- Email: [email protected]
Medical applications of synchrotron radiation in Australia
ARTICLE IN PRESS
Nuclear Instruments and Methods in Physics Research A 548 (2005) 23–29 www.elsevier.com/locate/nima
Medical applications of synchrotron radiation in Australia R.A. Lewis Centre for Synchrotron Science, Monash University, Clayton, Victoria 3800, Australia Available online 19 April 2005
Abstract The Australian synchrotron is being built at Monash University near Melbourne. The 3 GeV machine is well-suited to the mid X-ray region and will have nine beamlines in its initial phase. The high level of biomedical research in Australia has led to the demand for a beamline capable of supporting medical research in both imaging and therapy. The design features for a versatile imaging and hard X-ray beamline capable of operating in the energy range 10–120 keV are outlined here together with a short review of some of the science that is envisaged. r 2005 Elsevier B.V. All rights reserved. PACS: 87.59. e; 87.59.Bh; 87.53. j; 07.85.Qe Keywords: Synchrotron radiation; Phase contrast X-ray imaging; Microbeam radiotherapy; Lung imaging
1. Introduction The Australian synchrotron, currently under construction at Monash University near Melbourne, Victoria, is scheduled to begin operation in early 2007. The design of the machine was chosen to satisfy the following objectives [1]:
that it should be competitive with other third generation compact facilities under construction; that it should have adequate beamline and experimental stations to satisfy 95% of the research requirements of an expected Australian community of 1200 different researchers; and Tel.: +61 3 9905 3622; fax: +61 3 9905 3637.
E-mail address: [email protected].
provide internationally competitive performance for essentially all Australian industry requirements.
The chosen design parameters of the ring are given in Table 1. The machine is designed to provide high performance in the X-ray energy range, 100 eV to approximately 65 keV. The location of the Australian synchrotron is in the eastern suburbs of Melbourne some 20 km from the city center, on the main campus of Monash University, Australia’s largest university. At the time of writing 13 beamlines are planned covering the whole range of synchrotron techniques. Nine of these beamlines have been chosen for the first phase of funding and one of those is an
0168-9002/$ - see front matter r 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.nima.2005.03.061
ARTICLE IN PRESS R.A. Lewis / Nuclear Instruments and Methods in Physics Research A 548 (2005) 23–29
Table 1 Basic properties of the storage ring boomerang 20 [1] Energy (GeV) Circumference (m) Current (mA) Revolution time (ns) Usable straight sections Length of straight sections (m) Bending magnet field (T) Betatron tune—H Betatron tune—V Dispersion (m) Natural emittance (nm rad) Beam size in straights [H (mm), V (mm)] Beam size in dipoles [H (mm),V (mm)]
Centre, the largest teaching hospital in Victoria, is just 1.5 km from the synchrotron site.
3.0 216 200 720.5 12 5.397 1.3 13.30 5.20 0 15.81 389.21 98.72
2.4 6.98 340.13 77.48
imaging and medical applications beamline which is described in the following section.
2. Imaging and therapy beamline Australia has a well-developed biomedical research capability and Melbourne in particular has a large number of medical research groups. This community has identified a pressing need for a beamline capable of performing advanced studies on both biomedical imaging techniques and novel radiotherapies. An added impetus for such a facility arises from the unusual Australian ecology with its unique flora and fauna. The result is that there are diseases which are unique to Australia and others that are common elsewhere but which do not occur in Australia. The concomitant strict customs and quarantine laws mean that many samples may not be transported over national boundaries thereby providing a major drive for the establishment of a biomedical beamline. The location of the Australian synchrotron at Monash University provides some significant advantages for biomedical synchrotron work. Facilities already existing on campus include fully equipped biomedical, chemical, physics and computer laboratories as well as a major animal house. In addition the campus of Monash Medical
2.1. Beamline design The beamline will be sourced from a variable field superconducting wiggler covering the energy range 10–120 keV. A limiting factor imposed by the design of the beamline front end is that the deflection parameter of the insertion device, K, may not exceed 20. Coupled with a 48 mm magnetic period, the K limitation yields a maximum field of 4.4 T. A 31 period device having this field and period will deliver both high flux at high energy for therapy applications and also provide a wide intrinsic fan beam for large object imaging. The brightness of the proposed beamline is compared with the medical beamline at the ESRF and the biomedical imaging and therapy beamline being built at the Canadian light source, in Fig. 1. An important but difficult design goal of the beamline is to preserve flexibility without sacrificing performance. Flexibility is vital since we wish to explore a number of imaging modalities including propagation-based projection imaging [2] using both monochromatic and white beam as well as analyzer-based methods [3]. The flexibility will be implemented by having several in line hutches which can be used for a variety of purposes. The basic layout is illustrated in Fig. 2
Flux Density (phts/s/mr2/0.1%bw)
24
1E16
1E15
1E14 AS CLS
1E13
ESRF 1E12 1
10
100
10
Energy (keV)
Fig. 1. The brightness of the Australian imaging and therapy beamline (AS) compared with the proposed BMIT at the Canadian light source (CLS) and ID17 at the ESRF.
