Recent developments of ion sources for life-science studies at the Heavy Ion Medical Accelerator in Chiba (invited) Open Access

One of the important features of heavy-ion beams is a high linear energy transfer (LET). In the case of a relatively low dose, this characteristic provides different effectiveness on DNA structures: cell death or mutation. A proton beam shows a similar LET as do photons, like X rays and gamma rays. The higher LET obviously exists in the case of ions heavier than Li. Since the range of heavy-ion beams in materials is too short for living creatures, it is rare to find such a difference in the usual living environment. On the other hand, heavy ions like Fe are minor components of galactic cosmic ray.¹ The risk of heavy-ion beams with an energy of over several hundred MeV is one of the important topics used to study the space environment. Furthermore, heavy-ion beams are utilized for radiotherapy.² In the case of carbon ions, an energy of 430 MeV/u is necessary to realize a range of 30 cm in water. The relative biological effectiveness (RBE) is defined as the ratio of a biological effect by gamma rays to that by other radiation. RBEs in tumor cells and in normal tissues are basic essentials for heavy-ion radiotherapy.³ 

There are two experimental methods for the above-mentioned life-science studies. One is micro-beam experiments; low-energy single ions irradiate cell samples with an accuracy of sub-micrometers in order to investigate microscopic processes.⁴ The other utilizes relativistic high-energy heavy-ion beams to observe macroscopic phenomena under situations similar to the environment of space or radiotherapy. There are a few facilities with sufficient capability in the world. Some research facilities are dedicated to nuclear and high-energy physics, such as BEVALAC at the past Lawrence Berkeley Laboratory.⁵ Unfortunately, it has already been shut down. There are also AGS at the Brookhaven National Laboratory⁶ and SIS at the Gesellschaft fur Schwerionenforschung,⁷ which have carried out life-science studies. The heavy ion medical accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS) was constructed as the first medical-dedicated heavy-ion synchrotron in 1994. HIMAC treated more than 9000 patients since 1994.⁸ It is utilized as a second essential task to operate as a users facility for basic experiments in, e.g., physics, chemistry, material science, and life-science studies.

A schematic diagram of the HIMAC beam courses is shown in Fig. 1. HIMAC has six treatment rooms and four experiment rooms. One of the treatment rooms is under construction. The general irradiation room has two beam courses, named PH1 and PH2, and has the thickest wall of radiation shielding. The secondary beam-irradiation room has two beam courses, named SB1 and SB2, with on-line isotope separators in order to produce radioactive nuclear beams for various experiments, including medical applications. A medium-energy experiment room, named MEXP, utilizes ion beams with a fixed energy of 6 MeV/u from the injector linac. The biology irradiation room, named BIOC, has an irradiation system similar to one of the treatment rooms in order to reproduce the same conditions as the treatment; a sample changer is installed for cell and animal experiments. It is an important policy to separate a treatment room and a biology experiment room in order to prevent any biohazard. Patients have been treated during the daytime from 9 AM to 7 PM on weekdays. Half of every Monday is reserved for maintenance or research as well as developments without any beam. Experiments including life-science studies have been carried out during the night from 9 PM to 7 AM on weekdays and for a whole day on Saturday. Ten-hour treatments and 10-h experiments are done in a 2-h interval every weekday. Only carbon ions are delivered for these treatments. The exchange between carbon and other ion species should be performed during the 2-h intervals. A typical exchange time is less than 1 h.

