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Preclinical Image Guided Microirradiators: Concepts, Design

and ImplementationE.W.E.W. Izaguirre, B.L. Kassebaum, J. Birch, I. Izaguirre, B.L. Kassebaum, J. Birch, I. Su, P. Su, P.

Grigsby, and D.Grigsby, and D. A. Low.A. Low.

This work is supported by NIH grant 5R01EB007705

Brachytherapy Based Brachytherapy Based MicroRTMicroRT

Instrument Diagram

BrachytherapyBrachytherapy Based Based MicroRTMicroRT

xyz positioning system

Pinhole aperturecylindrical support

Parametric beam simulation

Image Guided Image Guided MicroirradiatorsMicroirradiators

•• Anatomical ImagingAnatomical Imaging••microCTmicroCT••microMRImicroMRI

•• Functional Imaging Functional Imaging ••microSPECTmicroSPECT••microPETmicroPET••Optical Optical ••microMRImicroMRI

UCSF MicrocT-MicroSPECTM. Sun, E.W. Izaguirre, J. Carver

and B. Hasegawa

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BackgroundBackground� Current commercial small animal imaging instrumentation : microCT, microMRI, microPET, microSPECT, and optical scanners.

� >50% of cancer patients receive radiation therapy.

� The development of small animal micro irradiation technology has not reached the sophistication of small animal imaging instrumentation.

� Highly conformal microirradiators with an on board anatomical imaging subsystem should be developed to foster preclinical radiobiology research.

� New instrumentation should provide a state of the art platform and to perform experiments that cannot be performed with the current irradiator technology.

MicroCT + MicroRT = MicroIGRTMicroCT + MicroRT = MicroIGRT

MicroCT

MicroRT

MicroIGRTMicroIGRT Instrument Instrument OverviewOverview

The designed micro image guided radio therapy (microIGRT) systemshowing the primary components. The instrument is designed in a tandem configuration where the animal bed is located in the microCT field of view for anatomical imaging and is then shifted to the micro irradiator subsystem for conformal irradiation.

The Washington University Image guided Micro Irradiator (MicroIGRT)

The microirradiator subsystem consists of a high power orthovoltage source with a high dissipation anode to achieve a small focal spot source capable of delivering high dose rates, percentage depth dose, and submillimeterbeam penumbra to small animals.

MicroCT

MicroRT

MicroIGRTMicroIGRT Instrument Instrument OverviewOverview

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MicroIGRTMicroIGRT : Design : Design •• Study the feasibility of using industrial Study the feasibility of using industrial orthovoltageorthovoltage sources to deliver sources to deliver

accurate dose distributions to radiobiological animal models.accurate dose distributions to radiobiological animal models.

•• Determine the best commercial Determine the best commercial orthovoltageorthovoltage source to achieve the source to achieve the following target values :following target values :

�� Dose Delivery Accuracy : 5 %Dose Delivery Accuracy : 5 %�� Dose Rate : 400Dose Rate : 400--4000 4000 cGycGy minmin--11�� Dose Homogeneity :5 %Dose Homogeneity :5 %�� Penumbra : 0.25 mm (90%Penumbra : 0.25 mm (90%--10%) 10%) �� Positioning Accuracy : 0.25 mm Positioning Accuracy : 0.25 mm �� Throughput :10 to 20 min/subjectThroughput :10 to 20 min/subject

•• Develop an accurate treatment planning system with a realistic mDevelop an accurate treatment planning system with a realistic model odel of the selected of the selected orthovoltageorthovoltage source.source.

OrthovoltageOrthovoltage Source Simulator Code Source Simulator Code Flow DiagramFlow Diagram

Anode Emission model

Source Filament model

Beam ModelOutputSpectrum

I(E), N(E), Itot

InputFilament Power Afil, ∆∆∆∆Vfil

Tube kVpTube mA

Tube msec

Animal Phantom model

OutputAnimal dose

The othtovoltagesource simulation program was developed using Visual C++.The code is fully compatible with DSP development tools forhardware/software optimization

Source Filament ModelSource Filament Model

Filament Input Power

Filament Electron Current

Anode Emission ModelAnode Emission Model

Photon EmissionDifferential Cross Section

BremsstrahlungIntensity

Emitted Photons per Interval of Energy

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Anode Emission ModelAnode Emission Model

