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Nanosecond pulsed proton microbeam
Nuclear Instruments and Methods in Physics Research B 267 (2009) 2008–2012
Contents lists available at ScienceDirect
Nuclear Instruments and Methods in Physics Research B journal homepage: www.elsevier.com/locate/nimb
Nanosecond pulsed proton microbeam G. Dollinger a,*, A. Bergmaier a, V. Hable a, R. Hertenberger b, C. Greubel a, A. Hauptner c, P. Reichart a a b c
Angewandte Physik und Messtechnik LRT2, Universität der Bundeswehr München, 85577 Neubiberg, Germany Sektion Physik, LMU München, 85748 Garching, Germany Physik Department E12, TU-München, 85748 Garching, Germany
a r t i c l e
i n f o
Available online 11 March 2009 PACS: 07.78. s 29.27.Eg 87.53.Ay 87.64.M Keywords: Pulsed beams Microbeam Radiobiology Cell irradiation
a b s t r a c t We show the preparation of a pulsed 20 MeV proton beam at the Munich tandem accelerator which offers a fluence of more than 1 109 protons/cm2 being deposited in a beam spot smaller than 100 lm in diameter and within a time span of 0.9 ns fwhm. Such a beam is produced by an ECR type proton source using charge exchange in cesium vapor to obtain a beam of negative hydrogen of high brightness that is bunched, chopped, accelerated and then focused by the superconducting multipole lens of the microprobe SNAKE. Single beam pulses are generated in order to irradiate cell samples or tissue and to measure their biological effect in comparison to continuous proton or X-ray irradiation. Ó 2009 Elsevier B.V. All rights reserved.
1. Introduction Laser driven proton or heavy ion beams are proposed as a less expensive alternative to conventional accelerators in producing high energy beams for tumor therapy [1–3] although the prospects and time scales of installation of laser accelerator based medical facilities are under debate [3,4]. Ion beams with sufficient energy (>200 MeV for protons, >400 MeV/nucl for carbon ions) are predicted from femtosecond laser pulses interacting with microstructures or nanometer sized foil targets at laser intensities of exceeding 1021 W/cm2 [2,5]. Those high laser intensities are generated from pulse energies up to 1 kJ, pulse duration of less than 100 fs and a focus diameter down to 1 lm. The laser may be circularly polarized in order to obtain proton or ion beams at highest energy, small energy spread and high efficiency in transforming laser energy into ion energy [6]. Conformal tumor irradiation is normally obtained by high energy proton or ion beams that are raster scanned to irradiate the tumor voxel by voxel irrespective of the mode of ion acceleration (Fig. 1) [7]. A typical therapy plan of a solid tumor may consist easily of much more than 100,000 voxels which have to be irradiated one after the other. All reported scenarios of laser driven ion beams show that those beams should be of high brightness with enough particles (>109 ions/cm2) to irradiate a certain voxel within a tu* Corresponding author. E-mail address: [email protected] (G. Dollinger). 0168-583X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.nimb.2009.03.006
mor. The pulse repetition rate of laser accelerated beams will not easily reach 1 kHz even when thinking of future improvements in laser technology while near future repetition rates of lasers of sufficient laser pulse energy may be limited to about 10 Hz. As a consequence, the number of beam pulses per voxel will be limited to a small number in order to not exceed reasonable total tumor irradiation times which should lie in the range of minutes. Thus, one has to consider irradiation of each voxel by only a few (in minimum one) high energy proton or ion pulses. Although the ion pulse is as short as a picosecond when it is created by the laser pulse the pulse width will spread in time due to transporting a beam with some energy spread to the patient. Dose deposition by a single pulse may last about a nanosecond when considering beam transport lines of more than 20 m and a relative energy spread of 1% at 100 MeV/nucl. The question arises from these considerations, whether irradiation of tissue by such a small number of individual, nanosecond pulses makes a difference in the radiobiological response compared to a continuous beam irradiation. There might be a change in radiobiological effectiveness (RBE) in producing apoptosis or other kind of cell death as well as in other cell reactions like mutations. Particle density which is necessary to deposit a biological relevant dose seems to be too low to make a significant difference in the molecular damage between nanosecond pulses and continuous irradiation. For instance, a 3 Gy dose deposition, that is similar to that used for a single fraction in tumor treatment, requires only seven protons of 20 MeV (LET = 2.65 keV/lm) per lm2. Since the
G. Dollinger et al. / Nuclear Instruments and Methods in Physics Research B 267 (2009) 2008–2012
2009
Fig. 1. Schematic drawing of a state of the art tumor therapy plant. Irrespective to the acceleration mode and how the particle and energy selection is done (with or without any magnet) the beam has to be scanned from voxel to voxel in order to obtain an optimized conformal irradiation of a solid tumor.
