Preliminary experiments in vitro and in vivo have indicated that a number of medical applications of the secondary particle and photon sources induced by high-intensity short-pulse lasers may become practical. Following is a summary of some of these applications.
Ultra-high-intensity laser interaction with solid and liquid targets can induce bright point-like sources of hard X-rays. Such sources can produce high resolution, high contrast X-ray transmission images through samples of interest. Phase-contrast imaging is also enabled by the spatial coherence of the X-rays generated by these sources. These features cannot be achieved with ordinary X-rays emitted from tubes.
D1.1 Phase-Contrast In-Line Imaging and X-ray Computed Tomography
An international study used Canada’s Advanced Laser Light Source with 200 TW ultra-high-contrast pulses (5 J, 28 fs, 10 Hz repetition rate) to generate hard X-rays to make phase-contrast images of biological objects.1
1 S. Fourmaux, S. Corde, K. Ta Phuoc, S. Buffechoux, S. Gnedyuk, A. Rousse, A. Krol, and J.C. Kieffer, 2011, Initial steps towards imaging tumors during their irradiation by protons with the 200TW laser at the Advanced Laser Light Source facility (ALLS), Proc. of SPIE 8079: 80791I-1.
Experiments have been under way to investigate the feasibility of phase-contrast imaging of tumors in an in-line geometry and proton acceleration for irradiation of tumors by protons, with the same laser producing both the X-ray imaging and the proton acceleration. Early experiments demonstrated that both single-shot phase-contrast imaging and proton acceleration to 12 MeV could be achieved with the same ultrafast laser.
In-line X-ray phase-contrast imaging provided improved density resolution imaging with applications in soft tissue biomedical imaging; it requires an X-ray source with a very small effective size so as to be spatially coherent. In 2005 a laser-based hard X-ray source was first demonstrated to produce high quality inline phase-contrast imaging with a single pulse. Different parts of the X-ray wave diffracted by the sample interfere with each other and provide the in-line phase contrast imaging. Multiple pulses can create multiple images that have been extended to micro-tomography of a bee, showing details not seen before.2
Quantitative phase-contrast micro-tomography from a compact laser-driven X-ray source was reported in 2015 by a group from Germany using their ATLAS laser, which generated X-rays at 8.8 keV by betatron radiation from laser wakefield-accelerated electrons. The 60 TW pulses delivered 1.6 J of energy in 28 fs, with peak intensity of 1019 W/cm2. Electrons from the plasma are trapped into this wave by wavebreaking and accelerated to relativistic energies around 200–400 MeV. The raw phase-contrast image exhibited edge enhancement, although there were no optical elements between the source and the detector; Fresnel diffraction caused the images. A single edge-enhanced image is, itself, useful to produce high-resolution features in the presence of poor absorption contrast.3 Researchers at Imperial College in London have a program to produce a bright μm-sized source of hard synchrotron X-rays (critical energy Ecrit > 30 keV) based on the betatron oscillations of laser wakefield-accelerated electrons using their Astra-Gemini laser facility.4 The potential of this source for medical imaging was demonstrated in 2015 by performing micro-computed tomography of a human femoral trabecular bone sample, allowing full 3D reconstruction to a resolution below 50 μm. The pulses were 40 fs long and 11 J was delivered to the target and focused with a parabolic mirror, with a peak intensity ~1.8 × 1019 Wcm–2. With high peak brightness, each image is recorded with a single exposure, reducing the time required for a full tomographic scan.
2 R. Toth, J.C. Kieffer, S. Fourmaux, T. Ozaki, and A. Krol, 2005, In-line phase-contrast imaging with a laser-based hard x-ray source, Rev. Sci. Instrum. 76: 083701.
3 J. Wenz, S. Schleede, K. Khrennikov, M. Bech, P. Thibault, M. Heigoldt, F. Pfeiffer, and S. Karsch, 2015, Quantitative X-ray phase-contrast microtomography from a compact laser-driven betatron source, Nature Communications 6: 7568.
4 J.M. Cole, J.C. Wood, N.C. Lopes, K. Pode1, R.L. Abe, S. Alatabi, J.S.J. Bryant, et al., 2015, Laser-wakefield accelerators as hard x-ray sources for 3D medical imaging of human bone, Scientific Reports 5: 13244.
These properties make this an interesting laboratory source for many tomographic imaging applications.