ARTICLE IN PRESS R.A. Lewis / Nuclear Instruments and Methods in Physics Research A 548 (2005) 23–29
25
Fig. 2. Proposed layout of the imaging and therapy beamline.
and shows 3 of the 4 proposed hutches. The first hutch will house the beam conditioning optics whilst the second and third hutches are multipurpose.
Table 2 Nominal dimensions of the beam in mm, at various distances from the source for different wiggler field strengths Distance (m)
Field (T)
20
2.2. Imaging modes For imaging there are a wide variety of options. The first main imaging station is located inside the experimental hall at a distance of approximately 40 m from the primary source, while the second station is located in a separate imaging center some 135–150 m from the source. This latter station is optimized for plane-wave experiments including large samples, live animal imaging, tomography, and topography. Eventually it is envisaged that humans will also be imaged and the imaging center will contain MRI, PET CT and other facilities in addition to the synchrotron imaging suite. Without any focussing, the beam dimensions are shown in Table 2. It is clear that the combination
Energy (keV)
150 150 150 40 40 40 20 20 20
4.4 3 2 4.4 3 2 4.4 3 2
60
100
X
Y
X
Y
X
Y
954 618 366 254 165 98 127 82 49
54 42 30 14.4 11.2 8 7.2 5.6 4
726 426 234 194 114 62 97 57 31
30 30 18 8 8 4.8 4 4 2.4
582 342 186 155 91 50 78 46 25
30 18 18 8 4.8 4.8 4 2.4 2.4
of high field and a long distance results in a horizontal beam width rather larger than required and so either focussing or an aperture will be required.
ARTICLE IN PRESS 26
R.A. Lewis / Nuclear Instruments and Methods in Physics Research A 548 (2005) 23–29
For projection-based imaging we intend to utilize both simple projection from the source as well as an effective secondary source produced by focusing devices. The focussing methods may include the use of bent crystals in Laue mode in the optics hutch as well as secondary focusing devices such as Kirkpatrick-Baez mirrors or a compound refractive lens inside the first experimental station. The beamline is intended to provide a flexible facility for use for in-line imaging both at high spatial resolution and/or large object size. It will provide the capability to develop and apply the inline approach in a near optimum fashion, both with white and narrow-band radiation, especially for biomedical and ultimately clinical medical imaging. For many of the envisaged in-line imaging applications it has been shown that broadband polychromatic radiation may well be sufficient [2]. The use of so-called pink beam produced using multi-layers having much broader band pass than crystal monochromators may also allow short exposure times and hence rapid dynamic imaging. 2.3. Therapy mode The main interest within Australia for the use of synchrotron radiation in radiotherapy is in microbeam radiotherapy [4]. For this method it is crucial that a high dose be delivered to the target tissue in a very short time. The reason behind this is that the beneficial aspects of this type of therapy are thought to arise from the unirradiated tissue located in the valleys between peaks of dose delivered by an array of micro-beams. Since the most effective spacing between the micro-beams appears to be around 100–200 mm [5], it is necessary that the dose be delivered in a timescale short enough that the subject has not moved enough to eliminate the valleys between the peaks. To that end it is important to perform the therapy as close as possible to the source point in order to maximize the available flux. In therapy mode therefore, it is planned to mount the collimator that creates the micro-beams in the first optics hutch whilst the animal and positioning system will be located in hutch 2 approximately
Table 3 Dose rates in the first experimental hutch for different wiggler field strengths Field (T)
Dose rate (Gy/s)
2 3 4.4
259 2789 13522
20 m from the source point. It is necessary to filter out the low energies and the beam energy filtration system will also be located in the first optics hutch. The predicted surface entrance dose rates in the first experimental hutch with 1.5 mm Cu filtration are given in Table 3. Other workers [4,6] have shown that dose rates in excess of 2000 Gy s 1 are sufficient for some successful experiments and so it can be seen that a field of 3 T or above will be necessary.
