RARAF: Microbeams, Broad Beams, and Beyond Andrew D. Harken, Guy Y. Garty, Malek Haj Tahar, Gerhard Randers-Pehrson, David J. Brenner Radiological Research Accelerator Facility Columbia University 136 S. Broadway, PO BOX 21 Irvington, NY 10562 [email protected] ABSTRACT The Radiological Research Accelerator Facility (RARAF) at Columbia University is dedicated to the delivery of known quantities of radiation to biological samples and the effects on these samples from the cellular to systemic level. Over the past 25 years, RARAF has been instrumental in the development of single-cell, single-particle ion microbeam irradiation systems. We have progressed from a pin hole aperture, to focusing electrostatic quadruplets, to a superconducting solenoid system with subsequent reduction in beam spot sizes through these developments. The RARAF facility has broad beam irradiation technologies that allow for large cell population and tissue irradiation simulation for comparison to the single cell irradiations from the microbeam. System intercomparisons allow for the elucidation of the effects of radiation from the cellular response to tissue response, ultimately, to systemic responses to radiation injury and treatments. We are developing a ‘heavy’ ion microbeam with future applications toward the simulation of heavy ion therapy using fixed field alternating gradient (FFAG) accelerators. KEYWORDS microbeam, heavy-ion therapy, biological irradiation, FFAG 1. INTRODUCTION The Radiological Research Accelerator Facility (RARAF) was founded in 1967 as a collaboration between Brookhaven National Labs and Columbia University [1]. RARAF, through the years, has developed many irradiation modalities to study the effects of radiation on biological samples. These modalities include neutrons, charged particles, and photons. The development of the microbeam facilities at RARAF have been ongoing for the past 25 years. These microbeams include charged particles, x-rays, UV and neutrons. Microbeams allow for sub-micrometer spatial and temporal placement of known quantities of radiation in a tissue. The RARAF microbeam has been used for cellular studies, tissue studies and small animal irradiation studies. RARAF is based at the Nevis Laboratories of Columbia University in Irvington, New York. We have approximately 10,000 square feet of laboratory space centered around our 5 MV Singletron Accelerator from High Voltage Engineering Europa (HVEE). Our laboratories are spread out across 3 floors and include full cell biology facilities as well as the beam lines and end stations of an accelerator facility. We are dedicated to radiobiology and radiation effects on living organisms. What is presented here is a review of the RARAF microbeam facilities with an emphasis on the charged particle microbeams, a comparison to our broad beam irradiation systems, and a discussion as to the future direction of the microbeam systems and irradiation technologies at RARAF. AccApp '17, Quebec, Canada, July 31-August 4, 2017 13 2. MICROBEAMS 2.1 Charged Particle Microbeams RARAF has designed, built and operated several variations of charged-particle microbeams: an aperture microbeam, an electrostatically focused microbeam, a permanent magnetic microbeam focused microbeam and a superconducting solenoid focused system. The primary use of the microbeam is the investigation of cell cultures where the delivery of particles to single cells is known, down to a single particle per cell. The microbeam also allows for studies where a certain percentage of the cells in culture, say 10%, are irradiated and guarantee that the remaining 90% do not receive any irradiation energy allowing for the basic study of non-targeted effects, i.e. bystander or abscopal effects. Each of the microbeams have their own characteristics and opportunities with their associated beam sizes in Table I. Table I. RARAF microbeam systems and corresponding beam sizes Type of microbeam Beam Size Aperture Microbeam 8 μm Permanent Magnet Quadrupole Triplet 5 μm Electrostatic Quadrupole Quadruplet 5 μm Electrostatic Double Quadrupole Triplet 0.6 μm Superconducting Solenoid 0.4 μm Superconducting Solenoid with Electrostatic Double Triplet 0.1 μm 2.1.1 Aperture microbeam The aperture microbeam was our first microbeam. The aperture system collimated the beam using a 5 μm diameter collimator followed 300 μm above by a 6 μm anti-scatter collimator [2]. This provided a main beam (~92%) 6 μm in diameter with a ‘‘penumbra’’ (~7%) 8 μm in diameter due to particles scattered by the first collimator that were transmitted through the second collimator. The beam size was measured using the knife edge occlusion method we still use today [3]. 