Medical Applications of Synchrotron Radiation:Growth and Outlook for an Emerging Field of Science

W. Thomlinson

Frau Roentgen’s Hand

Wilhelm Roentgen’s LaboratoryUniversity of Wurtzburg 1895 European Synchrotron Radiation Facility

Grenoble France, 2010

3D monochromatic high-resolutiondynamic digital imaging ANSTO

Nov. 30, 2010

115 YearsLater

Synchrotron Radiation is Extremely Intense Light!

The Electromagnetic Spectrum

Synchrotron Radiation

Light is produced by the Acceleration of Charged Particles.

In Synchrotron Facilities, these Particles are Electrons

ELECTRON AT REST

ELECTROSTATIC FIELDNO MAGNETIC FIELD

ELECTRON MOVING AT CONSTANT VELOCITYSTATIC

MAGNETICFIELD

ACCELERATING ELECTRON (LINEAR)

SLOW FAST

ELECTROMAGNETIC RADIATION = LIGHT

FAST ELECTRON MOVING IN A CIRCLE(RELATIVISTIC HIGH ENERGY ELECTRON

NEAR THE SPEED OF LIGHT)

EXTREMELY INTENSEHIGHLY COLLIMATEDBROAD BANDWIDTHLIGHT

Bending Magnet

InsertionDeviceMagnet

VacuumChamber

ElectronBeam

Synchrotron StorageRing

RadioFrequencyCavity

Synchrotron Electrons Circulate in a Storage Ring

Phot

ons/

s/0.

1%/m

rad

Photon Energy (KeV)

0 10 20 30 40 50 60 70 80 901E+09

1E+10

1E+11

1E+12

1E+13

1E+14

1E+15

XX--Ray tube Ray tube -- 110KV 110KV -- 2.5mm Al @meter/source2.5mm Al @meter/sourceESRF ID 17 @ 200mA ESRF ID 17 @ 200mA -- Wiggler: 1.4T Wiggler: 1.4T -- 1.6m 1.6m -- 150mm150mm

Synchrotron Brightness and Flux

Brightness of the X-ray Beams

ID17 Wiggler

Intense Lab Source

Typical Biomedical Beamline

X-raySource

Radiation DoseMonitors

Mirrors

Apertures/Slits/Filters Monochromator

PersonnelShielding

Sample/PatientRotation & Translation

Detector

X-ray BeamShutters

ImageDisplay

World Wide Synchrotron FacilitiesBiomedical Research Programs – 2010

2nd Generation 3rd Generation Biomedical Beamlines

ESRF

NSLS ELETTRASP-8

SSRF

AS

CLS

PF

The Beginning:Stanford Synchrotron Radiation Lightsource

SLAC

SSRL

Human Coronary Angiography

E. Rubenstein – Stanford MedicalR. Hofstadter – Stanford Physics

HIGH ENERGYHIGH ENERGYLOW ENERGYLOW ENERGY

DIFFERENCEDIFFERENCE

Photon Energy (keV)

Iodine

Bone

Water

31 32 33 34 35 360.1

1.0

10.0

100.0

Abs

orpt

ion

Coe

ffic

ient

(cm

2 /g)

K-Edge Subtraction Imaging (KES)

Stanford Angiography Beamline

Patient Chair

Angiography Hutch

yAngiography Hutch

PhysicianControl

MonoHutch

Ed Rubenstein,Bob Hofstadter andthe group relaxing at last!

First Images

First Human Angiography Images at SSRL May 22, 1986

Anxious moments…..

Photos courtesyBill Thomlinson

National Synchrotron LightsourceSynchrotron Medical Research Facility – SMERF

Collaborating Institutions:NSLS, BNL, Stanford U., SSRL, NSUH, SUNY, LBL, NCSU, UNC

Angiography, Computed Tomography, Mammography,Microbeam Radiation Therapy, Photon Activation Therapy

Bill’s Car!

NSLS SMERF Angiography Facility

FLUOROSCOPYROOM

RECEPTION ROOM

ANGIOGRAPHY ROOM

First Human Angiography Images at NSLS -- October 5, 1990

E. Rubenstein

J. Giacomini

NSLS/BNL/NSUH/LBLStanford &Palo Alto VA

International Collaboration

USA

Australia

Japan

Germany

FranceFinland

Diversification of Medical Research at NSLS

Diffraction Enhanced ImagingMammography

D. Chapman, W. Thomlinson, Z. Zhong, D. Sayers, E. Pisano, G. Johnson, F. Arfelli, R. Menk,

G. Tromba

Computed TomographyA. Dilmanian

Microbeam Radiation Therapy – MRTD. Slatkin, P. Spanne,A. Dilmanian, J. Laissue

Photon Activation Therapy – PATR. Fairchild, B. Laster,W. Thomlinson

European Synchrotron Radiation FacilityBiomedical Beamline ID17

Coronary Angiography, Computed Tomography, Lung-Imaging, Radiation Therapy

Bill’s Apartment(Behind Mountain)