Anode Mass Stopping Power

Fraction of Photons Exiting the Anode

Electron Penetration Distance

Mass Attenuation Coefficient

Bremsstrahlung Coefficient

Anode Focal Spot AnalysisAnode Focal Spot Analysis

Anode Focal Spot Anode Focal Spot Contour Level Map

Anode Line Profile Anode Line Profile

Anode Focal Spot: SimulationAnode Focal Spot: Simulation

Simulated Anode Focal Spot The emission is modulated with the empirical intensity

parameterizationAnode Emission Parameterization

Othovoltage Source Spectrum

Measured anode focal spot

Energy (keV)

I(A

.U.)

Spectrum emitted from an arbitrary anode point

Simulated anode focal spot

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Beam Penumbra Simulations Beam Penumbra Simulations

Average Penumbra0.25 mm

Beam Cross SectionBeam Width: 2x2 mm2

Beam Profile Collimator: 7 mm Tungsten

Source Collimator

FilteringFiltering

In order to reduce bone dose we propose to filter the radiation beam. Solid line (blue) unfiltered output, doted line (red) filtered output and dash line (black) bone f-factor. In our proposed filter most of the filtered beam spectrum lies above 150 keV, where the bone f-factor is within 10% of the muscle f-factor.

OrthovoltageOrthovoltage Source Spectrum Source Spectrum

Simulation of the 320kVp x-ray source without additional filtration and with a filter composed of 1.5 mm Lead, 5 mm Tin, 1 mm Copper, and 4 mm Aluminum. This filter removes the low energy x-ray components to raise the average bremsstrahlung energy to 4.6 mm of Cu. Unfiltered dose profile (red line) and filtered dose profile (green line).

Energy (keV)

Ener

gy f

luen

ce(a

.u.)

Total Body IrradiationTotal Body Irradiation

Dose rates of 16 Gy/min (filtered) and 40 Gy/min (unfiltered) can be delivered to an animal phantom if the source is operated at 1.5 mA. The maximum source current is 5 mA at the maximum voltage bias, so even greater dose rates will be possible. Animal Phantom: Modified MOBY, John Hopkins Univ.

Unfiltered Filtered

Unfiltered FilteredAbsorbed Dose Profile

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The The MicroIGRTMicroIGRT

.The 3D diagram shows the instrument tandem architecture.

Each subsystem can be independently operated.

The The MicroRTMicroRT SubsystemSubsystem

The MicroRT gantry showing the orthovoltage source,the collimation system, and primary beam shielding cup.

The The MicroRTMicroRT SubsystemSubsystem

The microRT gantry linear translation stages to support the orthovoltage source

The The MicroRTMicroRT SubsystemSubsystem

The microRT gantry showing the 320 kVp orthovoltage source mounted on a rotating and a linear stages.

Source distance to axis 6” to 12”.

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The The MicroRTMicroRT SubsystemSubsystem

The microRT primary beam shielding. The lead shield is located on the opposite side of the gantry to compensate the

high torque produced by the orthovoltage source weight.

The The MicroRTMicroRT SubsystemSubsystem

The microRT bearing system for accurategantry rotation. Rotation precision: 2 arc min.

Design Implementation

The The MicroRTMicroRT SubsystemSubsystemThe The MicroRTMicroRT SubsystemSubsystem

Source rotation system

HV generator

Gantry rotation system

Beam stopper + Mouse bed

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The The MicroIGRTMicroIGRT

Image of the Instrument - June 2008

Beam Diam. 4 mm

Beam profile

The Micro CT SubsystemThe Micro CT Subsystem

MicroCT gantry showing the flat panel detector and the microfocus x-ray source

The Micro CT SubsystemThe Micro CT Subsystem

The microCT bearing system for accurategantry rotation. Rot precision: 2 arc min.

The Micro CT SubsystemThe Micro CT Subsystem

The microCT gantry plate. The gantry is constructed using hollow beams for light weigh and high rigidity

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The Micro CT SubsystemThe Micro CT Subsystem

The microCT gantry showing the four high precision linear stages for imaging instrumentation radial positioning

The MicroCT Micro Focus SourceThe MicroCT Micro Focus Source

The micro focus source of the microCT subsystem.Source characteristics: tube potential 80 kVp, tube current

0.5mA, focal spot 75x75um2, and beam divergence 30o.