The design of the neutron shielding has limited the maximum intensities and energies of each ion species. In the cases between H and Si, the maximum energy was designed for a range of 30 cm in water. From Si to Xe, the energy was limited by the magnetic rigidity of the synchrotrons or beam-transport lines. The approved maximum intensities and energies of the beams at PH1 and PH2 are 1.8 × 10⁹ pps for 430 MeV/u C, 4.0 × 10⁸ pps for 800 MeV/u Si, 2.5 × 10⁸ pps for 750 MeV/u Fe, and 1.3 × 10⁸ pps for 610 MeV/u Xe. The approved maximum energies at BIOC for ions heavier than Ne, like Si, Fe, and Xe, are 600, 560, and 460 MeV/u, respectively. The stability of the beams is important. HIMAC is capable of realizing ultra-low-intensity beams with several particles per second. The reliability is also important. The failures that have disturbed the scheduled treatments and experiments were 0.2%–0.3% of the total beam time during every year.

The number of accepted proposals and the total beam time of the biology experiments per year were about 70 users and 1000 h, respectively. The experiment time in biology was generally shorter than the experiments in other fields, e.g., physics or material science. The mean time for one user was 2.2 h. In order to increase the operating efficiency, several users who used the same ion species and energy were gathered into one night as much as possible. They shared the beam time. Of course, if a user desires, changing the ion species and energies during one night is available, although additional intervals are required.

Another specific requirement for biology experiments has been a periodic irradiation. In order to study the DNA repair process or the dependence on cell cycles, some experiments required a series of irradiations divided into some fractions. An accurate interval between each fraction was necessary during several days or a few weeks. The scheduled beam time should not be delayed in such experiments. The ion species required by users of the biology experiment in the recent three years are also listed in Table I. Two thirds of the beam time were C beams. Kr and Xe were not included in these three years; however, these were sometimes required. Since the LET near the Bragg peak was determined by its charge, it is important for the biology users to cover a wide range of atomic numbers. On the other hand, the needs for specified isotopes are very rare for the biology users, as compared with those of the nuclear-physics users, except for medical applications of radioactive nuclear beams.⁹ 

Most biology experiments require a uniform irradiation field at cell samples or animals. The necessary beam intensity depends on the field size, the beam energy, and the efficiency of an irradiation method. In the case that it is necessary to use a uniform irradiation volume, we spread the range of the beam to vary the beam energy, the so-called “spread-out Bragg peak.” However, the transport efficiency is decreasing by about one order. For example, 1.8 × 10⁹ pps carbon beams satisfy 3 Gy/min in a diameter of 10 cm and a thickness of 6 cm at BIOC. An ion source is required to produce 200 eμA for C⁴⁺ or 100 for C²⁺. 2.5 × 10⁸ pps Fe beams to satisfy 5 Gy/min in a diameter of 10 cm at the mono-energy peak. An ion source is required to produce 200 eμA for Fe⁹⁺.

The short-term stability of the ion sources is not so sensitive because the fine structure of the beam pulse will mostly disappear during acceleration in the synchrotron. On the other hand, the long-term stability and reproducibility after restarting are more important. Some biology experiments require the measurements under the same dose rate. The stability and reproducibility should cause variations of less than 10%. This directly translates to the ion-source requirements.

The switching time between two different ion species at an ion source is too long for the 2-h intervals at HIMAC. Therefore, two ion sources have been set up for each ion production; then, they are switched at intervals. All ion sources are prepared during their off time. Since the daily accelerator operator is not a specialist of ion sources, the automatic setup system is important. The HIMAC ion source system controls and monitors all devices of the ion sources, including the power supplies, gas feedings, movable equipment, and vacuum pumps. It is able to store the good, optimized parameters of all devices, and to reproduce the same conditions. Of course, if an ion source is exposed to the atmosphere, such reproducibility is destroyed, and it takes a long time for recovering the vacuum condition. HIMAC generally hesitates to have any maintenance work conducted in the atmosphere. There were usually several maintenances per a half year.

