AU2020207873B2 - System for characterizing tissue and associated method - Google Patents

Abstract

A system (1) for characterizing tissue comprising: a probe that delivers a continuous and periodic mechanical vibration (PMV) to a tissue of a subject; and an ultrasound emitter that emits a sequence of ultrasound shots (80, 80', 80") and an ultrasound receiver that receives corresponding echo signals to track how the tissue is moved by the periodic mechanical vibration delivered to the tissue; and a control module programmed to provide homogeneity information (808, 808', 808") to an operator of the system, the homogeneity information being determined from at least some of said echo signals and being representative of the ability of the tissue to transmit elastic waves and of the homogeneity of the tissue with respect to the propagation of elastic waves. A method for characterizing tissue is also provided. Fig. 9 2020207873 24 Jul 2020

Description

2020207873 24 Jul 2020

Z subject of. the tissue

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11

1 50 2020207873

13 10 12

14

28 22 frontend Ultrasound Motion actuation 23 servo controller

T/R Fig. 7

Operator interface 30

Central unit 20 RX circuits 27 TX circuits

29

purpose

Control module 21 Special Processor circuit screen 31

26 display

MEM 25

4/14

251 250

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SYSTEM FOR SYSTEM FOR CHARACTERIZING CHARACTERIZING TISSUE TISSUE AND AND ASSOCIATED ASSOCIATED METHOD METHOD CROSS-REFERENCE CROSS-REFERENCE TOTORELATED RELATEDAPPLICATION(S) APPLICATION(S)

[0001] The present

[0001] The present application application is related is related to PCT to PCT application application PCT/EP2019/054656 PCT/EP2019/054656

55 filed Feb. filed Feb. 26, 26, 2019 2019and andto toPCTPCT application application PCT/EP2019/054658 PCT/EP2019/054658 filed 26, filed Feb. Feb.2019, 26, 2019, whichare which areherein hereinincorporated incorporated by reference by reference in their in their entireties. entireties.

TECHNICALFIELD TECHNICAL FIELD

[0002] The The

[0002] disclosed disclosed technology technology relates relates to non-invasive to non-invasive tissuecharacterizing tissue characterizing systems andininparticular systems and particular to to systems systemsand andmethod method for for systems systems for identifying for identifying 10 10 homogeneous homogeneous tissue tissue in which in which tissuetissue stiffness stiffness or content or fat fat content can becan be non-invasively non-invasively

assessed. assessed.

BACKGROUND BACKGROUND

[0003] It isIt well

[0003] is well known known that that the the stiffness stiffness of of livertissue liver tissuecorrelates correlates with with degrees degreesofof liver cirrhosis liver cirrhosisand andother otherdiseases, diseases, and and that that the the speed at which speed at which aa shear shearwave wave travels travels

15 through 15 through a region a region of interest of interest in a in a subject's subject's liver liver is directly is directly related related tostiffness to the the stiffness of theof the liver. As liver. matter of As aa matter of fact, fact, in in soft soft tissues, tissues, the stiffness (Young's the stiffness modulus)cancan (Young's modulus) be be deduced fromthe deduced from thetissue tissuedensity density (p) (p) and and the the shear shear wave wavespeed speed usingthe (Vs)using (Vs) theformulae formulae E=3pVs 2 .The E=3pVs². Thedensity density of soft of soft tissues tissues is close is close to 1000 to 1000 E is3. expressed kg/m³.kg/m E is expressed in in kilopascals and kilopascals and Vs in meter V in meter per second(m/s). per second (m/s).

20 [0004] 20 [0004] To characterize To characterize liverliver or other or other organ organ stiffness stiffness by shear by shear wave wave speed speed measurements, a technique measurements, a technique called called "harmonic "harmonic elastography" elastography" described described for example for example in in the document the document"Probe "Probe OscillationShear Oscillation Shear Wave Wave Elastography: Elastography: Initial Initial In Vivo In Vivo Results Results in in Liver" by Liver" D.C. Mellema by D.C. Mellemaet etal., al., published publishedininIEEE IEEE Transactions Transactions on Medical on Medical Imaging, Imaging,

volume37, volume 37, issue issue 5, 5, May May2018, 2018,has hasbeen beendeveloped. developed.

25 [0005] 25 [0005]According According to thistotechnique, this technique, an transducer an array array transducer for 2-dimensional for 2-dimensional B-mode B-mode

ultrasound imaging ultrasound imaging isis placed placedononcontact contactwith witha asubject's subject'sbody body andand vibrated vibrated at at a low a low

frequency, typically frequency, typically comprised between3030HzHz comprised between and and 100100 Hz. Hz. Ultrasound Ultrasound shots shots are are thenthen

emitted to track emitted to track how the tissue how the tissue of of the the subject subject is ismoved by this moved by this low low frequency periodic frequency periodic

vibration. vibration.An An instantaneous instantaneous 2-dimensional map(a(akind 2-dimensional map kind of of 2D 2D snapshot), snapshot),showing showingtissue tissue

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displacement caused displacement caused by low by the the frequency low frequency periodic periodic vibration vibration at different at different points points

distributed distributed over over aa 2-dimentional section of 2-dimentional section of the the tissue tissue of of the the subject, subject, and and at at aa same same instant, isisthus instant, thusdetermined determined (see (see figure figure 9a 9a of of the the above mentioneddocument above mentioned document by D.C. by D.C.

Mellemaetetal.). Mellema al.). A filtered 2-dimensional A filtered displacementmap 2-dimensional displacement mapis is then then determined determined by aby a 5 complex 5 complex spatial spatial mode mode filtering filtering (figure (figure 9b,9b, or of or 8b 8bMellema of Mellema et An et al.). al.).inversion An inversion algorithm then enables algorithm then enablestotoderive derive(from (from thethe 2-dimensionnal 2-dimensionnal deformation deformation map) amap) 2- a 2 dimensional maprepresenting dimensional map representing thethe value value of of thethe shear shear wavewave speedspeed at different at different points points

distributed overananentire distributed over entire 2-dimentional 2-dimentional section section of theoftissue the tissue (figure(figure 8c of Mellema 8c of Mellema et et al.). al.).With With this this technique, valuesof of technique, values the the shear shear wavewave speed speed are are thus thus derived derived from spatial from spatial

10 information 10 informationcontained containedininthe the instantaneous instantaneous2-dimensional 2-dimensionaldisplacement displacement map. map.

[0006] But But

[0006] implementing implementing suchsuch a method a method requires requires a quite a quite complex complex multibeam multibeam ultrasound device, ultrasound device, suitable suitable for for 2-dimensional ultrasound imaging. 2-dimensional ultrasound imaging. And Andthe theprocessing processing of aa single of single instantaneous instantaneous2-dimensional 2-dimensional deformation deformation map requires map requires a lot of lot of a time, time, typically 33 vibration typically vibrationperiods, periods, according according to to Mellema Mellema etet al. al. This This long longprocessing processingtime time 15 prevents 15 preventsfrom fromsampling sampling a whole a whole vibration vibration period period all all at at once, once, from from a temporal a temporal point point of of view (as view (as explained explainedinin the thecapture captureofoffigure figure3 3ofofMellema Mellema et al.).More et al.). More precisely, precisely, in in Mellema, aa couple Mellema, coupleofoftwo twoultrasound ultrasound shots shots is is emitted emitted (every (every 100100 ms) ms) and then, and then, two two corresponding ultrasound corresponding ultrasoundecho echo signals signals areare acquired acquired and and processed processed to compute to compute the the displacementsinin the displacements the medium mediumat at thethe time time thecouple the couple of of ultrasound ultrasound shots shots waswas emitted. emitted.

20 This 20 Thisprocedure procedure is is then then repeated repeated 100 100 ms later, ms later, and and so(with so on on (with a repetition a repetition rate rate of of 10 10

hertz). hertz). Due to the Due to the long long processing processingtime time required required to compute to compute and analyze and analyze each 2-each 2

dimensional deformation dimensional deformation map, map, this this procedure procedure cannot cannot beberepeated repeatedwith witha ahigher higher repetition rate. repetition rate. So, So, with with this this technique, technique,a whole a whole vibration vibration period period cannotcannot be sampled be sampled all all at once at once(as (asit itwould would require require a repetition a repetition raterate higher higher than than the frequency the frequency of the of the 25 mechanical 25 mechanical vibration,namely vibration, namely higher higher thanthan 100 100 hertz). hertz). So, So, thisthis harmonic harmonic elastography elastography

technique enables technique enables2-dimensional 2-dimensionalspatial spatialimaging imagingandand is is focused focused on on spatial spatial properties properties

of the of deformationfield, the deformation field,butbuthashas a poor a poor temporal temporal resolution resolution and is and is influenced influenced by tissueby tissue motion due motion due to to respiration respiration or or heart heart beating beating for for example. example.

[0007] Besides,

[0007] Besides,measuring measuringshear shearwave wavespeed speed by by harmonic harmonic elastography isis elastography 30 considered 30 considered as as less less reliableand reliable andless lessaccurate accuratethan thanbybytransient transient elastography, elastography, harmonic harmonic elastography generally elastography generally providing providing over-estimated over-estimated speed speedvalues. values.Indeed, Indeed, withharmonic with harmonic elastography,thethe elastography, periodic periodic mechanical mechanical vibration vibration delivered delivered to the travels to the subject subjectintravels the in the

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subject's tissue subject's tissueasasanan elastic elastic wavemixing wave mixingshear shearwaves and compression waves and compression waves waves (whosepropagation (whose propagationspeed speed is much is much higher higher than than the of the one one of shear shear waves), waves), these these two two components being components being hardly hardly separable separable due due to repetitive, to the the repetitive, continuous continuous nature nature of the of the

vibration. vibration.And harmonicelastography And harmonic elastographymeasurements measurements can be can also also be skewed skewed by elastic by elastic

55 wave wave reflectionsinside reflections insidethe the tissue, tissue, which maycreate which may createstationary stationarywaves wavespatterns patterns(again, (again, due to the due to therepetitive, repetitive, continuous continuous nature nature of the of the vibration). vibration).

