Erice, April 15th, 2004Workshop on “Particle Accelerators and Detectors: from Physics to Medicine” (Electron) Accelerators and Medical Diagnostics Medical

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


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


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


X-ray sources over the last 100 years: the story ofa marriage between electron beams and X-rays


• 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


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


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


DANE I = 400 mA

Av. Brilliance of SR from DANEcompared to existing facilities


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


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


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


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…)


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


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


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


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


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


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


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


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


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


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


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


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)


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


X-band advanced protoype


COFIN Proposal for a 2 year R&D program on Compact X-band Thomson Sources subm. to MIUR


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)


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


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


• 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


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!


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

Documents

Erice, April 15th, 2004Workshop on “Particle Accelerators and Detectors: from Physics to Medicine” (Electron) Accelerators and Medical Diagnostics Medical