The invention relates to an irradiation verification apparatus for beam therapy systems, wherein the irradiation verification apparatus contains living cell material which is fixed in location in the three spatial co-ordinates x, y and z in a container having an insert, on cell supports of the insert. An irradiation verification apparatus of such a kind is known from the publication of A. Mitaroff et al. entitled “Biological Verification of Heavy Ion Treatment Planning”, Radiat Environ Biophys (1998) 37, pp. 27-52. Irradiation verification apparatuses are used for checking the effectiveness of a radiation scheme before a beam therapy system is released for the treatment of humans.
In the case of the irradiation verification apparatus described in the above publication, the living cell material is mounted on plastics slides having a width of 9 mm, a length of 53 mm and a thickness of 1 mm. These slides, having been coated with cell material, are slid between two slotted plates, the slots in the plates corresponding to the width and thickness of the plastics slides and allowing room for the cell coating, so that they are located at a defined spacing horizontally relative to one another and are fixed using a third, uninterruptedly slotted plate.
An insert prepared in that manner, containing slides coated with living cell material, is placed in a cylindrical container and brought into an irradiation position, for example as a so-called “head phantom”, which position corresponds to the irradiation position of, for example, a human head for irradiation of a tumour. For verification, the radiation program is instituted and the “head phantom” is correspondingly irradiated, the position of the killed cells in the volume of the container being subsequently determined using the slides.
The known model has the disadvantage that for precise demarcation the slides having a width of 9 mm and a height of 52 mm provide a resolution orthogonal to the beam in the x and y directions which precludes a high degree of resolution. As a result, the transition region between irradiated tissue and non-irradiated tissue can be identified only relatively imprecisely in the edge regions or transition regions. In the irradiation direction, it is not possible to mount living cells because in that case it is only the side face of 1 mm of the slides that is available. This results in a resolution of 9 mm for the resolution in the x direction and in a resolution of 52 mm in the y direction, especially as the slides cannot be sub-divided.
It is furthermore disadvantageous that the cell support consisting of a slide is pulled through two slots in the holding plates before and after irradiation so that uncontrolled damage may occur to the cell material, thereby falsifying the results.
From the publication W. G. Wouters “Measurements of Relative Biological Effectiveness of the 70 MeV Proton Beam at TRIUMF using Chinese Hamster V 79 Cells and the High Precision Cell Sauter Assay”, Radiation Research Vol. 146, pp. 159-170 (1996), Radiation Research Society, there is known an irradiation verification apparatus wherein the living cells are contained within a nutrient gel which is used to fill a hollow tube which is beam-transparent. During the irradiation, the gel mass in the hollow tube is cooled down to 4° Celsius so that the gel becomes hard. After irradiation, the gel mass can be removed from the tube and separated into slices, and the local distribution of activatable living cells compared to killed material can be ascertained by means of reculturing. This irradiation verification apparatus would, if a number of tubes are stacked next to one another, provide a resolution in the x and y directions of only 12 mm, because a sufficient gel mass is necessary for the development and survival of the cells and the diameter of the hollow cylinders cannot be reduced further.
Even though, by separating the gel into thin slices of 2 mm, a high degree of resolution in the z direction can be achieved, carrying out the experiment has shown that there is a high risk of the slices not being cut with a uniform width so that, in that case, precise location determination of the sample position with associated dose determination is no longer possible.
Whilst the irradiation verification apparatus according to W. G. Wouters accordingly provides a good depth profile if the gel samples are taken with appropriate precision, the irradiation verification apparatus according to A. Mitaroff et al. provides additional information relating to the distribution in the x and y directions, but with less resolution potential.
The problem for the invention is to provide an irradiation verification apparatus for beam therapy systems whose resolution capability is greater and which also, as a result, allows more reliable checking of a planned irradiation scheme. Furthermore, the operability should be facilitated with improved resolution in order to provide more rapid results.
The problem is solved by the subject-matter of the independent claims. Advantageous developments of the invention are given by the dependent claims.
In accordance with the invention, an irradiation verification apparatus is provided which contains living cell material which is fixed in location in the three spatial co-ordinates x, y and z in a container having an insert, on cell supports. The cell supports are arranged between cell support holders. For irradiation verification, the z spatial co-ordinate in the irradiation verification apparatus is adjusted in the direction of the beam axis Z so that, after the irradiation, regions having killed cell material can be demarcated in spatial co-ordinates, with reference to an irradiation scheme, from regions having cell material of the irradiation verification apparatus that is still active.
The container having the insert for the cell supports and the cell support holders comprise a beam-transparent material. The cell support holders comprise a bottom plate and a top plate, between which the cell supports are arranged orthogonally to the holding plates. The holding plates have blind holes aligned with one another, in which the ends of the cell supports are arranged. The cell supports are solid rods on the outer surfaces of which the cell material is fixed or grown.
