Advances in gas avalanche radiation detectors for biomedicalapplicationsq

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 basicand applied research. Recent advances in detection techniques, involving multiplication and detection of single or a fewcharges deposited in gas media, or emitted from solid converters into gas, are described. The properties of radiationconverters and associated advanced gas multipliers are discussed, with an accent on the recently introduced gasavalanche imaging photomultipliers. Applications in the "elds of radiation damage studies to DNA, digital mammogra-phy and early detection of cancer tumors are presented.

1. Introduction

Gas avalanche radiation detectors have beenmassively employed over the past decades, mostlyin particle physics. The `modern eraa in this "eldstarted in the late 1960 s, with the introduction byCharpak of Multiwire Proportional Chambers of-ten named `Wire Chambersa [1]. For the "rst time,it was made possible to localize charged particles,X-ray photons and thermal neutrons with sub-millimeter accuracies, over detection areas exceed-ing a square meter and at very high repetition rates.This has revolutionized many "elds of science,particularly particle physics. Modern High-Energy

qInvited talk at SAMBA, Symposium on Applications ofRadiation Detectors in Medicine, Biology and Astrophysics.Siegen, Germany, October 6}8, 1999.

*Corresponding author. Tel.: #972-8-934-2645; fax: #972-8-934-2611.

E-mail address: fnbresk@wisemail.weizmann.ac.il (A.Breskin).

Physics Experiments massively employ suchdetectors, which have contributed to numerousimportant discoveries.

The "rst attempts of employing Wire Chambersfor digital medical radiography were made byPerez Mendez already in the early seventies [2].Ever since, gas avalanche radiation detectors, eitherWire Chambers [3] or more recent advancedMicro-pattern Detectors [4,5], have been widelyemployed in biology and medicine, as will be bie#ysummarized below.

Though there exist numerous other detectiontechniques, comprising scintillators, scintillating"bers, a variety of solid-state devices and others,gas avalanche detectors persist and improveimpressively, due to some important inherentproperties:

f large sensitive area and #exible geometries,f relatively simple and economic manufacture,f variety of real-time readout techniques: charge

integration or pulse counting,

f high multiplication factors: 104}108,f sensitivity: down to a single electron,f localization accuracy: down to 30lm,f time resolution: down to 100 ps,f counting rates: up to the MHz/mm2 scale.

On the other hand, gaseous detectors have usu-ally poor energy resolution due to relatively lowprimary ionization statistics and #uctuations in theavalanche process, low detection e$ciency for ener-getic X-ray or gamma photons, they often age un-der long-term operation at high radiation #ux andsu!er some gain limitations in such conditions.Gaseous detectors are mostly custom-made, arerarely sealed and therefore generally require gascirculation systems and often well-trained oper-ators.

In medical diagnostics, gaseous detectors arecurrently employed in digital X-ray radiography[6] and angiography [7]. In X-ray radiography,large-volume xenon-"lled detectors, with wiresoriented towards a narrow fanned beam, haveshown to successfully compete with traditional"lm-screen imagers. These line-scanning devices,operating in photon-counting or current-integra-tion modes, permit a considerable reduction of theradiation dose to patients [8]. In digital intra-venous coronary angiography, patients are scannedsimultaneously at two monochromatic X-ray ener-gies with a high-pressure ionization chamber. Thephoton energies are chosen above and below theK-edge of iodine contrast agent. Logarithmic sub-traction of the two data sets provides high-qualityangiographic images with a high dynamic range[9].

High-pressure gas ionization chambers havebeen also investigated, such as X-ray sensors inComputerized Tomography (CT). Having ratherlimited sensitivity to energetic gamma photons,methods were found to couple position-sensitivegas avalanche detectors to solid converters. This isthe case in gamma cameras, equipped with thickmetal-grid converter [10]. Such devices wereroutinely applied for medical inspection and morerecently, in a Positron Emission Tomography(PET) mode, for high-resolution 3D small-animalimaging [11]. Small-animal PET cameras were alsodeveloped, where UV-photons from BaF

2crystals

are detected in wire chambers operated witha photosensitive (TMAE) gas [12]. Current e!ortsto develop large-area gas avalanche photomultip-liers [13], to cope with Gamma scintillators, will bediscussed in this work.

