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Various dosimeters have been tested for assessing absorbed doses with microscopic spatial resolution in targets irradiated by high-flux, synchrotron-generated, low-energy (approximately 30-300 keV) x-ray microbeams. A MOSFET detector has been used for this study since its radio sensitive element, which is extraordinarily narrow (approximately 1 microm), suits the main applications of interest, microbeam radiation biology and microbeam radiation therapy (MRT). In MRT, micrometer-wide, centimeter-high, and vertically oriented swaths of tissue are irradiated by arrays of rectangular x-ray microbeams produced by a multislit collimator (MSC). We used MOSFETs to measure the dose distribution, produced by arrays of x-ray microbeams shaped by two different MSCs, in a tissue-equivalent phantom. Doses were measured near the center of the arrays and maximum/minimum (peak/valley) dose ratios (PVDRs) were calculated to determine how variations in heights and in widths of the microbeams influenced this for the therapy, potentially important parameter. Monte Carlo (MC) simulations of the absorbed dose distribution in the phantom were also performed. The results show that when the heights of the irradiated swaths were below those applicable to clinical therapy (1 mm) the MC simulations produce estimates of PVDRs that are up to a factor of 3 higher than the measured values. For arrays of higher microbeams (i.e., 25 microm x 1 cm instead of 25 x 500 microm2), this difference between measured and simulated PVDRs becomes less than 50%. Closer agreement was observed between the measured and simulated PVDRs for the Tecomet MSC (current collimator design) than for the Archer MSC. Sources of discrepancies between measured and simulated doses are discussed, of which the energy dependent response of the MOSFET was shown to be among the most important.

International audience; Microbeam radiation therapy is a novel preclinical technique, which uses synchrotron-generated X-rays for the treatment of brain tumours and drug-resistant epilepsies. In order to safely translate this approach to humans, a more in-depth knowledge of the long-term radiobiology of microbeams in healthy tissues is required. We report here the result of the characterization of the rat sensorimotor cortex tolerance to microradiosurgical parallel transections. Healthy adult male Wistar rats underwent irradiation with arrays of parallel microbeams. Beam thickness, spacing and incident dose were 100 or 600 mu m, 400 or 1200 mu m and 360 or 150 Gy, respectively. Motor performance was carried over a 3-month period. Three months after irradiation rats were sacrificed to evaluate the effects of irradiation on brain tissues by histology and immunohistochemistry. Microbeam irradiation of sensorimotor cortex did not affect weight gain and motor performance. No gross signs of paralysis or paresis were also observed. The cortical architecture was not altered, despite the presence of cell death along the irradiation path. Reactive gliosis was evident in the microbeam path of rats irradiated with 150 Gy, whereas no increase was observed in rats irradiated with 360 Gy

Intensive synchrotron X-ray microbeams form an integral part of microbeam radiation therapy (MRT). MRT is a novel radiation medicine modality being developed for inoperable and otherwise untreatable brain tumours. The extremely high dose rate (∼20 kGy/s), laterally fractionated radiation field and steep dose gradients utilized in this therapy make real-time dosimetry a significant challenge. In order for this treatment to advance to the clinical trial stage of development real-time dosimetry systems must be developed. This paper demonstrates the capabilities of a new dosimetry system based on an epitaxial silicon detector. The system combines high spatial resolution and real-time readout and we have measured the lateral dose profile of the MRT radiation field which incorporates 59 X-ray microbeams. All microbeam peaks and valley regions between two microbeams are clearly resolved. The measured detector response at any point is reproducible to within 0.5% after scaling for the known synchrotron storage ring beam current lifetime. The variation of the lateral dose profile at different depths in a PMMA phantom has been measured with the results compared to those from Penelope Monte Carlo simulations. The trend in the measured response with depth agrees with the simulation data (within the experimental variation of the central five microbeams peaks and valleys measured). However the measured peak-to-valley ratio response is a factor of 4.5 ± 0.1 times lower than that expected. The disagreement was further investigated and shown to be contributed to by charge recombination effects at the low bias voltages used.

