Printed in: Nucl. Instr. & Meth A454 (2000) pp. 26-39 Advances in gas avalanche radiation detectors for biomedical applications夽 A. Breskin* Department of Particle Physics, The Weizmann Institute of Science, 76100 Rehovot, Israel Abstract Gas avalanche detectors are instruments of choice for radiation detection and localization in numerous "elds of basic and applied research. Recent advances in detection techniques, involving multiplication and detection of single or a few charges deposited in gas media, or emitted from solid converters into gas, are described. The properties of radiation converters and associated advanced gas multipliers are discussed, with an accent on the recently introduced gas avalanche imaging photomultipliers. Applications in the "elds of radiation damage studies to DNA, digital mammography and early detection of cancer tumors are presented. 1. Introduction Gas avalanche radiation detectors have been massively employed over the past decades, mostly in particle physics. The `modern eraa in this "eld started in the late 1960 s, with the introduction by Charpak of Multiwire Proportional Chambers often named `Wire Chambersa [1]. For the "rst time, it was made possible to localize charged particles, X-ray photons and thermal neutrons with submillimeter accuracies, over detection areas exceeding a square meter and at very high repetition rates. This has revolutionized many "elds of science, particularly particle physics. Modern High-Energy 夽 Invited talk at SAMBA, Symposium on Applications of Radiation Detectors in Medicine, Biology and Astrophysics. Siegen, Germany, October 6}8, 1999. * Corresponding author. Tel.: #972-8-934-2645; fax: #9728-934-2611. E-mail address: fnbresk@wisemail.weizmann.ac.il (A. Breskin). -1- Physics Experiments massively employ such detectors, which have contributed to numerous important discoveries. The "rst attempts of employing Wire Chambers for digital medical radiography were made by Perez Mendez already in the early seventies [2]. Ever since, gas avalanche radiation detectors, either Wire Chambers [3] or more recent advanced Micro-pattern Detectors [4,5], have been widely employed in biology and medicine, as will be bie#y summarized below. Though there exist numerous other detection techniques, comprising scintillators, scintillating "bers, a variety of solid-state devices and others, gas avalanche detectors persist and improve impressively, due to some important inherent properties: E large sensitive area and #exible geometries, E relatively simple and economic manufacture, E variety of real-time readout techniques: charge integration or pulse counting, E E E E E high multiplication factors: 10}10, sensitivity: down to a single electron, localization accuracy: down to 30 lm, time resolution: down to 100 ps, counting rates: up to the MHz/mm scale. On the other hand, gaseous detectors have usually poor energy resolution due to relatively low primary ionization statistics and #uctuations in the avalanche process, low detection e$ciency for energetic X-ray or gamma photons, they often age under long-term operation at high radiation #ux and su!er some gain limitations in such conditions. Gaseous detectors are mostly custom-made, are rarely sealed and therefore generally require gas circulation systems and often well-trained operators. In medical diagnostics, gaseous detectors are currently employed in digital X-ray radiography [6] and angiography [7]. In X-ray radiography, large-volume xenon-"lled detectors, with wires oriented towards a narrow fanned beam, have shown to successfully compete with traditional "lm-screen imagers. These line-scanning devices, operating in photon-counting or current-integration modes, permit a considerable reduction of the radiation dose to patients [8]. In digital intravenous coronary angiography, patients are scanned simultaneously at two monochromatic X-ray energies with a high-pressure ionization chamber. The photon energies are chosen above and below the K-edge of iodine contrast agent. Logarithmic subtraction of the two data sets provides high-quality angiographic images with a high dynamic range [9]. High-pressure gas ionization chambers have been also investigated, such as X-ray sensors in Computerized Tomography (CT). Having rather limited sensitivity to energetic gamma photons, methods were found to couple position-sensitive gas avalanche detectors to solid converters. This is the case in gamma cameras, equipped with thick metal-grid converter [10]. Such devices were routinely applied for medical inspection and more recently, in a Positron Emission Tomography (PET) mode, for high-resolution 3D small-animal imaging [11]. Small-animal PET cameras were also developed, where UV-photons from BaF crystals -2- are detected in wire chambers operated with a photosensitive (TMAE) gas [12]. Current e!orts to develop large-area gas avalanche photomultipliers [13], to cope with Gamma scintillators, will be discussed in this work. In the last decades there has been considerable R&D activity in real-time 2D imaging detectors for X-ray di!raction, particularly due to newly installed intense synchrotron radiation facilities [14]. Large-area gas avalanche detectors, capable of providing di!raction images of complex organic molecules (e.g. in protein crystallography) in a few seconds are currently operational [15,16] or under advanced development stages [17]. Also here, wire chambers [15,16,18] are being replaced by wire-less detectors like the micro-CAT chamber , consisting of "ne-grid multiplication element followed by avalanche localization with an advanced 2D resistive readout system [17]. Many other potential multipliers will be reviewed. New, secondary electron emission (SEE) soft X-ray imaging detectors with high localization resolution and ns time response, will be described below [19]. Similarly. SEE detectors. combining novel composite thermal-neutron coverters with advanced gaseous multipliers [20], could be advantageously employed in neutron di!raction experiments in the "eld of biology, in future intense spallation sources. Gas avalanche imagers are currently employed in autoradiography [21,22], for real-time analysis of beta-labeled biomedical samples or electrophoretic gels. Some of the techniques permit to resolve details in tissue sections traced with lowenergy electron emitters, at the 30 lm level [21] (Fig. 1). There are numerous other applications of gaseous detecors in biomedicine, e.g. in beam monitoring in radiotherapy [23], in various "elds of radiation dosimetry, etc. New applications in nanodosimetry [24] will be discussed below. 2. Wireless electron multipliers The electron multiplier has the important role of converting the radiation-induced charges within the detector volume, into detectable signals. It is expected, in most cases, to provide high charge gain and the fastest possible response, to cope with Fig. 1. Autoradiographic images of Tc-labeled anatomic section (20 lm thick) of rabbit's kidney. The emitted low-energy electrons were measured with (a) a high-resolution (30 lm) gasavalanche (Beta Imager 2000 of Biospace Mesures, France) and (b) an autoradiographic "lm [21]. Courtesy of N. Barthe. operation under very large radiation #ux (repetition rates) and to allow for the accurate determination of the radiation impact location. As mentioned above, the current tendency in the "eld of gaseous detectors is replacing wire chambers by advanced micro-pattern electron multipliers, o!ering an order of magnitude improvement in spatial accuracy and counting-rate capability. Such multipliers consist, on one hand, of miniature anode and cathode strips or other electrode patterns deposited by micro-lithographic techniques on insulating substrates. In this family, one may recall Microstrip Gas Chambers (MSGC) [25], Micro-Gap Chambers (MGC) [26], Micro-Dot Chambers (MDOT [27,28]) and other variants of these techniques (reviewed in Refs. [4,5,29]). Due to the small anode-to-cathode distances, typically 50}200 lm, these multipliers o!er inherently good -3- localization accuracy, of a few tens of microns. Moreover, the rapid avalanche-ion collection by the near-by cathode patterns considerably reduces space charge buildup, responsible for counting-rate limitations typically observed in wire chambers. However, gain limitations and long-term instabilities often appear in these devices, due to the insulating nature of the substrates, gas pollution and to micro-discharges, which damage the electrode patterns [29]. Passivating the electrode edges and other technical improvements in electrode production can solve the latter. An interesting but more complex solution is the Microgap wire chamber, having anode wires located, through thin insulator, on top of narrow cathode strips [30]. Except for the MSGC and the recently introduced Small-Gap chamber [31], all other multipliers in this family provide 2D localization in a single-detector element. The MDOT device; produced in silicon technology, is a true pixelized device; due to the symmetric `circulara pixel geometry, it o!ers good stability at very high gain [27,28]. More robust electron multipliers are the MICROMEGAS [32], Micro-CAT [17], MicroGroove (MGD) [33] and