In the last decades there has been considerableR&D activity in real-time 2D imaging detectors forX-ray di!raction, particularly due to newly instal-led intense synchrotron radiation facilities [14].Large-area gas avalanche detectors, capable of pro-viding di!raction images of complex organic mol-ecules (e.g. in protein crystallography) in a fewseconds are currently operational [15,16] or underadvanced development stages [17]. Also here, wirechambers [15,16,18] are being replaced by wire-lessdetectors like the micro-CAT chamber , consistingof "ne-grid multiplication element followed by ava-lanche localization with an advanced 2D resistivereadout system [17]. Many other potential multi-pliers will be reviewed. New, secondary electronemission (SEE) soft X-ray imaging detectors withhigh localization resolution and ns time response,will be described below [19]. Similarly. SEE de-tectors. combining novel composite thermal-neu-tron coverters with advanced gaseous multipliers[20], could be advantageously employed in neu-tron di!raction experiments in the "eld of biology,in future intense spallation sources.

Gas avalanche imagers are currently employedin autoradiography [21,22], for real-time analysisof beta-labeled biomedical samples or elec-trophoretic gels. Some of the techniques permit toresolve details in tissue sections traced with low-energy electron emitters, at the 30 lm level [21](Fig. 1). There are numerous other applications ofgaseous detecors in biomedicine, e.g. in beammonitoring in radiotherapy [23], in various "eldsof radiation dosimetry, etc. New applications innanodosimetry [24] will be discussed below.

2. Wireless electron multipliers

The electron multiplier has the important role ofconverting the radiation-induced charges withinthe detector volume, into detectable signals. It isexpected, in most cases, to provide high chargegain and the fastest possible response, to cope with

Fig. 1. Autoradiographic images of 99.Tc-labeled anatomic sec-tion (20lm thick) of rabbit's kidney. The emitted low-energyelectrons were measured with (a) a high-resolution (30lm) gas-avalanche (Beta Imager 2000 of Biospace Mesures, France) and(b) an autoradiographic "lm [21]. Courtesy of N. Barthe.

operation under very large radiation #ux (repeti-tion rates) and to allow for the accurate determina-tion of the radiation impact location.

As mentioned above, the current tendency in the"eld of gaseous detectors is replacing wire cham-bers by advanced micro-pattern electron multi-pliers, o!ering an order of magnitude improvementin spatial accuracy and counting-rate capability.Such multipliers consist, on one hand, of miniatureanode and cathode strips or other electrode pat-terns deposited by micro-lithographic techniqueson insulating substrates. In this family, one mayrecall Microstrip Gas Chambers (MSGC) [25],Micro-Gap Chambers (MGC) [26], Micro-DotChambers (MDOT [27,28]) and other variants ofthese techniques (reviewed in Refs. [4,5,29]). Due tothe small anode-to-cathode distances, typically50}200lm, these multipliers o!er inherently good

localization accuracy, of a few tens of microns.Moreover, the rapid avalanche-ion collection bythe near-by cathode patterns considerably reducesspace charge buildup, responsible for counting-ratelimitations typically observed in wire chambers.However, gain limitations and long-term instabili-ties often appear in these devices, due to the insulat-ing nature of the substrates, gas pollution and tomicro-discharges, which damage the electrode pat-terns [29]. Passivating the electrode edges andother technical improvements in electrode produc-tion can solve the latter. An interesting but morecomplex solution is the Microgap wire chamber,having anode wires located, through thin insulator,on top of narrow cathode strips [30]. Except for theMSGC and the recently introduced Small-Gapchamber [31], all other multipliers in this familyprovide 2D localization in a single-detector ele-ment. The MDOT device; produced in silicontechnology, is a true pixelized device; due to thesymmetric `circulara pixel geometry, it o!ers goodstability at very high gain [27,28].