Shorter switching times of the ion sources are better for the daily operation efficiency. The switching time depends not only on the kinds of ions, but also on the hysteresis of the produced ions. The reproducibility and the stability after switching are strongly affected by the previous produced ions. One example of such a hysteresis is shown in Fig. 2. The beam intensities of C⁴⁺ were measured by one of the ECRISs. In case 1, the source was operated in a stable condition with CH₄ gas; it was then switched from CH₄ to Ne, and then returned to CH₄. The recovering time was less than 2 h, and the stability was sufficiently reproduced. However, in case 2, the source was switched from CH₄ to O₂, and then returned to CH₄; the recovering time was longer than 6 h and the beam became unstable. The deposition of carbon on the chamber wall caused a decreasing of the C⁴⁺ intensity. The original operation parameters were optimized as the stable condition in such a dirty situation. It seems that neon did not affect the carbon deposition; on the other hand, oxygen washed out the carbon atoms from the wall, or was absorbed into the deposited amorphous carbon. Therefore, the original operation parameters could not reproduce the previous condition in case 2. It is suggested that the balance of carbon and oxygen should be as constant as possible for good stability and reproducibility.

At the beginning of HIMAC operation in 1994, a low-duty pulsed PIGIS, named NIRS-PIG,¹⁰ and a 10 GHz ECRIS, named NIRS-ECR,¹¹ covered all requirements between He and Ar. However, NIRS-ECR was mostly occupied in the production of carbon ions for treatments, and there was hesitation to interrupt stable operation by the production of other ion species. NIRS-PIG had insufficient intensities for higher charged ions, and maintenance was a tremendous and ceaseless effort for unseasoned operators. In order to meet earnest and repeated requests to utilize ions heavier than Ar, NIRS decided to extend the ion species up to Xe, and to install a new ion source as the third ion source. An 18 GHz ECRIS, named NIRS-HEC, was constructed in 1996.¹² Afterward, an additional injector linac with a permanent magnet ECRIS, named Kei2,¹³ was installed, and utilized for the production of carbon ions. Although NIRS-ECR shares its responsibility for carbon production with Kei2; NIRS-HEC was dedicated to produce ions heavier than Ar.

In order to extend the range of available ion species, NIRS-HEC was designed to reach a high extraction voltage. This is because optimization of the extraction configuration is most effective for the production of intermediate charge-state ions with a charge-to-ratio of 1/7, which is required by the injector linacs. The extraction electrode is electrically isolated from the ground, and a high-voltage power supply on the source potential safely applies the extraction voltage between the plasma electrode and the extraction electrode, independent of the source potential. The maximum voltage between the plasma electrode and the extraction electrode is 60 kV. In order to facilitate electric insulation, NIRS-HEC has the vertical structure shown in Fig. 3. The position of the electrode can be easily changed. “HEC” means the high-voltage extraction configuration with two optimized parameters; the voltages and distances between the electrodes.

A microwave frequency of 18 GHz was chosen for a reasonable ECR zone by the normal conducted mirror magnets and the permanent sextupole magnet. The maximum mirror fields at the injection and extraction sides are 1.3 and 1.2 T, respectively. When NIRS-HEC was constructed, the diameter of the plasma chamber was 40 mm, and the radial sextupole magnetic field at the chamber wall was 1.1 T. However, the beam intensity was disappointing. The dependence on the radial magnetic field was optimized based on the following assumptions: highly charged ions are localized inside the ECR zone; and the ions’ trajectories are tightly bound to the magnetic flux line from the ECR zone to the extraction aperture. Optimization by the TrapCAD calculation code¹⁴ is described in Ref. 15. As a result, the inner diameter of the sextupole magnet was increased from 46 mm to 66 mm under the same radial magnetic field at the chamber wall. Thus, the extracted intensities increased by four times. Later, an 80 mm sextupole magnet was tested, and its intensity was lower than that of the previous one. Therefore, the optimization was confirmed at 66 mm, consistent with the simulation.

Any change of the vacuum condition is undesirable for the reproducibility as mentioned above. It is mainly caused by any change of the surface conditions on the chamber wall, or outgassing due to heating-up of the parts inside. In order to prevent outgassing, the plasma chamber and most parts in vacuum have cooling water channels. A 3 kW CW total power of microwaves is available by this cooling system. Pulsed operation of microwaves is also effective to reduce the transient time between different conditions.