GEM [34]. The MICROMEGAS, developed at Saclay, is a thin gap (50}100 lm) parallel-plate device, in which radiation-induced electrons drifting through a very thin dense mesh are multiplied; signals are collected on a strip anode. The micro-CAT is an expanded form of the CAT (`compteur a trousa) [35], in which electrons drifting from a conversion volume are multiplied within a hole in a metallic foil with an anode at the bottom. The Siegen University Detector Group has demonstrated that the microCAT, equipped with an interesting pixelized 2Dresistive anode readout, has good potential for X-ray di!raction and radiography applications (see Fig. 2) [36]. The Micro-Groove, proposed by the Pisa Group, could also be considered as a further derivative of the CAT. Here, electrons are multiplied within thin grooves in a metallized kapton foil, having anode strips running in an orthogonal direction at the bottom of the grooves (other face of the same foil). Recording the signals from the top and bottom strips [33] provides a 2D sensitivity. One of the most interesting developments in gas avalanche detectors is no doubt the Gas Electron and increased lifetime. It could be of a particular advantage as a preamplifying element in front of another micro-pattern multiplier like a MSGC [41]. It has been demonstrated that high-resolution X-ray imaging could be performed with a cascade of two GEM elements, coupled to a 2D readout board, as shown in Fig. 3 [42]. Stable operation at Fig. 2. An example of a 2D-di!raction pattern from a DSPC lipid sample, recorded with the Micro-CAT X-ray-imaging detector of the University of Siegen. The observed pattern is due to small individual resistive anode pads, providing an interpolating position encoding at high counting rates [17,36]. Multiplier (GEM), proposed by Sauli [34]. It consists of a thin insulating foil (usually 50 lm thick kapton), metal-clad on both sides, perforated by a regular dense matrix of holes (typically 50}80 lm in diameter, 100}200 lm apart). Upon the application of a potential across the foil (typically 400}500 V), a high dipole "eld develops within the holes. Radiation-induced electrons are focussed into the holes, where multiplication occurs under the very high electric "eld. A large fraction of the multiplied charge is transferred either to a collection electrode or to an additional electron multiplier. Multiplication factors reaching 10 are attainable with a single GEM element, as well as high-rate capability and good localization accuracy [37,38]; long-term stability under high radiation #ux has been recently demonstrated [39]. Compared to the other multipliers discussed above, the GEM has the unique advantage of being able to act as a preampli"er, namely to preamplify the primary ionization electrons and to transfer them to a further multiplier. This idea of a multi-step avalanche multiplier [40], permits reducing the gain of each multiplication element, resulting in higher stability -4- Fig. 3. A schematic view of a double-GEM X-ray-imaging detector equipped with a 2D readout board. Photography of a bat's claw and its X-ray radiographic image, taken at 8 keV, are shown. The localization resolution is of the order of 0.1 mm [42]. gains above 10 was reached in this con"guration. We will discuss below gas avalanche photomultipliers based on multi-GEM structure [43]. All gas avalanche multipliers discussed above can operate over a broad pressure range, from several atmospheres down to a few Torrs. The latter has been demonstrated in MSGC [44], MDOT [45] and GEM [46] multipliers. The lowpressure operation is usually characterized by very fast response, high-rate capability and high gains; the latter permits ultimate sensitivity down to single electrons. Factors governing the gain limitations of micro-pattern detectors are reviewed in Refs. [47,48]. 3. New applications in dosimetry Gaseous detectors, operating in both ionization and proportional modes, have been employed for many decades for radiation dosimetry. Their usual role has been in assessing radiation e!ects to the living tissue, by mesuring radiation-induced energy deposits in expanded tissue-equivalent gas models. Such measurements have strong relevance to radioprotection and radiotherapy. While current dosimetric techniques are limited to measuring global or integral radiation e!ects, contemporary radiobiological concepts advocate the di!erential measurements. Indeed, because of the highly #uctuating stochastic nature of the energy deposits, it is important to measure not only the deposited energy by an event, within a given tissue-equivalent