More robust electron multipliers are the MIC-ROMEGAS [32], Micro-CAT [17], Micro-Groove (MGD) [33] and GEM [34]. The MICRO-MEGAS, developed at Saclay, is a thin gap(50}100lm) parallel-plate device, in which radi-ation-induced electrons drifting through a very thindense mesh are multiplied; signals are collected ona strip anode. The micro-CAT is an expanded formof the CAT (`compteur a trousa) [35], in whichelectrons drifting from a conversion volume aremultiplied within a hole in a metallic foil withan anode at the bottom. The Siegen UniversityDetector Group has demonstrated that the micro-CAT, equipped with an interesting pixelized 2D-resistive anode readout, has good potential forX-ray di!raction and radiography applications (seeFig. 2) [36]. The Micro-Groove, proposed by thePisa Group, could also be considered as a furtherderivative of the CAT. Here, electrons are multi-plied within thin grooves in a metallized kaptonfoil, having anode strips running in an orthogonaldirection at the bottom of the grooves (other face ofthe same foil). Recording the signals from the topand bottom strips [33] provides a 2D sensitivity.

One of the most interesting developments in gasavalanche detectors is no doubt the Gas Electron

Fig. 2. An example of a 2D-di!raction pattern from a DSPClipid sample, recorded with the Micro-CAT X-ray-imaging de-tector of the University of Siegen. The observed pattern is due tosmall individual resistive anode pads, providing an interpolatingposition encoding at high counting rates [17,36].

Fig. 3. A schematic view of a double-GEM X-ray-imaging de-tector equipped with a 2D readout board. Photography of abat's claw and its X-ray radiographic image, taken at 8keV, areshown. The localization resolution is of the order of 0.1mm [42].

Multiplier (GEM), proposed by Sauli [34]. It con-sists of a thin insulating foil (usually 50lm thickkapton), metal-clad on both sides, perforated bya regular dense matrix of holes (typically 50}80lmin diameter, 100}200lm apart). Upon the applica-tion of a potential across the foil (typically400}500V), a high dipole "eld develops within theholes. Radiation-induced electrons are focussedinto the holes, where multiplication occurs underthe very high electric "eld. A large fraction of themultiplied charge is transferred either to a collec-tion electrode or to an additional electron multi-plier. Multiplication factors reaching 104 areattainable with a single GEM element, as well ashigh-rate capability and good localization accuracy[37,38]; long-term stability under high radiation#ux has been recently demonstrated [39]. Com-pared to the other multipliers discussed above, theGEM has the unique advantage of being able to actas a preampli"er, namely to preamplify the primaryionization electrons and to transfer them to a fur-ther multiplier. This idea of a multi-step avalanchemultiplier [40], permits reducing the gain of eachmultiplication element, resulting in higher stability

and increased lifetime. It could be of a particularadvantage as a preamplifying element in front ofanother micro-pattern multiplier like a MSGC[41]. It has been demonstrated that high-resolutionX-ray imaging could be performed with a cascadeof two GEM elements, coupled to a 2D readoutboard, as shown in Fig. 3 [42]. Stable operation at

gains above 105 was reached in this con"guration.We will discuss below gas avalanche photomulti-pliers based on multi-GEM structure [43].

All gas avalanche multipliers discussed abovecan operate over a broad pressure range, fromseveral atmospheres down to a few Torrs. Thelatter has been demonstrated in MSGC [44],MDOT [45] and GEM [46] multipliers. The low-pressure operation is usually characterized by veryfast response, high-rate capability and high gains;the latter permits ultimate sensitivity down tosingle electrons. Factors governing the gain limita-tions of micro-pattern detectors are reviewed inRefs. [47,48].

3. New applications in dosimetry

Gaseous detectors, operating in both ionizationand proportional modes, have been employed formany decades for radiation dosimetry. Their usualrole has been in assessing radiation e!ects to theliving tissue, by mesuring radiation-induced energydeposits in expanded tissue-equivalent gas models.Such measurements have strong relevance toradioprotection and radiotherapy.

While current dosimetric techniques are limitedto measuring global or integral radiation e!ects,contemporary radiobiological concepts advocatethe di!erential measurements. Indeed, because ofthe highly #uctuating stochastic nature of the en-ergy deposits, it is important to measure not onlythe deposited energy by an event, within a giventissue-equivalent volume, but also the spatial distri-bution of the ionization pattern. Most signi"cantdamage occurs at the sub-cell level, more preciselyto the DNA molecules [49]. It is currently estab-lished that irreversible radiation damage to a livingcell occurs when its DNA is considerably upset.This occurs when a signi"cant energy quantum isdeposited within a small DNA segment, typically30 bases long, causing multiple breaks in bothDNA strands [50]. In such events the cellular re-pair mechanism fails to correctly repair the dam-age, which results in cell mutations or death.