[0008] As aAsresult,

[0008] a result, thethe time-harmonicelastography time-harmonic elastographytechnique techniquedescribed described above above providesvaluable provides valuable spatial spatial information information regarding regarding the structure the structure of theof theofpart part the of the subject's subject's

body under body underexamination, examination, thanks thanks to 2-dimensional to its its 2-dimensional imaging imaging capabilities. capabilities. But it But it 10 10 generallyprovides generally providesshear shear wave wave speedspeed valuesvalues thatnot that are arevery notaccurate. very accurate. The The main main reasons for reasons for this this lack lackofof accuracy accuracyare arethe thecombination combinationofofshear shearand and compression waves, compression waves,

the influence the influenceofofdiffraction diffractioneffects effects duedue to large to the the large size size of the of the vibration vibration source, source, the the influence of influence of motions motionssuch suchas as respiratory respiratory motion motion given given that that the displacements the displacements are are usually captured usually capturedduring during several several cycles cycles of vibration of vibration andout and the theofout of motion plane plane that motion are that are 15 not 15 not measured. measured.These These problems problems result result in artefactson on in artefacts thethe image image thatthat mustmust be be interpreted with interpreted with aa lot lotofofcaution cautionespecially especiallywhen when quantitative quantitativemeasurements aretoto be measurements are be provided. provided.

Transient

[0009] Transient

[0009] elastography elastography thusseem techniquesthus techniques seem more more adequate thanthan adequate time time- harmonicelastography harmonic elastographytechniques techniques to to precisely precisely measure measure shearshear wave in wave speed speed quitein quite 20 large 20 largeand andhomogeneous homogeneous organs organs like like liverliver or or spleen. spleen.

[0010] Transient

[0010] Transient elastography elastography is based is based on a different on a different approach approach thanharmonic than the the harmonic elastography technique elastography techniquepresented presented above. above. Instead Instead of recording of recording an instantaneous an instantaneous 2- 2 dimentional map dimentional mapofofthe the tissue tissue deformation deformation (and (and deriving deriving shear wavespeed shear wave speedvalues valuesfrom from the spatial the spatial properties properties of of this this map), map), transient transient elastography elastographyisisfocused focusedon on a spatio a spatio-

25 temporal 25 temporal tracking tracking of a of a transient transient mechanical mechanical pulse delivered pulse delivered to the to the tissue. tissue.

[0011] A well

[0011] A well known known transient transient elastographysystem elastography systemisis the the FIBROSCAN® FIBROSCAN@ system system (an ultrasound-based (an ultrasound-based elastography elastography apparatus apparatus for measuring for measuring the (or the stiffness stiffness (or elasticity) elasticity)

and ultrasound and ultrasound attenuation attenuation of of tissues tissues and and organs), organs), produced andsold produced and soldbybyEchosens EchosensSA SA

of Paris, of Paris, France, France, which enablesananoperator which enables operatortotonon-invasively non-invasivelymeasure measure liver liver or or other other

30 organs 30 organs stiffnessto stiffness to assess assessthe the organ's organ's health. health.

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[0012] With With

[0012] the FIBROSCAN@ the FIBROSCAN® system, ansystem, an places operator operator theplaces tip ofthe tip of athat a probe, probe, that has aa rather has rather small small diameter diameter (typically (typically comprised comprised between 5 and between 5 10 mm), and 10 mm),inin contact contact with with the subject's the subject's body, body,in infront frontofofthetheexpected expected areaarea of a subject's of a subject's liver.liver. The operator The operator then then presses aabutton presses buttontotomake make the the probe's probe's headhead deliver deliver to subject to the the subject a transient, a transient, low low 5 frequency 5 frequencymechanical mechanical pulse pulse (the(the spectrum spectrum of this of this pulsepulse is centered is centered on a frequency on a frequency

comprised typically between comprised typically between 1010and and500500 hertz).This hertz). Thispulse pulsegenerates generates an an elastic elastic wave wave

that travels that travels ininthe thesubject's subject'sbody. body. An ultrasound transducer An ultrasound transducermounted mountedon on thethe probe's probe's

head, in head, in contact contact with with the the subject's subject'sbody, body,then then sends sends out out aa number ofultrasound number of shots ultrasound shots into the into the tissue, tissue,with witha ahigh high repetition repetition rate, rate, of 2of 2 kilohertz kilohertz at least. at least. Thesignals, The echo echo signals, 10 corresponding 10 correspondingto to thethe backscattering backscattering of different of the the different ultrasound ultrasound shotsshots emitted, emitted, are are acquired by the acquired by the probe probetototrack trackslight slight movements movements of of thethe tissue tissue caused caused by the by the elastic elastic

wavepassing wave passingthrough. through.The The trackingisisperformed tracking performedusing using correlationtechniques correlation techniques applied applied

to successive to echosignals. successive echo signals. The Thedetected detectedmovements movements enable enable to compound to compound an elastic an elastic

wavepropagation wave propagationimage image showing showing the the tissue tissue deformation deformation both both asfunction as a a function of of depth depth d, d, 15 and 15 andasasa function a functionofoftime timet (instead t (instead ofofcompounding compoundingan an image image showing showing tissue tissue deformation asa afunction deformation as functionofoftwo twodifferent differentspatial spatial coordinates, coordinates, but butatata agiven, given,fixed fixed instant). Figure instant). showssuch Figure 11 shows suchan an elastic elastic wave wave propagation propagation imageimage 105, sometimes 105, sometimes

referred to referred to as as anan"elastogram". "elastogram".

[0013] Contrary

[0013] Contrary to to otherelastography other elastography methods, methods, the the FIBROSCAN@'s probeuses FIBROSCAN®'s probe usesa a 20 favorable 20 favorablesymmetric symmetric design. design. TheThe ultrasound ultrasound transducer transducer is aissingle a single element element transducer transducer

mountedononthetheaxis mounted axisofofthe thevibrator. Theaxis vibrator. The axisofofthe theultrasound ultrasoundtransducer transducercoincides coincides with the with the axis axisofofthe thevibrator, vibrator,which whichis is whywhy the the displacements displacements inducedinduced by the vibrations by the vibrations

are largely longitudinal are largely longitudinal and therefore aligned and therefore aligned with withthe theultrasound ultrasound beam beam axis.axis. The The

measurement measurement of of thedisplacement the displacement is is significantly improved significantly in such improved in such conditions conditions since since the the 25 out-of-axis 25 out-of-axis displacement displacementareare much much moremore difficult difficult to to measure measure usingusing ultrasound. ultrasound. OtherOther

elastography devices, elastography devices, especially especially harmonic ones,are harmonic ones, aremore morecomplex. complex. They They use use multiple multiple

element ultrasound element ultrasound transducer transducer (usually (usually liner liner or convex or convex arrays)arrays) as they as aimthey aim at providing at providing

mapofofthe aa map themechanical mechanicalproperties properties in in 2D 2Doror3D3Dto tolocate heterogeneities. The locateheterogeneities. The symmetry of these symmetry of these systems systems is is much much more morecomplex. complex.Displacements Displacementsinduced inducedbybythe the 30 vibrations 30 vibrationsare arenot notaligned alignedwith withthe theultrasound ultrasoundbeam(s) beam(s) by by design. design. TheyThey require require moremore

computation timeasasthey computation time theyprocess processmuch much more more datadata (several (several ultrasound ultrasound lines) lines) and and use use

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sophisticated inversion algorithm sophisticated inversion algorithm to to assess assessthe themechanical mechanical properties properties in 2D in 2D or 3D. or 3D.

Furthermore,they Furthermore, they areare very very slowslow to operate. to operate.

[0014] TheThe

[0014] mechanical mechanical pulsedelivered pulse delivered by by the the FIBROSCAN® FIBROSCAN@ probe's probe's head head generates both a ashear generates both shearwave waveandand of aofcompression a compression wave.wave. In other In other words, words, the elastic the elastic

55 wave wavementioned mentionedabove abovecombines combines a shear a shear wave wave andand a compression a compression wave. wave. ButBut these these two waves two waveshave have very very differentpropagation different propagationspeeds speeds and, and, thanks thanks to the to the transientnature transient nature of of the mechanical the mechanical excitation, excitation, they they can can be easily be easily separated separated in time in time and and identified identified in the in the elastic elasticwave propagation image. wave propagation image.ForFor example, example, referringtotoFigure referring Figure1,1,this this figure figure shows shows

an elastic wave an elastic propagation image wave propagation image105. 105.InInfigure figure 1, 1, the the compression waveis isidentified compression wave identified 10 bybythe 10 thereference reference sign sign 105C, 105C, while while the the muchmuch slowerslower shear shear wave iswave is identified identified by the by the reference sign reference sign 105S. 105S. Also Also shown shown in figure in figure 1, 1, is isthe theregion regionofofinterest (ROI)which interest (ROI) whichisis boundbybytwo bound twodashed dashedlines linesatat25mm 25mmandand 65mm, 65mm, whichwhich corresponds corresponds to thetodepth the depth under under the patient the patient skin skin where liver isistypically where liver typicallylocated. located.This Thiselastic wave elastic wavepropagation propagation image image

can thus be can thus be used usedtotoprecisely precisely determine determinethe thepropagation propagationspeed speed of of shear shear waves waves in the in the

15 tissue 15 tissue to to be be characterized, characterized, from from which which the stiffness the stiffness of thisoftissue this tissue can be can be derived. derived. These These stiffness results 106 stiffness results 106are arethen thenprovided provided to the to the operator, operator, as represented as represented in figure in figure 1 which1 which

shows different graphs shows different graphs101, 101,102, 102,105105 andand indicators indicators 103, 103, 106,106, 107 107 displayed displayed to the to the

operator by means operator by meansofofaa display display screen screen of of the the FIBROSCAN@ system. FIBROSCAN® system.