International audience; To analyze the effects of the microbeam width (25, 50 and 75 microm) on the survival of 9L gliosarcoma tumor-bearing rats and on toxicity in normal tissues in normal rats after microbeam radiation therapy (MRT), 9L gliosarcomas implanted in rat brains, as well as in normal rat brains, were irradiated in the MRT mode. Three configurations (MRT25, MRT50, MRT75), each using two orthogonally intersecting arrays of either 25, 50 or 75 microm wide microbeams, all spaced 211 microm on center, were tested. For each configuration, peak entrance doses of 860, 480 and 320 Gy, respectively, were calculated to produce an identical valley dose of 18 Gy per individual array at the center of the tumor. Two, 7 and 14 days after radiation treatment, 42 rats were killed to evaluate histopathologically the extent of tumor necrosis, and the presence of proliferating tumors cells and tumor vessels. The median survival times of the normal rats were 4.5, 68 and 48 days for MRT25, 50 and 75, respectively. The combination of the highest entrance doses (860 Gy per array) with 25 microm wide beams (MRT25) resulted in a cumulative valley dose of 36 Gy and was excessively toxic, as it led to early death of all normal rats and of approximately 50% of tumor-bearing rats. The short survival times, particularly of rats in the MRT25 group, restricted adequate observance of the therapeutic effect of the method on tumor-bearing rats. However, microbeams of 50 microm width led to the best median survival time after 9L gliosarcoma MRT treatment and appeared as the better compromise between tumor control and normal brain toxicity compared with 75 microm or 25 microm widths when used with a 211 microm on-center distance. Despite very high radiation doses, the tumors were not sterilized; viable proliferating tumor cells remained present at the tumor margin. This study shows that microbeam width and peak entrance doses strongly influence tumor responses and normal brain toxicity, even if valley doses are kept constant in all groups. The use of 50 microm wide microbeams combined with moderate peak doses resulted in a higher therapeutic ratio.

International audience; The technical feasibility of temporal and spatial fractionations of the radiation dose has been evaluated using synchrotron microbeam radiation therapy for brain tumors in rats. A significant increase in lifespan (216%, p < 0.0001) resulted when three fractions of microbeam irradiation were applied to the tumor through three different ports, orthogonal to each other, at 24 h intervals. However, there were no long-term survivors, and immunohistological studies revealed that 9 L tumors were not entirely ablated.

Purpose Microplanar X-ray beams (microbeams) originated by synchrotron sources have been delivered to the visual brain cortex regions in rodents to create microscopically narrow lesions. The effects of microbeams mimic those generated by microsurgical subpial transections (also known as multiple subpial transections) but are obtained in a low-invasive way. Methods Image-guided atlas-based microbeam cortical transections have been generated on seven 1 month-old Wistar rats. An array of 10 parallel beams of 25 microns in thickness and spaced of 200 micron center-to-center was centered on the visual cortex and deposited an incident dose of 600 Gy. Results The procedure was well tolerated by rats. After recovery, rats showed regular behavior, no sign of gross visual impairment and regular weight gain. After 3 months, rats were sacrificed and brains histologically examined. Cortical transections resembling those obtained through a surgical incision were found over the irradiated region. Remarkable sparing of the cortical columns adjacent to the transections was observed. No sign of radionecrosis was evident at least at this time point. Conclusions The visual brain cortex transected by synchrotron-generated microbeams showed an incision-like path of neuronal loss while adjacent non irradiated columns remained intact. These preliminary findings, to be further investigated also using other techniques, suggest that microbeam radiosurgery can affect the cortex at a cellular level providing a potential novel and attractive tool to study cortical function.

The risk of developing normal tissue injuries often limits the radiation dose that can be applied to the tumour in radiation therapy. Microbeam Radiation Therapy (MRT), a spatially fractionated photon radiotherapy is currently tested at the European Synchrotron Radiation Facility (ESRF) to improve normal tissue protection. MRT utilizes an array of microscopically thin and nearly parallel X-ray beams that are generated by a synchrotron. At the ion microprobe SNAKE in Munich focused proton microbeams (“proton microchannels”) are studied to improve normal tissue protection. Here, we comparatively investigate microbeam/microchannel irradiations with sub-millimetre X-ray versus proton beams to minimize the risk of normal tissue damage in a human skin model, in vitro. Skin tissues were irradiated with a mean dose of 2 Gy over the irradiated area either with parallel synchrotron-generated X-ray beams at the ESRF or with 20 MeV protons at SNAKE using four different irradiation modes: homogeneous field, parallel lines and microchannel applications using two different channel sizes. Normal tissue viability as determined in an MTT test was significantly higher after proton or X-ray microchannel irradiation compared to a homogeneous field irradiation. In line with these findings genetic damage, as determined by the measurement of micronuclei in keratinocytes, was significantly reduced after proton or X-ray microchannel compared to a homogeneous field irradiation. Our data show that skin irradiation using either X-ray or proton microchannels maintain a higher cell viability and DNA integrity compared to a homogeneous irradiation, and thus might improve normal tissue protection after radiation therapy.