main dose deposition takes place only nanometers around the ion track, the distance between two protons is generally too large to change the damage compared to that created by too protons deposited at different times. In particular there is not much change expected from the interaction of excitation or ionization of two or more protons. However, biochemical reaction kinetics in the nano-
second to millisecond time scale are pretty unknown and it cannot be excluded that there might be interaction over larger distances. Thus, it is necessary to measure whether RBE values for various biological endpoints are different for single nanosecond pulses compared to continuous irradiation where a voxel of the tumor may be irradiated within a timescale of milliseconds to 100 ms.
Fig. 2. Scheme of pulsed 20 MeV proton beam preparation using an ECR ion source with Cs vapor charge exchange device, a low energy chopper and buncher system, the 14 MV Munich tandem accelerator, analyzing magnet and beam transport through SNAKE using two intermediate foci. The high energy chopper is used to adjust the low energy buncher system while the single shot chopper is used to prepare single bunches of protons. The superconducting lens makes a short focal length and thus a beam size of about 100 lm.
2010
G. Dollinger et al. / Nuclear Instruments and Methods in Physics Research B 267 (2009) 2008–2012
Up to date, there is not sufficient energy and sufficient quality in actual laser driven proton or ion beams to address the dose–response of biological objects to pulsed beams. Thus, we are studying pulsed beam effects in radiobiological experiments at the 14 MV Munich tandem accelerator in collaboration with biologists and physicians within the cluster of excellence program MAP (Munich center for Advanced Photonics). Here, we describe how we obtain, under the usage of the ion microprobe SNAKE, single proton pulses at a particle fluence being in accordance with a dose deposition of 3 Gy. The necessary fluence is approximately 7 108 protons/cm2 for 20 MeV protons that should be deposited by a single nanosecond pulse.
adjustment of the pulse structure are performed at the target position. Scattered protons are detected in a scintillator/photomultiplier detector positioned under 30° to beam direction after inserting a 100 lm thick aluminum foil instead of the Kapton foil at the exit window. The time signal is measured against the phase signal of the high frequency driver of the 5 MHz buncher. The measured time spectrum shows a close to Gaussian shape with fwhm of 0.9 ns (Fig. 4). Single proton pulses are delivered on demand as follows: the repetition rate of the beam pulses is reduced using the chopper
2. Pulsed beam preparation An ECR ion source with charge exchange in cesium vapor [8] delivers 30 lA of negative hydrogen ions. The emittance of the beam is cut by a pair of aperture slits to (0.15p mm mrad)2 after preacceleration to 119 keV which is only a small fraction of the acceptance of the tandem accelerator being (15 pmm mrad)2 [9]. A pulsed proton beam is prepared by using a 5 MHz buncher operating at a sinusoidal rf voltage amplitude of 3.5 kV that is placed in front of the tandem accelerator. A 70 ns wide gate is introduced by the low energy chopper in order to reject the part of the beam which cannot be focused by the buncher [10] (Fig. 2). The beam is transported through the accelerator and the proton beam is analyzed by a 90° magnet and a standard slit system in front and behind the magnet. The latter slits are also used to cut the beam size to 1 mm diameter. Thus, the energy spread accepted by the beam analyzing device is limited to DE/E < 2 10 4. Since the energy spread induced by the buncher voltage is DE/E 3.5 10 4 the beam current is substantially reduced by the analyzing device. The beam spot prepared by the slit system behind the magnet is used as an object for further beam preparation through SNAKE [11,12]. The beam is transported through the 0° SNAKE beam line of the Munich tandem accelerator in an unusual way. Standard SNAKE operation uses high demagnification of the object (up to a demagnification factor of 200 in x- and y-direction) which means that only a small divergence of the beam is accepted and, thus, only a very small fraction of the beam is transmitted through SNAKE. Here, however, we reduce demagnification to a factor of 10 in order to accept as much current as possible by using two standard quadrupole doublets on the way between the object and the superconducting multipole lens of SNAKE. Altogether we get a total proton