1. The information contained in this presentation is proprietary and confidential Βασικές αρχές της Ελαστογραφίας. Εξέλιξη της τεχνολογίας στην Ελαστογραφία ShearWave. Αθήνα, 23 Ιανουαρίου 2010 Θανάσης Λούπας, PhD Principal Scientist, SUPERSONIC IMAGINE SA, France 1

2. The information contained in this presentation is proprietary and confidential Elastography Background 2  In ancient Egypt, a link was established between a hard mass within the human body & pathology.  In Hippocratic medicine, palpation was an essential part of a physical examination.  In the 21 st century, «remote palpation» by means of elastographic imaging is becoming a reality.

3. The information contained in this presentation is proprietary and confidential Young’s Modulus E = Stress Strain e sSTRESS STRAIN kPa ELASTICITY High Strain  Easy to deform  Low Elasticity Low Strain  Hard to deform  High Elasticity 3  Palpation  Qualitative estimation of tissue elasticity  Young’s Modulus E quantifies elasticity in units of kiloPascals, as the ratio of the Stress S (compression) applied to a body divided by the Strain e (relative deformation) it produces.

4. The information contained in this presentation is proprietary and confidential  Different types of soft tissue have similar density but exhibit significant variation in elasticity.  Elasticity variations can help detect / characterize focal (e.g. malignant masses) and diffuse (e.g. fibrosis) pathologies. 4 Organ / Soft tissue typeYoung’s modulus E (kPa) Density (kg/L) Breast Normal fat18-24 1.0 ± 10% ~ water Normal glandular28-66 Fibrous tissue96-244 Carcinoma22-560 Prostate Normal anterior55-63 Normal posterior62-71 BPH36-41 Carcinoma96-241 Muscle 6-7 Liver Healthy tissue 0.4-6 Kidney Fibrous tissue10-55 “ Virtual ” Biopsy “ Remote ” Palpation Soft Tissue Elasticity

5. The information contained in this presentation is proprietary and confidential Elasticity Imaging R&D  Many R& D techniques have emerged since the 1990s, based on the Ultrasound and Magnetic Resonance imaging modalities.  Sonoelasticity: KJ Parker et al, 1990  Ultrasound Strain Elastography: J Ophir et al, 1991  MR Elastography: R Sinkus et al, 2000  Shear Wave Elastography: J Bercoff et al, 2004  All techniques are based on the same principle:  Generate a stress, and then use an imaging technique to map the tissue response to this stress in every point of the image. but differ substantially in terms of their performance characteristics:  Qualitative / quantitative nature, absolute / relative quantification.  Accuracy / precision / reproducibility, …  Spatial / temporal resolution, sensitivity / penetration, … COMMERCIALY AVAILABLE 5

6. The information contained in this presentation is proprietary and confidential  The basic principle used is the one proposed by Ophir’s group in the early 1990s: 1.Tissue compression (Stress) is induced manually by the user. 2.Multiple images are recorded using conventional imaging at standard frame rates. 3.The relative deformation (Strain) is estimated using Tissue Doppler techniques. 4.The derived strains are displayed as a qualitative elasticity image.  Initially introduced by Hitachi, and later on Siemens, in the early 2000s.  More manufacturers have followed in the last year(s). Strain Elastography Strain Elastography 6

7. The information contained in this presentation is proprietary and confidential Pre-compression RF line Post-compression RF line dT T Pre-compression RF lines Post-compression RF lines Local Cross Correlation Analysis STRAIN ESTIMATION  Strain represents relative deformation, and is expressed in qualitative units (soft / hard)  Soft objects  High Strain  Hard objects  Low Strain Strain = dT / T Strain Elastography Processing Strain Elastography Processing 7

8. The information contained in this presentation is proprietary and confidential  Stress Source  Manual Compression (user-dependent).  Stress Frequency  Static (user-induced vibration < 2 Hz).  Result Type  Qualitative image ( E=Stress/Strain, but Stress is unknown). Relative quantification (Background-to-Lesion-Ratio). Strain Elastography Summary Strain Elastography Summary  Straightforward implementation on current scanners ( standard acquisition architecture, plus Tissue-Doppler-like processing).  Stress penetration / uniformity issues. User-applied compression is attenuated by soft objects & depth, and cannot penetrate hard-shelled lesions.  User-dependence. The extent of tissue compression affects the elasticity image. 8