International audience; BACKGROUND AND PURPOSE: To quantify the late dose-related responses of the rat cervical spinal cord to X-ray irradiations by an array of microbeams or by a single millimeter beam. MATERIALS AND METHODS: Necks of anesthetized rats were irradiated transversely by an 11 mm wide array of 52 parallel, 35 μm wide, vertical X-ray microbeams, separated by 210 μm intervals between centers. Comparison was made with rats irradiated with a 1.35 mm wide single beam of similar X-rays. Rats were killed when paresis developed, or up to 383 days post irradiation (dpi). RESULTS: Microbeam peak/valley doses of ≈357/12.7 Gy to 715/25.4 Gy to an 11 mm long segment of the spinal cord, or single beam doses of ≈146-454 Gy to a 1.35 mm long segment caused foreleg paresis and histopathologically verified spinal cord damage; rats exposed to peak/valley doses up to 253/9 Gy were paresis-free at 383 dpi. CONCLUSIONS: Whereas microbeam radiation therapy [MRT] for malignant gliomas implanted in rat brains can be safe, palliative or curative, the high tolerance of normal rat spinal cords to similar microbeam exposures justifies testing MRT for autochthonous malignancies in the central nervous system of larger animals with a view to subsequent clinical applications.

Microbeam Radiation Therapy (MRT) is a radiation treatment technique under development for inoperable brain tumors. MRT is based on the use of a synchrotron generated X-ray beam with an extremely high dose rate ( ~ 20 kGy/sec), striated into an array of X-ray micro-blades. In order to advance to clinical trials, a real-time dosimeter with excellent spatial resolution must be developed for absolute dosimetry. The design of a real-time dosimeter for such a radiation scenario represents a significant challenge due to the high photon flux and vertically striated radiation field, leading to very steep lateral dose gradients. This article analyses the striated radiation field in the context of the requirements for temporal dosimetric measurements and presents the architecture of a new dosimetry system based on the use of silicon detectors and fast data acquisition electronic interface. The combined system demonstrates micrometer spatial resolution and microsecond real time readout with accurate sensitivity and linearity over five orders of magnitude of input signal. The system will therefore be suitable patient treatment plan verification and may also be expanded for in-vivo beam monitoring for patient safety during the treatment.

Microbeam Radiation Therapy (MRT) is an emerging cancer treatment that is currently being developed at the European Synchrotron Radiation Facility (ESRF) in Grenoble, France. This technique uses a highly collimated and fractionated X-ray beam array with extremely high dose rate and very small divergence, to benefit from the dose-volume effect, thus sparing healthy tissue. In case of any beam anomalies and system malfunctions, special safety measures must be installed, such as an emergency safety shutter that requires continuous monitoring of the beam intensity profile. Within the 3DMiMic project, a novel silicon strip detector that can tackle the special features of MRT, such as the extremely high spatial resolution and dose rate, has been developed to be part of the safety shutter system. The first prototypes have been successfully fabricated, and experiments aimed to demonstrate their suitability for this unique application have been performed. Design, fabrication and the experimental results as well as any identified inadequacies for future optimisation are reported and discussed in this paper., 23 pages, 16 figures

Purpose To explore the effects of microbeam radiation (MR) on vascular biology, we used the chick chorioallantoic membrane (CAM) model of an almost pure vascular system with immature vessels (lacking periendothelial coverage) at Day 8 and mature vessels (with coverage) at Day 12 of development. Methods and Materials CAMs were irradiated with microplanar beams (width, ∼25 μm; interbeam spacing, ∼200 μm) at entrance doses of 200 or 300 Gy and, for comparison, with a broad beam (seamless radiation [SLR]), with entrance doses of 5 to 40 Gy. Results In vivo monitoring of Day-8 CAM vasculature 6 h after 200 Gy MR revealed a near total destruction of the immature capillary plexus. Conversely, 200 Gy MR barely affected Day-12 CAM mature microvasculature. Morphological evaluation of Day-12 CAMs after the dose was increased to 300 Gy revealed opened interendothelial junctions, which could explain the transient mesenchymal edema immediately after irradiation. Electron micrographs revealed cytoplasmic vacuolization of endothelial cells in the beam path, with disrupted luminal surfaces; often the lumen was engorged with erythrocytes and leukocytes. After 30 min, the capillary plexus adopted a striated metronomic pattern, with alternating destroyed and intact zones, corresponding to the beam and the interbeam paths within the array. SLR at a dose of 10 Gy caused growth retardation, resulting in a remarkable reduction in the vascular endpoint density 24 h postirradiation. A dose of 40 Gy damaged the entire CAM vasculature. Conclusions The effects of MR are mediated by capillary damage, with tissue injury caused by insufficient blood supply. Vascular toxicity and physiological effects of MR depend on the stage of capillary maturation and appear in the first 15 to 60 min after irradiation. Conversely, the effects of SLR, due to the arrest of cell proliferation, persist for a longer time.