3. Phase contrast imaging One of the major applications planned for this beamline is X-ray phase contrast imaging. Much of the pioneering work in this field originated in Melbourne[2,7] and so it is particularly appropriate that the medical beamline on the Australian synchrotron have a strong emphasis on this kind of work. 3.1. Small animal imaging Whole animal models are increasingly important in biomedical research, particularly in understanding complex physiological processes, where the complex interrelationships between organ systems mean that it is necessary to study a complete functioning animal. There is, however, a significant problem with animal models in that it is often necessary to perform invasive procedures or even sacrifice the animals in order to acquire the necessary information. Such procedures can have significant unwanted effects upon the normal functioning of the animal and hence may confound the data. In addition, the common practice of sacrificing
ARTICLE IN PRESS R.A. Lewis / Nuclear Instruments and Methods in Physics Research A 548 (2005) 23–29
animals at different stages of an experiment, in order to follow a pathological process or treatment process, is predicated on the assumption that the disease (or treatment) progresses in the same manner in different animals. Obviously this may not be the case and it is clear that some form of non-invasive method of following through a process to completion in a single animal would be highly beneficial. The added contrast sensitivity of phase contrast X-ray imaging and its ability to visualize soft tissue with short exposures offers a means of obtaining information in a non-invasive manner. As such it may be possible to perform longitudinal studies of disease (or treatment) progression in each animal. Since many biomedical processes are distributed throughout the body involving multiple organ systems, it is important to be able to perform whole body scans. In principle, phase contrast Xray imaging can provide quantitative three-dimensional information at high spatial resolution over a whole animal, enabling investigation and crosscorrelation of separated processes. No other imaging method can currently combine micron level resolution with high sensitivity, good time resolution and soft tissue contrast. The vast majority of the work in X-ray phase contrast imaging to date has been concerned with developing the technique and exploring the limits of the imaging systems from a physics standpoint. Quite a few spectacular ‘demonstration’ images have been recorded but as yet the technique has found only limited application in the solving of real medical problems. Part of the reason for this is the need to extract quantitative information from the images and a considerable amount of work in this field has been performed in Australia. 3.2. Extracting quantitative information There are three main types of X-ray phase contrast imaging having varying degrees of applicability for medical imaging [8]. The first technique utilizes an interferometer [9] and whilst rather elegant and sensitive, is not well suited to either large or dynamic objects. Consequently it is not envisaged that the interferometric technique will be established on the Australian synchrotron, at
27
least in the early stages. The second method utilizes a crystal analyzer to determine the phase shifts [3,10] whilst the other makes use of free space propagation to allow interference to render the phase shifts visible as intensity changes [2]. A considerable amount of work has been performed in developing analysis techniques which can extract quantitative information from the resulting images [7,11–14]. Almost all of them, however, rely upon the acquisition of multiple images of the same object to allow the phase information to be extracted. In the context of biomedical imaging this represents a major problem since we are typically concerned with the imaging of dynamic objects which move significantly over timescales of milliseconds. In such circumstances it becomes impossible to record two or more images of the object which can then be satisfactorily used as input to the phase retrieval algorithms. New approaches developed by researchers at Monash University and CSIRO are seeking to address this issue [16–18]. A number of approaches are being explored but one solution would be a way to extract quantitative phase information from a single image. One method of attacking the problem is to make use of any a priori information about the object under investigation. In fact it transpires that the problem becomes soluble if one makes the assumption that the object is a single material embedded in a substrate of approximately uniform thickness [16]. Whilst such an assumption may appear at first sight to be ludicrously simplistic, there are a number of applications in biomedical imaging where it is not unreasonable. For example, phase contrast imaging of the lungs can be considered as imaging air within a liquid matrix. Whilst of course the situation is more complex than this, the algorithms developed to perform the phase extraction under this assumption turn out to be quite robust [16,19] and are therefore being applied in the area of lung imaging. 3.3. Phase contrast in developmental biology Phase contrast X-ray imaging is spectacularly successful in revealing lungs as illustrated by the
ARTICLE IN PRESS 28
R.A. Lewis / Nuclear Instruments and Methods in Physics Research A 548 (2005) 23–29
Fig. 3. Analyzer-based image of the thorax of a 1-month-old mouse recorded at Spring-8 using 33 keV X-rays and a Silicaon 3,3,3 reflection. Adapted from [15].