volume, but also the spatial distribution of the ionization pattern. Most signi"cant damage occurs at the sub-cell level, more precisely to the DNA molecules [49]. It is currently established that irreversible radiation damage to a living cell occurs when its DNA is considerably upset. This occurs when a signi"cant energy quantum is deposited within a small DNA segment, typically 30 bases long, causing multiple breaks in both DNA strands [50]. In such events the cellular repair mechanism fails to correctly repair the damage, which results in cell mutations or death. While ionization deposits at the cell nucleus scale (10 lm), or at the chromosome level (1 lm) can be studied with `microdosimetrica tools like -5- tissue-equivalent proportional counters (TEPC), the sub-micron scale, namely that of the chromatin "ber (25 nm) and, moreover, the DNA molecule (2 nm) require new `nanodosimetrica approaches. The evaluation of the lethality of a given radiation "eld depends indeed on the precise knowledge of the energy-loss distribution within the relevant (2 nm in diameter, 10}20 nm long) DNA segment [50]. Miniature TEPCs operating at very low gas pressures [51] could in principle reach sensitivities at the 5 nm scale, but they su!er from unwanted radiation interactions with the cell walls. A few other nanodosimeter techniques, capable of reliably assessing single ionization events, are currently being developed; they cover the sensitivity range from the chromosome down to the sub-DNA scale. One technique consists of recording the "ne structure of ionization patterns induced by particle tracks traversing the low-pressure (10}40 Torr) gas volume of a Time Projection Chamber (TPC). The ionization electrons deposited along each track are collected and multiplied, inducing avalanches, of which the emitted light is recorded with an intensi"ed CCD camera and a set of photomultipliers [52]. This technique permits recording ionization patterns induced by charged particles, photons and neutrons, in a few lm-size tissue-equivalent sensitive volumes, with a resolution of a few tens of nanometers. The local deposited energy is proportional to the light inensity recorded by the CCD camera, as shown in Fig. 4. The bright spots, like those seen at the end point of a stopping deltaelectron, correspond to large local ionization clusters, which are indeed those of high-potential lethality to DNA. The `optical TPCa is not sensitive to sinlge ionization charges, but rather to clusters of several charges. Its resolution is limited by electron di!usion, a!ecting both the ionization pattern structure and the avalanche-induced `lightspota size. Single-charge sensitivity, of prime importane for low-ionization pattern investigations, cannot be reached with detectors based on charge integration mode. The pulse-height resolution of such `proportionala detectors is seriously a!ected by the statistical #uctuations in the avalanche growth, which makes the di!erentiation of a single-electron event Fig. 4. Images of ionizing particle track patterns recorded in an optical avalanche microdosimeter, on a tissue-equivalent scale shown in the "gure. The 5 MeV protons and 19 MeV alpha particles traverse a gas volume at a pressure of 20 Torr. The potentially lethal to the DNA track spots are that of high local ionization, like the endpoints of the delta-electron trails, clearly observed in the "gure [52]. from that of a few-electron cluster, an impossible task. We have developed a new approach for the differential recording of small radiation-induced energy deposits in gas, based on single-charge counting techniques [53,54]. The idea, derived from early works on relativistic-particle identi"cation by electron-cluster counting techniques [55}57], is illustrated schematically in Fig. 5; it consists of extracting ionization charges, electrons or ions, radiation induced in a small gas-sensitive volume, followed by their individual multiplication and counting. The wall-less sensitive volume is de"ned by the charge extraction e$ciency; its size, which is the most critical element of the nanodosimeter, is a function of the extraction-slit size, the gas type and pressure and the electric "eld geometry. In the single-electron counting nanodosimeter [58], electrons are extracted through a small aperture into an electron multiplier (see Section 2), operating in the same gas pressure. The sensitive volume is strongly a!ected by electron di!usion, which sets a lower-pressure limit of a few Torr; below this pressure, the electron extraction e$ciency diminishes due to a quasi-ballistic electron transport. The