2.1.2 Electrostatic quadrupole quadruplet To eliminate the penumbra scattering and further decrease the beam size, RARAF designed and built a pair electrostatic focusing systems. The first focusing lens was an electrostatic quadrupole quadruplet design by Drs. Randers-Pehrson and Alexander Dymnikov [4] constructed of four ceramic rods with four electroplated gold sections with insulating separations as electrodes. The rods were held equally spaced from one another, clamped with v-blocks and precision ground spacers at the insulating sections, forming quadrupoles of the plated electrodes among the four rods. The lens was run with a ‘‘Russian’’ symmetry (potentials +A, –B, +B, –A) to produce a circular beam spot of minimum size. This system achieved a beam spot size of 5 μm. AccApp '17, Quebec, Canada, July 31-August 4, 2017 14 2.1.3 Electrostatic double quadrupole triplet Our second focused microbeam system was based on our electrostatic quadruplet system, but designed for sub-micron focusing [3]. Optics calculations for the design of a multiple quadrupole system to focus the beam to submicron size determined that two quadrupole triplets with a Russian symmetry (potentials +A, –B, +C, –C, +B, –A) would be required. This electrostatic double triplet quadrupole system consisted of two lenses of similar construction to the electrostatic quadrupole, but with only three elements per lens. The two lenses were separated by 2 m with the first lens providing the object for the second lens. The overall focusing system length from the object aperture to the focal point was just over 4 m. This system has a beam spot size on 0.6 μm. 2.1.4 Permanent magnet microbeam Development of a microbeam using permanent magnets began in 2004 [5]. The focusing design was the same as for the electrostatic double triplet microbeam: a pair of permanent magnet quadrupole triplets where strengths of the permanent magnets themselves are fixed and adjustments in quadrupole field strength are made by moving magnets slightly in or out relative to the quadrupole center. This permanent magnet microbeam (PMM) system was originally designed to be used as a stand-alone microbeam with a radioactive alpha source (210Po) as the ion source, however, it became politically untenable to get the amounts of polonium needed for the ion source after the poisoning incident in London. The object aperture was redesigned and the PMM was attached to our Singletron beamlines as the source for He++ ions. This microbeam system has a focused beam spot size of 5 μm and is used primarily as a development end station for our microfluidics projects [6-8]. 2.1.5 Superconducting solenoid microbeam We are currently developing a microbeam based around a superconducting solenoid system for focusing our ion beams to ~100 nm. This system will use a combination of the double triplet electrostatic lens as the first elements for the solenoid focusing lens. The solenoid alone, as a first development step, has focusing capabilities of less than 0.4 μm. This microbeam will replace the double triplet electrostatic microbeam as the primary microbeam system at RARAF. The solenoid microbeam system is undergoing final testing and will be more fully reported on in a future manuscript which is in preparation. 2.2 X-ray Microbeam A second type of microbeam that we have developed is an X-ray microbeam. This microbeam is designed using the principle of PIXE to generate soft x-rays [9]. Unlike electrons, protons generate relatively no bremsstrahlung and therefore an essentially monoenergetic X-ray beam is produced. A proton beam is focused by an electrostatic quadrupole quadruplet (from our previous microbeam incarnations) into an elliptical spot on a titanium target (4.5 keV Kα X rays) with an angled surface, which is embedded in a copper rod for cooling. X rays emitted in the vertical direction are focused using a 120-μm diameter zone plate to a 5 μm diameter beam spot determined, as for the charged particle microbeams, using a knife- edge occlusion method; however, in this case, only the amount of transmitted beam is measured as the occluded beam is absorbed. A beam current of 2 μA on the target yields an X-ray dose rate of 0.10 mGy/s (approximately 10 photons absorbed/targeted cell nucleus/sec). 2.3 Neutron Microbeam In 2009, RARAF began development on a neutron microbeam, which is particularly difficult since neutrons have no charge and therefore cannot be focused and neutron collimation is limited to much larger beams due to scattering. Near the threshold for the Li(p,n)7Be reaction at 1.881 MeV incident AccApp '17, Quebec, Canada, July 31-August 4, 2017 15 proton energy, low-energy neutrons (~60 keV) are emitted in a very narrow forward angular distribution. At the back of a very thin lithium target, the diameter of this cone can be tens of microns [10]. A quadrupole quadruplet focuses the 1.886 MeV proton beam onto a gold foil 20 μm thick with a 1 μm thick coating of 7LiF. In 2013 the proton beam was focused to a 10 μm diameter and a 36 μm diameter neutron beam was measured. This is the first neutron microbeam in the world. The neutron dose rate provided by the 10 nA proton current is estimated to be 270 mGy/min. 3. BROAD BEAM SYSTEMS 3.1 Track Segment Irradiator In 1976 the ‘‘track segment’’ facility was developed by Colvett and Rohrig to irradiate cell monolayers with charged particles having a narrowly defined LET [11].