An irradiation verification apparatus of such a kind has the advantage that it is quick and simple to assemble once the rod-shaped cell supports have living cell material on their outer surfaces. In addition, during assembly, that is to say when inserting the solid rods into blind holes in the base plate and when mounting the top plate on the cell rods by inserting the free ends of the cell rods into the blind holes of the top plate, the exposed outer surfaces having the cell material cannot be damaged as has been the case with the customary slide solution. Finally, the solid rods can be stacked between the holding plates with their blind holes so densely that a high degree of resolution is achieved both in the beam direction, or z co-ordinate, and in the horizontal x co-ordinate.
For the vertical y co-ordinate, an especially high degree of resolution can be achieved, by separating the solid rods, after the irradiation, into thin slices whose edges bear cell material. For cell supports, a cell-compatible material can be provided, especially having a density close to water of about 1 g/cm3 and, especially, free from metals and elements having a higher atomic number than oxygen. For the purpose, the cell supports are preferably of a polystyrene material, which has the advantage that it can be separated precisely and simply into individual slices with a small spacing and a low outlay.
The high packing density of the two holding plates is increased, in a preferred embodiment of the invention, by arranging the cell supports in rows offset from one another between the holding plates. In that arrangement, rows having an even number of solid rods, or cell supports, alternate with rows having an odd number of solid rods. If, at the same time, a minimum spacing between the rods is maintained, the resolution in the irradiation direction and in the horizontal x direction is substantially improved compared to previous irradiation verification apparatuses, especially as for a large test volume all three spatial directions can be checked.
In order to cover a large irradiation volume corresponding approximately to a human head and therefore also referred to as a “head phantom”, preference is given to using cell supports having a length l between 25 mm≦l≦75 mm, preferably a length l of about 50 mm. The measurement length, or outer surface, of those rods that is covered with living cells is, however, shorter, because, for example, such a rod is fixed about 10 mm into a blind hole in a base plate and also, for fixing the free end in a top plate, part of the length, for example 5 mm, disappears in turn into a blind hole in a top plate of such a kind.
The diameter d of the solid rods is crucial to the resolution in the irradiation direction Z, that is to say of depth measurement using the irradiation verification apparatus, and to horizontal deflection X of the beam in the x direction.
That diameter d in millimetres is 1.0 mm≦d≦5 mm, especially 1.5 mm≦d≦5 mm; the diameter is preferably about 3 mm.
The resolution in the beam direction and the resolution of the horizontal deflection of the beam also depends on the minimum spacing a, in millimetres, between the cell supports, that spacing a being between 0.5 mm≦a≦5 mm; the spacing a in millimetres is preferably 2.5 mm.
In order that the solid rods of polystyrene are not loaded with a high clamping pressure between the two holding plates or damaged, projections are provided at the peripheral sides of the holding plates, which rest on spacers between the holding plates so that the rod-shaped cell supports are advantageously positioned in the base plate and top plate with a loose fit. In addition, the depth of the blind holes in the base plate can be greater than the depth of the blind holes in the top plates so that the rods introduced into the base plate, despite a loose fit, are subject to more precise alignment in the direction of the top plate.
In order to facilitate the introduction of the pillar-shaped, or rod-shaped, cell supports into the blind holes, the blind holes in the holding plates have a tapered countersink of their outer edges. As a result of this countersink, the rod-shaped cell supports slide into the blind holes provided, without any damage. The irradiation verification apparatus preferably has a number S of cell supports in the form of solid rods of 150≦S≦900 and especially 400≦S≦900.
The living cells on the outer surfaces of the solid rods have and need to be supplied with nutrients, for which gas(es) can be dissolved in the nutrient medium, for example oxygen and/or carbon dioxide. Therefore, in a further preferred embodiment, one of the two holding plates is provided with through-holes in addition to the blind holes; in a preferred embodiment of the invention a through-hole is provided always in the centre of a triangle formed by three neighbouring blind holes, in order to allow, for example, nutrient solution to flow through.
In order to allow precise assignment of the positions of the rod-shaped cell supports, preference is given to providing the rod positions on the base plate and/or on the top plate with marking lines or consecutive position numbers.
In addition, the insert has, as extensions to the spacers for the holding plates, further extensions directed to the base of the container which serve as standing legs.
Because, in the case of a biological irradiation verification apparatus of such a kind, the nutrient liquid at the rods has to be kept moving, the container has, in the base region between the base plate of the insert and the base of the container, at least one stirring system, which is arranged in an intermediate space created by the standing legs. The container, which for installation of the insert is open to the top, additionally has at least one inlet aperture and outlet aperture for media such as nutrient liquid and/or oxygen. By means of the media apertures it is possible for the internal space of the container to be supplied with appropriate nutrient solutions and/or oxygen whilst the loading aperture at the top is closed once the insert has been put into position.