[0015] The The

[0015] FIBROSCAN@ FIBROSCAN® system system also enables also enables one toone to measure measure the attenuation the attenuation of of 20 the 20 theultrasound ultrasoundsignals signals that that areare usedused to track to track the shear the shear wave, wave, which which is is as useful useful as ultrasoundattenuation ultrasound attenuation correlates correlates withwith the amount the amount of fat of fat content content in the(see in the liver liverfigure (see figure 1, ultrasound 1, attenuationresults ultrasound attenuation results 107). 107).

[0016] WhileWhile

[0016] the FIBROSCAN@ the FIBROSCAN® technologytechnology works works well, well, it is it is sometimes sometimes difficultdifficult for for an operatortotoknow an operator know if he/she if he/she has correctly has correctly positioned positioned the in the probe, probe, frontinoffront of an an area of area of

25 homogeneous 25 homogeneous liver tissue, liver tissue, or if he/she or if he/she is evenisaiming even the aiming probethe at probe at the the liver liverRibs at all. at all. Ribs in front in front of of the theliver, liver, blood bloodvessels, vessels, liquid liquid pockets pockets (ascites) (ascites) or artifacts or other other artifacts of non-of non homogeneous homogeneous tissue tissue such such a cysts a cysts or or tumors tumors in the in the livertissue liver tissuecan canproduce produce erroneous erroneous

measurements measurements of of both both tissue tissue stiffness stiffness andand ultrasound ultrasound attenuation. attenuation. In addition, In addition, an an operatormay operator may believe believe thatthat he/she he/she is aiming is aiming the probe the probe at the at the liver, liver, when when in fact inthe fact the probe probe 30 isistoo 30 tooclose closetoto the the lungs lungs oror other other internal internal organs. organs. As result, the As aa result, the system maynot system may notbebe able able to to obtain obtainaccurate accurate measurements. measurements.

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[0017] ToTohelp

[0017] helpthethe operatorfind operator find an anadequate adequateprobe probe position, the position, the FIBROSCAN@ FIBROSCAN® system system is configured is configured to continuously to continuously transmit transmit ultrasound ultrasound shots shots and toand to

acquire correspondingecho acquire corresponding echo signalswhile signals whilethethe operator operator is is searching searching forfor an an adequate adequate

probe position. probe position. A-mode andTM-mode A-mode and TM-mode graphs graphs are displayed are displayed and refreshed and refreshed in real in real timetime

55 totohelp helpthe theoperator operatorfind find the the adequate adequateprobe probe position.Figure position. Figure1 shows 1 shows an example an example of of such an A-mode such an A-modegraph graph 101101 andand TM-mode TM-mode graph graph 102. A102. A TM-mode TM-mode graph represents graph represents the the ultrasound echo ultrasound echo signals signals successively successivelyacquired acquiredafter after the the ultrasound ultrasound echo echosignals signalshave have been processed. been processed.Processing Processing of the of the ultrasound ultrasound echoecho signals signals includes, includes, e.g., e.g., envelope envelope

computation and decimation. computation and decimation. The TheTM-mode TM-mode graph graph shownshown in Figure in Figure 1 is a1 2-is a 2 10 dimensional 10 dimensionalimage image in which in which each each column column represents represents one one of theofprocessed the processed ultrasound ultrasound

echo signals acquired. echo signals acquired. Each Each column columnis isrepresentative representativeofofan an instantaneous instantaneous 1- 1 dimensional image dimensional imageshowing, showing, as as a function a function of of depth depth d, d, howhow the the partpart of subject's of subject's body body

located that located that is is inin alignment alignmentwith withthethe probe probe backscatters backscatters ultrasound ultrasound waves.waves. The The successive ultrasoundecho successive ultrasound echosignals signalsacquired acquired areare displayed displayed side-by-side side-by-side to show to show the the

15 evolution 15 evolution over over timetime of this t of t this image image 1-dimensional 1-dimensional (this evolution (this evolution beingbycaused being caused slight by slight probe movements probe movements or or byby organ organ movements movements caused caused by respiratory by respiratory motion). motion).

[0018] As As

[0018] shown shown in Figures in Figures 1 and 1 and 2, the 2, the TM-graphs TM-graphs may may provide provide useful useful informationregarding information regardingthethe probe probe 3 positioning. 3 positioning. Indeed, Indeed, when when the theaxis probe probe X is axis x is aligned aligned with aa thick, with thick, homogeneous partof ofthetheliver homogeneous part liver4, 4, the the TM-graph TM-graph402402 usually usually looks looks likea like a 20 stack 20 stackofofthin thin horizontal horizontal sheets sheets and andhas hasa ahomogeneous homogeneous aspect, aspect, both both horizontally horizontally and and vertically, as vertically, as shown shown ininfigure figure4.4.ByBy contrast, contrast, when when the probe the probe axis X axis x is to is close close to an an edge edge of of the the liver liver4,4,the theTM-mode graph202, TM-mode graph 202,302302 often often hashas a discontinuous a discontinuous aspect, aspect, either either

horizontally (figure 2) or vertically (figure 3). horizontally (figure 2) or vertically (figure 3).

[0019] Still,

[0019] Still,positioning positioning the the probe probe adequately adequately on on the the basis basis ofof the the TM-graphs TM-graphs 25 remains 25 remains quitedifficult quite difficult and requires aa proper and requires proper training training of of the the operator. operator. Furthermore, as Furthermore, as

will be will appreciatedby by be appreciated thethe skilled skilled artisan, artisan, an an inadequate inadequate probe probe positioning positioning may leadmay to lead to an inadequatemeasurement an inadequate measurementandand an inaccurate an inaccurate diagnostic diagnostic of the of the patient's condition. patient'scondition.

[0020] Ultrasound

[0020] Ultrasound signals signals displayed displayed in TM-mode in TM-mode or A-mode or A-mode graphs,graphs, though though providing some providing some information information regarding regarding the position the position of theof the probe, probe, are notare not predictive predictive of the of the 30 shear 30 shearwave wave propagation. propagation. In some In some situations, situations, these these graphs graphs may may appear appear adequate, adequate, as if as if the conditions the conditions were weresuitable suitablefor for transient transient elastography elastographymeasurements, measurements, whereas whereas no no shear wave shear wave can canactually actually propagate. propagate. This This can canhappen happenin inthethe presence presence of liquid of liquid

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interposition (see interposition (see the the TM-mode graph602602 TM-mode graph of figure6),6),air of figure airinterposition interposition (see (see the the TM- TM modegraph mode graph602' 602'ofoffigure figure 6), 6), narrow intercostals space, narrow intercostals space, etc.... Furthermore, etc. Furthermore, though though a a vessel may vessel maynot notbebeobserved observed on on thethe ultrasound ultrasound signals signals because because it isit isoechoic, is isoechoic, it itmay may disturb disturb the the shear shear wave propagation. Figure wave propagation. Figure66 shows showsa TM-mode graphgraph a TM-mode 602" 602"' acquired acquired

5 ininthe 5 thepresence presence of of an isoechoic an isoechoic vessel, vessel, in which in which the vessel the vessel remains remains invisible invisible (the (the position of position of this this vessel is identified vessel is identified by an arrow). by an arrow).

[0021] The guidance

[0021] The guidance using ultrasound using ultrasound data isdata not is not enough good good enough because because it cannotit cannot predict the predict the propagation propagationof of thethe shear shear wavewave as ultrasound as ultrasound and are and elastic elastic not are not sensitive sensitive to to the same the conditions. AA good same conditions. goodultrasound ultrasoundsignal signaldoes doesnotnotalways always resultininaagood result goodshear shear 10 wave 10 wave propagation. propagation. Some Some elements elements that influence that influence the shear the shear wave propagation wave propagation do not do not affect ultrasoundpropagation. affect ultrasound propagation. ThisThis is the is the casecase of isoechoic of isoechoic partscan parts that that be can be a vessel, a vessel,

cyst,aaliquid aa cyst, liquidwith with particles, particles, a stiff a stiff or soft or soft tumor, tumor, etc. etc.

[0022]

[0022] Due toto the Due the limitations limitations of of the the conventional conventional TM-graph guiding,the TM-graph guiding, theoperator operator generally generally does not find does not find an an adequate adequateprobe probe locationatatthe location thefirst first try try he/she he/she attempts to attempts to

15 position 15 position thethe probe. probe. In practice, In practice, it turns it turns out the out that thatoperator the operator often hasoften has tothetrigger to trigger the transient elastography transient measurement elastography measurement several several times, times, testing testing differentpositions different positionsbybytrial trial and error, before and error, before finding finding an adequate position an adequate position and and recording recording ananelastic elastic wave wave propagationimage propagation image appropriate appropriate to characterize to characterize liver stiffness. liver stiffness. This isThis time is time consuming, consuming,

all all the the more thatthe more that theoperator operator has has to hold to hold the probe the probe stillfirmly still and and firmly before before triggering triggering a a 20 transient 20 transientelastography elastographymeasurement. measurement. As will As will be be appreciated appreciated by by thethe skilledartisan, skilled artisan, such such attempts can be attempts can be unpleasant unpleasantfor for the the patient patient under examination asasthe under examination thepatient patient receives receives aa small mechanicalpunch small mechanical puncheach each time time the the operator operator conducts conducts a measurement. a measurement. Moreover, Moreover,

such attemptscan such attempts candiscourage discourage the the operator operator to find to find an adequate an adequate position position and thus and thus

increasethe increase thefailure failurerate. rate.