9. The information contained in this presentation is proprietary and confidential  The Elasticity formula is of little practical relevance because it is extremely difficult to estimate the Stress applied at each point of the image.  In the late 1990s and early 2000s, an novel approach was pursued in order to achieve quantitative Elastography, by relying on an alternative Elasticity formula: where  is the tissue density (~ 1 kg/L) c S is the speed of a Shear Wave propagating through the medium. From Strain to Shear Wave Elastography From Strain to Shear Wave Elastography E = Stress Strain kPa E = 3  c S 2 kPa  Sarvazyan AP: Method and device for shear wave elasticity imaging. US Patent 5,606,971 1997.  Sarvazyan et al : Shear wave elasticity imaging -- A new ultrasonic technology of medical diagnostics. Ultrasound Med Biol 1998; 24:1419-35.  L Sandrin, S Catheline, M Tanter, C Vinçonneau, M Fink : 2D Transient Elastography Acoust. Imag., Vol. 25, pp 485-492, 2000.  M Tanter, J Bercoff, L Sandrin, M Fink : Ultrafast compound imaging for 2D motion vector estimation : Application to transient elastography IEEE Trans UFFC, Vol. 49, pp 1363-1374, 2002. 9

10. The information contained in this presentation is proprietary and confidential Shear Waves in Medical Ultrasound Until now, Medical Ultrasound imaging has been based entirely on Longitudinal waves. Two types of acoustic waves propagating in the human body:  Longitudinal (or bulk) waves  Propagation direction parallel to tissue motion.  High frequency (typically, > 1 MHz), and high propagation speed (~ 1500 m/s).  Shear (or transverse) waves  Propagation direction perpendicular to tissue motion.  Low frequency (typically, < 1 kHz), and low propagation speed (~ 5 – 10 m/s). Propagation Direction Propagation Direction Tissue Motion SHEAR WAVE LONGITUDINAL WAVE 10

11. The information contained in this presentation is proprietary and confidential Shear Wave Sources Natural Heart External Mechanical force Focused Ultrasound PW Doppler  SuperSonic Imagine has developed a novel method called SonicTouch, which is based on focused ultrasound, and can remotely generate Shear Wave-fronts providing uniform coverage of a 2D area interest. 11

12. The information contained in this presentation is proprietary and confidential Shear Wave Generation  Focused ultrasound is transmited at multiple points along a line of interest.  An individual Shear Wave is generated and starts propagating around each focal point.  The superposition of the individual Shear waves creates a Shear Wave-front similar to the Super Sonic Mach Cone. SonicTouch 12  The SonicTouch Shear Wave generation process is completely automated and user-independent.

13. The information contained in this presentation is proprietary and confidential Shear Wave Detection Shear Wave Speed = 5 m/s 1 mm in 0.2 milliseconds  The typical Shear Wave speed c S in soft tissue is ~ 5 m/s.  This means that the Shear Wave needs 0.2 ms to travel 1 mm.  Thereforein order to have a spatial resolution of 1 mm, we must image the Shear Wave once every 0.2 ms, i.e. 5000 times per second. 5000 images per second needed! Almost 100 times more than the frame rates that current ultrasound scanners can offer (best case, 50-100 frames/second).  SuperSonic Imagine has developed a unique system architecture in order to achieve the Ultrafast Imaging performance needed to image the Shear Wave propagation across a 2D area of interest. 13

14. The information contained in this presentation is proprietary and confidential Ultrafast Imaging  Plane-wave transmissions are performed, each of them covering the whole image area.  For each transmission, the data received from all points of the image are processed using advanced reconstruction techniques to form the full image at once.  One frame is produced for every transmission, resulting in frame rates of up to 20 000 Hz. More than one transmit events may be combined to improve image quality by trading-off some frame rate. 14 Shear Wave Detection

15. The information contained in this presentation is proprietary and confidential Shear Wave Imaging Steps Uniform-elasticity phantom ~ 100 µs Step 1 Shear Wave generation 60 frames at a frame rate of 3000 Hz 0.33 ms Total duration: 20 ms ! Step 3 Shear Wave propagation image formation 15 Shear Waves Longitudinal Waves SonicTouch Ultrafast Imaging Step 2 Shear Wave Detection

16. The information contained in this presentation is proprietary and confidential Shear Wave Elastography Shear Wave Imaging sequence @ 3000Hz Breast Elastography phantom with uniform background + hard lesion E= 3cS23cS2 J. Bercoff, M. Tanter, M. Fink: Supersonic shear imaging: A new technique for soft tissue elasticity mapping IEEE Trans Ultrason Ferroelectr Freq Control, pp 396-409, 2004 16 Key Reference  Shear Wave Speed c S Estimation

17. The information contained in this presentation is proprietary and confidential Shear Wave Elastography Real-time operation 17

18. The information contained in this presentation is proprietary and confidential Shear Wave Elastography Mean =5.1 kPa StdDev =0.15 kPa (3%) Mean =10.5 kPa StdDev =0.8 kPa (7%) 10-13 Kpa 5 -7 Kpa Calibrated Elastometer values Accuracy / precision testing using calibrated elasticity phantoms Shear-Wave Elastography measurements TRULY-QUANTITATIVE NATURE Absolute elasticity quantification High accuracy / precision. 18

19. The information contained in this presentation is proprietary and confidential Shear Wave Elastography TRULY-QUANTITATIVE NATURE Absolute elasticity quantification High accuracy / precision 19 Simulated Tissue « Fat 1 »« Fat 2 »« Glandular »« Cancer » Reference Elasticity (kPa) 15.823.937.4105.7 SWE Mean (kPa) 142036.4105 SWE StdDev (kPa) 2.33.15.411.5  Extensive validations using calibrated tissue-mimicking phantoms.

