1. 11.05.2006 E.Grigoriev – EuroMedim 2006 1 Silicon Photomultipliers and their bio-medical applications E.Grigoriev 3,4, A.Akindinov 4, M.Breitenmoser 3, S.Buono 1, E.Charbon 2, I.Desforges 3, C.Niclass 2, R.Rocca 1 1 AAA (Advanced Accelerator Applications), Saint Genis, France 2 EPFL, AQUA group, Lausanne, Switzerland 3 FORIMTECH S.A., Geneva, Switzerland 4 ITEP, Moscow, Russia

2. 11.05.2006 E.Grigoriev – EuroMedim 2006 2 Outline Introduction: from silicon SPAD to SiPM and SPAD arrays SPAD arrays – features and applications SiPM – current status and main features SiPM – examples of applications in physics SiPM – examples of applications in medicine Prospects of use in bio-medical applications Summary

3. 11.05.2006 E.Grigoriev – EuroMedim 2006 3 SPAD – principle of operation SPAD – Single Photon Avalanche Diode Operates at V op =V bd +  V when a self-sustaining avalanche process can be initiated by a single charge-carrier n+ n-well p-substrate p+ [Haitz, 1965]

4. 11.05.2006 E.Grigoriev – EuroMedim 2006 4 SPAD: main characteristics Typical size 10-100  m V breakdown 20-40 V QE peak ~ 45 % at ~500 nm C junction ~ 10-100 fF Dark count rate ~ 0.1-10 Hz /  m 2 Q=C(V op -V bd )=M (“gain”) V bd V op V photon arrival Avalanche quenching SPAD recharge Rochas, Ph.D. Thesis, EPFL, 2003

5. 11.05.2006 E.Grigoriev – EuroMedim 2006 5 Passive and Active Recharge R q V op V IAIAIAIA V p+ = VDD + |V H | > V bd OUT digital pulse VDD V p+ IAIAIAIA Tq t recharge < 40 nsec t recharge > 100 nsec Niclass and Charbon, ISSCC 2005

6. 11.05.2006 E.Grigoriev – EuroMedim 2006 6 SPAD limitations Capabilities of SPAD quite limited: Small geometrical acceptance 1 photon at a time + ~40 nsec for recharge NB: many fluorescent processes are characterized by lifetimes in 0.1-10 nanoseconds band  time- resolved measurement impossible with one SPAD Need for devices with many sensitive elements and/or high dynamic range

7. 11.05.2006 E.Grigoriev – EuroMedim 2006 7 Two types of SPAD arrays SPAD chips Loose packing (fill factor ~ 1-6%) Individual addressing No special optical isolation (standard CMOS process) Dynamic range = 1 Active recharge (t rec  < 40 nsec) SiPM Dense packing (fill factor ~ 50-80%) Common readout Special optical isolation (MESA technology,…) Dynamic range ~ N pix Passive recharge (t rec > 100 nsec)

8. 11.05.2006 E.Grigoriev – EuroMedim 2006 8 CMOS 32x32 Pixel Array LFSR 1k pixel array Osc. ROWDECODER COL. DECODER 2.5mm 2.8mm Guard Ring Anod e Logic Gates Niclass,Charbon et al., JSSC 05 0.8  m CMOS Active area diam. 7  m Pitch = 58  m Fill factor ~ 1% QE at 635 nm ~ 12% Time jitter ~ 50 psec Dead time < 40 nsec

9. 11.05.2006 E.Grigoriev – EuroMedim 2006 9 Example: 3D Vision Lateral resolution:  64x64 pixels Depth resolution:  1.3mm Range:  3.75m [Niclass and Charbon, ISSCC 2005]

10. 11.05.2006 E.Grigoriev – EuroMedim 2006 10 [Niclass, Sergio, Charbon, DATE 06] CMOS Deep-submicron SPAD array Features  World’s first DSM SPAD array  World’s smallest pitch (25  m) and largest single photon streak camera (112x4 pixels)  Event-driven readout  Fill factor: 6%