Diagnosis and treatment of osteoporosis requires knowing their microstructure, which cannot be seen in regular radiography. The small-scale structure of bone requires 3D imaging with at least 100 μm spatial resolution. X-ray computed micro-tomography (μCT) is now the leading method for determining the internal microstructure of human bone. It requires, however, higher beam energy to be medically relevant. By using wakefield acceleration to near-GeV levels, the X-ray spectrum and brightness were sufficient for single-shot bone imaging while maintaining the advantageously small X-ray source size.
Hadron ion beams (i.e., protons and heavier ions) are preferred in the radiotherapy of malignant tumors, compared to widely used X-rays or electrons, because they show little spatial scattering and their kinetic energy is deposited primarily near the end of their trajectory. Compared to X-rays or high-energy electron beams, a high-energy hadron beam more precisely irradiates tumors with considerably smaller deposition in surrounding healthy tissue. The existing accelerator technology for high-energy ion beams, cyclotrons, and synchrotrons, plus the beam transport technology and radiation shielding, is complex, very costly, and available only in a few large-scale facilities. The demand for more compact, flexible, and less costly high-gradient acceleration and beam transport techniques is, however, evident.
High-intensity laser-driven ion beams have been suggested as a potential alternative to conventional ion accelerators for radiotherapy. When a laser pulse with intensity above 1018 W/cm2 interacts with a thin foil target in vacuum, a strong electrostatic field exceeding 1 TV/m is generated at the downstream surface, which can surpass the ion-acceleration field typical of conventional accelerators by six orders of magnitude. A unique feature of laser acceleration is the extremely high peak current attributed mostly to the short duration of a single proton bunch.
Global research is under way, with the hope that laser-accelerated proton beams can become the dominant technology for proton radiotherapy. However, this goal is still a long way off: laser-driven hadron accelerators must have medically relevant beam parameters and performance levels suitable for clinical usage.5 Research toward the practicality of laser-accelerated ion beam therapy for cancer patients is under way in a number of countries.6
D2.1 Initial Biological Experiments
In 2009 the first experiments to demonstrate the biological effects of high-current, short-bunch ion beams accelerated by lasers took place in Japan. The researchers demonstrated that laser-generated proton irradiation causes breaks in
5 K.W.D. Ledingham, P. McKenna, T. McCanny, S. Shimizu, J.M. Yang, L. Robson, J. Zweit, et al., 2004, High power laser production of short-lived isotopes for positron emission tomography, J. Phys. D: Appl. Phys. 37(16): 2341.
6 Countries include Japan (J-KAREN), Germany (Dresden Laser Acceleration Source and CALA [a collaboration between LMU and TUM]), United Kingdom (LIBRA collaboration at TARANIS and the Terawatt laser at Queen’s University), and the United States (Brookhaven at the Accelerator Test Facility using a CO2 laser and Philadelphia’s Fox Chase Cancer Center).
This initial research was followed by groups of researchers in a number of countries to determine the dose dependence and to better understand the biological damage created in tumor cells. A group in Dresden, Germany, formed a collaboration between medical personnel and physicists to study dose-dependent biological damage due to irradiation of in vitro tumor cells with laser-accelerated proton pulses.8
D2.2 Recent Progress Toward Cancer Therapy
Progress in Japan was achieved in 2011 by modifying the previous J-KAREN laser system to produce a monoenergetic proton beamline for laser-generated protons.9 The experiments were planned to determine the relative biological effectiveness for cell inactivation by laser-accelerated MeV ions of cultured cancer cells from the
7 A. Yogo, K. Sato, M. Nishikino, M. Mori, T. Teshima, H. Numasaki, M. Murakami, et al., 2009, Application of laser-accelerated protons to the demonstration of DNA double-strand breaks in human cancer cells, Applied Physics Letters 94(18): 181502.
8 S.D. Kraft, C. Richter, K. Zeil, M. Baumann, E. Beyreuther, S. Bock, M. Bussmann, et al., 2010, Dose-dependent biological damage of tumour cells by laser-accelerated proton beams, New J. Phys. 12: 085003.
