Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
(Electron) Accelerators and Medical Diagnostics
Medical Diagnostics: imaging of biological tissues, micro-
imaging of cells/proteins using radiation beams (IR to X-rays)
Luca Serafini - INFN / Milano
• IR spectro-microscopy @ DANE, Solar UV effect studies with UV
beamline @ DANE, X-ray Absorption Spectroscopy on thin samples
• Radiological imaging with mono-chromatic tunable X-rays (10-500 keV)
generated by Thomson scattering @ SPARC
• Proteine Cristallography with coherent X-rays generated by the X-FEL (SPARX)
3 Examples of Advanced Medical Diagnostics performed by means of
Accelerators delivering High (peak/average) Brightness Electron Beams
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
X-Ray beam quality goes along with upgrade of electron beams
Since the invention of Crookes tubes (step! Roengten…)DC 106 photons/sin 1 (mm.mrad)2
0.1 % bandwidth10-50 keV electrons
Up to modern (still under design) photo-LINACs
producing high brightness electron beams to
drive X-FELs (coherent X-ray beams)1034 ph/s in 1 (mm.mrad)2 0.1 % bandwidth 100 fs pulses
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Linac CenterLine
Sector 20 Linacs
Straight AheadTune-Up Dump
Sector 21-1B
5 meters
Scale:
L0-1
L0-2
RF TransverseDeflector
EmittanceWire Scanners Energy Wire
Scanner & OTR
Matching Section
Quadrupole,typ.
RFGun
Cathode LoadLock
DL1 Bend
Linac Solenoid
Gun Solenoid
Gun-to-Linac
L0 Linacs
Linac Coherent Light Source@ SLAC
X-Ray Free Electron Laser
SLAC Linac
Two Chicanes for bunch compression
FFTB TunnelUndulator Hall
Near Hall
Far Hall
Courtesy of Max Cornacchia
15 GeV e- beam using1/3 of SLAC Linac
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
X-ray sources over the last 100 years: the story ofa marriage between electron beams and X-rays
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
• Brilliance (10 orders of magn. > 3rd generation SR sources)
• Transverse Coherence (diffraction limited) Pulse time structure < 100fs
• Spontaneous Radiation peaked atr u / 22(1 + K2) u = 2 cm = 3.104 (15 GeV) r =1 Å, 12 keV
Synchrotron radiation rules next generations: Thomson back-scattering of virtual photons
vs.
Bremsstrahlung on metallic targets
w
r
rad
Free electron laser
Undulator
Wiggler
Dipole in storage ring
mrad
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
SASE-FELs will allow anunprecedented upgrade in
Source Brilliance
Brilliance of X-ray radiation sources
Covering from the VUV to the 1 Å X-ray spectral range:
new Research Frontiers
SPARX
TTF
12.4 1.24 0.124 (nm)
PLASMON-X
Compact Thomson Sourcesextend SR to hard X-ray range
allowingAdvanced Radiological
Imaging inside Hospitals
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Design parameters
Beam energy : 510 MeV
Max number of bunches : 120
Bunch spacing : 2.7 ns
Bunch current : 40 mA
Single bunchluminosity : 4·1030 cm2 s1
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
DANE I = 400 mA
Av. Brilliance of SR from DANEcompared to existing facilities
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Solar Ultraviolet Effect and UV beamline at DANE-L
Application investigation of the biologicaleffects on human cell cultures (HeLa-x humanskin fibroblast) of irradiation by UV B band:i) dose and wavelength dependence;ii) threshold effects;iii) death & neoplastic transformations.
0 5 10 15 20 25 30 35 40 45 50 55 600.1
0.2
0.3
0.4
0.5
0.6
0.7
0.80.9
11.1
292 nm 285 nm 295 nm
Surviving fraction
Dose ( J/ m 2 ) 0 10 20 30 40 50 60
0
2
4
6
8
10
12
Dose (J/m2 )Transformation frequency/surviving cell
(10
-5)
285 nm 292 nm 295 nm
Characteristics JobinYvon gratingMonochromator and mirrors in air:i) UVB band (280-320 nm);ii) resolution better than 0,3 %;iii) doses from 20 to 40 J/m2 .