current of 80 nA at a beam diameter of approximately 100 lm at 20 MeV beam energy and at a pulse repetition rate of 2.5 MHz. The beam spot as obtained in one of our experiments is plotted in the insert of Fig. 3(a). A minimum size of 75 100 lm2 was achieved containing 2 105 protons per pulse that has been analyzed in air behind an exit window covered by a 7.5 lm Kapton foil. The resulting fluence exceeds 2 109 protons/cm2 and, thus, deposits more than 5 Gy by a single proton pulse. In order to adjust the dose delivered by one proton pulse to the desired value (e.g. 3.0 Gy have been applied in our first experiment) the beam current from the proton source was adjusted while three percent accuracy to the desired value could be observed. The time focus of the buncher system is adjusted by means of a high energy chopper (Fig. 2) that is also driven at 5 MHz high frequency by a sinusoidal voltage. It deflects the beam in y-direction. The phase of the chopper is adjusted to transmit the desired beam pulses without deflection through the intermediate slits when the chopper high frequency voltage crosses zero. By adjusting in addition the buncher amplitude beam current is maximized and pulse length is minimized. Then an accurate characterization and a fine
Fig. 3. (a) Pulsed beam irradiation field as it is obtained from scanning 551 single pulses in a close to rectangular shape which has an area of in total 1.5 2 mm2. The picture is obtained from a CsI scintillator that was placed in the focal plane and imaged through a microscope using a 2.5-fold objective. The camera integrated for 5 s in order to obtain the whole irradiated field imaged by one picture. From the intensity modulation we estimate an intensity fluctuation from point to point of less than 20% across the field. The insert shows an image of a single shot of 2 105 ions with its approximately 100 lm beam size. (b) Irradiation field of continuous beam (64 ms duration) imaged the same way as in (a) but using a fresh scintillator.
G. Dollinger et al. / Nuclear Instruments and Methods in Physics Research B 267 (2009) 2008–2012
2011
in order to get a total fluence of 109 protons/cm2 as being sufficient for a dose bigger than 3 Gy. The duration of cell exposure is accurately done using the single pulse chopper (Fig. 2) which is opened the time span as requested to obtain the desired dose as calculated from the current density.
4. Conclusion
Fig. 4. Time spectrum of protons scattered from a 100 lm thick Al foil and detected by a plastic scintillator at 30° scattering angle. The time t is measured against a stop signal which is generated from the 5 MHz rf-signal driving the buncher and chopper on the low energy side of the tandem accelerator.
on the low energy side of the tandem accelerator (Fig. 2) which can be run at a reduced gate rate of 5 MHz/2n with n = 1, 2, 3, ... , 12. We use n = 6 while we get a pulse repetition rate of 156.25 kHz and thus a time interval of 6.4 ls between two consecutive beam pulses. In order to cut single pulses from these frequent pulses we use the single shot chopper on the high energy side which is installed 9 m in front of SNAKE (Fig. 2). This second chopper is also used to produce single ions from a low beam current (kHz particle rate) for single ion irradiation of cells [12]. In order to generate a single proton pulse the beam is switched off by this chopper until a beam pulse is requested manually or by an automated irradiation system. For the irradiation of cells cultivated in thin containers as they are used for single ion cell irradiation [13] we use a scintillator detector to switch off the beam after one beam pulse (or an arbitrary number of beam pulses) is registered. Switching off the beam takes less than 300 ns which mainly consist of the time the particles travel from the single shot chopper to the target. The switch off time is by far sufficient to reject the next pulses from entering the cell sample. In principle, a single beam pulse can also be delivered on demand using a fixed gate relative to the buncher/chopper phase without detection of the beam pulse as long as stable beam conditions are available. The beam is scanned over an area of 1.5 2 mm2 to irradiate homogeneously sufficient cells for radiobiological experiments setting single proton pulses side by side (Fig. 3(a)). The remaining intensity fluctuation on the picture integrated for the 551 pulses used to scan the field is dominated by the changing of optical quality of the scintillator while intensity fluctuations are estimated to be smaller than ±10% relative to the mean.