image in Fig. 3. A peculiarly Australian aspect in the context of developmental biology is that of lung development in marsupials. The tammar wallaby, for example, is born after only 4 weeks gestation and lives external of the womb from day 28 of development. At birth the neonate is highly underdeveloped, however, it displays some remarkable adaptations for external life including developed lungs and associated air passages. This is in stark contrast to prematurely born humans where breathing difficulties caused by underdeveloped lungs are common. One fledgling project in Australia led by Dr Whitley, from the Department of Primary Industries in Victoria is using high-resolution phase contrast X-ray imaging of the tammar wallaby lung to try to understand how lungs develop. Initial results are extremely encouraging and a test image is shown in Fig. 4. As can be seen from this figure, the lack of development of bones makes the wallaby neonate an almost pure phase object. With almost all the contrast arising from air tissue
Fig. 4. Propagation-based phase contrast image of a 2-day-old tammar wallaby recorded on BL20XU at Spring-8 with 33 keV X-rays. Adapted from [20].
interfaces in the lungs making propagation-based phase contrast imaging ideal for such studies. 3.4. Clearance of lung liquid and aeration of the lung at birth Another important biomedical problem where phase contrast X-ray imaging can play a major part is in understanding the dynamics of liquid clearance from the airways at birth. The problem is significant in that the survival of newborn infants is critically dependent upon the lungs taking over the role of gas exchange immediately upon birth. Prior to birth, gas exchange occurs across the placenta and the lungs are filled with lung liquid [21]. The transition to
ARTICLE IN PRESS R.A. Lewis / Nuclear Instruments and Methods in Physics Research A 548 (2005) 23–29
pulmonary gas exchange at birth is dependent upon a complex interaction of physiological, physical and biochemical processes. The absence to date of an adequate method of producing rapid time resolved lung images has greatly hindered understanding of these mechanisms. For example, the process of the clearance of liquid from the lungs at birth and the impact of patient position on the distribution of retained liquid within the lung remains unknown. Since much of the fluid is cleared within less than a minute of birth, time resolved imaging is crucial. Propagation-based phase contrast imaging with a synchrotron is ideally suited to the production of X-ray movies of this process due to the simplicity of the system and the high flux levels permitting short exposure times.
4. Conclusion The Australian synchrotron will provide a much needed facility that will enable most aspects of synchrotron related science to be performed on Australian soil. The imaging and therapy beamline will enable not only physics-based imaging and therapy research, but also a wide range of biomedical projects which cannot currently be considered due to the difficulty of transporting samples. In particular, the demonstrated capability of phase contrast X-ray imaging to visualize lungs in vivo has given rise to several projects within Australia, which will exploit this technique in order to improve the understanding of lung development and physiology.
Acknowledgements I am grateful to Drs. Steven Wilkins, Andrew Stevenson, Sherry Mayo and Karen Siu for their enormous help and expert input into the imaging and therapy beamline. I am also greatly indebted to Drs. Jane Whitley and Stuart Hooper for having the great vision and enthusiasm that initiated the lung imaging projects.
29
References [1] J.W. Boldeman, D. Einfeld, Detect. Assoc. Equip. 521 (2–3) (2004) 306. [2] S.W. Wilkins, T.E. Gureyev, D. Gao, A. Pogany, A.W. Stevenson, Nature 384 (6607) (1996) 335. [3] V.N. Ingal, E.A. Beliaevskaya, J. Phys. D-Appl. Phys. 28 (11) (1995) 2314. [4] J.A. Laissue, G. Geiser, P.O. Spanne, F.A. Dilmanian, J.O. Gebbers, M. Geiser, X.Y. Wu, M.S. Makar, P.L. Micca, M.M. Nawrocky, D.D. Joel, D.N. Slatkin, Int. J. Cancer 78 (5) (1998) 654. [5] E. Brauer-Krisch, A. Bravin, M. Lerch, A. Rosenfeld, J. Stepanek, M. Di Michiel, J.A. Laissue, Med. Phys. 30 (4) (2003) 583. [6] D.N. Slatkin, P. Spanne, F.A. Dilmanian, J.O. Gebbers, J.A. Laissue, Proc. Nat. Acad. Sci. USA 92 (19) (1995) 8783. [7] K.A. Nugent, D. Paganin, T.E. Gureyev, Phys. Today 54 (8) (2001) 27. [8] R.A. Lewis, Phys. Med. Biol. 49 (2004) 3573. [9] A. Momose, T. Takeda, Y. Itai, A. Yoneyama, K. Hirano, J. Synchrotron Radiat. 