The almost twenty-year old NIRS-HEC has had problems due to deterioration, year by year. We encountered some failures during these three years, e.g., a small leakage of cooling water in the vacuum, an abrasion on the beam slits, as well as damage to the motors in the blowers and movable rods, and so on. Routine checks are important to maintain the quality.

No oven, no insertion rod, and no electron-beam evaporator have been utilized for operating NIRS-HEC at present. Although trials concerning the evaporation systems from solid materials have continued,¹⁶ we still have not found any solutions concerning the above-mentioned situation of the biology experiments. The metal ion volatile compound method (MIVOC) is a method¹⁷ used to apply metallic vapors from volatile metallic compounds including the requested elements. MIVOC was adapted for the production of Fe and Ni ions. The biggest advantage of MIVOC is to be able to use a solid sample as if it is a gas. It is easy to operate and to maintain, and the equipment is small. The ion species can be changed without exposing the vacuum chamber to the atmosphere. A drawback of MIVOC is generally a huge contamination of carbons, which causes a decrease in the intensities of highly charged ions and the reproducibility. However, this drawback is negligible in our situation. Our sources are always dirty due to carbon depositions. As mentioned before, the production of carbon ions is the first priority at HIMAC.

NIRS-HEC has a long-distance gas feed line. Its small conductance sometimes causes an insufficient flow rate of gasses. We developed a thermal control system for the MIVOC container.¹⁸ It is able to maintain a sufficient flow rate by increasing the temperature of the container. In addition, this control system was designed to decrease the consumptive rate of compounds by cooling. It is thus cost effective to use expensive compounds, including rare isotopes.¹⁹ Moreover, control of the temperature is suitable to obtain sufficient reproducibility for easy operation.

The two-frequency heating technique (see Section III B) is very sensitive to the gas pressure, especially in cases of highly charged ions. It works between 0 °C and above room temperature. We developed a seamless temperature control system, and carried out trials.

NIRS-HEC successfully supplied most of the required ion species; however, the intensity of heavier ions, like Xe, does not reach the limitation of the neutron radiation shielding. We thus fed RF power into an ECRIS at two frequencies; the so-called two-frequency heating technique.

This two-frequency heating technique was initiated by ECR pioneers Jongen and Lyneis in Berkeley, and some years later more successfully by Xie and Lyneis, again at Berkeley.²⁰ Since then many ECR laboratories have tested this technique. The two-frequency heating technique has advantages: it is effective for any kind of ion species, it is coexistent with most other techniques, and no modification of the existing structure is necessary. Between 1998 and 2013 numerous experiments were carried out at NIRS; in each experiment a positive effect of the second microwave was demonstrated.²¹ The mechanism is still not completely clear. Our basic observation is that when the primary microwave power increases, the plasma shows instability. When additional microwaves are added in the above situation, the plasma stability is improved at some larger microwave power obtained by the mixture of two different frequencies of microwaves. The important points needed to obtain the highest effectiveness with this technique are as follows:

• To supply sufficient power for both microwaves.

• To precisely adjust the additional frequency. The best frequency depends on the operation parameters: magnetic configuration, vacuum pressure, and so on.

The primary microwave source is an 18 GHz fixed-frequency klystron (KLY) amplifier system with a maximum power of 1500 W. The additional source is a traveling-wave tube (TWT) amplifier system with a frequency range from 17.10 to 18.55 GHz and with a maximum power of 1200 W. Of course, power stability is important for reproducibility. Therefore, both microwave systems have an installed power feedback system.