While ionization deposits at the cell nucleusscale (10lm), or at the chromosome level (1lm)can be studied with `microdosimetrica tools like

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 knowledgeof the energy-loss distribution within therelevant (2 nm in diameter, 10}20nm long) DNAsegment [50].

Miniature TEPCs operating at very low gaspressures [51] could in principle reach sensitivitiesat the 5 nm scale, but they su!er from unwantedradiation interactions with the cell walls. A fewother nanodosimeter techniques, capable of reli-ably assessing single ionization events, are current-ly being developed; they cover the sensitivity rangefrom the chromosome down to the sub-DNA scale.

One technique consists of recording the "nestructure of ionization patterns induced by particletracks traversing the low-pressure (10}40Torr) gasvolume of a Time Projection Chamber (TPC). Theionization electrons deposited along each track arecollected and multiplied, inducing avalanches, ofwhich the emitted light is recorded with an intensi-"ed CCD camera and a set of photomultipliers[52]. This technique permits recording ionizationpatterns induced by charged particles, photons andneutrons, in a few lm-size tissue-equivalent sensi-tive volumes, with a resolution of a few tens ofnanometers. The local deposited energy is propor-tional to the light inensity recorded by the CCDcamera, as shown in Fig. 4. The bright spots, likethose seen at the end point of a stopping delta-electron, correspond to large local ionization clus-ters, which are indeed those of high-potentiallethality to DNA. The `optical TPCa is not sensi-tive to sinlge ionization charges, but rather to clus-ters of several charges. Its resolution is limited byelectron di!usion, a!ecting both the ionization pat-tern structure and the avalanche-induced `light-spota size.

Single-charge sensitivity, of prime importane forlow-ionization pattern investigations, cannot bereached with detectors based on charge integrationmode. The pulse-height resolution of such `propor-tionala detectors is seriously a!ected by the statist-ical #uctuations in the avalanche growth, whichmakes 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 inthe "gure. The 5 MeV protons and 19 MeV alpha particles traverse a gas volume at a pressure of 20 Torr. The potentially lethal to theDNA 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 impossibletask.

We have developed a new approach for the dif-ferential recording of small radiation-induced en-ergy deposits in gas, based on single-chargecounting techniques [53,54]. The idea, derivedfrom early works on relativistic-particle identi"ca-tion by electron-cluster counting techniques[55}57], is illustrated schematically in Fig. 5; itconsists of extracting ionization charges, electronsor ions, radiation induced in a small gas-sensitivevolume, followed by their individual multiplicationand counting. The wall-less sensitive volume is de-"ned by the charge extraction e$ciency; its size,which is the most critical element of thenanodosimeter, is a function of the extraction-slitsize, the gas type and pressure and the electric "eldgeometry.

In the single-electron counting nanodosimeter[58], electrons are extracted through a small aper-ture into an electron multiplier (see Section 2),operating in the same gas pressure. The sensitivevolume 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$cien-cy diminishes due to a quasi-ballistic electrontransport. The electron-counting technique is pres-ently limited to tissue-equivalent sensitive volumesof the order of 20}30nm [59], namely to thechromatin scale.

In the single-ion counting nanodosimeter [24], theions are more e$ciently extracted into vacuum,with very small di!usion losses. The pressure can bereduced to a fraction of a Torr, leading to possiblesub-nanometer tissue-equivalent sensitive volumes.The ions are accelerated into a vacuum-operatedsecondary-electron multiplier, yielding fast pulsetrails. It has been demonstrated that the ion-count-ing technique provides alpha-particle ion densitydistribution spectra in a cubic nanometer equiva-lent gas volume, compatible with those theoret-ically predicted [60,61]. A nanodosimeter builtaccording to this principle is presently being testedat the Loma Linda proton synchrotron accelerator.It permits attaining biologically relevant sensitivepropane volumes on the order of 2 nm in diameterand 25 nm long [62]. Other types of ion nano-dosimeters are developed, based on ionizationmeasurements in gas jets [63].