5 (3) (1998) 309. [10] R.A. Lewis, C.J. Hall, A.P. Hufton, S. Evans, R.H. Menk, F. Arfelli, L. Rigon, G. Tromba, D.R. Dance, I.O. Ellis, A. Evans, E. Jacobs, S.E. Pinder, K.D. Rogers, Br. J. Radiol. 76 (905) (2003) 301. [11] D. Chapman, W. Thomlinson, R.E. Johnston, D. Washburn, E. Pisano, N. Gmur, Z. Zhong, R. Menk, F. Arfelli, D. Sayers, Phys. Med. Biol. 42 (11) (1997) 2015. [12] M.N. Wernick, O. Wirjadi, D. Chapman, Z. Zhong, N.P. Galatsanos, Y. Yang, J.G. Brankov, O. Oltulu, M.A. Anastasio, C. Muehleman, Phys. Med. Biol. (23) (2003) 3875. [13] A. Ishisaka, H. Ohara, C. Honda, Opt. Rev. 7 (6) (2000) 566. [14] Y. Suzuki, N. Yagi, K. Uesugi, J. Synchrotron Radiat. 9 (Pt. 3)) (2002) 160. [15] M.J. Kitchen, R.A. Lewis, Br. J. Radiol. (2004) Submitted for publication. [16] D. Paganin, T.E. Gureyev, K.M. Pavlov, R.A. Lewis, M. Kitchen, Opt. Commun. 234 (1–6) (2004) 87. [17] K.M. Pavlov, T.E. Gureyev, D. Paganin, Y.I. Nesterets, M.J. Morgan, R.A. Lewis, J. Phys. D: Appl. Phys. (2004). [18] K.K.W. Siu, M.J. Kitchen, K.M. Pavlov, J.E. Gillam, R.A. Lewis, K. Uesugi, N. Yagi, Nucl. Instr. and Meth. A (2004) Submitted for publication. [19] M.J. Kitchen, D. Paganin, R.A. Lewis, N. Yagi, K. Uesugi, S.T. Mudie, Phys. Med. Biol. 49 (2004) 4335. [20] J. Whitley, R.A. Lewis, S.J. Hooper, in preperation, 2004. [21] S.B. Hooper, R. Harding, SO—Clin. Exp. Pharmacol. Physiol. 22 (4) (1995) 235.
Nuclear Instruments and Methods in Physics Research A 548 (2005) 23–29 www.elsevier.com/locate/nima
Medical applications of synchrotron radiation in Australia R.A. Lewis Centre for Synchrotron Science, Monash University, Clayton, Victoria 3800, Australia Available online 19 April 2005
Abstract The Australian synchrotron is being built at Monash University near Melbourne. The 3 GeV machine is well-suited to the mid X-ray region and will have nine beamlines in its initial phase. The high level of biomedical research in Australia has led to the demand for a beamline capable of supporting medical research in both imaging and therapy. The design features for a versatile imaging and hard X-ray beamline capable of operating in the energy range 10–120 keV are outlined here together with a short review of some of the science that is envisaged. r 2005 Elsevier B.V. All rights reserved. PACS: 87.59. e; 87.59.Bh; 87.53. j; 07.85.Qe Keywords: Synchrotron radiation; Phase contrast X-ray imaging; Microbeam radiotherapy; Lung imaging
1. Introduction The Australian synchrotron, currently under construction at Monash University near Melbourne, Victoria, is scheduled to begin operation in early 2007. The design of the machine was chosen to satisfy the following objectives [1]:
that it should be competitive with other third generation compact facilities under construction; that it should have adequate beamline and experimental stations to satisfy 95% of the research requirements of an expected Australian community of 1200 different researchers; and Tel.: +61 3 9905 3622; fax: +61 3 9905 3637.
E-mail address: [email protected].
provide internationally competitive performance for essentially all Australian industry requirements.
The chosen design parameters of the ring are given in Table 1. The machine is designed to provide high performance in the X-ray energy range, 100 eV to approximately 65 keV. The location of the Australian synchrotron is in the eastern suburbs of Melbourne some 20 km from the city center, on the main campus of Monash University, Australia’s largest university. At the time of writing 13 beamlines are planned covering the whole range of synchrotron techniques. Nine of these beamlines have been chosen for the first phase of funding and one of those is an
0168-9002/$ - see front matter r 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.nima.2005.03.061
ARTICLE IN PRESS R.A. Lewis / Nuclear Instruments and Methods in Physics Research A 548 (2005) 23–29
Table 1 Basic properties of the storage ring boomerang 20 [1] Energy (GeV) Circumference (m) Current (mA) Revolution time (ns) Usable straight sections Length of straight sections (m) Bending magnet field (T) Betatron tune—H Betatron tune—V Dispersion (m) Natural emittance (nm rad) Beam size in straights [H (mm), V (mm)] Beam size in dipoles [H (mm),V (mm)]
Centre, the largest teaching hospital in Victoria, is just 1.5 km from the synchrotron site.
