Medical Imaging - Opportunities for Business Seminar 24/01/12 Session 2 Technology Showcase Three technologies developed or enhances at the University of Leicester are presented

1. 24.01.12
Henry Wellcome Building
University of Leicester
A Space IDEAS Hub Event
In association with:
Medical Imaging – Opportunities
for Business

2. • A knowledge exchange project from the
Space Research Centre of the University of
Leicester
• Feed expertise developed from space
missions into commercial benefit for UK
industry.
• Delivering Innovative Design, Engineering,
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• UK companies can access and benefit from
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If your organisation would like to benefit from
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About Space IDEAS Hub

3. 11:35 Detectors for high speed photon imaging
and timing
Dr Jon Lapington
11:55 Single Molecule Imaging Technology
Prof George Fraser
12:15 High Resolution SFOV Gamma Camera
Systems for Medical Imaging
Dr John Lees
Session 2 – Technology Showcase

4. Dr Jon Lapington, Reader in Space Physics, University of Leicester
Space Research Centre

5. Space Research Centre
 Why photon counting?
 How to image single photons
 Microchannel plate detectors
 HiContent
 C-DIR
 Applications
 Conclusions

6. Space Research Centre
 Provides the ultimate sensitivity
 Extends dynamic range to lowest light levels
 Capable of picosecond (or better) time
resolution
 Can provide of high resolution imaging
 Necessary for time coincidence or energy
discrimination techniques
 Is intrinsically linear up to detector rate limit

7. Space Research Centre
 Imaging technologies depend on photon energy
 X-rays and γ-rays
 produce measurable signal in silicon detectors e.g.
CCD
 Optical photons
 only produce 1 to a few electrons in silicon
 Require some form of preamplification – gain
 Silicon devices under development, but..
 Only vacuum tube devices combine:
▪ High resolution imaging
▪ Low dark noise
▪ High time resolution

8. Space Research Centre
Farnsworth 1930 patent
Development of
resistive lead glass
Technology (1950s)
The Channeltron or
channel electron multiplier
Invention of the continuous
dynode technique
Miniaturization and
duplication (1960s)
The Microchannel plate
Conductive coating
Microchannel Plate Cross-section
Incident Radiation
-
+
Output Electrons
HV

9. Space Research CentreMCP
operation
 Lead Glass MCP
 Secondary emitter
 Electrodes
 High voltage
supply
 Vacuum
 Readout device
 Particle detection
 Electron, ion
 Neutron
 Photon (vacuum)
 Photon (optical)
 Optical window
 Vacuum tube
Cross section through MCP detector
Readout Device
- +
n
OpticalWindow

10. Space Research Centre
Specification
 High throughput multi-channel photon-counting
 Photon timing with 25 picosecond accuracy
 Up to 1024 parallel detection channels
 Throughput up to 10M count/sec/channel
 Compact integrated detector system
 Retrofit-able to biological microscopes
 Application-specific adaptability
 Programmable digital processing capability
Techniques and Applications
 Time resolved spectroscopies
 Multi-channel TCSPC
 FLIM, FRET, FCS, polarization anisotropy, Raman
 High Content bio-assay
 e.g. drug discovery, cell screening
 confocal microscopy, optical tomography
Ratio of detected flux to input flux
0
0.2
0.4
0.6
0.8
1
1.2
1.00E+05 1.00E+06 1.00E+07 1.00E+08
Counts/cm^2/s
Outputrate/inputrate
UK/CERN Collaboration
 Detector know-how from Astronomy
 Electronics expertise from Particle Physics
 Tube design from UK’s top manufacturer
 Life science expertise