25 [0023] 25 [0023]It is thus It is thus desirable desirable to develop to develop a system a system for characterizing for characterizing tissue,tissue, suitable suitable

for aa precise for precisecharacterization characterization of the of the viscoelastic viscoelastic properties properties of thisoftissue this tissue and and having having improved guiding improved guiding capabilities capabilities compared to the compared to the FIBROSCAN® FIBROSCAN@ system system described described above.above.

SUMMARY SUMMARY

[0024] To address

[0024] To address at least at least somesome of above-mentioned of above-mentioned problems, problems, the disclosed the disclosed 30 technology 30 technology is isdirected directedtotoa asystem systemforforidentifying identifying homogeneous homogeneous tissue tissue in ain subject a subject or or

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patient. Upon patient. detection of Upon detection of an of homogeneous area of an area tissue,ananoperator homogeneous tissue, caninitiate operatorcan initiate the the measurement measurement of of tissuestiffness tissue stiffness and/or and/or an ultrasound parameter an ultrasound parameterdetermination. determination.

[0025]

[0025] In some In embodiments, some embodiments, thethe system system comprises: comprises:

probe, to a probe, a to be be hold holdagainst againstthe thebody body of of a subject a subject andand thatthat comprises comprises a vibrator a vibrator to to 55 delivermechanical deliver mechanical vibrations vibrations to a to a tissue tissue of subject; of the the subject;

an ultrasound emitter an ultrasound emitter that that is isconfigured configuredtotoemit emita asequence sequence of of ultrasound ultrasound shots shots and and an an

ultrasoundreceiver ultrasound receiverconfigured configured to receive to receive corresponding corresponding echo signals; echo signals; and and

aa control control module programmed module programmed to to make make thethe system system executing executing the the following following steps: steps:

a) delivering a) delivering aa continuous and periodic continuous and periodic mechanical mechanicalvibration vibration toto the the 10 tissue 10 tissueofofthe the subject, subject, the the periodic periodic mechanical vibration comprising mechanical vibration comprising of of aa same samevibration vibration pattern repeatedseveral pattern repeated several times times successively successively over time; over time;

b) emitting b) emitting aa sequence sequence ofofultrasound ultrasound shots shots bybymeans means of the of the ultrasound emitter ultrasound emitter and acquiring corresponding and acquiring corresponding echo echosignals signalsreceived receivedby by thethe ultrasound receiver ultrasound receiver toto track track how howthethe tissue tissue is moved is moved byperiodic by the the periodic mechanical mechanical

15 vibration 15 vibrationdelivered delivered to the to the tissue; tissue;

c) providing c) providing homogeneity informationtotoananoperator homogeneity information operatorofofthe thesystem, system, the homogeneity the homogeneityinformation informationbeing beingdetermined determined from from at at least least some some of the of the echo echo signals signals

acquiredininstep acquired stepb),b),thethe homogeneity homogeneity information information being representative being representative of the of the ability of ability of the tissue the tissue to to transmit transmitelastic elasticwaves wavesandand of the of the homogeneity homogeneity of the of the tissue tissue with respect with respect to to 20 the 20 thepropagation propagationofofelastic elastic waves. waves.

[0026] The control

[0026] The control module module is programmed is programmed so that so thatb) steps steps and b) c) and are c) are executed executed by by the system the systemcontinuously, continuously, several several times times successively. successively.

[0027] The The

[0027] homogeneity homogeneity information, information, obtained obtained by tracking by tracking how a how a periodic periodic mechanical vibration travels mechanical vibration travels through throughthe thetissue, tissue,constitutes constitutesa avery efficient guiding veryefficient guiding 25 information 25 informationthat thathelps helps thethe operator operator find find quickly quickly and easily and easily an appropriate an appropriate probe probe position, located inin front position, located front of of aa thick, thick, homogeneous homogeneous part part of anoforgan an organ to be to be characterized. characterized.

[0028] It will

[0028] It will be be appreciated appreciated that that a 2-dimensional a 2-dimensional elasticwaves elastic waves speed speed map map like like the the

one described one describedinin Mellema Mellemaetetal. al. (or (or in in the the document "In vivo document "In vivo time-harmonic ultrasound time-harmonic ultrasound

elastography of elastography of the the human humanbrain braindetects detectsacute acute cerebralstiffness cerebral stiffnesschanges changes induced induced by by 30 intracranial 30 intracranial pressure pressurevariations" variations"bybyH. H. Tzschatzsch Tzschatzsch et published et al., al., published in Scientific in Scientific

9 2020207873 24 Jul 2020

Reports, volume Reports, volume8, 8, articlenumber article number 17888, 17888, 2018, 2018, for instance) for instance) do not constitute do not constitute

homogeneityinformation homogeneity informationrepresentative representativeofofthe theability ability of of aa tissue tissue to to propagate propagate elastic elastic wavesand waves andofofthe thehomogeneity homogeneity of the of the tissue tissue withrespect with respectto tothe thepropagation propagation of of elastic elastic

waves. Indeed, waves. Indeed, such such maps maps do do not not actually actually provide provide informationregarding information regardingwave wave 5 propagation, 5 propagation, as as these these maps mapsonly onlyrepresent represent instantaneous instantaneous snapshots snapshots of of the the organ organ under examination under examination

[0029] In anInembodiment

[0029] an embodiment according according to the disclosed to the disclosed technology, technology, the homogeneity the homogeneity

informationprovided information providedby by thethe system system indicates indicates whether whether spatio-temporal spatio-temporal characteristics characteristics of of deformation ofofthethetissue, aa deformation tissue,that thatis iscaused caused by periodic by the the periodic mechanical mechanical vibration vibration

10 mentioned 10 mentionedabove, above,are arethose thoseofofa awave travelling in wavetravelling in aa homogeneous homogeneousmedium medium (the(the deformation deformation in inquestion question being being tracked tracked byecho by the the signals echo signals acquired acquired in step b). in step b).

[0030] As shown

[0030] As shown in figures in figures 14,1716,and1718, 14, 16, andspatio-temporal 18, spatio-temporal characteristics of a of characteristics a tissue deformation tissue deformation relative relative to to thethe propagation propagation of elastic of elastic waveswaves throughthrough the that the tissue, tissue, that is to is saycharacteristics to say characteristicsrepresentative representative of variation of the the variation of deformation of this this deformation both as both a as a 15 function 15 functionofoftime timeand andasas a functionof ofat atleast a function leastone onespatial spatialcoordinate coordinate(and (and thus thus really really

representative of representative of the the way waythethe elasticwave elastic wave propagates), propagates), reveal reveal the or the more more lessor less homogeneous homogeneous nature nature of the of the tissue tissue in ain very a very straightforward straightforward and and easyeasy to apprehend to apprehend

manner. Such manner. Suchspatio-temporal spatio-temporalcharacteristics characteristicsmay maycomprise comprise data data representative representative of of thethe variation over variation depth of over depth of aa phase phasedelay delayof of thethe periodicdeformation periodic deformation of the of the tissue, tissue, forfor

20 instance. 20 instance. As As shown shown in figure in figure 14, phase 14, this this phase delay substantially delay varies varies substantially linearly linearly with with depth depth whenthethe when tissue tissue is is homogeneous, homogeneous, which which is easy is to easy to identify identify for the for the operator. operator. The The spatio- spatio temporal characteristics temporal characteristics mentioned mentionedabove above maymay alsoalso comprise comprise data data representative representative of of the deformation the deformationof of thethe tissue, tissue, both both as aas a function function of depth of depth asand d and d as a function a function of of time t. time t. As shown As shownininfigures figures 1616and and1818(graph (graph188a), 188a), a graph a graph representing representing thethe deformation deformation of of 25 the 25 thetissue tissueasasa function a functionof of depth depth andand as aas a function function of time of time comprises comprises of diagonal, of diagonal,

substantially linear substantially linearstripes, stripes,that can that canbe be readily readily identified identifiedbybythe theoperator, operator,when the when the

tissue isishomogeneous. tissue homogeneous.

[0031] The way

[0031] Thesuch wayperiodic such periodic elasticelastic waves waves propagate propagate is much ismore much more sensitive sensitive to to the structure the structure ofofthe thetissue tissueand andto to itsitselastic elasticproperties propertiesthan than TM-mode TM-mode graphs,graphs, as shownas shown 30 ininfigure 30 figure 18. 18.

[0032] The The

[0032] lastlast three three columns columns of of thethetable tableofof figure figure 18 18 shows shows TM-mode graphs TM-mode graphs 182c, 182d, 182c, 182d, 182e, 182e,elastic elasticwave wave propagation propagation images images 188c, 188c, 188d,acquired 188d, 188e 188e acquired in in

10 2020207873 24 Jul 2020

periodic mode periodic (periodic elastic mode (periodic elastic wave wave propagation graphs) and propagation graphs) and elastic elastic wave propagation wave propagation

imagesacquired images acquiredinin transient transient mode mode185c, 185c,185d, 185d,185e 185e forfor threedifferent three different situations, situations, one one

corresponding corresponding toto aa probe probeposition positionclose closetotoananedge edge of of liver(column liver (column c),c), andand thethe twotwo

others beingsituations others being situations with with liquid(column liquid (column d)air d) or or interposition air interposition (column (column e). Ase). canAs be can be

5 seen 5 seen in figure in figure 18,18, in these in these situations, situations, the TM-mode the TM-mode graphs graphs look as iflook the as if the situation situation were were appropriate for transient appropriate for transient elastography measurements elastography measurements (likeinincolumn (like columna),a), whileininfact while fact they are they are not not (see (see transient transient elastography elastographyimages images 185c, 185c, 185d, 185d, 185e). 185e). In other In other words, words,

TM-mode imaging TM-mode imaging doesdoes not discriminate not discriminate between between a proper a proper probe probe positioning positioning and an and an

improper probe improper probepositioning positioningsince sinceit itcannot cannot accurately accurately detect detect whether whether the probe the probe is is 10 located 10 located close close to edge to an an edge of theofliver the liver or whether or whether there there is air is or air or liquid liquid interposed betweenbetween interposed the probe the probe and andthethe targeted targeted organ. organ. In striking In striking contrast, contrast, the periodic the periodic elastic elastic wave wave

propagation images propagation images188c, 188c,188d, 188d, 188e, 188e, which which are are noisy, noisy, comprise comprise numerous numerous irregular irregular

fragments, as fragments, as opposed opposedto to oneone or several or several diagonal diagonal stripes stripes with with smooth smooth (substantially (substantially

linear) edges. linear) Thus, the edges. Thus, the periodic periodic elastic elastic wave propagationimages wave propagation images 188c, 188c, 188d, 188d, 188e188e

15 show 15 showimmediately immediately an adequate an adequate probe probe positioning positioning for transient for transient elastography elastography measurements.Furthermore, measurements. Furthermore, the the presence presence of a vessel, of a vessel, even and even small small and isoechoic, isoechoic,

which isis invisible which invisible inin the the ultrasound ultrasound signals signals (see graph 182b (see graph 182bofoffigure figure18), 18),isis readily readily detectable in an detectable in an elastic elasticwave wave propagation imageacquired propagation image acquiredinin periodic periodic mode mode(see (seegraph graph 188bofoffigure 188b figure18). 18).