The ion-counting technique, in which ionsformed in gas are multiplied in vacuum, hasthe additional advantage of being able to operatewith any gas. The equivalent nanometer resolutionin condensed matter could have numerousapplications beyond those discussed above. Animportant example is the study of radiationdamage to advanced nanoelectronics, e.g. usingsilane gas to simulate silicon, etc. It could haveimportant implications in accelerator physics andspace science.

Fig. 5. (a) A schematic view of the nanodosimeter concept:ionization charges (electrons or ions), deposited by the primaryradiation in a low-pressure gas volume, are extracted by anelectric "eld through a small aperture. The extraction e$ciencyde"nes a wall-less sensitive volume. The charges are individuallymultiplied, deteced and counted: electrons are detected witha gaseous avalanche electron multiplier, providing pulse-trialsshown in (b), while ions are detected with a vacuum-operateddetector, resulting in similar pulse-trials shown in (c).

Fig. 6. The principle of the gas avalanche photomultiplier.A photon-induced electron is emitted from a solid photocathodeinto the gas. Avalanche multiplication takes place in the electronmultiplier, close to an anode of a micropattern device. In thiscon"guration, most avalanche-induced ions are collected on theneighboring cathodes and some drift to the photocathode.

4. Gas avalanche imaging photomultipliers

Photomultiplier tubes (PMT) are currently andmassively used in medical diagnostics instrumenta-tion, for recording light from large scintillator ar-rays mostly in gamma cameras and CT apparatus.Standard vacuum PMTs are slowly being replaced,in small gamma camera systems, by position-sensi-tive PMTs [64] or hybrid photodiodes (HPD) [65],of which the cost is rather prohibitive.

An alternative and probably more economicsolution for light recording from large scintillatoror scintillating-"ber arrays would be the use of gasavalanche imaging photomultipliers, combininga thin solid photocathode with a gaseous electronmultiplier (Fig. 6). Such photomultipliers, recentlyreviewed in Ref. [13], have been developed over thelast decade, particularly for single UV-photon loc-alization in Ring Imaging Cherenkov (RICH)counters used for relativistic particle identi"cation[66]. These fast photon detectors are graduallyreplacing the much slower wire chambers "lledwith UV-photosensitive `gaseous photocathodesa(TEA, TMAE) [67], also employed for PET incombination with BaF

2crystals [12]. The

quantum e$ciency (QE) spectra of some UV-photocathodes, relatively stable in air, are shown inFig. 7. CsI photocathodes, reviewed in Ref. [68],are widely employed for RICH, where MWPC-based photon detectors, reaching square meter di-mensions, are under construction for future particlephysics experiments [66].

The gas avalanche photomultipliers, operating atatmospheric pressure, can be made 10}20mm thin,

Fig. 7. Typical quantum e$ciency spectra (in vacuum) of an-nealed CsI [68] annealed CsBr [72] and hydrogenated CVDdiamond [73] photocathodes, suited for operation under gasmultiplication.

Fig. 8. The evolution of the absolute quantum e$ciency ofK}Cs}Sb photocathodes exposed to oxygen. Shown are theresults at a wavelength of 312 nm, for bare and coated photo-cathodes (200 and 250As CsI), as function of the residual oxygenpressure. Each data point represents 5 min of exposure to oxy-gen followed by quantum e$ciency measurement in vacum [78].

employing modern gas electron multipliers (seeSection 2). They are sensitive to single photons andcan operate at photon #ux reaching a MHz/mm2.Unlike vacuum PMTs, they can operate at intensemagnetic "elds [66]. They are usually equippedwith highly pixelized readout electronics, de-veloped for particle physics applications [69].

The CsI photocathode, having its red boundarycuto! around 210nm (Fig. 7) has very low sensitiv-ity to the fast component of BaF

2scintillation.