pollinelinfociticellule ematichebiomassevirus
SINBAD@10 microns
IR spectromicroscopy
BRUKER Equinox 55BRUKER IRscope 1
March 18, 2004March 18, 2004
by A. Marcelli
Mid-IR
Transmission of 10 m pinhole
IR
Spectromicroscopy
• Cancer cells investigation
• W. Kwiatek•The Henryk Niewodniczański Institute of Nuclear Physics
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
X-ray Absorption Near Edge Spectroscopyof low Z elements (Mg, Al, P, S, Cl, K, Ca) and transition metals (up to Cd)
The Soft X-ray beamline at DANE:Fixed exit monochromator with double Si(111) or Quartz(1010) crystalsIon Chamber detectors for appling XAS in transmission on thin samplesEnergy range from 1 up to 4 keV
2.466 2.468 2.470 2.472 2.474 2.476 2.478 2.480 2.482 2.484 2.486
0.0
0.5
1.0
1.5
2.0
2.5
3.0
GSH (reduced)one sulfur atom
GSSG (oxidized)one disulfur bond
Abs [a.u.]
E [keV]
Sulfur redox state in proteinsX-ray spectroscopy of S in Glutathione (mM)
2.13 2.14 2.15 2.16 2.17 2.18
0.0
0.2
0.4
0.6
0.8
1.0
P4 red δ =/E eV
280 & /pts sec pt
[ . .]A a u
[ ]E keV
Phosphorus K edge
Gianfelice Cinque
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
From 3rd to 4th Generation…..
• SASE-FELs (protein single shot imaging)
• Thomson Sources (compact 3rd generation sources
aiming at advanced medical imaging inside hospitals)
All need High Brightness e- beams
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Brightness of Electron Beams isthe Key Issue
Quality Factor : beam peak current density normalizedto the rms beam divergence angle (linked to transverse beam coherence)€
Bn , Bn{ } ≡2 I , I{ }
εnxεny
A
m2rad 2
⎡
⎣ ⎢ ⎤
⎦ ⎥I = peak current in fs to ps long electron bunch<I> = average current over 1 snx = rms normalized transverse emittance
z
’
x
x’
eq
’high
’low
Brightness is crucial to maintain colliding or copropagating (e-, h) beams well overlapped (enhancing coherence…)
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Brightness is crucial formany Applications
Lg ∝γ32
K Bn 1+K2 2( )
NX ∝ ΣT fN
e−Nhν
εnβ* γ ; β* >σz
Φp ≈50 μm
λp ≈30−100 μm
SASE FEL’s for coherent X-rays
Plasma Accelerators @ 100 GV/m
Relativistic Thomson Monochromatic X-Ray Sources
εn ≤ γΔnp
np
λp
2π
Courtesy of D. Umstadter, Univ. of Michigan
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Photo-Linacs (driven by RF Photo-Injectors) rule over SR rings
Bn ≡2I
εnxεny
A
m2rad2⎡ ⎣ ⎢
⎤ ⎦ ⎥ LCLS (requested @ 15 GeV) 4.1015
nx =ny=1.5 m
SPARC ultimate goal (Ph. 2) 2.1015
ESRF (storage ring) < 1014
nx =20 m ny=0.07 m
I = bunch peak current > kA
h
h
RF Laser Driven Photo-Injectors:a break-through in High Brightness e- beams
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
SPARC: an Advanced Photo-Injector to drive a SASE-FEL @ LNF/INFN
Co-funded by MIUR (2003-2006) and pursued by an inter-institutionalcollaboration INFN-ENEA-CNR-INFM-Univ.TorVergata-ST
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Two additional beam lines at SPARC for plasma acceleration and monochromatic X-ray
beams - the Project PLASMON-X
100 fs synchr.Ti:Sa multi-TW
Laser System
1 J, 10 ps gaus
1 J, 100 fs gausCompr.20 mJ, 10 ps flat top
500 J 20 pC, 20 fs$
2 nC, 10 ps*
*n=2 m, =50 m
$n=0.2 m, =10 m 1 nC, 10 ps, n=1 m
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Compact Sources of Monochromatic X-raysbased on Relativistic Thomson back-scattering
X las / 42((1-cos)/2) las = 0.8 m =80 (40 MeV)
X =0.32 Å, 37 keV
NX ∝ ΣT fN
e−Nhν
σcoll2
ΣT =7⋅10−29 m2
€
NX = 2 ⋅109 /11 ph / s
f = 10Hz,Ne_ = 1010,Nhν = 1018 ,σ coll = 50,5μm( )
Blue-sky effectThomson scattering if h << m0c2 (no e- recoil)
Spontaneous Synchrotron Radiation emitted byelectrons oscillating in the intense laser field
Laser Synchrotron Radiation Source
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
1 J Laser pulse interacting with 1 nC 10 ps electron bunch @ 30 MeV w0=20 m, 0=10 m, Z0=1.5 mm , *= 6 mm
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
n=5 xn=x, vxn=5vx
Ntot=8,4 107,=6,8%
5,0x1018 5,5x10180,0