electron-counting technique is presently limited to tissue-equivalent sensitive volumes of the order of 20}30 nm [59], namely to the chromatin scale. -6- In the single-ion counting nanodosimeter [24], the ions are more e$ciently extracted into vacuum, with very small di!usion losses. The pressure can be reduced to a fraction of a Torr, leading to possible sub-nanometer tissue-equivalent sensitive volumes. The ions are accelerated into a vacuum-operated secondary-electron multiplier, yielding fast pulse trails. It has been demonstrated that the ion-counting technique provides alpha-particle ion density distribution spectra in a cubic nanometer equivalent gas volume, compatible with those theoretically predicted [60,61]. A nanodosimeter built according to this principle is presently being tested at the Loma Linda proton synchrotron accelerator. It permits attaining biologically relevant sensitive propane volumes on the order of 2 nm in diameter and 25 nm long [62]. Other types of ion nanodosimeters are developed, based on ionization measurements in gas jets [63]. The ion-counting technique, in which ions formed in gas are multiplied in vacuum, has the additional advantage of being able to operate with any gas. The equivalent nanometer resolution in condensed matter could have numerous applications beyond those discussed above. An important example is the study of radiation damage to advanced nanoelectronics, e.g. using silane gas to simulate silicon, etc. It could have important implications in accelerator physics and space science. Fig. 6. The principle of the gas avalanche photomultiplier. A photon-induced electron is emitted from a solid photocathode into the gas. Avalanche multiplication takes place in the electron multiplier, close to an anode of a micropattern device. In this con"guration, most avalanche-induced ions are collected on the neighboring cathodes and some drift to the photocathode. Fig. 5. (a) A schematic view of the nanodosimeter concept: ionization charges (electrons or ions), deposited by the primary radiation in a low-pressure gas volume, are extracted by an electric "eld through a small aperture. The extraction e$ciency de"nes a wall-less sensitive volume. The charges are individually multiplied, deteced and counted: electrons are detected with a gaseous avalanche electron multiplier, providing pulse-trials shown in (b), while ions are detected with a vacuum-operated detector, resulting in similar pulse-trials shown in (c). 4. Gas avalanche imaging photomultipliers Photomultiplier tubes (PMT) are currently and massively used in medical diagnostics instrumentation, for recording light from large scintillator arrays mostly in gamma cameras and CT apparatus. Standard vacuum PMTs are slowly being replaced, in small gamma camera systems, by position-sensitive PMTs [64] or hybrid photodiodes (HPD) [65], of which the cost is rather prohibitive. -7- An alternative and probably more economic solution for light recording from large scintillator or scintillating-"ber arrays would be the use of gas avalanche imaging photomultipliers, combining a thin solid photocathode with a gaseous electron multiplier (Fig. 6). Such photomultipliers, recently reviewed in Ref. [13], have been developed over the last decade, particularly for single UV-photon localization in Ring Imaging Cherenkov (RICH) counters used for relativistic particle identi"cation [66]. These fast photon detectors are gradually replacing the much slower wire chambers "lled with UV-photosensitive `gaseous photocathodesa (TEA, TMAE) [67], also employed for PET in combination with BaF crystals [12]. The quantum e$ciency (QE) spectra of some UVphotocathodes, relatively stable in air, are shown in Fig. 7. CsI photocathodes, reviewed in Ref. [68], are widely employed for RICH, where MWPCbased photon detectors, reaching square meter dimensions, are under construction for future particle physics experiments [66]. The gas avalanche photomultipliers, operating at atmospheric pressure, can be made 10}20 mm thin, Fig. 7. Typical quantum e$ciency spectra (in vacuum) of annealed CsI [68] annealed CsBr [72] and hydrogenated CVD diamond [73] photocathodes, suited for operation under gas multiplication. employing modern gas electron multipliers (see Section 2). They are sensitive to single photons and can operate at photon #ux reaching a MHz/mm. Unlike vacuum PMTs, they can operate at intense magnetic "elds [66]. They are usually equipped with highly pixelized readout electronics, developed for particle physics applications [69]. The CsI photocathode, having its red boundary cuto! around 210 