (CXCL1, CXCL10, Eotaxin, IL1-beta, IL-6, MCP-1, Mip1alpha, TNF-alpha, TNF-beta, VEGF, G-CSF, GM-CSF and TGF- β1). Plasma and skin levels of TGF-β1, skin toxicity and leg contracture were all significantly decreased in FLASH compared to Conv groups of mice. FLASH and Conv PBS had similar efficacy with regards to growth control of MOC1 and MOC2 head and neck cancer cells transplanted into syngeneic, immunocompetent mice. These results demonstrate consistent delivery of FLASH PBS radiation from 1 to 115 Gy/s in a clinical gantry. Radiation response following delivery of 35 Gy indicates potential benefits of FLASH versus conventional PBS that are related to skin and soft tissue toxicity. [ABSTRACT FROM AUTHOR]

FLASH radiotherapy is the delivery of ultra-high dose rate radiation several orders of magnitude higher than what is currently used in conventional clinical radiotherapy, and has the potential to revolutionize the future of cancer treatment. FLASH radiotherapy induces a phenomenon known as the FLASH effect, whereby the ultra-high dose rate radiation reduces the normal tissue toxicities commonly associated with conventional radiotherapy, while still maintaining local tumor control. The underlying mechanism(s) responsible for the FLASH effect are yet to be fully elucidated, but a prominent role for oxygen tension and reactive oxygen species production is the most current valid hypothesis. The FLASH effect has been confirmed in many studies in recent years, both in vitro and in vivo, with even the first patient with T-cell cutaneous lymphoma being treated using FLASH radiotherapy. However, most of the studies into FLASH radiotherapy have used electron beams that have low tissue penetration, which presents a limitation for translation into clinical practice. A promising alternate FLASH delivery method is via proton beam therapy, as the dose can be deposited deeper within the tissue. However, studies into FLASH protons are currently sparse. This review will summarize FLASH radiotherapy research conducted to date and the current theories explaining the FLASH effect, with an emphasis on the future potential for FLASH proton beam therapy. [ABSTRACT FROM AUTHOR]

This review summarizes the most widely used mechanisms in memory devices based on conjugated polymers, such as charge transfer, space charge traps, and filament conduction. In addition, recent studies of conjugated polymers for memory device applications are also reviewed, discussed, and differentiated based on the mechanisms and structural design. Moreover, the electrical conditions of conjugated polymers can be further fine-tuned by careful design and synthesis based on the switching mechanisms. The review also emphasizes and demonstrates the structure-memory properties relationship of donor-acceptor conjugated polymers for advanced memory device applications.

Flash memory is the most widely used non-volatile memory device nowadays. In order to keep up with the demand for increased memory capacities, flash memory has been continuously scaled to smaller and smaller dimensions. The main benefits of down-scaling cell size and increasing integration are that they enable lower manufacturing cost as well as higher performance. Charge trapping memory is regarded as one of the most promising flash memory technologies as further down-scaling continues. In addition, more and more exploration is investigated with high -k dielectrics implemented in the charge trapping memory. The paper reviews the advanced research status concerning charge trapping memory with high -k dielectrics for the performance improvement. Application of high -k dielectric as charge trapping layer, blocking layer, and tunneling layer is comprehensively discussed accordingly.