Development of
Nanodosimetry for
Biomedical Applications
Project Goals and Current
Status
May 01
RWS
Project Participants
Loma Linda University (LLU) (Rad. Medicine)
Reinhard Schulte
Vladimir Bashkirov
George Coutrakon
Pete Koss
Weizmann Institute of Science (WIS)
(Rad. Detection Physics Lab.)
Amos Breskin
Guy Garty
Rachel Chechik
Itzhak Orion
Sergei Shchemelinin
University of California at San Diego (UCSD)
(Radiobiology)
John F. Ward
Jamie Milligan
Joe Aguilera
University of California Santa Cruz (UCSD)
(Santa Cruz Institute of Particle Physics)
Abe Seiden
Patrick Spradlin
Hartmut Sadrozinski
Brian Keeney
Wilko Kroeger
May 01
RWS
What is Nanodosimetry?
A new experimental technique that
measures energy deposition by
ionizing radiation in wall-less
low-pressure gas volumes
equivalent to tissue-equivalent
volumes of nanometer size
May 01
RWS
Radiation Damage to the DNA
Ionization event
(formation of water
radicals)
Light damagereparable
Primary particle track
delta rays
eWater radicals
attack the DNA
OH•
Clustered damageirreparable
The mean diffusion distance of OH radicals before
they react is only 2-3 nm
May 01
RWS
What do we want to know?
To better understand DNA damage we want to
know how many ionization events occurred and
where did they occur.
Problem:
How can we measure the formation of ions with
nanometer precision?
Using conventional techniques impossible
We can only measure ion formation with
millimer resolution
If we had millimeter DNA - no problem.
Solution: We measure ionization
patterns in low-pressure gas
May 01
RWS
Project Goals
• Establishment of a nanodosimetric gas
model to simulate ionizations in DNA
and associated water
• Plasmid-based DNA model to measure
DNA damage
• Develop models to correlate
nanodosimetric spectra with DNA
damage
May 01
RWS
Project Schedule
YEAR 4
3D tracking system
YEAR 3
ND characterization
YEAR 2
ND fabrication (2 versions)
YEAR 1
2001
2000
1999
Ion counting nanodosimetry
(proof of principle)
1998
Plasmid assays
SV mapping
ND improvements
2 D particle tracking
ND spectra
MC simulation
May 01
RWS
May 01
RWS
x
y
Gas
based
electron
multiplier
z
(weak)
primary particle
detector
(pulsed)
low pressure gas low
pressure
gas
E1
E3
electron
vacuum
ion counter
(strong)
E2
ion
d electron
primary charged particle
Single-Charge Counting Dosimetry
Current Status of the Ion
Counting ND
• Principle proven (1998)
• Two prototype of NDs have been
built:
– LLUMC ND adapted to the proton
synchrotron beam line
– WIS ND adapted to the Pelletron
beam line
• 2-D particle selection
implemented
• Data Acquisition System
– first version successfully
implemented
– new version under development
May 01
RWS
Prototype
Nanodosimeter
Side view
Front view
Ionization cell
Scintillator/PMT
Pump 2
 Source
Ion counter
Pump 1
May 01
RWS
Sensitive Volume
Mapping
The sensitive volume of the ND is
defined by the relative ion collection
efficiency map
May 01
RWS
ND Ion Cluster Spectra
Event with 6 ions
0
-5
-20
0
1
2
microseconds
3
A primary particle event is followed
by an ion trail registered by the ion
counter (electron multiplier)
For low-LET irradiation, most
events are empty
May 01
RWS
ND Ion Cluster Spectra
Ion cluster spectra depend on
particle type and energy as well as
position of the primary particle track
The average cluster size increases
with increasing LET
May 01
RWS
Radiobiological Model
• Plasmid (pHAZE)
– Irradiation of thin film of plasmid
DNA in aqueous solution
– Three structural forms:
• superhelical (no damage)
• open circle (single strand break)
• linear (double strand break)
– Separation by agarose gel
electrophoresis
– Fluorescent staining and
dedicated imaging system
May 01
RWS
Correlation between
Nanodosimetry and
Radiobiology
Relative frequency
Ionization
Cluster Spectra
Radiation
Nanodosimeter
%90
%88
%86
%16
%14
%12
%10
%8
%6
%4
%2
%0
protons 4 MeV
 5 MeV
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Cluster size
ssb
dsb
intact
mobility
0 minutes
15 minutes
30 minutes
60 minutes
120 minutes
Plasmid Sample
Gel
Electrophoresis
Incubation with
Base Excision
Enzymes
May 01
RWS
Frequency of
lesions of different
complexities
ND Data Acquisition
(non-position sensitive)
+ HV
Degrader
Plastic Scintillators
Ionization Cell
Primary Particle
PMTs
Time-to-Digit
Converter
PCI Bus
Preamplifiers
Discriminators
Accelerator Gate Signal
Data Acquisition PC
In the prototype ND all primary
particles can contribute to the ion
cluster size spectra
The position of the primary particles
is undefined
May 01
RWS
Primary
Particle Trigger
Ion
Counter
ND Data Acquisition
(particle-position sensitive)
In this (newer) version the primary
beam is “imaged” by a MWPC
Only particles that pass a narrow
collimator in front of the rear
scintillator/PMT are selected for
analysis
May 01
RWS
The Goal: 3-D Position- and
Energy-Sensitive Particle
Tracking System
primary particle
Y
X
May 01
RWS