nm (Fig. 7) has very low sensitivity to the fast component of BaF scintillation. It could be employed in combination with other, less e$cient UV-scintillators, e.g. KMgF [70] or with high-pressue or liquid xenon scintillators (peak emission around 170 nm) [71], which has an interesting potential in medical imaging. CsBr [72] and the very robust CVD-diamond [73] "lms are interesting solar-blind photocathodes, provided some e$cient crystals can match their spectral range It is obvious that the most important applications of gas avalanche photomultipliers are in the visible spectral range, in which there is a large variety of scintillating crystals. Unlike UV-photocathodes, those sensitive in the visible range, e.g. the currently employed alkali- or bi-alkali-antimonides, are very reactive to even minute amounts of impurities. Therefore, "rst attempts to operate gaseous photomultipliers with such photocathodes [74,75] were not pursued. -8- Fig. 8. The evolution of the absolute quantum e$ciency of K}Cs}Sb photocathodes exposed to oxygen. Shown are the results at a wavelength of 312 nm, for bare and coated photocathodes (200 and 250 As CsI), as function of the residual oxygen pressure. Each data point represents 5 min of exposure to oxygen followed by quantum e$ciency measurement in vacum [78]. Visible photocathodes could be proected by thin deposited "lm [76]. Only recently, it has been demonstrated that thin alkali}halide "lms (CsI, CsBr) deposited on Cs Sb, and K}Cs}Sb photocathodes e$ciently protect them against exposure to large amounts of oxygen (Fig. 8) [77,78]. The protective "lm prevents the photocathode from having contact with gas impurities, but at the expense of a reduction by about a factor of 6 in QE due to photoelectron losses. Protected K}Cs}Sb photocathodes reach typically QE values of the order of 5% at 350 nm, as shown in Fig. 9; this is a viable QE in many applications. We are currently developing gas avalanche imaging photomultipliers for visible light, equipped with MSGC electron multipliers, for X-ray mammography [79]. They will localize X-ray-induced photons, being directly coupled to an appropriate converter. As discussed in Secton 2 and in Ref. [13], the electron multiplier plays an important role in this type of application, where high sensitivity to single photoelectrons is of prime importance. Our recent developments in this "eld indicate that multi-GEM photomultipliers, in which three GEMs in cascade are coupled to a photocathode (Fig. 10), could provide a solution of choice [43,80]. In such back to the photocathode. This permits, for the "rst time, the operation of gas avalanche proportional detectors at gains exceeding 10 in pure noble-gas mixtures [43,80] (Fig. 11). This is an important fact that could pave the way towards the operation of gas avalanche photomultipliers with non-protected visible photocathodes. E!orts are presently being directed at the development of other novel gas-stable photocathodes, with an extended spectral range. 5. X-ray and thermal neutron secondary electron emission detectors Fig. 9. Typical absolute quantum e$ciency spectra of K}Cs}Sb photocathodes, bare and coated with 300 As thick CsBr and 250 As thick CsI "lms [78]. Fig. 10. The multi-GEM photomultiplier concept: 3 GEMs in cascade are coupled to a photocathode. Each GEM operates at a low gain, resulting in a high total gain. The avalanche-induced pulses are recorded on a printed-circuit board, arranged to provide 2D localization. devices, the GEM elements e$ciently screen the photocathode from avalanche-induced photonfeedback e!ects and in addition reduce ion feed- -9- An important research tool in structural biology is X-ray and neutron scattering from complex molecules. High-luminosity Synchrotron Radiation Facilities and intense neutron Spallation Sources require advanced real-time imaging detectors capable of coping with the high radiation #ux. Modern applications, involving dynamic studies of rapidly evolving processes, are requesting very fast ((100 ns) detector response. Though a variety of detectors based on radiation conversion and multiplication in gas, are successfully operating and others being under advanced developments, their time resolution, localization accuracy and rate capability are often limited due to phenomena related to electron transport in gas. The gas conversion gap induces localization parallax errors under angular incidence, often requiring special costly detector geometries [18,81]. Secondary Electron Emission (SEE) detectors [82}84], based on a similar principle to that of gas avalanche photomultipliers