ID17 MedicalFacility

ESRF Biomedical Beamline ID17

EXPERIMENTAL HUTCH

MONOCHROMATORS

Animalerie Experimental Hall

ESRFStorage Ring

First Human Angiography Imagesat ESRF Jan. 26, 2000

Synchrotron image Intravenous injectionImage nb 2 – LAO 40

Conventional angiographyIntra arterial injection

Patient 1 - weight: 70 kg - iodine: 42ml

K-edge subtraction imaging of lungs using xenon as contrast agent

2 X-ray beams have energies above and below the K-edge of xenonIn subtraction image only areas filled with xenon are visible

Ek = 34.56 keV

Negligible absorption for

xenon

Marked absorption for xenonSubtraction image

103

102

101

100

10-1

Xenon

Bone Tissue

20 40 60 80 Energy (keV)

Mass attenuationμ/ρ (cm2/g)

Slide courtesy of Liisa Porra

Xe in the bronchial tree

Pixel size 0.35x0.35mm

Maximum image width 15.0 cm

Xenon in lung tissue (air spaces)

Voxel size 0.35x0.35x0.7mm3

Cross sections of the airways

Max 1 image /s

Airways

Lung tissue

Bayat et al. Phys Med Biol 2001

Projection imageCT image

In-vivo imaging of airways and lungs filled with Xe in rabbit for experimental asthma studies

Slide courtesy of Liisa Porra

Ventilation distributions after histamine aerosol provocation in experimental asthma

Porra et al. J Appl Physiol 2004, Bayat et al. submitted

Images of specific ventilation sV

Baseline 20min 40min

After histamine

4

2 sV(1/min)

0

Wash-in filling of xenon after histamine

CXe

(mg/

ml)

0 20 40 60 80

Time (s)

4

2

0

After histamine filling of lungs is heterogeneous

Exponential filling of air spaces Distributions of ventilation

Baseline

20 min

40 min

0 2 4 6

sV(1/min)

Baseline

Poorly ventilated areas

Slide courtesy of Liisa Porra

Discovery of X-raysAbsorption Imaging

Discovery of X-raysRoentgen November 1895

X-ray of frogs1896

Medical X-rayDartmouth College

February 1896

X-ray of frog2008

Not much has changed!

Phase (wave) effects can be large in comparison with absorption!

The dream: high contrast & low dose images

Clinical Imaging Utilizes Only Absorption Information!

Object

X-rays “refracted” by object

Radiography SetupDetector Object Si(333) Double Crystal

Monochromator

Synchrotron Beam

Synchrotron Radiography and DEI

Si(333) Bragg Analyzer

Diffracted Beam

DEI Bragg Case Setup

Image contrast due to refraction (phase) andabsorption in object

Image contrast due toabsorption in object

Human Breast Tissue -- DEI ImageDEI GROUP NSLS Feb. 1998

D. Chapman, E. Pisano. E. Johnson, D. Sayers, Z. Zhong, W. ThomlinsonRadiograph Apparent Absorption

Refraction At Peak of Rocking Curve

“Low Dose” DEIFibrils and Masses

~0.020mGy exposure25 times less exposure

than conventional

Conventional X-Ray ~5mGy exposure

DEI

collagen strandscollagen strands

fatfat

Ca in collagenCa in collagenskinskin--musclemuscle

Toshiba Asteion TSX - 021A80 kVp clinical CT-scanner

Histo-pathology DEI-CT (33 keV)50μm resolution

S. Fiedler, A. Bravin, J. Keyriläinen, M. Fernández, P. Suortti, W. Thomlinson, M. Tenhunen, P. Virkkunen, M-L. Karjalainen-Lindsberg, Phys. Med. Biol. 49 (2004) 175 - 188.

DEI – CT Applied to Mammography

ESRF Biomedical Beamline ID17

Lung ImagingSynchrotron –Stereotactic Radiation Therapyand Micro-beamRadiation Therapy

Imaging and Radiation Therapy

INSERM Team

Microbeam Radiation Therapy (MRT)D. Slatkin, P. Spanne, A. Dilmanian – BNL; J. Laissue – U. Bern

• Normal tissue tolerance is very high to microbeams• High sensitivity of tumours to microbeams• High Dose: 350 – 500 Gy

Curtis et al 1960

140Gy

1mm

4000Gy

25 microns

Each beam ~ 25 microns wide Beam separation ~ 200 microns

Microbeam Array

Height~ 10 mm

High dose Low dose

Slatkin 1991

Courtesy of Avraham DilmanianBNL Medical Dept.