3.0 216 200 720.5 12 5.397 1.3 13.30 5.20 0 15.81 389.21 98.72
2.4 6.98 340.13 77.48
imaging and medical applications beamline which is described in the following section.
2. Imaging and therapy beamline Australia has a well-developed biomedical research capability and Melbourne in particular has a large number of medical research groups. This community has identified a pressing need for a beamline capable of performing advanced studies on both biomedical imaging techniques and novel radiotherapies. An added impetus for such a facility arises from the unusual Australian ecology with its unique flora and fauna. The result is that there are diseases which are unique to Australia and others that are common elsewhere but which do not occur in Australia. The concomitant strict customs and quarantine laws mean that many samples may not be transported over national boundaries thereby providing a major drive for the establishment of a biomedical beamline. The location of the Australian synchrotron at Monash University provides some significant advantages for biomedical synchrotron work. Facilities already existing on campus include fully equipped biomedical, chemical, physics and computer laboratories as well as a major animal house. In addition the campus of Monash Medical
2.1. Beamline design The beamline will be sourced from a variable field superconducting wiggler covering the energy range 10–120 keV. A limiting factor imposed by the design of the beamline front end is that the deflection parameter of the insertion device, K, may not exceed 20. Coupled with a 48 mm magnetic period, the K limitation yields a maximum field of 4.4 T. A 31 period device having this field and period will deliver both high flux at high energy for therapy applications and also provide a wide intrinsic fan beam for large object imaging. The brightness of the proposed beamline is compared with the medical beamline at the ESRF and the biomedical imaging and therapy beamline being built at the Canadian light source, in Fig. 1. An important but difficult design goal of the beamline is to preserve flexibility without sacrificing performance. Flexibility is vital since we wish to explore a number of imaging modalities including propagation-based projection imaging [2] using both monochromatic and white beam as well as analyzer-based methods [3]. The flexibility will be implemented by having several in line hutches which can be used for a variety of purposes. The basic layout is illustrated in Fig. 2
Flux Density (phts/s/mr2/0.1%bw)
24
1E16
1E15
1E14 AS CLS
1E13
ESRF 1E12 1
10
100
10
Energy (keV)
Fig. 1. The brightness of the Australian imaging and therapy beamline (AS) compared with the proposed BMIT at the Canadian light source (CLS) and ID17 at the ESRF.
ARTICLE IN PRESS R.A. Lewis / Nuclear Instruments and Methods in Physics Research A 548 (2005) 23–29
25
Fig. 2. Proposed layout of the imaging and therapy beamline.
and shows 3 of the 4 proposed hutches. The first hutch will house the beam conditioning optics whilst the second and third hutches are multipurpose.
Table 2 Nominal dimensions of the beam in mm, at various distances from the source for different wiggler field strengths Distance (m)
Field (T)
20
2.2. Imaging modes For imaging there are a wide variety of options. The first main imaging station is located inside the experimental hall at a distance of approximately 40 m from the primary source, while the second station is located in a separate imaging center some 135–150 m from the source. This latter station is optimized for plane-wave experiments including large samples, live animal imaging, tomography, and topography. Eventually it is envisaged that humans will also be imaged and the imaging center will contain MRI, PET CT and other facilities in addition to the synchrotron imaging suite. Without any focussing, the beam dimensions are shown in Table 2. It is clear that the combination
Energy (keV)
150 150 150 40 40 40 20 20 20
4.4 3 2 4.4 3 2 4.4 3 2
60
100
X
Y
X
Y
X
Y
954 618 366 254 165 98 127 82 49
54 42 30 14.4 11.2 8 7.2 5.6 4
726 426 234 194 114 62 97 57 31
30 30 18 8 8 4.8 4 4 2.4
582 342 186 155 91 50 78 46 25
30 18 18 8 4.8 4.8 4 2.4 2.4
of high field and a long distance results in a horizontal beam width rather larger than required and so either focussing or an aperture will be required.