International audience; Microbeam radiation therapy (MRT) uses highly collimated, quasi-parallel arrays of X-ray microbeams of 50-600keV, produced by third generation synchrotron sources, such as the European Synchrotron Radiation Facility (ESRF), in France. The main advantages of highly brilliant synchrotron sources are an extremely high dose rate and very small beam divergence. High dose rates are necessary to deliver therapeutic doses in microscopic volumes, to avoid spreading of the microbeams by cardiosynchronous movement of the tissues. The minimal beam divergence results in the advantage of steeper dose gradients delivered to a tumor target, thus achieving a higher dose deposition in the target volume in fractions of seconds, with a sharper penumbra than that produced in conventional radiotherapy. MRT research over the past 20 years has yielded many results from preclinical trials based on different animal models, including mice, rats, piglets and rabbits. Typically, MRT uses arrays of narrow ( approximately 25-100 microm wide) microplanar beams separated by wider (100-400 microm centre-to-centre) microplanar spaces. The height of these microbeams typically varies from 1 to 100 mm, depending on the target and the desired preselected field size to be irradiated. Peak entrance doses of several hundreds of Gy are surprisingly well tolerated by normal tissues, up to approximately 2 yr after irradiation, and at the same time show a preferential damage of malignant tumor tissues; these effects of MRT have now been extensively studied over nearly two decades. More recently, some biological in vivo effects of synchrotron X-ray beams in the millimeter range (0.68-0.95 mm, centre-to-centre distances 1.2-4 mm), which may differ to some extent from those of microscopic beams, have been followed up to approximately 7 months after irradiation. Comparisons between broad-beam irradiation and MRT indicate a higher tumor control for the same sparing of normal tissue in the latter, even if a substantial fraction of tumor cells are not receiving a radiotoxic level of radiation. The hypothesis of a selective radiovulnerability of the tumor vasculature versus normal blood vessels by MRT, and of the cellular and molecular mechanisms involved remains under investigation. The paper highlights the history of MRT including salient biological findings after microbeam irradiation with emphasis on the vascular components and the tolerance of the central nervous system. Details on experimental and theoretical dosimetry of microbeams, core issues and possible therapeutic applications of MRT are presented.

Purpose The aim of this study is to explore the effects of Microbeam Radiation (MR) on vascular biology using the chick chorio-allantoic membrane (CAM). Methods CAMs were irradiated with multiple planar synchrotron X-ray beams at doses between 100 and 300 Gy and were evaluated morphologically and in vivo at days 8 and 12. Results In vivo monitoring and morphological investigations of day 8 CAM immature vasculature 6 hr after MR revealed a near total destruction of the capillary plexus within the beams’ width. Surprisingly, arteries and veins were not affected. Conversely, at day 12, only well defined lesions in the microvasculature (mature ones, covered by pericytes) were observed. After 300 Gy MR, TEM revealed enlargement of the interendothelial cell junctions which could explain the oedema, the microvessels along the beam path showed signs of disruption and apoptosis. The remaining vasculature recovered rapidly and CAM regained its normal thickness. Between 1 hr and 6 hr no additional morphological changes were observed. Conclusions The effects of MR are most likely mediated by capillary damage. The vascular toxicity of MR depends on the stage of capillary maturation: the immature vessels are much more vulnerable than the mature ones. The physiological effects of MR appear within a short time, the most important structural alterations being present between 15 and 60 minutes after irradiation.

In radiation cancer therapy, the aim is to destroy the tumour cells in the treated area while minimizing damage to the surrounding normal tissue. Synchrotron microbeam radiation therapy offers considerable promise in this respect, based on knowledge that normal tissue can tolerate high doses of radiation over small volumes. At the ESRF microbeam radiation therapy facility, one of the several aspects being investigated is measurement of very high dose gradients (changing by hundreds of Gy over ∼10 μm), as there is no established physical dosimetric system simultaneously providing accurate measurements of the doses in the microbeam peaks and valleys. Monte Carlo simulations have been obtained but these have yet to be validated by measurements. One possible means of obtaining micro dosimetric evaluations is use of the thermoluminescence (TL) produced by optical fibres. Previous studies at conventional electron linac radiotherapy facilities have shown that germanium-doped silica fibres offer useful sensitivity to radiotherapy doses it is being further established that commercially produced Ge-doped optical fibres can provide a TL-yield reproducibility of better than 4% (1 SD). Present experiments have investigated the thermoluminescence response of such fibres at incident energies of several tens of keV, for a wide range of doses, from 1 Gy to 10 kGy, revealing a linear correlation of r2≥0.998 up to a dose of 2 kGy, encompassing the dosimetric needs of both conventional and synchrotron microbeam radiotherapy.