Bidirectional Irradiation (MRT)

Normal Tissues Repair

Tumor Tissue Dies

Tumor + Iodine

BoneBrain

X-rays

Contrast Enhanced Synchrotron Stereotactic Radiotherapy

Radiation Dose

ContrastAgent

Mammography , Medical Radiology, X-Ray Dosimetry

SYRMEP - ELETTRAE. Castelli

Giuliana Tromba - Elettra 36

Aim: In vivo mammography studies on cases selected by the Radiologist.

Target: Dense breasts;

conventional radiographs with uncertain diagnosis.

Set-ups: I Phase: PHC radiography with commercial detectors

II Phase: PHC imaging with digital detectors;

III Phase: low-dose tomography with custom Si microstrip detector.

Breast imaging at Elettra: the SYRMA project(SYnchrotron Radiation for MAmmography)

Agreement among the Public Hospital of Trieste, the University of Trieste and Elettra

Clinical trial started on March 13, 2006Clinical trial started on March 13, 2006

Slide courtesy of Giuliana Tromba

Giuliana Tromba - Elettra 37

Patient positioning

Slide courtesy of Giuliana Tromba

Translation and Rotation

Translation and Rotation

X-ray Beam

DEI – Bones & JointsKES – Biomedical ImagingRadiation Therapy – MRTVeterinary Sciences

Canadian Light SourceBioMedical Imaging and Therapy (BMIT)

D. Chapman and T. Wysokinski

Bill’s Car!

BioMedical Imaging and Therapy Beamline

HumanMedical Area

ID LineVeterinary

AreaBM Line

DEI Radiograph

Proof of principle08-09 during commissioning of BMITCadaveric specimen (soft tissue intact)

Cooper et al. Can Assoc Radiol J. 2010 Jun 29.

DEI of Trabecular Bone at the Human Wrist

Australian SynchrotronImaging and Medical Beamline (IMBL)

Daniel Hausermann and Chris Hall

Lung ImagingPhase ContrastRadiation Therapy

Australian Synchrotron

Satellite building with stations 3A and 3B – 150 m

IMBL in Experimental Hall

Imaging and Medical Beamline

Phase 3.1/3.2: 3A and 3B

Phase 2.1,2.2: 2A and 2B

Phase 1.1,1.21A and 1B

Australian Synchrotron

Case Study: Lung Aeration at BirthR. Lewis, A. Fouras, S. Dubsky, M. Kitchen, S. Hooper

■ During fetal life the future airways of the lungs are liquid-filled■ At birth lungs must rapidly transform from being liquid to air filled■ How this happens is poorly understood but the process

♦ Develops late in pregnancy♦ Is initiated by labour

■ Preterm and caesarean section infants often develop problems♦ Incidence is increasing♦ Require weeks of assisted ventilation (>$2,000/day)

■ We know that ventilating infants causes injury♦ ~30% develop chronic lung disease♦ Becomes apparent after 15 years

Australian Synchrotron

Phase Contrast X-ray imaging

Object Detector

Distance

Intensity

Australian Synchrotron

Phase Contrast Imaging

■ Air bubbles in water. Pixel Size = 2.8 μm, Energy=25 keV

X-ray set: R1=1.0 m

Source fwhm: 100×100μm

400μm

SP8 BL20B2: R1=210.0 m

Source fwhm: 150×10μm

Australian Synchrotron

Lung aeration (Standard Model): Airway liquid clearance

Sodium channels create osmotic gradient that draws liquid out of airways

Australian Synchrotron

Lung aeration (New Model): Airway liquid clearance

Inspiration forces liquid out of airways

-P

-P

-P

KES IMAGING –CIRCULATION/VENTILATION

COMPUTEDTOMOGRAPHY –

NEUROSCIENCES

Phase IMAGINGSOFT TISSUES

RADIATION THERAPY –MRT, SSRT

DEI IMAGINGCARTILAGE &

BONES

Medical Applications of Synchrotron Radiation

Gene Expression Mapping

Preparing for Clinical

And Pre-Clinical Trials - ESRFHuman Trials Complete

SSRL, NSLS, HASYLAB,

PF, ESRF

Human Trials Possible

IMBL@AS

Human Trials In-progress

SYRMEP@ ELETTRA

Human Trials Possible

BMIT@CLS

Medical Applications of SR started with an ideaand was made possible by many talented colleagues and friends!

Thank you for your

attention!