11. 11.05.2006 E.Grigoriev – EuroMedim 2006 11 SiPM design principles Maximize geometrical fill factor Common readout of all channels (analog sum of quasi-digital signals) Passive quenching with individual resistors in each pixel Good optical isolation between pixels (MESA,…) -V oper Readout G. Bondarenko, V. Golovin, M. Tarasov, patent N 2142175 (Russia 1999)

12. 11.05.2006 E.Grigoriev – EuroMedim 2006 12 SiPM layout N. Basharuli, G. Bondarenko, V. Golovin et al., Como 2001

13. 11.05.2006 E.Grigoriev – EuroMedim 2006 13 SiPM pulseheight spectra Spectrum from a pulsed low-light source. Peak widths reflect spread in pixel capacitance values and breakdown voltages A.Akindinov et al., Beaune 2005 to be published in NIM

14. 11.05.2006 E.Grigoriev – EuroMedim 2006 14 Probability to have more than one pixel fired from a single primary e-h pair  = (N n+1 )/ (N n ) A. Akindinov, V. Golovin, E. Grigoriev et al., Proceedings of 8 th ICATPP conference Villa Erba, Como, 2004 SiPM optical cross-talk

15. 11.05.2006 E.Grigoriev – EuroMedim 2006 15 Y. Musienko, S. Reucroft, J. Swain Northeastern University, Boston A.V. Akindinov et al., Instrum. Exp. Tech. 48-3 (2005) 355 P.D.E. = Q.E. *  g * R ε g – geometrical fill-factor R – probability to initiate Geiger avalanche Q.E. – quantum efficiency SiPM photon detection efficiency This spectral sensitivity well matches the wavelenghs of most of fluorescent proteins

16. 11.05.2006 E.Grigoriev – EuroMedim 2006 16 Single photoelectron timing resolution for SiPM and PMT B. Dolgoshein et al. / Nucl. Instr. Methods A 504 (2003) 48–52 SiPM timing properties Resolution for multiphoton events improves as 1/sqrt(N)

17. 11.05.2006 E.Grigoriev – EuroMedim 2006 17 SiPM characteristics operating voltage ~ 20-40 V power consumption ~ 50  W / mm 2 single-photon response ~ 10 5 -10 6 e optical cross-talk ~ 10% peak detection efficiency ~ 25% at 520nm timing resolution ~ 100 psec typical size ~ 1 mm 2 dynamic range ~ 1000 low sensitivity to ionizing particles non-sensitivity to magnetic field RT operation, low temperature dependence mechanical and electrical robustness low price

18. 11.05.2006 E.Grigoriev – EuroMedim 2006 18 SiPM features Large photosensitive area Large dynamic range Deadtime negligible if N ph << N pixels Possibility of dark count discrimination (dark count is predominantly single-electron) BUT: Significant dark count rate (~10 5 -10 6 Hz / mm 2 ) Enhanced optical cross-talk (~10%) Therefore area is practically limited to few mm 2 Best application - in time-correlated measurements with fibers, microlenses or in microdevices

19. 11.05.2006 E.Grigoriev – EuroMedim 2006 19 Physics: particle detectors with SiPM Z. Sadygov et al. / Nucl. Instr. Methods A 550 (2005) 212–216 Particle tracking with Scintillating fibers – Beam Profile Monitor Cosmic triggering with scintillating tiles and WLS fibers (START) A.Akindinov, E. Grigoriev, V. Golovin et al., - Nucl. Instrum. Methods A539 (2005) 172-176 2 planes of 80 tiles

20. 11.05.2006 E.Grigoriev – EuroMedim 2006 20 Physics: calorimetry with SiPM Hadron calorimeter (CALICE Collab.) B. Dolgoshein, M. Danilov et al. / Nucl. Instr. Methods A 540 (2005) 368–380

21. 11.05.2006 E.Grigoriev – EuroMedim 2006 21 Medicine: SciFi+SiPM probe for diagnostics and radio-guided surgery AAA/FORIMTECH design (patent pending) In collaboration with University Hospitals of Grenoble, Geneva and Lausanne Work supported by INTERREG Grant 49/BL/9.3/3