9 A. Yogo, T. Maeda, T. Hori, H. Sakaki, K. Ogura, M. Nishiuchi, A. Sagisaka, et al., 2011, Measurement of relative biological effectiveness of protons in human cancer cells using a laser-driven quasimonoenergetic proton beamline, Applied Physics Letters 98: 053701.
human salivary gland (HSG cells). Irradiated cells were immediately removed and placed in an incubator for 13 days, after which they were fixed and stained. Any colony consisting of more than 50 cells was counted as a surviving colony. The ratio of biological effectiveness in killing cells of a laser-generated proton beam was compared to 4 MeV X-rays from a clinical Linac, given the same amount of absorbed energy. The proton beam was slightly more effective in killing cancer cells than the X-rays by a ratio of 1.2.
Laser-accelerated protons have the unique characteristic of being deposited in bunches at very high intensity. Several experiments have compared laser-accelerated protons with conventionally accelerated protons. The experiments irradiate living tumor cell cultures, determine their killing rates, and compare them with the rates of conventionally accelerated proton beams.10
The UK has been carrying out similar research through a UK-wide consortium called Laser Induced Beams of Radiation and Applications (LIBRA). Its aim has been also to develop laser-driven ion sources with a particular focus on biomedical applications, noting that particularly high-profile application for laser-driven ion beams is particle therapy for cancer treatment. The LIBRA program, centered at The Queen’s University of Belfast, realized that practical systems will require significant improvements from the performance of today’s laser-driven accelerators.11
The next year, in a collaboration with University of Birmingham and its hospital as well as the Ion Beam Centre at University of Surrey, the same researchers studied proton irradiation and the biological effect of proton irradiation on human V79 cells and compared it to data obtained with the same cell line irradiated with an X-ray source with peak 225 kV energy conventionally accelerated protons. They saw a similar relative biological effectiveness in killing cells as was seen in Japan: the Relative Biological effectiveness was 1.4, which means the protons were 40 percent more likely to kill cells at the same dose rate than the X-rays.12
Recent research in Munich with the 200 TW ARCTURUS laser system at the University of Düsseldorf, Germany, found that laser-accelerated proton bunches might provide a real advantage over the longer synchrotron pulses. Their studies suggest that, while the biological effectiveness of laser-accelerated protons and
10 S. Raschke, S. Spickermann, T. Toncian, M. Swantusch, J. Boeker, U. Giesen, G. Iliakis, O. Willi, and F. Boege, 2016, Ultra-short laser-accelerated proton pulses have similar DNA-damaging effectiveness but produce less immediate nitroxidative stress than conventional proton beams, Nature Scientific Reports 6: 32441.
11 M. Borghesi, S.Kara, R. Prasada, F.K. Kakolee, K. Quinn, H. Ahmed, G. Sarri, et al., 2011, Ion source development and radiobiology applications within the LIBRA project, Proc. of SPIE 8079: 80791E-1.
12 F. Hanton, D. Doria, K.F. Kakolee, S. Kar, S.K. Litt, F. Fiorini, H. Ahmed, et al., 2013, Radiobiology at ultra-high dose rates employing laser-driven ions, Proc. of SPIE 8779: UNSP 87791E.
conventionally accelerated protons are roughly equal with regard to double strand breaks in DNA and tumor cell killing, they have found that laser-accelerated proton pulses apparently produce less immediate nitroxidative stress.
D2.3 Consortia Working on Laser-Accelerated Proton Beams for Cancer Therapy
While these experiments were carried out and reported, research consortia have been formed and funded throughout Europe to investigate the clinical future of proton irradiation, particularly with femtosecond bunches of protons, with technology originating from mode-locked Ti-sapphire lasers.
Clinical trials using proton and carbon beams are under way in several countries with traditional cyclotron and synchrotron accelerators. One of the chief obstacles to wide-scale use of particle-based therapy, however, is the large cost of the accelerators. For example, the Heavy Ion Medical Accelerator in Chiba, Japan, had a construction cost of almost 300 million dollars, but it can treat only 200 patients a year—a small fraction of cases that could benefit from this form of cancer therapy. Motivated by a desire to reduce the size and cost of radiotherapy facilities, researchers in Japan are setting out to combine a 100 TW, 20 fs laser with a special purpose pulsed synchrotron that will accelerate carbon ions. The ultimate goal of this effort is to produce a device that can be installed in a hospital, with reductions in size, by an order of magnitude, and in cost, by a factor of five compared with existing devices.