It could be employed in combination with other,less e$cient UV-scintillators, e.g. KMgF

3[70] or

with high-pressue or liquid xenon scintillators(peak emission around 170nm) [71], which has aninteresting potential in medical imaging. CsBr [72]and the very robust CVD-diamond [73] "lms areinteresting solar-blind photocathodes, providedsome e$cient crystals can match their spectralrange

It is obvious that the most important applica-tions of gas avalanche photomultipliers are in thevisible spectral range, in which there is a largevariety of scintillating crystals. Unlike UV-photo-cathodes, those sensitive in the visible range, e.g. thecurrently employed alkali- or bi-alkali-antimon-ides, are very reactive to even minute amounts ofimpurities. Therefore, "rst attempts to operate gas-eous photomultipliers with such photocathodes[74,75] were not pursued.

Visible photocathodes could be proected by thindeposited "lm [76]. Only recently, it has been dem-onstrated that thin alkali}halide "lms (CsI, CsBr)deposited on Cs

3Sb, and K}Cs}Sb photocathodes

e$ciently protect them against exposure to largeamounts of oxygen (Fig. 8) [77,78]. The protective"lm prevents the photocathode from having con-tact with gas impurities, but at the expense ofa reduction by about a factor of 6 in QE due tophotoelectron losses. Protected K}Cs}Sb photo-cathodes reach typically QE values of the order of5% at 350 nm, as shown in Fig. 9; this is a viableQE in many applications.

We are currently developing gas avalanche imag-ing photomultipliers for visible light, equipped withMSGC electron multipliers, for X-ray mammogra-phy [79]. They will localize X-ray-inducedphotons, being directly coupled to an appropriateconverter.

As discussed in Secton 2 and in Ref. [13], theelectron multiplier plays an important role in thistype of application, where high sensitivity to singlephotoelectrons is of prime importance. Our recentdevelopments in this "eld indicate that multi-GEMphotomultipliers, in which three GEMs in cascadeare coupled to a photocathode (Fig. 10), couldprovide a solution of choice [43,80]. In such

Fig. 9. Typical absolute quantum e$ciency spectra of K}Cs}Sbphotocathodes, bare and coated with 300As thick CsBr and250As thick CsI "lms [78].

Fig. 10. The multi-GEM photomultiplier concept: 3 GEMs incascade are coupled to a photocathode. Each GEM operates ata low gain, resulting in a high total gain. The avalanche-inducedpulses are recorded on a printed-circuit board, arranged toprovide 2D localization.

devices, the GEM elements e$ciently screen thephotocathode from avalanche-induced photon-feedback e!ects and in addition reduce ion feed-

back to the photocathode. This permits, for the "rsttime, the operation of gas avalanche proportionaldetectors at gains exceeding 105 in pure noble-gasmixtures [43,80] (Fig. 11). This is an important factthat could pave the way towards the operation ofgas avalanche photomultipliers with non-protectedvisible photocathodes. E!orts are presently beingdirected at the development of other novel gas-stablephotocathodes, with an extended spectral range.

5. X-ray and thermal neutron secondary electronemission detectors

An important research tool in structural biologyis X-ray and neutron scattering from complex mol-ecules. High-luminosity Synchrotron RadiationFacilities and intense neutron Spallation Sourcesrequire advanced real-time imaging detectors ca-pable of coping with the high radiation #ux. Mod-ern applications, involving dynamic studies ofrapidly evolving processes, are requesting very fast((100 ns) detector response.

Though a variety of detectors based on radiationconversion and multiplication in gas, are success-fully operating and others being under advanceddevelopments, their time resolution, localizationaccuracy and rate capability are often limited dueto phenomena related to electron transport in gas.The gas conversion gap induces localization para-llax errors under angular incidence, often requiringspecial costly detector geometries [18,81].

Secondary Electron Emission (SEE) detectors[82}84], based on a similar principle to that of gasavalanche photomultipliers discussed above, havebeen developed for soft X-ray [19] and thermalneutron [20] localization. In such SEE detectorsshown in Fig. 12, radiation is converted in a thinfoil, producing multiple low-energy (eV) electronsemitted into gas. The secondary electrons initiatemultiplication, in a parallel-plate avalanche mode,at their emission location; the electron avalanche istransmitted into a second multiplication stage,where fast timing and 2D-localization is measured.The second multiplier can be a wire-chamber orone of the micro-pattern devices described in Sec-tion 2. The radiation converter is selected upon theapplication.