3. Continuous beam preparation The pulsed beam experiments on biological cell material are directly compared to continuous beam experiment by just changing from a pulsed mode irradiation to a continuous mode irradiation keeping the irradiation conditions like cell handling and irradiation procedure the same. This comparison keeps systematic errors as small as possible. We prepare the continuous beam by switching off the low energy buncher and chopper devices and by also switching off the superconducting multipole lens. By using the aperture slits in front of the superconducting lenses we prepare a rectangular beam spot with a size of approx. 2 2 mm2 (Fig. 3(b)). When using beam currents of 100 pA we need 64 ms
First experiments have been performed where cell cultures grown on 6 lm Mylar foils were irradiated. We investigated the number of micronuclei formed after mitosis [14] comparing pulsed and continuous beam irradiation by protons at a dose of 3 Gy. There has not been detected any significant difference between pulsed and continuous beam irradiation yet. A detailed discussion of these experiments is given in [14]. In conclusion, we have shown that an accurate, more than 3 Gy dose deposition can be obtained by single proton pulses when using an ECR type ion source with charge exchange and the excellent pulsing facility at the Munich tandem accelerator in combination with the short focal length superconducting multipole lens of SNAKE. Further experiments are planned with regard to other endpoints than micronuclei in cells like looking for chromosome aberrations or cell survival. It is also intended to extend the pulsed mode irradiation to heavy ions like 90 MeV carbon ions. Even experiments on artificial tissues and mouse tumor treatments are planned in order to reveal whether there is a difference between continuous beam irradiation or a dose deposition by single nanosecond proton or heavy ion pulses. In future we plan to install a multicusp ion source at the Munich tandem accelerator which has a more than 30-fold brightness than the ECR source used here. Thus, we should be able to produce a sub micrometer pulsed beam where a single pulse contains more than 100 protons. From this high proton density we intend to investigate increasing rate of double strand break induction from ion tracks that interact within the short time scales and short distances of radical evolution.
Acknowledgements We thank the staff of the Maier-Leibnitz-Laboratorium for operating the accelerator. This work was supported by Grants of the European Science Foundation (ESF) under the EUROCORES Programme EuroDYNA and the DFG Cluster of Excellence Munich Centre for Advanced Photonics (MAP).
References [1] K. Flippo, B.M. Hegelich, B.J. Albright, L. Yin, D.C. Gautier, S. Letzring, M. Schollmeier, J. Schreiber, R. Schulze, J.C. Fernández, Laser Part. Beams 25 (2007) 3. [2] H. Schwoerer, S. Pfotenhauer, O. Jäckel, K.-U. Amthor, B. Liesfeld, W. Ziegler, R. Sauerbrey, K.W.D. Ledingham, T. Esirkepov, Nature 439 (2006) 445. [3] U. Linz, J. Alonso, Phys. Rev. ST Accel. Beams 10 (2007) 094801. and references therein. [4] C.-M.C. Ma, R.L. Maughan, C.G. Orton, Med. Phys. 33 (2006) 571. [5] L. Yin, B.J. Albright, B.M. Hegelich, K.L. Bowers, K.A. Flippo, T.J.T. Kwan, J.C. Fernández, Phys. Plasmas 14 (2007) 056706. [6] T.V. Liseikina, A. Macchi, Appl. Phys. Lett. 91 (2007) 171502. [7] T. Haberer, W. Becher, D. Schardt, G. Kraft, Nucl. Instr. and Meth. A 330 (1993) 296. [8] R. Hertenberger, A. Metz, Y. Eisermann, K. el Abiary, A. Ludewig, C. Pertl, S. Trieb, H.-F. Wirth, P. Schiemenz, G. Graw, Nucl. Instr. and Meth. A 536 (2005) 266. [9] W. Assmann, J. de Boer, U. Meyer-Berkhout, S. Skorka, E. Huenges, P. Kienle, H. Morinaga, E. Nolte, H. Vonach, H. Münzer, L. Rohrer, H. Schnitter, Nucl. Instr. and Meth. 122 (1974) 191. [10] L. Rohrer, H. Jakob, K. Rudolph, S.J. Skorka, Nucl. Instr. and Meth. 220 (1984) 161.
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G. Dollinger et al. / Nuclear Instruments and Methods in Physics Research B 267 (2009) 2008–2012
[11] G. Datzmann, G. Dollinger, C. Goeden, A. Hauptner, H.-J. Körner, P. Reichart, O. Schmelmer, Nucl. Instr. and Meth. B 181/1–4 (2001) 20. [12] G. Dollinger, V. Hable, A. Hauptner, R. Krücken, P. Reichart, A.A. Friedl, G. Drexler, T. Cremer, S. Dietzel, Nucl. Instr. and Meth. B 231 (2005) 195.
[13] A. Hauptner, S. Dietzel, G.A. Drexler, P. Reichart, R. Krücken, T. Cremer, A.A. Friedl, G. Dollinger, Radiat. Environ. Biophys. 42 (2004) 237. [14] T.E. Schmid, G. Dollinger, A. Hauptner, V. Hable, C. Greubel, A.A. Friedl, M.Molls, B. Röper, Rad. Res., in press.