The maximum output current of 200 eμA for Xe²¹⁺ was obtained by a two-frequency heating technique under good conditions. However, this maximum current decreased under the dirty daily condition. The typical output current for Xe²¹⁺ of NIRS-HEC was 120 eμA. The injected and extracted beam intensities of the synchrotron were 50 eμA for Xe⁴²⁺ and 4.1 × 10⁷ pps for Xe⁵⁴⁺, respectively. There is still room for further development to improve the performance of the established NIRS-HEC. The present maximum output currents of NIRS-HEC are given in Table II.

Recently, another interest has arisen from the fruitful results of the two-frequency heating technique. Several organizations have made plans to construct a hospital-specified carbon-ion radiotherapy facility. However, in order to carry out biological experiments to encourage basic research, there are occasionally requirements to produce various other ion species. Since the injector design is fixed for the acceleration of ions with a charge-to-mass ratio of about 1/3, the performance of the Kei-series, which has been installed in the existing facilities, does not satisfy such requirements. We developed a new compact ECRIS, named Kei3,²² for ion species between He⁺ and Si⁹⁺. Kei3 is now under commissioning. However, the production of highly charged ions, like Ar¹³⁺ or Fe¹⁸⁺, will not be possible with that source. We thus tested the ion production with a charge-to-mass ratio of 1/3 by NIRS-HEC.

Fig. 4 shows a typical mass spectrum of Fe from ferrocene. All operation parameters were optimized for Fe¹⁷⁺, and its intensity was 12 eμA. In this case, the after-glow technique was effective. The microwave powers of 18.0 GHz and 17.87 GHz were 700 W and 600 W, respectively, while both generators were set with a microwave width of 50 ms. The injection and extraction side mirror magnetic fields are 1.21 T and 0.77 T, respectively. The extraction voltage and distance between the plasma electrode and the extraction electrode are 31 kV and 20 mm, respectively. The gas flow of O₂ is 0.030 atm cm³/min. The temperature of the MIVOC container is 13 °C. The vacuum pressure at the injection-side chamber was 2.5 × 10⁻⁵ Pa. Although the peak of Fe¹⁸⁺ was covered by the peak of O⁵⁺, the intensity was estimated at about 2 eμA from measurements with the narrower slit width and from the appeared charge-state distribution. With this current, the HIMAC can deliver a dose rate of several Gy/min within a diameter of 20 mm at BIOC. However, it is better to obtain more intensities for a wider irradiation area or animal experiments at a hospital-specified facility.

The importance of fine tuning of the second microwave frequency was observed in early stages of our development.²³ It is usually considered that the plasma instability of ECR heating plasma with a minimum B structure is not a magnetohydrodynamic instability, called “macroscopic instability,” but a “microscopic instability,” like a velocity space instability. Especially, in an ECR ion source for the production of highly charged ions, a great deviation of the electron energy distribution from a Maxwell-Boltzmann distribution and anisotropy of its velocity distribution may adversely affect the plasma stability. We guessed that the additional frequency controls the anisotropy of the electrons’ velocity distribution, which may affect the plasma instability. Some recent observations of the additional frequency dependence suggested that an electron orbit effect might play some role.²¹ One approach to verify or to reject this assumption is a computer simulation. Calculations by the TrapCAD code have continued.

Ion-beam technology is a powerful tool for life-science studies. There are still many continuous needs for medical research and various biology experiments with relativistic high-energy ion beams. A rich variety of ion species, from hydrogen to xenon ions, is expected by users in order to study the dependence on the charge of ions. Since the mean time of biology experiments is about 2 h, it is difficult to satisfy all of them by only an ion source, due to a long interval necessary for switching ion species. Therefore, any facility, which hopes to carry out life-science studies, should probably have a few ion sources at present.

Heavy ion radiotherapy has awakened worldwide interest recently.² Presently, there are eight facilities in operation, and six facilities are under construction. There are many other constructions under planning or budget requests. The possibility to fit out such a hospital-specified facility for biology experiments can be realized through improvements of the ion source’s performance by the MIVOC technique, the two-frequency heating technique, and so on. The switching interval time becomes a serious problem.