Fig. 11. Gain vs. voltage characteristics of a 3-GEM photomultiplier with a CsI photocathode, in di!erent gas mixtures. For somemixtures 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 surfaceemission and multiplication, make the detector in-depenent of the radiation incidence angle, leadingto high-resolution parallax-free imaging. The fastavalanche process, which follows the surface emis-sion, leads to ns time resolutions.

5.1. X-ray imaging detectors

The best-known soft X-ray (E(10keV) conver-ter is CsI, previously discussed as a UV-photo-cathode. Compared to other "lms, it has relativelyhigh conversion e$ciency (Z"54) and moreovera large secondary electron escape length, of theorder of 20 nm. The latter results in good emissionproperties, typically of 20}30 secondary electronsper 6 keV photon [83}85]. The converter thicknessis selected according to the X-ray energy [19]. Theelectron escape length limits the e!ective converterthickness, and consequently the conversion e$cien-cy, unless employed in geometries where radiationimpinges the converter under a small grazing angle[19,82]. A SEE detector of 200]200mm2, withdelay-line readout, was investigated with Synchro-tron Radiation, under high photon #ux [86]. Anexample of a X-ray scattering pattern from collagen

is shown in Fig. 13, recorded at a photon rateapproaching a MHz/mm2.

Such detectors, which can operate at low oratmospheric gas pressures, are rather unique toolsfor time-resolved studies of fast-evolving phe-nomena on a ns or even sub-ns time scale. Theycould play an important role in protein crystallog-raphy, where the sample properties evolve underintense irradiation. Their present drawback is therelatively low conversion e$ciency, of the order of5% at 6 keV under normal incidence [19]. E!ortsare being made towards the design of detectorswith more e$cient converters. One could think of`columnara CsI converters, in which secondaryelectrons emitted from `needle likea converters arefocussed within the space between the needles intoa multiplier [87]. One could also employ multi-layer converter}detector systems [88], of which anelegant solution based on a CsI-coated multi-GEMsystem was recently proposed [89].

5.2. Neutron imaging detectors

Thermal neutrons can be localized by gaseousdetectors, via detection of charged particlesresulting from their nuclear reaction with gas

Fig. 12. The operation principle of secondary electron emission(SEE) X-ray and thermal neutron gas avalanche imaging de-tectors. (a) In the X-ray detector, each photon converted ina thin solid "lm (usually CsI) induces the emission of multiplelow-energy (eV) secondary electrons. They start multiplicationat their emission location and are further multiplied and localiz-ed in a second multiplier (e.g. here a wire chamber). (b) In theneutron detector, nuclear reactions between the incident neu-tron and a solid converter (here Li) result in charged particleemission (here alpha or 3H). These emit multiple low-energysecondary electrons when crossing a CsI "lm deposited on theconverter surface. Multiplication of these electrons occurs in twosteps, like in (a); the second stage here is, e.g. a GEM coupled toa readout board.

Fig. 13. An example of a X-ray image recorded with the SEEdetector shown in Fig. 12a, representing small-angle scatteringfrom collagen in rat tail. The image was recorded at an intensesynchrotron radiation beam at ESRF-Grenoble, duing 20 s, ata rate of 850 kHz [86].

molecules [90,91] or with solid converters coupledto the multiplier [92]. Details about potential con-verters and cross-sections are given elsewhere [20].While gas conversion results in the emission oflong-range charged particles, which does not per-mit an accurate localization, solid converters likeGd or Li immediately followed by an avalanchemultiplier, provide better accuracy. This is due tothe exponential avalanche development, leading to

a higher sensitivity of the multiplier to the ioniz-ation electrons deposited by the energetic chargedparticles in the gas, close to the converter surface[92]. However, the particle emission being iso-tropic, tracks emitted under large angle (to thenormal) still induce image smearing.