discussed above, have been developed for soft X-ray [19] and thermal neutron [20] localization. In such SEE detectors shown in Fig. 12, radiation is converted in a thin foil, producing multiple low-energy (eV) electrons emitted into gas. The secondary electrons initiate multiplication, in a parallel-plate avalanche mode, at their emission location; the electron avalanche is transmitted into a second multiplication stage, where fast timing and 2D-localization is measured. The second multiplier can be a wire-chamber or one of the micro-pattern devices described in Section 2. The radiation converter is selected upon the application. Fig. 11. Gain vs. voltage characteristics of a 3-GEM photomultiplier with a CsI photocathode, in di!erent gas mixtures. For some mixtures having secondary scintillation e!ects in the photocathode-to-GEM gas gap, leading to a larger (but slower) total signal, both `fasta (primary) and `totala (primary plus photon-mediated) gain curves are shown. For details see Ref [43]. The surface conversion, followed by surface emission and multiplication, make the detector indepenent of the radiation incidence angle, leading to high-resolution parallax-free imaging. The fast avalanche process, which follows the surface emission, leads to ns time resolutions. 5.1. X-ray imaging detectors The best-known soft X-ray (E(10 keV) converter is CsI, previously discussed as a UV-photocathode. Compared to other "lms, it has relatively high conversion e$ciency (Z"54) and moreover a large secondary electron escape length, of the order of 20 nm. The latter results in good emission properties, typically of 20}30 secondary electrons per 6 keV photon [83}85]. The converter thickness is selected according to the X-ray energy [19]. The electron escape length limits the e!ective converter thickness, and consequently the conversion e$ciency, unless employed in geometries where radiation impinges the converter under a small grazing angle [19,82]. A SEE detector of 200;200 mm, with delay-line readout, was investigated with Synchrotron Radiation, under high photon #ux [86]. An example of a X-ray scattering pattern from collagen -10- is shown in Fig. 13, recorded at a photon rate approaching a MHz/mm. Such detectors, which can operate at low or atmospheric gas pressures, are rather unique tools for time-resolved studies of fast-evolving phenomena on a ns or even sub-ns time scale. They could play an important role in protein crystallography, where the sample properties evolve under intense irradiation. Their present drawback is the relatively low conversion e$ciency, of the order of 5% at 6 keV under normal incidence [19]. E!orts are being made towards the design of detectors with more e$cient converters. One could think of `columnara CsI converters, in which secondary electrons emitted from `needle likea converters are focussed within the space between the needles into a multiplier [87]. One could also employ multilayer converter}detector systems [88], of which an elegant solution based on a CsI-coated multi-GEM system was recently proposed [89]. 5.2. Neutron imaging detectors Thermal neutrons can be localized by gaseous detectors, via detection of charged particles resulting from their nuclear reaction with gas Fig. 13. An example of a X-ray image recorded with the SEE detector shown in Fig. 12a, representing small-angle scattering from collagen in rat tail. The image was recorded at an intense synchrotron radiation beam at ESRF-Grenoble, duing 20 s, at a rate of 850 kHz [86]. Fig. 12. The operation principle of secondary electron emission (SEE) X-ray and thermal neutron gas avalanche imaging detectors. (a) In the X-ray detector, each photon converted in a thin solid "lm (usually CsI) induces the emission of multiple low-energy (eV) secondary electrons. They start multiplication at their emission location and are further multiplied and localized in a second multiplier (e.g. here a wire chamber). (b) In the neutron detector, nuclear reactions between the incident neutron and a solid converter (here Li) result in charged particle emission (here alpha or H). These emit multiple low-energy secondary electrons when crossing a CsI "lm deposited on the converter surface. Multiplication of these electrons occurs in two steps, like in (a); the second stage here is, e.g. a GEM coupled to a readout board. molecules [90,91] or with solid converters coupled to the multiplier [92]. Details about potential converters and cross-sections are given elsewhere [20]. While gas conversion results in the emission of long-range charged particles, which does not permit an accurate