Contents lists available at ScienceDirect
Nuclear Instruments and Methods in Physics Research B journal homepage: www.elsevier.com/locate/nimb
Nanosecond pulsed proton microbeam G. Dollinger a,*, A. Bergmaier a, V. Hable a, R. Hertenberger b, C. Greubel a, A. Hauptner c, P. Reichart a a b c
Angewandte Physik und Messtechnik LRT2, Universität der Bundeswehr München, 85577 Neubiberg, Germany Sektion Physik, LMU München, 85748 Garching, Germany Physik Department E12, TU-München, 85748 Garching, Germany
a r t i c l e
i n f o
Available online 11 March 2009 PACS: 07.78. s 29.27.Eg 87.53.Ay 87.64.M Keywords: Pulsed beams Microbeam Radiobiology Cell irradiation
a b s t r a c t We show the preparation of a pulsed 20 MeV proton beam at the Munich tandem accelerator which offers a fluence of more than 1 109 protons/cm2 being deposited in a beam spot smaller than 100 lm in diameter and within a time span of 0.9 ns fwhm. Such a beam is produced by an ECR type proton source using charge exchange in cesium vapor to obtain a beam of negative hydrogen of high brightness that is bunched, chopped, accelerated and then focused by the superconducting multipole lens of the microprobe SNAKE. Single beam pulses are generated in order to irradiate cell samples or tissue and to measure their biological effect in comparison to continuous proton or X-ray irradiation. Ó 2009 Elsevier B.V. All rights reserved.
1. Introduction Laser driven proton or heavy ion beams are proposed as a less expensive alternative to conventional accelerators in producing high energy beams for tumor therapy [1–3] although the prospects and time scales of installation of laser accelerator based medical facilities are under debate [3,4]. Ion beams with sufficient energy (>200 MeV for protons, >400 MeV/nucl for carbon ions) are predicted from femtosecond laser pulses interacting with microstructures or nanometer sized foil targets at laser intensities of exceeding 1021 W/cm2 [2,5]. Those high laser intensities are generated from pulse energies up to 1 kJ, pulse duration of less than 100 fs and a focus diameter down to 1 lm. The laser may be circularly polarized in order to obtain proton or ion beams at highest energy, small energy spread and high efficiency in transforming laser energy into ion energy [6]. Conformal tumor irradiation is normally obtained by high energy proton or ion beams that are raster scanned to irradiate the tumor voxel by voxel irrespective of the mode of ion acceleration (Fig. 1) [7]. A typical therapy plan of a solid tumor may consist easily of much more than 100,000 voxels which have to be irradiated one after the other. All reported scenarios of laser driven ion beams show that those beams should be of high brightness with enough particles (>109 ions/cm2) to irradiate a certain voxel within a tu* Corresponding author. E-mail address: [email protected] (G. Dollinger). 0168-583X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.nimb.2009.03.006
mor. The pulse repetition rate of laser accelerated beams will not easily reach 1 kHz even when thinking of future improvements in laser technology while near future repetition rates of lasers of sufficient laser pulse energy may be limited to about 10 Hz. As a consequence, the number of beam pulses per voxel will be limited to a small number in order to not exceed reasonable total tumor irradiation times which should lie in the range of minutes. Thus, one has to consider irradiation of each voxel by only a few (in minimum one) high energy proton or ion pulses. Although the ion pulse is as short as a picosecond when it is created by the laser pulse the pulse width will spread in time due to transporting a beam with some energy spread to the patient. Dose deposition by a single pulse may last about a nanosecond when considering beam transport lines of more than 20 m and a relative energy spread of 1% at 100 MeV/nucl. The question arises from these considerations, whether irradiation of tissue by such a small number of individual, nanosecond pulses makes a difference in the radiobiological response compared to a continuous beam irradiation. There might be a change in radiobiological effectiveness (RBE) in producing apoptosis or other kind of cell death as well as in other cell reactions like mutations. Particle density which is necessary to deposit a biological relevant dose seems to be too low to make a significant difference in the molecular damage between nanosecond pulses and continuous irradiation. For instance, a 3 Gy dose deposition, that is similar to that used for a single fraction in tumor treatment, requires only seven protons of 20 MeV (LET = 2.65 keV/lm) per lm2. Since the
G. Dollinger et al. / Nuclear Instruments and Methods in Physics Research B 267 (2009) 2008–2012
2009
Fig. 1. Schematic drawing of a state of the art tumor therapy plant. Irrespective to the acceleration mode and how the particle and energy selection is done (with or without any magnet) the beam has to be scanned from voxel to voxel in order to obtain an optimized conformal irradiation of a solid tumor.