1,0x10-10
2,0x10-10
dN/d
5,0 0x 8 5,5 0x 80,0
5,0 0x -
/dN dn=5 xn=2.236x,vxn=2.236vx
Ntot=1,98107,=7,5%
€
′x =εn
σ xγ≈ 1.5 mrad
Beam rms angle m=5 mrad
Thomson Source frequency spectrum @ 20 keV
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Thomson Source frequency spectrum@ 500 keV
(a)Beam rms angle m=1 mrad
Ntot=8,5107 =7,9%
(b) Beam rms angle 0.7<m<1.4 mrad
Ntot=1.06 108 =11%1,00E+020 1,20E+020 1,40E+020
0,0
5,0x10-12
1,0x10-11
(b)
(a)dN/d
(a)iris (b) hollow
€
′x =εn
σ xγ≈ 0.3 mrad
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Dynamic IVCAG (Intravenous Coronary Arteriography) using monochromatic X-rays produced by Synchrotron Radiation and monochromators was clinically tested at KEK-AR and Tsukuba University, obtaining clear dynamic images (33 shots/s) of the coronary artery, with 37 keV X-rays , 1011 photons/s generated by an undulator at the AR ring (intravenous contrast agent applied instead of invasive artery cateter insertion).
Non-invasive Coronaric Angiography
Our aim: develop Compact Systemscompatible for operation in hospitals
Mono-chromatic X-rays allow to perform mass screening of coronaric artery deaseses,
responsible for a large fraction of mortatility in western countries
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Mammography with Mono-chromatic X-Rays
Mammography images of adenocarcinoma. (a) conventional mammogr.; (b)monochromatic beam at 22.2 keV; (c) phase contrasst image; (d) histological section.
The constrast (sensitivity to tissue density variations) goes from 8% to 0.1%, while thespatial resolution goes from 0,15 -0,3 mm to 0.01-0.015 mm. This means the capability todetect a tumor 30 times smaller in volume, i.e. a 2 year earlier detection of the tumor.
1 Boone JM, Seibert JA. A Figure of Merit Comparison between Bremsstrahlungand Monoenergetic X-ray Sources for Angiography. Journal of X-ray Science andTechnology . 4:334-345, 1994.
2 Carroll FE, Waters JW, Pri ce RR, Brau CA, Roos CF, Tolk NH, Pickens DR,Stephens WH. Nearmonochromatic x-ray beams produced by the free electronlaser and Compton backscatter. Invest Radiol 25:465-471, 1990.
3 Johns PC, Yaffe MJ. X-ray characterization of normal and neoplastic breasttissues. Phys Med Biol 32:675-695, 1987.
4 Ingal V.N., Beliasevskaya E.A., Phase dispersion radiography of biologicalobjects. Physica Medica, vol XII , 1996, vedi anche www.xraysite.com
5 Davis TJ, Gao D, EA, Phase contrast immaging of weekly absorbing materialsusing hard x-rays , Nature 1995:373, 595-598
6 Ingal V.N., Beliasevskaya E.A.,Gambaccini M, E.A., X Ray imaging of a synteticmammography structure, Physica Medica, vol XIV , 1998
7 S.Pani, F.Arfelli , E.A., Tomographic imaging with synchrotron radiation,PHYSICA MEDICA XVI (3) (2000) 155, 20
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Zona Range Fotoni/(mm2*mAs)(Totale 5.7x105 /(mm2*mAs)
A E<6.5keV 2.2 0x 5
B 6.5 <keV E<23keV 3.3 0x 5
C E>23keV .3 0x
MaMBO Experiment: Mammography Monochromatic Beam Outlook
Main aim: conducting test experiments on phantoms with the PLASMON-X Mono-chromatic X-ray beam @ 20 keV, in order to avoid absorption of low energy photons in the tissue (dose without informations) as well as the scattering of the high energy photons
(image contrast degradation) in the spectrum of a typical X-ray tube for mammography
Request: 1011 ph/s with 10% frequency spread
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Projects world-wide on Thomson Sources for Mono-chromatic X-rays
Sumitomo-Festa (S-band, medical)
Univ. of Tokyo - NERL (S-band, medical)
NIRS - Univ. of Tokyo - KEK (X-band, medical)
SLAC (X-band, medical)
Brookhaven ATF (S-band, by-product in laser acceleration)
Livermore (S-band, material studies, nuclear weapons)
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
70mm
Measured spatial profile of the scattered X-raysMeasured spatial profile of the scattered X-rays
YY
XX