During the past decade microbeam radiation therapy has evolved from preclinical studies to a stage in which clinical trials can be planned, using spatially fractionated, highly collimated and high intensity beams like those generated at the x-ray ID17 beamline of the European Synchrotron Radiation Facility. The production of such microbeams typically between 25 and 100 microm full width at half maximum (FWHM) values and 100-400 microm center-to-center (c-t-c) spacings requires a multislit collimator either with fixed or adjustable microbeam width. The mechanical regularity of such devices is the most important property required to produce an array of identical microbeams. That ensures treatment reproducibility and reliable use of Monte Carlo-based treatment planning systems. New high precision wire cutting techniques allow the fabrication of these collimators made of tungsten carbide. We present a variable slit width collimator as well as a single slit device with a fixed setting of 50 microm FWHM and 400 microm c-t-c, both able to cover irradiation fields of 50 mm width, deemed to meet clinical requirements. Important improvements have reduced the standard deviation of 5.5 microm to less than 1 microm for a nominal FWHM value of 25 microm. The specifications of both devices, the methods used to measure these characteristics, and the results are presented.

International audience; The aim of this work focuses on the description of the short-term response of a 9L brain tumor model and its vasculature to microbeam radiation therapy (MRT) using magnetic resonance imaging (MRI). Rat 9L gliosarcomas implanted in nude mice brains were irradiated by MRT 13 days after tumor inoculation using two orthogonal arrays of equally spaced 28 planar microbeams (25 microm width, 211 microm spacing and dose 500 Gy). At 1, 7 and 14 days after MRT, apparent diffusion coefficient, blood volume and vessel size index were mapped by MRI. Mean survival time after tumor inoculation increased significantly between MRT-treated and untreated groups (23 and 28 days respectively, log-rank test, p < 0.0001). A significant increase of apparent diffusion coefficient was observed 24 h after MRT in irradiated tumors versus non-irradiated ones. In the untreated group, both tumor size and vessel size index increased significantly (from 7.6 +/- 2.2 to 19.2 +/- 4.0 mm(2) and +23%, respectively) between the 14th and the 21st day after tumor cell inoculation. During the same period, in the MRT-treated group, no difference in tumor size was observed. The vessel size index measured in the MRT-treated group increased significantly (+26%) between 14 and 28 days of tumor growth. We did not observe the significant difference in blood volume between the MRT-treated and untreated groups. MRT slows 9L tumor growth in a mouse brain but MRI results suggest that the increase in survival time after our MRT approach may be rather due to a cytoreduction than to early direct effects of ionizing radiation on tumor vessels. These results suggest that MRT parameters need to be optimized to further damage tumor vessels.

International audience; Cerebral edema is one of the main acute complications arising after irradiation of brain tumors. Microbeam radiation therapy (MRT), an innovative experimental radiotherapy technique using spatially fractionated synchrotron x-rays, has been shown to spare radiosensitive tissues such as mammal brains. The aim of this study was to determine if cerebral edema occurs after MRT using diffusion-weighted MRI and microgravimetry. Prone Swiss nude mice's heads were positioned horizontally in the synchrotron x-ray beam and the upper part of the left hemisphere was irradiated in the antero-posterior direction by an array of 18 planar microbeams (25 mm wide, on-center spacing 211 mm, height 4 mm, entrance dose 312 Gy or 1000 Gy). An apparent diffusion coefficient (ADC) was measured at 7 T 1, 7, 14, 21 and 28 days after irradiation. Eventually, the cerebral water content (CWC) was determined by microgravimetry. The ADC and CWC in the irradiated (312 Gy or 1000 Gy) and in the contralateral non-irradiated hemispheres were not significantly different at all measurement times, with two exceptions: (1) a 9% ADC decrease (p < 0.05) was observed in the irradiated cortex 1 day after exposure to 312 Gy, (2) a 0.7% increase (p < 0.05) in the CWC was measured in the irradiated hemispheres 1 day after exposure to 1000 Gy. The results demonstrate the presence of a minor and transient cellular edema (ADC decrease) at 1 day after a 312 Gy exposure, without a significant CWC increase. One day after a 1000 Gy exposure, the CWC increased, while the ADC remained unchanged and may reflect the simultaneous presence of cellular and vasogenic edema. Both types of edema disappear within a week after microbeam exposure which may confirm the normal tissue sparing effect of MRT.