main dose deposition takes place only nanometers around the ion track, the distance between two protons is generally too large to change the damage compared to that created by too protons deposited at different times. In particular there is not much change expected from the interaction of excitation or ionization of two or more protons. However, biochemical reaction kinetics in the nano-
second to millisecond time scale are pretty unknown and it cannot be excluded that there might be interaction over larger distances. Thus, it is necessary to measure whether RBE values for various biological endpoints are different for single nanosecond pulses compared to continuous irradiation where a voxel of the tumor may be irradiated within a timescale of milliseconds to 100 ms.
Fig. 2. Scheme of pulsed 20 MeV proton beam preparation using an ECR ion source with Cs vapor charge exchange device, a low energy chopper and buncher system, the 14 MV Munich tandem accelerator, analyzing magnet and beam transport through SNAKE using two intermediate foci. The high energy chopper is used to adjust the low energy buncher system while the single shot chopper is used to prepare single bunches of protons. The superconducting lens makes a short focal length and thus a beam size of about 100 lm.
2010
G. Dollinger et al. / Nuclear Instruments and Methods in Physics Research B 267 (2009) 2008–2012
Up to date, there is not sufficient energy and sufficient quality in actual laser driven proton or ion beams to address the dose–response of biological objects to pulsed beams. Thus, we are studying pulsed beam effects in radiobiological experiments at the 14 MV Munich tandem accelerator in collaboration with biologists and physicians within the cluster of excellence program MAP (Munich center for Advanced Photonics). Here, we describe how we obtain, under the usage of the ion microprobe SNAKE, single proton pulses at a particle fluence being in accordance with a dose deposition of 3 Gy. The necessary fluence is approximately 7 108 protons/cm2 for 20 MeV protons that should be deposited by a single nanosecond pulse.
adjustment of the pulse structure are performed at the target position. Scattered protons are detected in a scintillator/photomultiplier detector positioned under 30° to beam direction after inserting a 100 lm thick aluminum foil instead of the Kapton foil at the exit window. The time signal is measured against the phase signal of the high frequency driver of the 5 MHz buncher. The measured time spectrum shows a close to Gaussian shape with fwhm of 0.9 ns (Fig. 4). Single proton pulses are delivered on demand as follows: the repetition rate of the beam pulses is reduced using the chopper
2. Pulsed beam preparation An ECR ion source with charge exchange in cesium vapor [8] delivers 30 lA of negative hydrogen ions. The emittance of the beam is cut by a pair of aperture slits to (0.15p mm mrad)2 after preacceleration to 119 keV which is only a small fraction of the acceptance of the tandem accelerator being (15 pmm mrad)2 [9]. A pulsed proton beam is prepared by using a 5 MHz buncher operating at a sinusoidal rf voltage amplitude of 3.5 kV that is placed in front of the tandem accelerator. A 70 ns wide gate is introduced by the low energy chopper in order to reject the part of the beam which cannot be focused by the buncher [10] (Fig. 2). The beam is transported through the accelerator and the proton beam is analyzed by a 90° magnet and a standard slit system in front and behind the magnet. The latter slits are also used to cut the beam size to 1 mm diameter. Thus, the energy spread accepted by the beam analyzing device is limited to DE/E < 2 10 4. Since the energy spread induced by the buncher voltage is DE/E 3.5 10 4 the beam current is substantially reduced by the analyzing device. The beam spot prepared by the slit system behind the magnet is used as an object for further beam preparation through SNAKE [11,12]. The beam is transported through the 0° SNAKE beam line of the Munich tandem accelerator in an unusual way. Standard SNAKE operation uses high demagnification of the object (up to a demagnification factor of 200 in x- and y-direction) which means that only a small divergence of the beam is accepted and, thus, only a very small fraction of the beam is transmitted through SNAKE. Here, however, we reduce demagnification to a factor of 10 in order to accept as much current as possible by using two standard quadrupole doublets on the way between the object and the superconducting multipole lens of SNAKE. Altogether we get a total proton