ARTICLE IN PRESS 26
R.A. Lewis / Nuclear Instruments and Methods in Physics Research A 548 (2005) 23–29
For projection-based imaging we intend to utilize both simple projection from the source as well as an effective secondary source produced by focusing devices. The focussing methods may include the use of bent crystals in Laue mode in the optics hutch as well as secondary focusing devices such as Kirkpatrick-Baez mirrors or a compound refractive lens inside the first experimental station. The beamline is intended to provide a flexible facility for use for in-line imaging both at high spatial resolution and/or large object size. It will provide the capability to develop and apply the inline approach in a near optimum fashion, both with white and narrow-band radiation, especially for biomedical and ultimately clinical medical imaging. For many of the envisaged in-line imaging applications it has been shown that broadband polychromatic radiation may well be sufficient [2]. The use of so-called pink beam produced using multi-layers having much broader band pass than crystal monochromators may also allow short exposure times and hence rapid dynamic imaging. 2.3. Therapy mode The main interest within Australia for the use of synchrotron radiation in radiotherapy is in microbeam radiotherapy [4]. For this method it is crucial that a high dose be delivered to the target tissue in a very short time. The reason behind this is that the beneficial aspects of this type of therapy are thought to arise from the unirradiated tissue located in the valleys between peaks of dose delivered by an array of micro-beams. Since the most effective spacing between the micro-beams appears to be around 100–200 mm [5], it is necessary that the dose be delivered in a timescale short enough that the subject has not moved enough to eliminate the valleys between the peaks. To that end it is important to perform the therapy as close as possible to the source point in order to maximize the available flux. In therapy mode therefore, it is planned to mount the collimator that creates the micro-beams in the first optics hutch whilst the animal and positioning system will be located in hutch 2 approximately
Table 3 Dose rates in the first experimental hutch for different wiggler field strengths Field (T)
Dose rate (Gy/s)
2 3 4.4
259 2789 13522
20 m from the source point. It is necessary to filter out the low energies and the beam energy filtration system will also be located in the first optics hutch. The predicted surface entrance dose rates in the first experimental hutch with 1.5 mm Cu filtration are given in Table 3. Other workers [4,6] have shown that dose rates in excess of 2000 Gy s 1 are sufficient for some successful experiments and so it can be seen that a field of 3 T or above will be necessary.
3. Phase contrast imaging One of the major applications planned for this beamline is X-ray phase contrast imaging. Much of the pioneering work in this field originated in Melbourne[2,7] and so it is particularly appropriate that the medical beamline on the Australian synchrotron have a strong emphasis on this kind of work. 3.1. Small animal imaging Whole animal models are increasingly important in biomedical research, particularly in understanding complex physiological processes, where the complex interrelationships between organ systems mean that it is necessary to study a complete functioning animal. There is, however, a significant problem with animal models in that it is often necessary to perform invasive procedures or even sacrifice the animals in order to acquire the necessary information. Such procedures can have significant unwanted effects upon the normal functioning of the animal and hence may confound the data. In addition, the common practice of sacrificing
ARTICLE IN PRESS R.A. Lewis / Nuclear Instruments and Methods in Physics Research A 548 (2005) 23–29
animals at different stages of an experiment, in order to follow a pathological process or treatment process, is predicated on the assumption that the disease (or treatment) progresses in the same manner in different animals. Obviously this may not be the case and it is clear that some form of non-invasive method of following through a process to completion in a single animal would be highly beneficial. The added contrast sensitivity of phase contrast X-ray imaging and its ability to visualize soft tissue with short exposures offers a means of obtaining information in a non-invasive manner. As such it may be possible to perform longitudinal studies of disease (or treatment) progression in each animal. Since many biomedical processes are distributed throughout the body involving multiple organ systems, it is important to be able to perform whole body scans. In principle, phase contrast Xray imaging can provide quantitative three-dimensional information at high spatial resolution over a whole animal, enabling investigation and crosscorrelation of separated processes. No other imaging method can currently combine micron level resolution with high sensitivity, good time resolution and soft tissue contrast. The vast majority of the work in X-ray phase contrast imaging to date has been concerned with developing the technique and exploring the limits of the imaging systems from a physics standpoint. Quite a few spectacular ‘demonstration’ images have been recorded but as yet the technique has found only limited application in the solving of real medical problems. Part of the reason for this is the need to extract quantitative information from the images and a considerable amount of work in this field has been performed in Australia. 3.2. Extracting quantitative information There are three main types of X-ray phase contrast imaging having varying degrees of applicability for medical imaging [8]. The first technique utilizes an interferometer [9] and whilst rather elegant and sensitive, is not well suited to either large or dynamic objects. Consequently it is not envisaged that the interferometric technique will be established on the Australian synchrotron, at