20. The information contained in this presentation is proprietary and confidential Shear Wave Elastography Elasticity RatioAxial Res (mm)Lateral Res (mm) 211.1 31.2 101.31.1 Lateral resolution Axial resolution Custom-made two-layer phantoms with multiple elasticity ratios High spatial resolution Typically, ~ 1 mm axially & laterally for the SL 15-4 linear transducer. 20

21. The information contained in this presentation is proprietary and confidential Shear Wave Elastography Highly-localized estimation of tissue elasticity Especially, inside hard lesions Phantom with liquid center inside hard lesion Strain Elastography interprets the whole lesion as hard, because the applied manual compression cannot penetrate the hard shell. Shear Wave Elastography can “see” inside the hard lesion, because the shear waves can propagate through the hard shell. 21

22. The information contained in this presentation is proprietary and confidential Strain vs. Shear Wave Elastography 22 Strain Elastography tends to produce a binary classification, where the whole lesion is either hard or soft. Shear Wave Elastography provides richer & more complex information with many cases of hard borders plus soft centers. The differences between Strain and Shear Wave Elastography are not surprising, given the very different principles on which they are based.

23. The information contained in this presentation is proprietary and confidential  Stress Source  Automatically-generated Shear Waves (user-independent).  Stress Frequency  Broadband (typical Shear Waves from 50 to 500 Hz).  Result Type  Fully quantifiable images (kPascal, plus E ratio). Shear Wave Elastography Summary Shear Wave Elastography Summary  Unique to SuperSonic Imagine, due to need for advanced capabilities (SonicTouch, Ultrafast Imaging), and intellectual property protection.  Rich / complex mapping of hard lesions, with heterogeneous elasticity in the lesion periphery and/or center. 23

24. The information contained in this presentation is proprietary and confidential Shear Wave Elastography Applications Shear Wave Elastography Applications  SWE is fully-integrated feature of the Aixplorer premium Ultrasound scanner. 24  Organs currently targeted by SWE include: Breast, Thyroid, and Liver.  Work-in-progress encompasses: Prostate, Musculoskeletal, and 3D Breast applications.  R&D efforts focus on Cardiovascular and Ophthalmology applications.

25. The information contained in this presentation is proprietary and confidential 25 Multi-center Breast Elastography Trial Assessment Of The Clinical Benefits Of SuperSonic Shear Wave Elastography In The Ultrasonic Evaluation Of Breast Lesions  Dates: Q2 2008 to Q2 2010  Sites : 11 centers in Europe & 6 centers in USA  Primary aim: Assess the benefit of Shear Wave Elastography for the characterization of breast lesions.  Secondary aim: Assess the benefit of Shear Wave Elastography for the visualisation of breast lesions.  Clinical trial and data analysis currently under way.  Preliminary results very promising. Improved sensitivity and specificity of breast ultrasound BIRADS diagnosis with SWE + ECHO versus ECHO only.

26. The information contained in this presentation is proprietary and confidential Clinical Evaluation of SWE for Liver Fibrosis Staging 26 SWE:Fibroscan: Bavu et al, “Non-invasive in-vivo Liver Fibrosis staging using Supersonic Shear Imaging: a Clinical Study”, Gastroenterology, 2010 (in press).

27. The information contained in this presentation is proprietary and confidential  Elastography is a perfect adjunct for Ultrasound Imaging.  Elastography has recently emerged as a new imaging mode in ultrasound systems, currently targeting Breast, Thyroid, Liver, and Prostate Imaging applications.  Multiple-vendor systems, but only two versions of Elastography Imaging: Strain Elastography and Shear Wave Elastography.  Strain Elastography has been adopted by many manufacturers, due to its technological maturity and ease of implementation.  Shear Wave Elastography is based on innovative technologies, developed in order to expand the capabilities of existing solutions (full quantification, highly-localized estimation, user-independence).  There is still a long way to go with regards to equipment improvements bright and clinical understanding, but the future of Elastography looks bright. CONCLUDING REMARKS CONCLUDING REMARKS 27

28. The information contained in this presentation is proprietary and confidential 28