The Technical University of Munich and Ludwig Maximilians University of Munich have jointly built a new 70-million-Euro laser center expanding on their already existing, broad range of research into laser science and technology for applications in the fields of life sciences and medicine. Research at CALA aims at developing laser-based technologies in order to improve the cure rates of cancer patients through a combination of early detection and targeted particle therapy. These technologies also offer the potential for the early detection of other chronic diseases such as osteoarthritis, atherosclerosis, and diffuse lung diseases, which—like cancer—seem to show increasing prevalence. It was initially scheduled to be commissioned in 2016 but has seen some delays.
CALA’s plan is first to include brilliant X-rays produced by a compact laser-driven or laser-assisted source to localize the tumor by means of advanced imaging techniques. This procedure, if successfully demonstrated, will allow recognition of the primary tumor at a stage when the probability for metastases is still very low. Secondly, knowing precisely the anatomical site of the tumor offers the prospect of curing the patient with a localized, high-precision, laser-driven radiation and particle therapy. Both parts of the clinical procedure are expected to use the same laser source. The novel techniques hold promise for improving present diagnostic
and therapeutic capabilities as well as reducing the socioeconomic cost of combat-ting several chronic diseases.
In the UK, acceleration to high energies (several tens of MeV/nucleons) has been possible only on large Nd:glass systems, such as the Vulcan laser at RAL, up to hundreds of joules in ps pulses. But they operate only on a single shot basis (i.e., a laser shot every 20 minutes or so). Biomedical applications are expected to require many well-controlled pulses, and most interesting systems are based on Ti:Sapphire technology, which reach high powers by providing smaller amounts of energy (up to a few joules) in pulses a few tens of fs long, and can operate at higher repetition rate. For example, the Gemini system currently operational at RAL delivers laser pulses at 20-second intervals, but emerging laser technologies based on diode pumping of the amplifier media have the potential to deliver within a few years high power pulses with much higher repetition. These high repetition rates will be needed for use in cancer therapy or radioisotope production, and upgrades to simultaneously increase intensity and repetition rates are the direction of their research.
D2.4 Medical Research Under Extreme Light Infrastructure
The Extreme Light Infrastructure (ELI) project described in Chapter 3 identifies several great challenges in molecular, biomedical, and material sciences of the 21st century:
- Measuring the mechanisms of physical and chemical processes at the atomic scale.
- Controlling electronic processes in matter. In addition to that, nuclear dynamics following the electronic events should represent a subject of control.
- Understanding the complexity—efficient methods should be developed to control and investigate various processes in real, i.e., highly complex, systems in the state as they are present in nature.
- Nanometer scale imaging of arbitrary objects in their native state, e.g., capturing a living cell at nanometer resolution. Nanometrically resolved dynamics of their responses to various stimuli.
The well-known medical procedure positron emission tomography (PET) at present requires the nearby presence of a synchrotron to create the short-lived radioactive sources that provide the positrons. Ultra-intense lasers show promise of creating the necessary radioactive sources, although none have yet been demonstrated to be practical. Initial studies are under way in UK, Japan, and elsewhere. This is one of the justifications for ELI, and studies are under way to investigate the feasibility of this approach.
PET is a powerful medical diagnostic/imaging tool. Many chemical compounds can be labeled with positron emitting isotopes, and their bio-distribution can be determined through PET imaging as a function of time: “Positron emission tomography (PET) is a powerful diagnostic/imaging technique requiring the production of the short-lived positron emitting isotopes 11C, 13N, 15O, and 18F by proton irradiation of natural/enriched targets using cyclotrons. The development of PET has been hampered due to the size and shielding requirements of nuclear installations. Recent results show that when an intense laser beam interacts with solid targets, MeV protons capable of producing PET isotopes are generated using a petawatt laser beam. The potential for developing compact laser technology for this purpose is high.”13 Research in this area is also under way in the UK using the new petawatt arm of the Vulcan Nd: Glass laser at RAL. Esirkepov et al. have discussed the production of mono-energetic protons using layered targets.14 Some recent calculations at Strathclyde conclude that if quasi-monoenergetic protons replace the present quasi-exponential distribution, then a further significant improvement is possible.
13 K.W.D. Ledingham, et al., 2004, High power laser production.
14 H. Schwoerer, S. Pfotenhauer, O. Jäckel, K.-U. Amthor, B. Liesfeld, W. Ziegler, R. Sauerbrey, K.W.D. Ledingham, and T. Esirkepov, 2006, Laser-plasma acceleration of quasi-monoenergetic protons from microstructured targets, Nature 439: 445–448.