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least in the early stages. The second method utilizes a crystal analyzer to determine the phase shifts [3,10] whilst the other makes use of free space propagation to allow interference to render the phase shifts visible as intensity changes [2]. A considerable amount of work has been performed in developing analysis techniques which can extract quantitative information from the resulting images [7,11–14]. Almost all of them, however, rely upon the acquisition of multiple images of the same object to allow the phase information to be extracted. In the context of biomedical imaging this represents a major problem since we are typically concerned with the imaging of dynamic objects which move significantly over timescales of milliseconds. In such circumstances it becomes impossible to record two or more images of the object which can then be satisfactorily used as input to the phase retrieval algorithms. New approaches developed by researchers at Monash University and CSIRO are seeking to address this issue [16–18]. A number of approaches are being explored but one solution would be a way to extract quantitative phase information from a single image. One method of attacking the problem is to make use of any a priori information about the object under investigation. In fact it transpires that the problem becomes soluble if one makes the assumption that the object is a single material embedded in a substrate of approximately uniform thickness [16]. Whilst such an assumption may appear at first sight to be ludicrously simplistic, there are a number of applications in biomedical imaging where it is not unreasonable. For example, phase contrast imaging of the lungs can be considered as imaging air within a liquid matrix. Whilst of course the situation is more complex than this, the algorithms developed to perform the phase extraction under this assumption turn out to be quite robust [16,19] and are therefore being applied in the area of lung imaging. 3.3. Phase contrast in developmental biology Phase contrast X-ray imaging is spectacularly successful in revealing lungs as illustrated by the
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Fig. 3. Analyzer-based image of the thorax of a 1-month-old mouse recorded at Spring-8 using 33 keV X-rays and a Silicaon 3,3,3 reflection. Adapted from [15].
image in Fig. 3. A peculiarly Australian aspect in the context of developmental biology is that of lung development in marsupials. The tammar wallaby, for example, is born after only 4 weeks gestation and lives external of the womb from day 28 of development. At birth the neonate is highly underdeveloped, however, it displays some remarkable adaptations for external life including developed lungs and associated air passages. This is in stark contrast to prematurely born humans where breathing difficulties caused by underdeveloped lungs are common. One fledgling project in Australia led by Dr Whitley, from the Department of Primary Industries in Victoria is using high-resolution phase contrast X-ray imaging of the tammar wallaby lung to try to understand how lungs develop. Initial results are extremely encouraging and a test image is shown in Fig. 4. As can be seen from this figure, the lack of development of bones makes the wallaby neonate an almost pure phase object. With almost all the contrast arising from air tissue
Fig. 4. Propagation-based phase contrast image of a 2-day-old tammar wallaby recorded on BL20XU at Spring-8 with 33 keV X-rays. Adapted from [20].
interfaces in the lungs making propagation-based phase contrast imaging ideal for such studies. 3.4. Clearance of lung liquid and aeration of the lung at birth Another important biomedical problem where phase contrast X-ray imaging can play a major part is in understanding the dynamics of liquid clearance from the airways at birth. The problem is significant in that the survival of newborn infants is critically dependent upon the lungs taking over the role of gas exchange immediately upon birth. Prior to birth, gas exchange occurs across the placenta and the lungs are filled with lung liquid [21]. The transition to
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pulmonary gas exchange at birth is dependent upon a complex interaction of physiological, physical and biochemical processes. The absence to date of an adequate method of producing rapid time resolved lung images has greatly hindered understanding of these mechanisms. For example, the process of the clearance of liquid from the lungs at birth and the impact of patient position on the distribution of retained liquid within the lung remains unknown. Since much of the fluid is cleared within less than a minute of birth, time resolved imaging is crucial. Propagation-based phase contrast imaging with a synchrotron is ideally suited to the production of X-ray movies of this process due to the simplicity of the system and the high flux levels permitting short exposure times.
4. Conclusion The Australian synchrotron will provide a much needed facility that will enable most aspects of synchrotron related science to be performed on Australian soil. The imaging and therapy beamline will enable not only physics-based imaging and therapy research, but also a wide range of biomedical projects which cannot currently be considered due to the difficulty of transporting samples. In particular, the demonstrated capability of phase contrast X-ray imaging to visualize lungs in vivo has given rise to several projects within Australia, which will exploit this technique in order to improve the understanding of lung development and physiology.
Acknowledgements I am grateful to Drs. Steven Wilkins, Andrew Stevenson, Sherry Mayo and Karen Siu for their enormous help and expert input into the imaging and therapy beamline. I am also greatly indebted to Drs. Jane Whitley and Stuart Hooper for having the great vision and enthusiasm that initiated the lung imaging projects.
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