**The lines represent the results of the theoretic analysis****The lines represent the results of the theoretic analysis**
(The electron beam is in the plane of the laser polarization)(The electron beam is in the plane of the laser polarization)
Sumitomo - Festa Collab. (Tokyo)
X-ray energy: 4.6keV(peak)X-ray energy: 4.6keV(peak) Pulse length (calc.): 3ps(rms),Pulse length (calc.): 3ps(rms), Intensity: 1.5x10Intensity: 1.5x1055/pulse/pulse Intensity fluctuation: 10%Intensity fluctuation: 10%
Energy: 14 MeVEnergy: 14 MeVBunch charge: 0.5 nCBunch charge: 0.5 nCFocused beam size: 100 Focused beam size: 100 m(rms)m(rms)
Pulse energy: 85mJ/pulsePulse energy: 85mJ/pulsePulse length: 100fs(rms)Pulse length: 100fs(rms)Focused beam size: 108Focused beam size: 108m@0m@0oo-collision-collision
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
X-band advanced protoype
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
COFIN Proposal for a 2 year R&D program on Compact X-band Thomson Sources subm. to MIUR
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
What is a SASE-FEL Radiation Source?a Bright Electron Beam propagating through an Undulator
Spontaneous Radiation:
peaked atr u / 22(1 + K2) ; ≥ 2.103
Beam rms divergence ’ 1/ 00rad (Thomson Backscattering of undulator virtual photons)
I r e ; e number of electrons per bunch ( 109)
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Interaction of e- with Spontaneous Radiation causes Microbunching and SELF-AMPLIFICATION of Spontaneous
Emission (SASE)
In the SASE mode the Intensity:
I ph e > 4/3 ; e number of electrons ( 109)
Amplification gives extraordinary High Photon Flux (diffraction limited beam)
Beam rms divergence ’ 2e fewrad
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
This Ultra-Bright Coherent Radiation opens up new Research Frontiers in several fields:
• Atomic physics• Plasma and warm dense matter• Femtosecond chemistry• Life science• Single Biological molecules and clusters• Imaging / holography• Micro and nano lithography
X-rays are the ideal probe for determining the structureof matter on the atomic and molecular scale
“Science with Soft X-Rays”, Nevill Smith, Physics Today, January 2001
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
• WATER WINDOW (280-530 eV) is of extreme interest for BIOLOGY see Review ( Neutze, R., et al., Potential for biomolecular imaging with femtosecond X-ray pulses. Nature, 2000. 406: p. 752-757 ) where many Applications are summarized:
• CHROMOSOMES
• MALARIA INFECTED ERYTROCYTES
• CALCIFIED TISSUES
• MUSCLES
• LIPID MEMBRANES
• POLYMERS
Biology and Protein Crystallography
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Single Shot Protein Crystallographywith Single 100 fs X-Ray pulses
R.Neutze, R.Wouts D. van der Spoul,,
E. Weckert, J. Hajdu;
Nature 406, 752, (2000)
No Need to makeCrystalline Proteins !Most Proteins cannotbe made crystallineIn vivo imaging possible
Full ionization of the whole protein molecule, Coulomb explosion on a time scale of 50-100 fsFEL pulse must be faster to bring information to detector!
Erice, April 15th, 2004 Workshop on “Particle Accelerators and Detectors: from Physics to Medicine”
Conclusions
• DANE is an ideal example of how a machine designed and operated to
provide a cutting edge beam with very challenging performances (ultra-high
luminosity) for basic research could generate (as a fringe benefit) a broad-
band spin-off on medical/biological applications with frontier innovative
research studies
• The combined SPARC & PLASMON-X projects will generate a mono-chromatic
tunable soft and hard X-ray beam within 2007, available to experiments in the
advanced medical diagnostics field (MaMBO, etc.): serious chance to become a
key european test facility
• Vigorous R&D should be pursued (and funded! funding agencies solicited…) on
the design and tests of compact hospital-based Thomson Sources, in order to
perform a first prototype commissioning, followed by the launch of mass
production within this decade
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