11. Space Research Centre
 Event charge is localized on resistive layer
 Transient signal induced through dielectric
 Dielectric substrate part of vacuum housing
 Induced signal sensed by C-DIR readout
 C-DIR - a capacitively coupled electrode array
Capacitive division – breakthrough performance
 A new concept in centroiding readouts
 Purely capacitive – picosecond timing potential
 No resistive noise – no partition noise
 25 x 25 mm2 C-DIR – pattern capacitance of <8 pF!
 Very low total noise (<200 e- rms at τ=250ns)
→ 1000 × 1000 pixel2 at 106 electrons.
 Simple linear algorithm – minimal processing
 Excellent linearity - utilize >80% of anode
 Capacitances intrinsic in pattern geometry
Applications
 Wide-field fluorescence lifetime imaging (FLIM)
 Photon-timing/imaging e.g. LIDAR, TOFPET, 3D
 pptv trace gas measurement using BBCEAS
 Quantum Imaging, Quantum astronomy
 TOF mass spectrometry
 Molecular dynamics
 Ring Imaging Cherenkov detectors for sLHC, FAIR
C-DIR – the “Capacitive Division Image Readout”
Proof-of-concept prototype
Prototype image data
C-DIR equivalent circuit
Optimised flex-PCB C-DIR readout
Linearity simulation

12. Space Research Centre
 Time correlated single photon
counting
 Pulsed, focussed laser
 Laser spot scanned in x and y
 Measure fluorescence decay time
(x,y) by accumulating histogram
 PMT or gated intensifier (CCD)
 Fluorescence limited to 0.01 events
per laser pulse with single channel
PMT
 HiContent detector (641024 ch)
 Multiple photons per pulse, or
 Multiple imaged areas (Multiwell plate)
 High content, high throughput bioassay
 drug discovery

13. Space Research Centre
Figures courtesy Schwille, “Fluorescence Correlation Spectroscopy” ebook

14. Space Research Centre
 Pixellated photon counting
detector replaces CCD
camera
 Event timing allows
 Image reconstruction
 Observation of dynamic signals
 Advantages
 Ultimate sensitivity
 Reduced dark noise
 No pixel aliasing effects
 Much higher time resolution
Cucurbita; 6x6 Configuration vsWidefield; 20x Objective
Data and figure courtesy of Prof. Nick Hartell,UoL
BBSRC-funded project: DigitalConfocal Microscope For High Speed Microscopy

15. Space Research Centre
Revision: Cavity RingDown Spectroscopy
• Using a pulsed coherent light source
• Cavity output tails off exponentially
• No spectral information
• Requires pulsed laser
Laser Input
Pulse
Pulse in cavity
Cavity output
Intensity

16. Space Research Centre
fibre-optic
alignment mirrors
• Photon-counting provides phase shift of modulated
light source
• Uses broadband LED light source (no laser reqd.)
• Monitor LED source and cavity output simultaneously
• Simultaneous measurement at multiple wavelengths
• Discriminate multiple species simultaneously
• Technique is can be self calibrating
• Capable of parts per trillion sensitivity
C-DIR MCP
detector
Broadband Cavity Enhanced Absorption Spectroscopy
Broadband LED light source
cavity

17. Space Research Centre
 We have developed complementary readout systems
to exploit microchannel plate performance envelope
for single photon counting
 HiContent: Pixellated detector system with parallel
multichannel electronics (up to 1024 channels with
picosecond timing and very high throughput – 2.5
Mcount/ch/s)
 C-DIR: Flexible, lost cost system with intrinsic high
time resolution and customisable imaging
performance - very high spatial resolution or
moderate resolution with high throughput
 We’re now exploit opportunities in a range of
applications in the life science and other fields

18. 11:35 Detectors for high speed photon imaging
and timing
Dr Jon Lapington
11:55 Single Molecule Imaging Technology
Prof George Fraser
12:15 High Resolution SFOV Gamma Camera
Systems for Medical Imaging
Dr John Lees
Session 2 – Technology Showcase

19. Space IDEAS Hub Workshop , 24th January 2012.
Space Research Centre
Department of Physics and Astronomy,
Michael Atiyah Building,
University of Leicester
Single Molecule Imaging Technology
GW Fraser
e-mail gwf.le.ac.uk
Tel 0116 252 3542 (direct line) or 3491 (PA)
1. Superconducting Tunnel Junctions (STJs) to register the energy, position and arrival
time of single optical photons by measuring the charge deposited in a tantalum
superconductor at a temperature of 0.3K
2. Insights into the basic fluorescence process, coupled to in-depth knowledge of
detector physics, leading to novel algorithms for microarray analysis ?