20 [0033] 20 [0033] As will As be will appreciated be appreciated by skilled by the the skilled artisan, artisan, a periodicelastic a periodic wave elastic wave propagation image propagation imagewith with diagonal diagonal stripes stripes substantially substantially uniform uniform and/or and/or with with smooth smooth

edges, like the edges, like the image image188a 188a of figure of figure 18, 18, indicates indicates immediately immediately that probe that the the probe is is properly positioned properly positioned and andthat thatthethe situation situation is is adequate adequate for transient for transient elastography elastography

measurement measurement (see (see thethe transientelastic transient elastic wave propagationimage wave propagation image 185a 185a of of figure18). figure 18).

25 [0034] 25 [0034] It was It found was found that, that, in practice, in practice, the the homogeneity homogeneity information, information, which which is is continuously refreshed and continuously refreshed andprovided providedtotothe theoperator, operator, most mostoften oftenenables enablesan an operator, operator,

even even ananuntrained untrained one, one, to find to find a proper a proper probe probe position position right right the first the first time.time.

[0035] Moreover,

[0035] Moreover, the periodic the periodic mechanical mechanical vibration vibration delivered delivered to subject to the the subject underunder

examination is less examination is less unpleasant to him unpleasant to him than than the the short, short, transient transient mechanical pulses that mechanical pulses that 30 would 30 wouldotherwise otherwise be repeatedly be repeatedly triggered triggered by operator by the the operator untiluntil he/she he/she findsfinds a proper a proper

probeposition, probe position,allallthe themore more thanthan the vibration the vibration amplitude amplitude requiredrequired for elastic for periodic periodic elastic wavesmonitoring waves monitoringisisnoticeably noticeablysmaller smallerthan thanthetheoneone required required to to achieve achieve a transient a transient

11 2020207873 24 Jul 2020

elastography measurement. elastography measurement. In addition, In addition, the the continuous continuous naturenature of the of the mechanical mechanical

excitation excitation employed the system in the employed in systemofofthe thedisclosed disclosedtechnology technology to to guide guide thethe operator operator

enables enables aa continuous guiding. continuous guiding.

The spatio-temporal

[0036] The spatio-temporal

[0036] monitoring monitoring of theof the deformation deformation caused caused by the periodic by the periodic

55 mechanical mechanical vibrationdelivered vibration deliveredto tothethe subject subject cancan be achieved be achieved usingusing a single-beam a single-beam

(single transducer) (single transducer) ultrasound ultrasound system, with no system, with no 2D 2Doror3D3Dimaging capabilities. Indeed, imagingcapabilities. Indeed, monitoring the monitoring the propagation propagationofofa awave, wave, from from a spatio-temporal a spatio-temporal point point of view, of view, can can be be achieved bymonitoring achieved by monitoring the the tissue tissue deformation deformation asasa afunction function of of time time and and of of one one spatial spatial dimension only dimension only(namely (namelydepth). depth).In Inother otherwords, words, a spatio-temporal a spatio-temporal monitoring monitoring can can be be 10 carried 10 carried ononusing usinga 2a dimensional 2 dimensional sampling sampling of deformation, of the the deformation, one dimension one dimension being being time and time and the the other other being being depth, depth, instead instead of of using using 22 sampling samplingdimensions dimensions thatareareboth that both spatial dimensions spatial dimensions (depth (depth and and lateral lateral shift, shift, likelike in in Mellema Mellema at al.). at al.). As As willwill be be appreciated appreciated

by the by the skilled skilled artisan, artisan,using usinga a single-beam ultrasound system, single-beam ultrasound system, instead instead ofof 2D 2Dimaging imaging ultrasound system, ultrasound system, enables enablesone one to to process process quickly quickly thethe echo echo signals signals acquired, acquired, which which

15 are 15 aremono-dimensionnal mono-dimensionnal from from a spatial a spatial point point of view. of view. This permits This permits to increase to increase the the temporalsampling temporal sampling raterate withwith which which the elastic the elastic deformation deformation of theistissue of the tissue is tracked. tracked. The The elastic elastic deformation of the deformation of the tissue tissue is is thus thus monitored with aa higher monitored with higher temporal temporalresolution resolution than inin prior than prior art art harmonic elastography harmonic elastography methods. methods.

[0037] Moreover,

[0037] Moreover, the the high high temporalsampling temporal samplingrate rate enables enables one one to to sample sample aa same same 20 period, 20 period,ororatatleast least the the major major part part of of aa same sameperiod periodofofthe theperiodic periodicdeformation deformationofofthe the tissue, all tissue, all at at once, asaawhole. once, as whole.This This is is very very interesting interesting compared compared to a stroboscopic-like to a stroboscopic-like

technique in technique in which which the the periodic periodic deformation deformation ofofthe the tissue tissue would wouldbebesampled sampled by by small small

parts, sampling parts, samplinga asmall small part part (for (for instance instance a single a single instant) instant) of aof a period, period, then then a small a small part part of of a subsequentperiod a subsequent periodandand so so on reconstruct, on to to reconstruct, a posteriori, a posteriori, an an image image showing showing a a 25 whole 25 whole vibrationperiod vibration period(like (likethe thepropagation propagationimage image 130 130 of figure of figure 13).13). Indeed, Indeed, withwith a a stroboscopic technique, stroboscopic technique, the the lag lag time timerequired required totoobtain obtaina anew, new,completely completely refreshed refreshed

image showing image showinga whole a whole vibrationperiod vibration period is ismuch much longer longer thanthan whenwhen a same same period a period is is sampled sampled allallatatonce once with with a high a high sampling sampling ratethe rate (in (inexample the example of 13, of figure figure the 13, lag the time lag time

is approximately is four times approximately four longer than times longer than when whena asame same period period is sampled is sampled all once). all at at once). 30 More 30 Moreimportantly, importantly, aa temporal temporal image imageobtained obtainedby by samplingis isoften stroboscopicsampling stroboscopic often impairedbybyspurious impaired spurious effects effects and and noise, noise, due due in in particular particular to tissue to tissue displacement displacement caused caused by respiration by respiration or or to to slight slight displacements displacementsofofthetheprobe. probe. Furthermore, Furthermore, the temporal the temporal

12 2020207873 24 Jul 2020

resolution of resolution of propagation propagation images images obtained obtained by stroboscopic by stroboscopic sampling sampling is generally is generally

smaller smaller than than when sameperiod when aa same periodisissampled sampledallallatatonce once(the temporalresolution (thetemporal resolution of of the the propagations propagations images images 131134toof134 131 to of figure figure 13, for13, for instance, instance, is better is better than than the one the one of the of the propagation image propagation image130). 130).

55 [0038]As willAsbewill

[0038] by the by be appreciated appreciated the skilled skilled artisan, artisan, graphs graphs showing showing the periodic the periodic

deformation of the deformation of the tissue tissue in in aa spatio-temporal spatio-temporal manner manner(as(as those those of figure of figure 18), 18), as as a a

function ofofdepth function depthandand time, time, are are easyeasy to understand to understand as theyas they are. are. This is This quite is quite surprising surprising

whencompared when comparedto to priorart prior art harmonic harmonicelastography elastography techniques techniques likethose like thoseofofMellema Mellemaet et

al. al. or or Tzschatzsch et al., Tzschatzsch et al., in in which the graphs which the graphs representing representing the the instantaneous instantaneous 10 deformation 10 deformationof of thethe tissue tissue (as (as a function a function ofspatial of two two spatial coordinates) coordinates) are are hardly hardly comprehensible comprehensible (see(see figure figure 9a de9a de Millena Millena et figure et al. or al. or figure 3a of Tzschatzsch 3a of Tzschatzsch et al., foret al., for

example) andrequire example) and requirecomplex complex post-processing post-processing to obtain to obtain information information useful useful to an to an

operator (such operator (such as as aa 2D 2D shear shear wave wavespeed speed map). map).

[0039] To summarize,

[0039] To summarize, a system a system for characterizing for characterizing tissuetissue according according to theto the 15 disclosed 15 disclosedtechnology technology hashas very very good good guiding guiding capabilities, capabilities, enabling enabling an an operator operator to find to find

quickly and quickly and easily easily an an area area of of homogeneous tissue,adequate homogeneous tissue, adequate fortransient for transient elastography elastography measurements, measurements, or or to to determine determine an an ultrasound ultrasound parameter parameter relative relative to ultrasound to ultrasound wave wave

propagationwithin propagation withinthethe tissue. tissue.