The MicroCT Micro Focus SourceThe MicroCT Micro Focus Source

The micro focus source collimator. The source is collimated to limit the beam scattering and unnecessary

irradiation to non-imaged portions of the animal body

The MicroCT Micro Focus SourceThe MicroCT Micro Focus Source

The micro focus source shutter. A high speed rotary solenoid is used to shut on and off the beam between exposures

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The MicroCT Micro Focus SourceThe MicroCT Micro Focus Source

The micro focus source multiple filter system. The microCT is optimized to acquire high contrast

low dose tomographic images of small rodents.

The Micro CTThe Micro CT

Design Implementation

The Micro CT SubsystemThe Micro CT Subsystem

Complete microCT subsystem with the animal bedThe combined circular motion of the gantry with the linear motion

of the couch allows circular and helical tomographic scanning

The Micro CT SubsystemThe Micro CT Subsystem

Rotation gear Cable collection belt

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The MicroCT The MicroCT SubsystemSubsystem• micro-focus 80kVp x-ray source • Focal Spot 75x75 mm2 focal

spot • Flat panel amorphous silicon

detector with 1024x1024 pixels. • High efficiency CsI(Tl)

scintillator.• High precision gantry rotation

( 1/60 deg, 0.0001 axis tilt) • Micrometric source and detector

positioning (50 mm)• microCT spatial resolution ~ 120

mm • Dose less than 1cGy/scan.

MicroIGRTMicroIGRT

Design

Implementation

Instrumentation Software Instrumentation Software

Software Platform : Visual C++ (Microsoft) + National Instruments drivers + In house developed drivers

Treatment Planning Software Treatment Planning Software

Source model

Mouse Phantom

Pencil Beam

Monte Carlo

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Mouse Bed and Animal HandlingMouse Bed and Animal Handling

•• Gas Anesthesia: Gas Anesthesia: IsofluraneIsoflurane•• Temperature control :Temperature control :

IR lamp heaterIR lamp heater•• Respiratory motion sensorsRespiratory motion sensors•• Gas flow sensorsGas flow sensors

Shielding ?Shielding ?

Al Al

Pb

Box frame

Shielding panels construction

Brachytherapy Based Brachytherapy Based MicroRTMicroRT

Instrument Diagram

Brachytherapy Brachytherapy MicroRTMicroRT

2 months 3 months 4 monthsTime

New pinhole

Previous pinhole

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Sensitization of Orthotopic Glioblastomas to Radiotherapy by Transglutaminase 2

Inhibitors

Average Fold Change of Tumor Size in Individual Mice

0.9

0.95

1

1.05

1.1

1.15

1.2

1.25

Start Date

Jan

20

Jan 20

- Ja

n 23

Jan 20

- Ja

n 27

Jan 20

- Ja

n 30

Tu

mo

r S

ize

(Lo

g o

f A

vg C

han

ge i

n B

iolu

min

esce

nce

)

.

Control

Radiation Only

Radiation & Drug

Optical Imaging

Collaboration with Dr Keith Rich , Neurosurgery , WU

List of Collaborative ProjectsList of Collaborative Projects• MRI imaging of necrosis induced by ionizing

radiation J. Garbow

• Extracellular matrix and Sensitization of orthotopic glioblastomas to radiotherapy by Transglutaminase 2 inhibitors K. Rich

• PET tracers to optimize tumor treatment in xenograph models of breast cancer: K. Shoghi-Jadid

• Variations in cancer cell motility induced by ionizing irradiation. P. Grigsby, M. Taylor, A. Laszlo and E. Izaguirre

Multiple Beam Conformal IrradiationMultiple Beam Conformal Irradiation

Mouse phantom Mouse phantom

Mask generation using back propagationMask generation using back propagation

Liver phantom Liver phantom Collimator exchangeCollimator exchange

Multiple beam irradiationMultiple beam irradiation

Results and ConclusionsResults and Conclusions•• We are constructing a small animal imaged guided micro irradiatoWe are constructing a small animal imaged guided micro irradiator which consist in a r which consist in a

microRT subsystem integrated with an on board microCT subsystem.microRT subsystem integrated with an on board microCT subsystem.