current of 80 nA at a beam diameter of approximately 100 lm at 20 MeV beam energy and at a pulse repetition rate of 2.5 MHz. The beam spot as obtained in one of our experiments is plotted in the insert of Fig. 3(a). A minimum size of 75 100 lm2 was achieved containing 2 105 protons per pulse that has been analyzed in air behind an exit window covered by a 7.5 lm Kapton foil. The resulting fluence exceeds 2 109 protons/cm2 and, thus, deposits more than 5 Gy by a single proton pulse. In order to adjust the dose delivered by one proton pulse to the desired value (e.g. 3.0 Gy have been applied in our first experiment) the beam current from the proton source was adjusted while three percent accuracy to the desired value could be observed. The time focus of the buncher system is adjusted by means of a high energy chopper (Fig. 2) that is also driven at 5 MHz high frequency by a sinusoidal voltage. It deflects the beam in y-direction. The phase of the chopper is adjusted to transmit the desired beam pulses without deflection through the intermediate slits when the chopper high frequency voltage crosses zero. By adjusting in addition the buncher amplitude beam current is maximized and pulse length is minimized. Then an accurate characterization and a fine
Fig. 3. (a) Pulsed beam irradiation field as it is obtained from scanning 551 single pulses in a close to rectangular shape which has an area of in total 1.5 2 mm2. The picture is obtained from a CsI scintillator that was placed in the focal plane and imaged through a microscope using a 2.5-fold objective. The camera integrated for 5 s in order to obtain the whole irradiated field imaged by one picture. From the intensity modulation we estimate an intensity fluctuation from point to point of less than 20% across the field. The insert shows an image of a single shot of 2 105 ions with its approximately 100 lm beam size. (b) Irradiation field of continuous beam (64 ms duration) imaged the same way as in (a) but using a fresh scintillator.
G. Dollinger et al. / Nuclear Instruments and Methods in Physics Research B 267 (2009) 2008–2012
2011
in order to get a total fluence of 109 protons/cm2 as being sufficient for a dose bigger than 3 Gy. The duration of cell exposure is accurately done using the single pulse chopper (Fig. 2) which is opened the time span as requested to obtain the desired dose as calculated from the current density.
4. Conclusion
Fig. 4. Time spectrum of protons scattered from a 100 lm thick Al foil and detected by a plastic scintillator at 30° scattering angle. The time t is measured against a stop signal which is generated from the 5 MHz rf-signal driving the buncher and chopper on the low energy side of the tandem accelerator.
on the low energy side of the tandem accelerator (Fig. 2) which can be run at a reduced gate rate of 5 MHz/2n with n = 1, 2, 3, ... , 12. We use n = 6 while we get a pulse repetition rate of 156.25 kHz and thus a time interval of 6.4 ls between two consecutive beam pulses. In order to cut single pulses from these frequent pulses we use the single shot chopper on the high energy side which is installed 9 m in front of SNAKE (Fig. 2). This second chopper is also used to produce single ions from a low beam current (kHz particle rate) for single ion irradiation of cells [12]. In order to generate a single proton pulse the beam is switched off by this chopper until a beam pulse is requested manually or by an automated irradiation system. For the irradiation of cells cultivated in thin containers as they are used for single ion cell irradiation [13] we use a scintillator detector to switch off the beam after one beam pulse (or an arbitrary number of beam pulses) is registered. Switching off the beam takes less than 300 ns which mainly consist of the time the particles travel from the single shot chopper to the target. The switch off time is by far sufficient to reject the next pulses from entering the cell sample. In principle, a single beam pulse can also be delivered on demand using a fixed gate relative to the buncher/chopper phase without detection of the beam pulse as long as stable beam conditions are available. The beam is scanned over an area of 1.5 2 mm2 to irradiate homogeneously sufficient cells for radiobiological experiments setting single proton pulses side by side (Fig. 3(a)). The remaining intensity fluctuation on the picture integrated for the 551 pulses used to scan the field is dominated by the changing of optical quality of the scintillator while intensity fluctuations are estimated to be smaller than ±10% relative to the mean.