22. 11.05.2006 E.Grigoriev – EuroMedim 2006 22 SciFi probe Principle of directional selectivity Extremely high sensitivity to positrons has been already demonstrated!  Numerous applications in local dynamic multi- positional detection of different radio-tracers (intravascular, transcutaneous, intracavital) AAA / FORIMTECH design (patent pending) Work supported by INTERREG Grant 49/BL/9.3/3

23. 11.05.2006 E.Grigoriev – EuroMedim 2006 23 SciFi probe: directional resolution versus threshold for different fiber diameters

24. 11.05.2006 E.Grigoriev – EuroMedim 2006 24 New ideas & applications SiPM matrix Matrix of scintillating elements or single plate WLS-optical fibers FORIMTECH design (patent pending) Applications: PET Portal imaging with plastic scintillator and high threshold Imaging of large objects with high- energy , n, p Large Area Radiation Imager NB SiPM can be easily transformed in a multichannel device by modifying the top Al layer

25. 11.05.2006 E.Grigoriev – EuroMedim 2006 25 New ideas & applications FORIMTECH design (patent pending) Universal time-resolved fluorescence probe. Fiber(s) can be clear or WLS, can be inserted in a catheter or seringe needle for study of dynamic processes using optically stimulated fluorescence Simulteneous detection of several fluorochromic labels

26. 11.05.2006 E.Grigoriev – EuroMedim 2006 26 Optical Dielectrophoresis Monitoring [Romani et al. ISSCC 04] Single photon detection islands Artist rendering of a dielectrophoresis system based on [Romani et al, ISSCC 04] with the proposed addition of optical monitoring New ideas & applications

27. 11.05.2006 E.Grigoriev – EuroMedim 2006 27 Simplified FLIM optical setup (Calcium-sensitive dyes) Transmission configuration Advantage of SPAD array: Can process multiple points at a time through deep sub-micron highly parallel sensor picosecond accuracy with non-cooled sensor (Two-Photon) Fluorescence Lifetime Imaging (FLIM) [Agronskaia et al., 2004] Detector Timing Analysis Laser Confocal optics Confocal optics

28. 11.05.2006 E.Grigoriev – EuroMedim 2006 28 New ideas (medicine, biology, environment protection) Single-photon sensitivity, RT operation, good timing resolution allow SiPM and SPAD arrays to be used in compact and robust devices which can measure molecular signatures and are based on time-resolved fluorescence, delayed luminescence, photon scattering or radio-tracing: DNA analysis, measuring protein dynamics using light scattering, two-photon fluorescence microscopy automated DNA sequencing machines particle and droplet sizing optical biopsy study of cancer processes using fluorescent proteins fluorescence or diffuse optical tomography implantable or endovascular probes this list can be very long… Potential partners interested to develop jointly any of these are welcome!

29. 11.05.2006 E.Grigoriev – EuroMedim 2006 29 Recently approved project: RAPSODI (FP6 / CRAFT) GOAL: implementation of SiPM in a range of medical devices for dosimetry and radio- protection Participants: University of Insubria (Como) – coordinator ITEP (Moscow) University of Technology (Krakow) FORIMTECH (Geneva) PTW (Freiburg) SensL (Cork) Jiry-Plch SMM (Prague)

30. 11.05.2006 E.Grigoriev – EuroMedim 2006 30 SUMMARY SiPMs and SPAD arrays have already demonstrated superior performances in particle physics and several other applications Their commercial availability and customisation open numerous wide opportunities for replacement of traditional photodetectors and minutuarization of bio-medical devices Small size, low voltage and power consumption, RT operation, single-photon sensitivity, sub- nanosecond resolution and low cost open possibilities of a breakthrough in developing new procedures using compact multi-channel systems for bio-medical and pharmaceutical research

31. 11.05.2006 E.Grigoriev – EuroMedim 2006 31 BACKUP slides

32. 11.05.2006 E.Grigoriev – EuroMedim 2006 32 Functional Brain Scanning Principle: Reflectivity of emoglobin results in variable scattering depending upon oxygenation levels or Voltage Sensitive Dye based imaging Advantage of SPADs: Much higher saturation enables reduction of Poisson noise effects [Grinvald et al., 2001]

33. 11.05.2006 E.Grigoriev – EuroMedim 2006 33 Spare for upper slide