[0040] To benefit

[0040] To benefit from from these these guiding guiding capabilities, capabilities, in embodiment in an an embodiment of a system of a system

20 for 20 forcharacterizing characterizing tissue tissue according according toto the the disclosed disclosed technology, technology,the thecontrol control module moduleofof the system the system isis further further programmed programmed to to determine determine at least at least oneone physical physical property property of the of the

tissue comprising tissue comprisingoneone of: of:

an ultrasound an ultrasound parameter, parameter,relative relativetotoultrasound ultrasoundwave wave propagation propagation within within the tissue the tissue

attenuationvalue; attenuation value;

25 a amechanical 25 mechanical property property of of thethe tissuerelated tissue relatedtotoshear shearwave wave propagation, propagation, determined determined by by transient elastography. transient elastography.

[0041] The ultrasound

[0041] The ultrasound parameter parameter comprises comprises for instance for instance an ultrasound an ultrasound attenuation attenuation

parameter, thatreflects parameter, that reflectsultrasonic ultrasonicattenuation attenuationin the in the tissue, tissue, like like a Broadband a Broadband

Ultrasound Attenuation Ultrasound Attenuation (BUA, usually expressed (BUA, usually expressed in in dB/cm/MHz), dB/cm/MHz),ananattenuation attenuation 30 measured 30 measured at aatparticular a particular frequency frequency (expressed (expressed in dB/cm), in dB/cm), or aorControlled a Controlled Attenuation Attenuation

13 2020207873 24 Jul 2020

Parameter(CAP). Parameter (CAP).However, However, thisnot this is is limiting not limiting as additional as additional parameters parameters could could be be determined in other determined in other embodiments. embodiments.

[0042] The mechanical

[0042] The mechanical property property of the of the tissue tissue relatedrelated to shear to shear wave propagation wave propagation

maybebea aquantity may quantityrelated relatedtotothe thetissue tissuestiffness, stiffness, such such asasthe thepropagation propagationspeed speed of of 55 shear shear waves wavesV,Vs,the theshear modulus shearmodulus of of thetissue the tissue or or the the Young's modulus EEofofthe Young's modulus the tissue. It tissue. It may alsobebea aquantity may also quantity related related to to lowlow frequency frequency shearshear wave attenuation wave attenuation in the in the tissue, like viscosity. tissue, like viscosity.

[0043]

[0043] It will It willbebeappreciated appreciatedthat thata asystem system for fordetermining determining aa mechanical property mechanical property

by transient by transient elastography, elastography, and in which and in which the thepropagation propagationofofa aperiodic periodicelastic elastic wave waveisis 10 10 preliminarymonitored preliminary monitoredtotofind find homogeneous homogeneous tissue, tissue, is is system a asystem thatisissomehow that somehow initially initially

configured for transient configured for transient elastography andfurther elastography and further modified modifiedtotoimplement implement thethe guiding guiding

technique presented technique presentedabove, above, which which is very is very different, different, and and even even antagonistic antagonistic from afrom a transient elastography transient technique (which elastography technique (whichaims aims at at separating separating compression compression waveswaves and and shear waves)and shear waves) andfrom fromprior priorart art harmonic harmonicelastography elastographytechniques techniques (which (which areare focused focused

15 onon 15 almost almost purely purely spatial spatial features features of theofdeformation the deformation field, field, and do and do not not aim aim atthe at helping helping the operatortotoproperly operator properlyposition positionthetheprobe). probe).

[0044] In an

[0044] In embodiment an embodiment according according to theto disclosed the disclosed technology, technology, the control the control moduleisis programmed module programmed to determine, to determine, from from at least at least some some of the of the echoecho signals signals acquired acquired

in step in b), data step b), data representative representative ofof aa periodic periodic deformation deformationof ofthethe tissue,at atdifferent tissue, different 20 depths 20 depthswithin withinthe thetissue tissueand andatatdifferent different moments moments of of theperiodic the periodicmechanical mechanical vibration vibration

delivered to the delivered to thetissue tissue

[0045] In anInembodiment

[0045] an embodiment according according to the disclosed to the disclosed technology, technology, the homogeneity the homogeneity

informationcomprises information comprisesone one of following: of the the following:

graphrepresenting aa graph representing the the variation variation overover depthdepth of at of at least least one temporal one temporal characteristic characteristic of of 25 thethe 25 temporal, temporal, periodic periodic variation variation of deformation of the the deformation of the of the tissue; tissue; or or

an indicationspecifying an indication specifying whether whether said said characteristic characteristic varies varies withasdepth with depth if theas if the tissue tissue

were homogeneous were homogeneousoverover a given a given range range of depth, of depth, or or not. not.

[0046] The The

[0046] graph graph may may represent: represent:

-- the the variation of the variation of the deformation over deformation over time, time, as as a function a function of depth; of depth;

30 - a- aphase 30 phase delay delay of the of the periodic periodic deformation deformation of the of the tissue, tissue, as a function as a function of of depth; depth;

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-- an an amplitude amplitude ofofanan envelope envelope of this of this periodic periodic deformation, deformation, as a function as a function of depth. of depth.

[0047]

[0047] In an In an embodiment, thegraph embodiment, the graphmentioned mentioned above above represents represents the the deformation deformation

of the of the tissue tissue at at different different depths within the depths within the tissue tissue and andatatdifferent different moments moments of the of the

periodic periodic mechanical vibration delivered mechanical vibration deliveredtoto the the tissue, tissue,the the graph graph being being aa two- two 55 dimensionalimage dimensional image whose whose pixels pixels row row index index represents represents depth depth and whose and whose pixels pixels columncolumn

index represents time, index represents time, or or conversely, conversely, each each pixel pixel having having aa pixel pixel value value representing the representing the

deformationofofthethetissue deformation tissue at at the the depth depth and and time time associated associated to the to the considered. pixel pixel considered.

[0048] In an

[0048] In embodiment, an embodiment, the indication the indication mentioned mentioned above above specifies specifies whether whether a a graph, which graph, which represents representsthe thedeformation deformation of of thethe tissue tissue at at different depths differentdepths withinthethe within

10 tissue 10 tissueand andatatdifferent different moments momentsof of thethe periodic periodic mechanical mechanical vibration vibration delivered delivered to to thethe

tissue, the tissue, the graph being aa two-dimensional graph being two-dimensionalimage image whose whose pixels pixels row index row index represents represents

depth and whose depth and whosepixels pixelscolumn columnindex index represents represents time time or or conversely,each conversely, each pixelhaving pixel having pixel value aa pixel value representing representingthethe deformation deformation of tissue of the the tissue at theat depth the depth and time and time

associated associated totothe thepixel pixelconsidered, considered, is comprised is comprised of diagonal of diagonal stripes stripes over over said said range of range of

15 depth, 15 depth,orornot. not.

[0049] In an

[0049] In embodiment an embodiment the system the system comprises comprises a manual a manual adjustment adjustment control, control, such as such asa acursor, cursor,a aslider, slider, aa button buttonorora aknob, knob,that thatenables enables thethe operator operator to adjust to adjust

manually theamplitude manually the amplitude of the of the periodic periodic mechanical mechanical vibration. vibration. This is This usefulis in useful in case the case the

amplitude of amplitude of the the periodic periodic deformation deformation of of the the tissue, tissue,caused caused by by the the periodic periodicmechanical mechanical

20 vibration 20 vibration delivered delivered to to it, it, isistootoo lowlow or or tootoo high. TheThe high. system systemmay may comprise comprise an amplitude an amplitude

indicator for indicator for displaying displaying to to the operator information the operator information regarding regardingthe theamplitude amplitude of the of the

periodic deformation periodic deformation of of thethe tissue. tissue.

[0050] In anInembodiment

[0050] an embodiment the system the system is configured is configured to automatically to automatically (that (that is without is without

requiring an requiring action of an action of the the operator) operator) adjust adjust the the amplitude amplitude ofofthe theperiodic periodic mechanical mechanical 25 vibration 25 vibration based basedon on thethe amplitude amplitude of the of the resulting resulting periodic periodic deformation deformation of the of the tissue. tissue.

More precisely, More precisely, the the system maybebeconfigured system may configuredtotoincrease increasethe the amplitude amplitudeofofthe the periodic periodic mechanicalvibration mechanical vibration when whenthe theamplitude amplitude of of thethe resultingperiodic resulting periodicdeformation deformationof of the the

tissue is tissue is too too low low (lower (lower than than aa given given threshold), threshold),and and to to decrease decrease the amplitude of the amplitude of the the periodic mechanical periodic vibration when mechanical vibration the amplitude when the amplitudeofofthe the resulting resulting periodic periodic deformation deformation

30 of of 30 the the tissue tissue is is too too high high (above (above another another amplitude amplitude threshold). threshold).

15 2020207873 24 Jul 2020

[0051] In anInembodiment

[0051] an embodiment the system the system is configured is configured to the to adjust adjust the amplitude amplitude of the of the transient mechanical transient pulse, delivered mechanical pulse, delivered to to the the subject subject totomeasure mechanicalproperty measure aa mechanical property of of the tissue related the tissue related to to shear shearwave wave propagation propagation by transient by transient elastography, elastography, based onbased the on the amplitude chosenfor amplitude chosen forthe theperiodic periodicmechanical mechanical vibration.InInthis vibration. this case, case,the thepreliminary preliminary 55 characterization ofofthe characterization thetissue tissuebyby periodic periodic elastography elastography enables, enables, in addition in addition to to the the different different benefits presented above, benefits presented above, to determine to determine an amplitude an amplitude of the transient of the transient

mechanical pulse mechanical pulse suitable suitable to to carry carry ononthethesubsequent subsequent transient transient elastography elastography measurement. measurement.