•• Simulated microCT reconstructed tomographic data demonstrates thSimulated microCT reconstructed tomographic data demonstrates that a resolution of at a resolution of 120 120 µµm is achievable using 128 projections and a maximum radiation dom is achievable using 128 projections and a maximum radiation dose of 1cGy. se of 1cGy.

•• Automatic animal positioning and handling could be performed witAutomatic animal positioning and handling could be performed within a precision of hin a precision of 100 100 µµm. The treatment beam can be aimed at different latitude and lonm. The treatment beam can be aimed at different latitude and longitude angles gitude angles in steps of 2 arc min. and translated at 50in steps of 2 arc min. and translated at 50µµm steps (x,y,z). The beam cross section m steps (x,y,z). The beam cross section can be modulated with submillimeter precision using steps of 50 can be modulated with submillimeter precision using steps of 50 µµmm. .

•• We determined that a source of nominal maximum potential output We determined that a source of nominal maximum potential output of 320kVp and of 320kVp and focal spot of 0.4x0.4 mm2 outperformed other available sources. focal spot of 0.4x0.4 mm2 outperformed other available sources. We designed a We designed a ThoraeusThoraeus--like filter to obtain a like filter to obtain a bremsstrahlungbremsstrahlung spectrum energy greater than 4mm of spectrum energy greater than 4mm of Cu to increase skin spare and reduce bone dose. Cu to increase skin spare and reduce bone dose.

•• An average beam penumbra of 0.25mm and a dose rate of 16 An average beam penumbra of 0.25mm and a dose rate of 16 GyGy/min is possible /min is possible using this filtered beam.using this filtered beam. Higher energy sources would increase cost and shielding Higher energy sources would increase cost and shielding thickness. Lower energies sources showed limited intensities whethickness. Lower energies sources showed limited intensities when they were n they were aggressively filtered.aggressively filtered.

•• The construction of the device will be finished shortly. The comThe construction of the device will be finished shortly. The commissioning of the missioning of the complete system is expected by the end of this year complete system is expected by the end of this year

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AcknowledgmentsAcknowledgmentsCollaboratorsCollaboratorsDaniel Low Daniel Low

Jeff MichalskiJeff MichalskiMarie Taylor Marie Taylor

Robert MyersonRobert MyersonSasa MuticSasa Mutic

ParaqParaq Parikh Parikh Perry GrigsbyPerry Grigsby

Keith RichKeith RichJoseph Deasy Joseph Deasy Joel Garbow Joel Garbow

Kooresh ShoghiKooresh ShoghiSreekrishna M GodduSreekrishna M GodduJose Garcia RamirezJose Garcia Ramirez

Dharanipathy RangarajDharanipathy RangarajJoseph Joseph RotiRoti RotiRoti

D. D. HallahanHallahanAndrei LaszloAndrei LaszloBuck RogersBuck Rogers

SuzanaSuzana GonzaloGonzaloIlonaIlona FleischerFleischer

Animal PhantomAnimal PhantomJohn Hopkins Univ.John Hopkins Univ.Paul Paul SegarsSegarsBenhaminBenhamin Tsui Tsui

Laboratory MembersBethany Kassebaum Xiumin DiaoJordan Birch I-Tan Su

Thank you ! Thank you !

We are looking for a postdoc !!!

High Resolution Low Dose MicroCTHigh Resolution Low Dose MicroCTCurrent Imaging of Tumor Current Imaging of Tumor

VasculatureVasculature

-- Techniques to image tumor Techniques to image tumor vasculature are based in multiple vasculature are based in multiple micro CT images (8 frames /view).micro CT images (8 frames /view).--Unnecessary high dose delivered Unnecessary high dose delivered to the animal to the animal KindlmannKindlmann et al.et al.

New technique: New technique: Low dose micro CTLow dose micro CT-- High efficiency detectors for small High efficiency detectors for small animal: 80kVpanimal: 80kVp--The only option is to change the The only option is to change the scintillatorscintillator--Dual energy microCT Dual energy microCT

Study of the Tumor Micro EnvironmentStudy of the Tumor Micro Environment

Goals of the project :

Imaging angiogenesis

Determine vascular renormalization induced

during treatment

Correlate tumor vascularity with

oxygen distribution

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Dual Energy MicroCTDual Energy MicroCT

X-ray Source Spectrum Dual energy simulations