localization, solid converters like Gd or Li immediately followed by an avalanche multiplier, provide better accuracy. This is due to the exponential avalanche development, leading to -11- a higher sensitivity of the multiplier to the ionization electrons deposited by the energetic charged particles in the gas, close to the converter surface [92]. However, the particle emission being isotropic, tracks emitted under large angle (to the normal) still induce image smearing. A more advanced method consists of employing a composite converter, namely, a neutron conversion foil (e.g. Li, Gd, etc.) coated with a secondary electron emitter (e.g. CsI); the converter is coupled to a low-pressure gas avalanche multiplier [20]. A neutron absorbed in the converter emits an energetic charged particle (electron, alpha, triton, etc.) which emits a cloud of eV secondary electrons upon crossing the CsI layer. These secondary electrons initiate a multiplication process at the location of the charged particle emission from the converter. Due to the relatively low ionization induced by this particle in the low-pressure gas (10}20 Torr) and to the exponential nature of the avalanche process, the detector has very low sensitivity to the charged particles themselves. It therefore provides good localization (Fig. 14), independent of the neutron incidence angle or that of the emitted particle. Similarly to the SEE X-ray detectors, the avalanche following surface emission results in intrinsic time resolution in the ns range. Detectors with CsI-coated natural Gd and Li foils, optimized in thickness, provided localization resolution of the order of 0.4 mm (FWHM) [20]. Calculations indicate an average SEE yield of 60 Fig. 14. Comparative radiographic images of a small (25 mm in diameter) metal ball bearing, made with thermal neutrons (lambda 0.2 mm) with: (a) a photographic "lm preceded by a Li/ZnS converter; (b) an SEE detector equipped with a Li/CsI converter The images indicate clearly the presence (top) or the absence (bottom) of grease in the bearing [83,84]. are proposed, with high sensitivities, down to a single charge: an electron or an ion induced by radiation in gas or solid media. Such fast, real-time imaging detectors, equipped with advanced micropattern electron multipliers, can e$ciently detect light emitted from scintillator arrays, localize Xrays and neutrons scattered from large complex molecules or traversing objects under radiographic conditions, to help assessing radiation damage to the living cell, to monitor radiation, etc. The steady progress in detector science is strongly motivated by the variety of interesting problems and advanced applications. Some of them, like for example the detection of cancerous tumors at the early stages of their formation are very di$cult ones and require, in addition to precise detectors, better or multiple imaging modalities. Presently, the detection threshold for small tumors, at maximal permissible radiation doses, is de"ned not only by the detector's performance but also mainly by the di!erence in X-ray attenuation secondary electrons per neutron-induced triton crossing the CsI "lm; the SEE yield from coated Gd is about 10 folds lower. Multipliers placed on both sides of Li and Gd converters coated with CsI emitters, are expected of providing respective detection e$ciencies of the order of 30% and 45% for 0.25 nm wavelength neutrons [20,93]. The complex technique of preparing Li converters has been recently mastered [94], paving the way towards the construction of fast, large-area thermal neutron imaging detectors. Such devices, equipped with advanced micro-pattern multipliers, are projected by us and by others [95] for neutron scattering experiments and radiography. 6. Concluding remarks Gas avalanche detecors, conceived and heavily employed in particle physics, have numerous applications in life sciences. New detection concepts -12- Fig. 15. Film-screen radiography of a Pt}CMdex}Z treated mouse (top) and of a normal mouse (bottom). The liver of the treated mouse, loaded with about 80 ppm of Pt, is clearly delineated and its border is easily outlined, while that of the normal mouse is indistinguishable from the gastrointestinal system. Note the darker area of the bladder, due to partial clearance of the contrast agent [97]. between malignant and normal tissue, which is very small. A possible solution would consist of increasing the detection contrast by modifying the tumor characteristics prior to mammography or radiography, making it more `opaquea to X-ray radiation [96]. 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