[0052] It will

[0052] It will that, that, be appreciated be appreciated according according to the to the disclosed disclosed technology, technology, the the 10 different 10 different embodiments embodiments presented presented above above can becan be combined combined together,together, according according to all to all technically possible technically possiblecombinations. combinations.

Optional,

[0053] Optional,

[0053] nonlimitingfeatures nonlimiting thesystem featuresofofthe systemforfor characterizing tissue characterizing tissue presented above presented aboveare aredefined, defined,according accordingtotothe thedisclosed disclosedtechnology, technology,bybyclaims claims 3 to7 3 to 7 and 10toto1818asasfiled. and 10 filed.

15 [0054] 15 [0054]The disclosed The disclosed technology technology providesprovides also a for also a method method for characterizing characterizing tissue, tissue,

carried carried on on by by means of aa system means of systemcomprising: comprising: probe,toto bebehold a probe, a holdagainst against thethe skin skin ofsubject of a a subject and and that that comprises comprises a vibrator a vibrator to to deliver mechanical deliver mechanical vibrations vibrations to to a tissue a tissue of of a subject; a subject;

an ultrasound emitter an ultrasound emitter that that is isconfigured configured to toemit emita asequence of ultrasound sequence of ultrasound shots shots 20 and 20 andan an ultrasound ultrasound receiver receiver that that is is configured configured to to receive receive corresponding corresponding echoecho signals; signals;

and and aa control control module programmed module programmed to to make make the the system system executing executing the following the following steps steps

of of the the method: method:

a) delivering aa continuous a) delivering continuousandand periodic periodic mechanical mechanical vibration vibration to the tissue to the tissue

25 25 of of the subject, the the subject, periodic mechanical the periodic vibration comprising mechanical vibration comprisingofofa asame same vibration pattern vibration pattern repeated repeatedseveral several times times successively successively over over time; time; b) emitting b) emitting aa sequence sequence ofofultrasound ultrasoundshots shotsbyby means means of the of the ultrasound ultrasound

emitter emitter and acquiring corresponding and acquiring corresponding echo echo signals signals received received bybythe the ultrasound receiver ultrasound receiver to to track track how howthethe tissue tissue is is moved moved by periodic by the the periodic 30 30 mechanical mechanical vibration vibration delivered delivered to the to the tissue; tissue;

c) c) providing providing homogeneity informationtotoananoperator homogeneity information operator of of thesystem, the system, thethe

homogeneityinformation homogeneity informationbeing being determined determined from from at least at least some some of the of the

16 2020207873 24 Jul 2020

echo signals acquired echo signals acquiredininstep stepb),b),thethe homogeneity homogeneity information information being being

representativeofofthe representative theability abilityofofthe thetissue tissueto totransmit transmit elastic elastic waves waves and and of of the homogeneity the homogeneityofofthe thetissue tissuewith withrespect respecttotothe thepropagation propagationofofelastic elastic waves; waves; 55 the control the control module being programmed module being programmedso so that stepsb) b)andand thatsteps c) c) areare executed bythe executed by the system systemcontinuously, continuously, several several times times successively successively

[0055]

[0055] The features The features of of the different embodiments the different embodiments ofofthe thesystem described systemdescribed above above

may applyalso may apply also to to thismethod this method for for characterizing characterizing tissue. tissue.

BRIEF DESCRIPTION BRIEF DESCRIPTION OF OFTHE THEDRAWINGS DRAWINGS

10 10 Figure

[0056] Figure

[0056] 1 shows 1 shows different different graphs graphs and indicators and indicators displayed displayed to antooperator an operator by by means means ofofaadisplay display screen screen of of aa FIBROSCAN® FIBROSCAN@ system; system;

Figures

[0057] Figures

[0057] 2 to 24 to 4 show show different different TM-mode TM-mode graphs, graphs, displayed displayed to an operator to an operator for for different positions different positionsof ofa aFIBROSCAN@'s probewith FIBROSCAN®'s probe withrespect respectto toan an organ organ to to be be characterized; characterized;

15 [0058] 15 [0058] Figure Figure 5 shows 5 shows a TM-mode a TM-mode graph graph acquired when acquiredwhen thetheFIBROSCAN®'s FIBROSCAN@'s probe probe isis well well positioned, positioned,with withits itsaxis axiscentered centeredon on thethe organ organ to betocharacterized; be characterized;

[0059] Figure

[0059] Figure 6 shows 6 shows TM-mode differentTM-mode different graphs graphs acquiredwhen acquired thethe when probeisisnot probe not properly positioned,itsitsaxis properly positioned, axisbeing beingclose close to to an an edgeedge of organ of the the organ to be to be characterized, characterized, or or in situations with in situations with liquid, liquid, air, air, or or vessel vesselinterpositions interpositionsthat that areare not not suitable suitable for afor a proper proper

20 mechanical 20 mechanical characterizationofofthe characterization theorgan; organ;

[0060]

[0060] Figure 77 isis a ablock Figure blockdiagram diagram of aofsystem a system for characterizing for characterizing tissue tissue in in accordance with some accordance with someembodiments embodiments of the of the disclosed disclosed technology; technology;

[0061] Figure

[0061] Figure 8 is 8 is flow flow chartchart of a of a method method for characterizing for characterizing tissue tissue in accordance in accordance

with some with embodiments some embodiments of of thethe disclosedtechnology; disclosed technology;

25 [0062] 25 [0062]Figure Figure shows 9 shows9 a a continuous continuous and periodic and periodic mechanical mechanical vibrationvibration delivered delivered to to tissue of a tissue a of aa subject, subject,sequences of ultrasound sequences of shots emitted ultrasound shots emitted to to track track aa deformation of deformation of

the tissue the tissue caused causedbybythis thisvibration vibrationand andelastic elasticwave wave propagation propagation images images obtained obtained

thereof, according thereof, according to to some embodiments some embodiments of of thedisclosed the disclosedtechnology; technology;

17 2020207873 24 Jul 2020

[0063] Figure

[0063] Figure 10 shows 10 shows a continuous a continuous and periodic and periodic mechanical mechanical vibration vibration delivered delivered

to aa tissue to tissue of of aa subject, subject, and andanother anotherwayway to emit to emit sequences sequences of ultrasound of ultrasound shots to shots track to track deformation of aa deformation of the the tissue tissue caused causedbybythis this vibration, vibration, according according to to some embodiments some embodiments

of of the disclosedtechnology; the disclosed technology;

55 [0064]Figure Figure

[0064] 11 ashows 11 shows a continuous continuous and periodic and periodic mechanical mechanical vibration vibration delivereddelivered

to aa tissue to tissue of of aa subject, subject,still still another waytotoemit another way emitsequences sequences of ultrasound of ultrasound shots shots to to track track deformationof ofthethe aa deformation tissue tissue caused caused by vibration by this this vibration and periodic and periodic elastic elastic wave wave propagation images propagation imagesobtained obtainedthereof, thereof, according accordingtoto some someembodiments embodiments of the of the disclosed disclosed

technology; technology;

[0065] Figure 10 [0065] 10 Figure 12 shows 12 shows the periodic howperiodic how the elastic elastic wavewave propagation propagation images images of of figure 11 figure can bebetemporarily 11 can temporarilyaligned alignedforforoperator operatorviewing viewing in in accordance accordance withwith somesome

embodiments embodiments of of thedisclosed the disclosedtechnology; technology;

[0066] Figure

[0066] Figure 13 illustrates 13 illustrates differences differences between between a low a low sampling sampling rate,rate, stroboscopic stroboscopic

like method like for tracking method for tracking aa periodic periodic deformation of aa tissue, deformation of tissue, and high sampling and aa high samplingrate rate 15 method 15 method forfor trackingsuch tracking sucha periodic a periodicdeformation deformationof ofa atissue, tissue,inin which which aa same sameperiod periodofof the deformation the deformation of of the the tissue tissue is is monitored all atatonce, monitored all once,as as aa whole, whole, in inaccordance with accordance with

some embodiments some embodiments of the of the disclosed disclosed technology; technology;

Figure

[0067] Figure

[0067] 14 shows 14 shows phaseofdelay a phasea delay of an elastic an elastic wave atwave at a particular a particular depth depth in in the tissue the tissue isisdetermined determined ininaccordance accordance with with some embodimentsofofthe some embodiments thedisclosed disclosed 20 technology; 20 technology;

[0068] Figure

[0068] Figure 15 shows 15 shows different different graphs graphs and and an an indicator, indicator, displayed displayed to operator to an an operator by aa system by systemfor forcharacterizing characterizing tissue tissue inin accordance accordancewith withsome some embodiments embodiments of the of the disclosed technology; disclosed technology;

[0069] Figure

[0069] Figure 16 and 16 and 17 shows 17 shows illustrative illustrative elasticwave elastic wave propagationimages, propagation images, 25 respectively 25 respectively from homogeneousand from homogeneous and non-homogeneous non-homogeneous tissue, tissue, in accordance in accordance with with someembodiments some embodiments of the of the disclosed disclosed technology; technology;

[0070] Figure

[0070] Figure 18 shows 18 shows illustrative illustrative TM-graphs, TM-graphs, periodic periodic elastic elastic wave wave propagation propagation

imagesand images andtransient transientelastic elastic wave wave propagation propagation images, images, provided provided to operator to the the operator in in accordance withsome accordance with some embodiments embodiments of theofdisclosed the disclosed technology, technology, these graphs these graphs and and 30 images 30 images being being obtained obtained in in a number a number of differentsituations of different situations and and probe probepositions. positions.