3. Continuous beam preparation The pulsed beam experiments on biological cell material are directly compared to continuous beam experiment by just changing from a pulsed mode irradiation to a continuous mode irradiation keeping the irradiation conditions like cell handling and irradiation procedure the same. This comparison keeps systematic errors as small as possible. We prepare the continuous beam by switching off the low energy buncher and chopper devices and by also switching off the superconducting multipole lens. By using the aperture slits in front of the superconducting lenses we prepare a rectangular beam spot with a size of approx. 2 2 mm2 (Fig. 3(b)). When using beam currents of 100 pA we need 64 ms
First experiments have been performed where cell cultures grown on 6 lm Mylar foils were irradiated. We investigated the number of micronuclei formed after mitosis [14] comparing pulsed and continuous beam irradiation by protons at a dose of 3 Gy. There has not been detected any significant difference between pulsed and continuous beam irradiation yet. A detailed discussion of these experiments is given in [14]. In conclusion, we have shown that an accurate, more than 3 Gy dose deposition can be obtained by single proton pulses when using an ECR type ion source with charge exchange and the excellent pulsing facility at the Munich tandem accelerator in combination with the short focal length superconducting multipole lens of SNAKE. Further experiments are planned with regard to other endpoints than micronuclei in cells like looking for chromosome aberrations or cell survival. It is also intended to extend the pulsed mode irradiation to heavy ions like 90 MeV carbon ions. Even experiments on artificial tissues and mouse tumor treatments are planned in order to reveal whether there is a difference between continuous beam irradiation or a dose deposition by single nanosecond proton or heavy ion pulses. In future we plan to install a multicusp ion source at the Munich tandem accelerator which has a more than 30-fold brightness than the ECR source used here. Thus, we should be able to produce a sub micrometer pulsed beam where a single pulse contains more than 100 protons. From this high proton density we intend to investigate increasing rate of double strand break induction from ion tracks that interact within the short time scales and short distances of radical evolution.
Acknowledgements We thank the staff of the Maier-Leibnitz-Laboratorium for operating the accelerator. This work was supported by Grants of the European Science Foundation (ESF) under the EUROCORES Programme EuroDYNA and the DFG Cluster of Excellence Munich Centre for Advanced Photonics (MAP).
References [1] K. Flippo, B.M. Hegelich, B.J. Albright, L. Yin, D.C. Gautier, S. Letzring, M. Schollmeier, J. Schreiber, R. Schulze, J.C. Fernández, Laser Part. Beams 25 (2007) 3. [2] H. Schwoerer, S. Pfotenhauer, O. Jäckel, K.-U. Amthor, B. Liesfeld, W. Ziegler, R. Sauerbrey, K.W.D. Ledingham, T. Esirkepov, Nature 439 (2006) 445. [3] U. Linz, J. Alonso, Phys. Rev. ST Accel. Beams 10 (2007) 094801. and references therein. [4] C.-M.C. Ma, R.L. Maughan, C.G. Orton, Med. Phys. 33 (2006) 571. [5] L. Yin, B.J. Albright, B.M. Hegelich, K.L. Bowers, K.A. Flippo, T.J.T. Kwan, J.C. Fernández, Phys. Plasmas 14 (2007) 056706. [6] T.V. Liseikina, A. Macchi, Appl. Phys. Lett. 91 (2007) 171502. [7] T. Haberer, W. Becher, D. Schardt, G. Kraft, Nucl. Instr. and Meth. A 330 (1993) 296. [8] R. Hertenberger, A. Metz, Y. Eisermann, K. el Abiary, A. Ludewig, C. Pertl, S. Trieb, H.-F. Wirth, P. Schiemenz, G. Graw, Nucl. Instr. and Meth. A 536 (2005) 266. [9] W. Assmann, J. de Boer, U. Meyer-Berkhout, S. Skorka, E. Huenges, P. Kienle, H. Morinaga, E. Nolte, H. Vonach, H. Münzer, L. Rohrer, H. Schnitter, Nucl. Instr. and Meth. 122 (1974) 191. [10] L. Rohrer, H. Jakob, K. Rudolph, S.J. Skorka, Nucl. Instr. and Meth. 220 (1984) 161.
2012
G. Dollinger et al. / Nuclear Instruments and Methods in Physics Research B 267 (2009) 2008–2012
[11] G. Datzmann, G. Dollinger, C. Goeden, A. Hauptner, H.-J. Körner, P. Reichart, O. Schmelmer, Nucl. Instr. and Meth. B 181/1–4 (2001) 20. [12] G. Dollinger, V. Hable, A. Hauptner, R. Krücken, P. Reichart, A.A. Friedl, G. Drexler, T. Cremer, S. Dietzel, Nucl. Instr. and Meth. B 231 (2005) 195.
[13] A. Hauptner, S. Dietzel, G.A. Drexler, P. Reichart, R. Krücken, T. Cremer, A.A. Friedl, G. Dollinger, Radiat. Environ. Biophys. 42 (2004) 237. [14] T.E. Schmid, G. Dollinger, A. Hauptner, V. Hable, C. Greubel, A.A. Friedl, M.Molls, B. Röper, Rad. Res., in press.