20.  Measurement of light fundamental to life sciences research
 Current measuring devices (PMTs,CCDs) have major limitations
Monochrome
High noise
Low sensitivity
 Life Sciences need detectors with:
The ability to scan entire colour spectrum, photon-by-photon
Greater sensitivity
Less noise and better linearity
 Solution – the Superconducting Tunnel Junction (STJ)
Developed by the European Space Agency (ESA) for optical astronomy
Requires closed-cycle cooler capable of 0.3 K (or below!)
Only coarse (12 x 10) pixel arrays available

21. S-CAM
 Developed by Tone Peacock, Mike
Perryman et al. at ESTEC, from
1992 onwards
 Successfully employed for stellar
and planetary astronomy on the
William Herschel Telescope
STJ

22. 0
1
2
3
4
5
6
7
8
9
10
1 1.5 2 2.5 3
Photon energy (eV)
Alexa 594
Alexa 488
The detection of multiple fluorescent labels using
superconducting tunnel junction (STJ) detectors
G.W. Fraser*, J.S. Heslop-Harrison†, T. Schwarzacher†, A.D.Holland*, P. Verhoeve‡ and A. Peacock (*Space
Research Centre, Department of Physics and Astronomy and Department of Biology†, University of Leicester, Leicester LE1 7RH, UK. ‡ Science Payloads
Technology Division SCI-ST , Research and Scientific Support Department , Postbus 299, ESA/ESTEC, 2200 AG Noordwjik, The Netherlands.)
Review of Scientific Instruments, Volume 74, September 2003.

23. 0
0.1
0.2
400 500 600 700 800
Wavelength (nm)
Counts/10nm/second (a) Raw Spectra
Second ESTEC Campaign – single pixel Tantalum STJ

24. 0
0.05
0.1
0.15
0.2
400 500 600 700 800
Wavelength (nm)
Counts/10nm/second
(b)Background Subtracted Spectra

25. Third ESTEC Campaign – 2010 Limitations of sparse pixel array

26. Time Series – Photobleaching and Glitches

27. N3x25 triple measurement
All Red Green
Blue

28. Sample I2 single colour STJ images
(DAPI, A594, A488) after super-
resolution and smoothing compared
with simultaneous CCD imagery
CCD

29. I8_1_DAPI_0001 I8_1H2AX_488
Sample I8 single fluorophore (top) and
simultaneous pulse-height resolved measurements
Blue Green

30. BioAstral Cooltronics

31. 2. Applications
in Life
Sciences
3. Requirement
for closed-cycle
cryogenic cooler
4.
Requirement
for Super
Resolution
Software
5. New
Applications
in Exoplanet
Detection?
1.Novel
Astronomical
Detector
Technology – the
optical STJ

32. 0
1
2
3
4
5
0 5 10 15 20
n , Fluorophores/molecule
S(n)
Alexa 488
Fluorescein-EX
Alexa 546
Self-quenching

37. MA plot after collapse of two-colour microarray data set on to
“line of parity” and imposition of noise threshold

38. Estimating the size
of the population of
expressed genes by
comparison with null
(Gaussian) cumulative
distribution

39. The Future of Biology is the Detection of Light
Acknowledgements
Trude Schwarzacher, Pat Heslop-Harrison, David Ray, David Gough, Alyson Reed
Rob Limpenny, Gauthier Torricelli, Sarah Botterill, Simon Lindsay, Daniel Brandt
Peter Verhoeve and Didier Martin

40. 11:35 Detectors for high speed photon imaging
and timing
Dr Jon Lapington
11:55 Single Molecule Imaging Technology
Prof George Fraser
12:15 High Resolution SFOV Gamma Camera
Systems for Medical Imaging
Dr John Lees
Session 2 – Technology Showcase

41. Dr John Lees
University of Leicester
High resolution SFOV
gamma camera systems for
medical imaging
Medical Imaging - Opportunities for Business
Due to confidentiality restrictions,
this presentation is not available online

42. If your organisation would like to benefit from
our knowledge and expertise, please contact us.
Space IDEAS Hub
W: www.spaceideashub.com
E: enquiries@spaceideashub.com
T: 0116 229 7700
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