The irradiation verification apparatus according to the invention is preferably used in beam therapy systems such as X-ray beam therapy systems or proton beam therapy systems; in particular, the irradiation verification apparatus according to the invention has been developed for helium ion beam therapy systems and/or carbon ion beam therapy systems.
A method for the operation of the irradiation verification apparatus according to the invention comprises the following method steps. First, outer surfaces of rod-shaped cell supports are provided with active living cell material. That is then followed by assembly of an insert for a container of the irradiation verification apparatus. For that purpose, the cell supports having living cell material are put together between two holding plates, with the assembled insert being secured by means of spacers. In the process, marking of the base plate is of benefit to assembly and subsequent disassembly, as is also the provision of deeper blind holes in the base plate, in which the rod-shaped cell supports can be aligned and erected securely.
The complete insert is then introduced into the container, which in the meantime has been filled with nutrient liquid. In addition, oxygen is supplied to the container by way of an inlet aperture and, if necessary, also with additional fresh nutrient solution. Afterwards, orientation of the x, y and z spatial co-ordinates of the irradiation verification apparatus relative to the beam direction Z of the irradiation system is carried out. The planned irradiation scheme can then be implemented, with simultaneous or subsequent temperature control, for example cooling or warming, of the nutrient liquid in order to preserve the results. After disassembly of the cell supports from the insert, they are separated into slices. The cell material that is still alive on the edges of the slices is detected. Subsequently, the results can be compared to the irradiation plan with reference to the selected analytical end-points.
This method of operation clearly shows the advantage of this irradiation verification apparatus compared to customary techniques for the biological verification of beam therapy systems.
The invention will now be explained in greater detail with reference to the accompanying Figures.
The base plate 5 shown here in the assembly position has a thickness of about 12 mm and has rows of blind bores or blind holes 8, which are arranged at a pitch of 5.5 mm next to one another in rows 14 and 15. The depth of the blind bores 8 in the base plate 5 is greater than that of the blind bores 9 in the top plate 6. In this embodiment of the invention, the blind bores 8 and 9 have a diameter of 3.2 mm, whilst the rod-shaped cell supports 3 have a diameter of 3 mm. For the purpose, the solid rods 12 of the cell supports 3 are made from polystyrene and have on their outer surfaces 13 living cell colonies. The number of rods in this embodiment of the invention is 587.
This cell material 12 covers the outer surface 13 and extends over the entire length l of the rod-shaped cell supports 3 as far as the first end 10, which is introduced to 10 mm in blind holes 8 in the base plate 5 with a play fit. Of the rod length l of 50 mm, a further 3.5 mm is arranged in blind holes 9 in the top plate 6 so that a net rod length, where the outer surface 13 is covered with cell material, of 36.5 mm is available perpendicular to the beam axis for the biological verification of a planned irradiation scheme. The top plate, which is only 5 mm thick, has, in addition to the blind holes 9 for accommodating the cell supports 3, through-holes 27, through which oxygen and nutrient solution can flow into the region of the cell cultures. For that reason, the top plate 6 shown here will, in the irradiation position, occupy the lower holding plate position.
The pieces projecting out beyond the top plate 6 in
The rod-shaped cell carriers 3 are arranged in 24 rows and rows of 23 or 24 solid rods 12 having cell material on the outer surfaces 13 are arranged offset relative to one another between the cell support holders 5 and 6, or holding plates 5 and 6. In order to maintain a prespecified spacing between the plates 5 and 6 without subjecting the rod-shaped cell carriers 3 to loading, pocket holes having a diameter of 8 mm and a central through-hole of 3.2 mm are arranged in four projections 17-20, so that hollow cylinders having an internal thread can be used as spacers 16 so that the upper cell support holder 5 can be fixed to the spacer using Nylon threaded rods or screws and the lower cell support 6 is connected by means of threaded rods and the standing legs 30 screwed onto the threaded rods. As a result of the spacers 16 with internal thread rods a precise framework for fixing the cell supports in location relative to the base of the container is provided, it being possible for the standing legs to be introduced into prefabricated elements (not shown) on the base 30 of the container 2 in order to accomplish precise adjustment of the cell supports 3 relative to the beam direction Z of the irradiation system in the irradiation position.
Number | Date | Country | Kind |
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10 2006 011 828.6 | Mar 2006 | DE | national |
10 2006 031 496.4 | Jul 2006 | DE | national |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/EP2007/002156 | 3/12/2007 | WO | 00 | 9/15/2008 |