A more advanced method consists of employinga composite converter, namely, a neutron conver-sion foil (e.g. Li, Gd, etc.) coated with a secondaryelectron emitter (e.g. CsI); the converter is coupledto a low-pressure gas avalanche multiplier [20].A neutron absorbed in the converter emits an ener-getic charged particle (electron, alpha, triton, etc.)which emits a cloud of eV secondary electrons uponcrossing the CsI layer. These secondary electronsinitiate a multiplication process at the location ofthe charged particle emission from the converter.Due to the relatively low ionization induced by thisparticle in the low-pressure gas (10}20Torr) and tothe exponential nature of the avalanche process, thedetector has very low sensitivity to the chargedparticles themselves. It therefore provides good loc-alization (Fig. 14), independent of the neutron inci-dence angle or that of the emitted particle. Similarlyto the SEE X-ray detectors, the avalanche followingsurface emission results in intrinsic time resolutionin the ns range.

Detectors with CsI-coated natural Gd and Lifoils, optimized in thickness, provided localizationresolution of the order of 0.4mm (FWHM) [20].Calculations indicate an average SEE yield of 60

Fig. 14. Comparative radiographic images of a small (25mm indiameter) metal ball bearing, made with thermal neutrons(lambda 0.2 mm) with: (a) a photographic "lm preceded bya Li/ZnS converter; (b) an SEE detector equipped with a Li/CsIconverter The images indicate clearly the presence (top) or theabsence (bottom) of grease in the bearing [83,84].

Fig. 15. Film-screen radiography of a Pt}CMdex}Z treatedmouse (top) and of a normal mouse (bottom). The liver of thetreated mouse, loaded with about 80 ppm of Pt, is clearly delin-eated and its border is easily outlined, while that of the normalmouse is indistinguishable from the gastrointestinal system.Note the darker area of the bladder, due to partial clearance ofthe contrast agent [97].

secondary electrons per neutron-induced tritoncrossing the CsI "lm; the SEE yield from coated Gdis about 10 folds lower. Multipliers placed on bothsides of 6Li and 157Gd converters coated with CsIemitters, are expected of providing respective detec-tion e$ciencies of the order of 30% and 45% for0.25nm wavelength neutrons [20,93]. The complextechnique of preparing 6Li converters has beenrecently mastered [94], paving the way towards theconstruction of fast, large-area thermal neutronimaging detectors. Such devices, equipped with ad-vanced micro-pattern multipliers, are projected byus and by others [95] for neutron scattering experi-ments and radiography.

6. Concluding remarks

Gas avalanche detecors, conceived and heavilyemployed in particle physics, have numerous ap-plications in life sciences. New detection concepts

are proposed, with high sensitivities, down toa single charge: an electron or an ion induced byradiation in gas or solid media. Such fast, real-timeimaging detectors, equipped with advanced micro-pattern electron multipliers, can e$ciently detectlight emitted from scintillator arrays, localize X-rays and neutrons scattered from large complexmolecules or traversing objects under radiographicconditions, to help assessing radiation damage tothe living cell, to monitor radiation, etc.

The steady progress in detector science is strong-ly motivated by the variety of interesting problemsand advanced applications. Some of them, like forexample the detection of cancerous tumors at theearly stages of their formation are very di$cultones and require, in addition to precise detectors,better or multiple imaging modalities.

Presently, the detection threshold for small tu-mors, at maximal permissible radiation doses, isde"ned not only by the detector's performance butalso mainly by the di!erence in X-ray attenuation

between malignant and normal tissue, which is verysmall.

A possible solution would consist of increasingthe detection contrast by modifying the tumorcharacteristics prior to mammography or radi-ography, making it more `opaquea to X-rayradiation [96]. This is achieved by targeting asigni"cant amount of an e$cient contrast agentinto the cancerous tumor, in a selective way, similarto that practiced in `speci"c drug-deliverya inchemotherapy. The speci"city of the delivery relieson physiological di!erences between normal andcancerous tissue. This `tumor-speci"cradiographya technique is independent on thedetector type and complementary to detectordevelopment. An example of an enhanced radio-graphic visualization of mouse liver, followingspeci"c delivery of 80 ppm of platinum bound toa targeting polymer, is shown in Fig. 15. E!orts arecurrently made to develop e$cient delivery agentsinto tumors and associated radiographic modalities[97].

Acknowledgements

I would like to thank Dr. Rachel Chechik andGuy Garty for their assistance in preparing thismanuscript.

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