18 2020207873 24 Jul 2020

DETAILED DESCRIPTION DETAILED DESCRIPTION

[0071]

[0071] Figure 77isis aa block Figure blockdiagram diagramof of an an ultrasound ultrasound system system 1 for characterizing 1 for characterizing

tissue, configured tissue, configured for fordetecting detectinghomogeneous tissue. This homogeneous tissue. This system comprises: system 11 comprises:

-- aa probe 10,toto bebehold probe 10, holdagainst against thethe body body of aof a subject subject 50 that 50 and and comprises that comprises a vibrator a vibrator

55 1212 adapted adapted to deliver to deliver mechanical mechanical vibrations vibrations to a tissue to a tissue 51 subject; 51 of the of the subject; - an - ultrasoundemitter an ultrasound emitterthat thatisisconfigured configuredto to emit emit a sequence a sequence of ultrasound of ultrasound shots shots and and an ultrasound an ultrasoundreceiver receiver configured configured to receive to receive corresponding corresponding echo signals, echo signals, to track to howtrack how the subject's the subject's tissue tissueisis moved movedby by such such mechanical mechanical vibrations; vibrations;

- aa control - control module module 2020 to to control control thethe probe probe 10 to 10 and andprocess to process data acquired data acquired by the by the 10 ultrasound 10 ultrasoundreceiver. receiver.

[0072]

[0072] Theexpression The expression "tissue" "tissue" is is understood understood to mean to mean a part aofpart the of theofbody body the of the subject 5050(either subject (eitheraahuman human or animal). or an an animal). This This expression expression does does not not necessarily necessarily

designate aa whole designate whole organ organoror aa single single organ. organ. The tissue 51, The tissue 51, to towhich which mechanical mechanical

vibrations are vibrations aredelivered deliveredand and thethe deformation deformation of which of which is tracked is tracked by the by the ultrasound ultrasound

15 shots, 15 shots, is is a partof ofthethesubject's a part subject's body body located located in vicinity in the the vicinity of the of the probe probe 20, along 20, along an an axis of the axis Zz of probe. the probe.

[0073]

[0073] The system The system1 1isis configured configured to to determine homogeneityinformation determine aa homogeneity informationthat that indicates whether indicates whether the the tissue tissue 51 51 is homogeneous is homogeneous and it and whether whether it can elastic can transmit transmit elastic waves,ininparticular waves, particularshear shear waves, waves, or not, or not, using using a periodic a periodic elastography elastography technique, technique, and and 20 to toprovide 20 provide this this information information to the to the operator operator by means by means of an operator of an operator interfaceinterface 30. 30.

[0074]

[0074] Thehomogeneity The homogeneity information information constitutes constitutes guiding guiding information information thatthehelps that helps the operator positionand operator position and align align thethe probe probe 20 with 20 with an organ an organ to be to be characterized, characterized, such as such as

liver or liver or spleen. Oncethe spleen. Once theprobe probe 20 20 is adequately is adequately positioned positioned thanks thanks to this to this guiding guiding

information, one information, oneororseveral several physical physical properties properties of the of the tissue tissue candetermined can be be determined to to 25 characterize 25 characterize thisthis organ, organ, for for instance instance usingusing transient transient elastography. elastography.

[0075] In this

[0075] In this document, document, the expression the expression "elastic "elastic wave" wave" is understood is understood to mean to mean a a low frequency low mechanicalwave frequency mechanical waveoror tissuedeformation, tissue deformation,that that is is to to say say aa mechanical wave mechanical wave

or or tissue deformationwhose tissue deformation whose central central frequency frequency is smaller is smaller than than 500 500 orhertz, hertz, even or even

smaller than100 smaller than 100 hertz, hertz, in incontrast contrast with with ultrasound ultrasound shotsshots or echo or echo signals, signals, whose central whose central

30 frequency 30 frequency is istypically typically higher higher than than 0.1 0.1 megahertz or even megahertz or higher than even higher than 11 megahertz megahertz(such (such ultrasound waves ultrasound wavesalso also create create some somekinds kindsofofelastic elastic deformations, deformations, while while propagating propagating

19 2020207873 24 Jul 2020

throughthe through thetissue, tissue,but butatatvery veryhigh highfrequency, frequency, and and they they aredesignated are not not designated as "elastic as "elastic

waves",ininthis waves", this document). document).

[0076]

[0076] To provide To provide the the homogeneity homogeneityinformation, information, the the control control module 20 is module 20 is more more precisely programmed precisely programmed totomake makethethe system system 1 forcharacterizing 1 for characterizingtissue tissue executing executing the the 55 following steps: following steps:

a) delivering a) continuous delivering aa continuous andand periodic periodic mechanical mechanical vibration vibration PMV to PMV to the51tissue the tissue of 51 of the subject the subject50, 50,the theperiodic periodicmechanical mechanical vibration vibration comprising comprising of avibration of a same same vibration pattern pattern VPrepeated VP repeated several several times times successively successively over(see over time timefigure (see 9, figure 9, for instance); for instance);

b) emitting b) sequence emitting aa sequence of ultrasound of ultrasound shotsshots (like (like the sequence the sequence 80, 80, 80', 80"80', 80" of 9) of figure figure 9) 10 bybymeans 10 means of of thethe ultrasound ultrasound emitter1111and emitter andacquiring acquiringcorresponding corresponding echo echo signals signals

receivedbybythe received theultrasound ultrasound receiver receiver 11track 11 to to track howtissue how the the tissue 51 is 51 is moved moved by the by the periodic mechanical periodic mechanical vibration vibration PMV PMV delivered delivered to theto the tissue; tissue;

c) providing c) providing the thehomogeneity information mentioned homogeneity information mentionedabove abovetotothe theoperator operator4040ofof the the system, the system, the homogeneity homogeneityinformation informationbeing beingdetermined determinedfrom from at at leastsome least someof of theecho the echo 15 signals 15 signals acquired acquired in step in step b). b).

[0077] TheThe

[0077] controlmodule control module20 20 is isprogrammed programmed to to executesteps execute stepsb)b)and andc) c) continuously(i.e. continuously (i.e.without withoutinterruption), interruption), repeatedly, repeatedly, untiluntil the operator the operator 40 presses 40 presses the the control control button 13 and button 13 andtriggers triggers the thetransient transient elastography elastography measurement. measurement.The The homogeneityinformation homogeneity informationprovided providedto tothetheoperator operator 40 40 is thus is thus continuously continuously refreshed, refreshed,

20 which 20 whichhelps helps theoperator the operatorfind find an anadequate adequateprobe's probe'sposition. position.

[0078] The system

[0078] The system 1 may 1bemay be configured configured to determine to determine the homogeneity the homogeneity information information

mentioned above mentioned above so that so that it indicates it indicates moremore precisely precisely whether whether the 51 the tissue tissue is 51 is homogeneous homogeneous over over a given a given depth depth range range or region or region of of interest, or interest, or not. not. This This depth depth range range

is is for for instance depthrange instance aa depth range over over which which the the subject's subject's liverliver is expected is expected to extend, to extend,

25 should 25 shouldthe theprobe probe 2020 be be adequately adequately positioned. positioned. This This depth depth range range maymay for for instance instance

extend betweena adepth extend between depthofof2525millimeters millimeters and and aa depth depth of of 65 65 millimeters millimeters under the under the

subject's skin subject's skin (between (between which which liver liver is is typically typically located), located), or or between between a depth a depth of 35 of 35 millimeters anda adepth millimeters and depth of of 75 75 millimeters. millimeters. ThisThis depth depth rangerange delimits, delimits, withinwithin the tissue the tissue

51, regionofofinterest a region 51, a interest ROI ROIofofthe thetissue tissue to to be be characterized characterized (in figure (in figure 15, 15, thisthis region region of of

30 interest 30 interest extends extendsbetween betweenthethetwo twohorizontal horizontaldashed dashed lines). lines).

20 2020207873 24 Jul 2020

[0079] The control

[0079] The control module module 20 is 20 is also also programmed programmed to determine to determine at one at least least one physical property physical propertyofofthe thetissue tissue51,51,soso that that thethe organ organ of interest of interest can can be characterized, be characterized,

once the probe once the probe 10 10 adequately adequatelypositioned. positioned. This This physical physical property property may comprise: may comprise:

an ultrasound an ultrasoundparameter parameter relative relative to ultrasound to ultrasound wave propagation wave propagation within within the the tissue tissue 55 value,for value, for instance instance an an ultrasound ultrasound attenuation attenuation value value such as aa BUA, such as BUA,aaCAP CAP and/or and/or anan

attenuation measured attenuation measured at aat a particular particular frequency; frequency;

mechanicalproperty a mechanical a property of of the the tissue tissue related relatedtotoshear shearwave propagation, determined wave propagation, by determined by

elastography, such transient elastography, transient such as as the propagation speed the propagation of shear speed of wavesV,Vs,the shear waves theshear shear modulus modulus of of the the tissue, tissue, the the Young's Young's modulus modulus E of E of the the tissue, tissue, or the or the tissue tissue viscosity viscosity at at 10 low 10 lowfrequency frequency(that (thatisis below below 500 500hertz). hertz).

[0080]

[0080] Moreprecisely, More precisely,the thesystem system of figure 1 of1 figure 7 can 7 can be configured be configured to determine to determine

mechanical mechanical properties properties of tissues, of tissues, related related to shear to shear wave wave propagation, propagation, for tissues for tissues that that have aa Young's have Young'smodulus modulus comprised comprised between between 1 and 1 and 100 kilopascals 100 kilopascals (which (which is suitable is suitable

to study to liver or study liver or spleen stiffness). The spleen stiffness). Thesystem system 1 may 1 may also also be configured be configured to determine to determine

15 ultrasound 15 ultrasoundattenuation attenuationvalues valuesinin tissues tissues for for which which CAP valuesare CAP values are comprised comprisedbetween between and 500 50 and 500dB/m. dB/m.

[0081]

[0081] Thestructure The structureofofthe thesystem system of figure 1 of1 figure is now 7 now 7 is be described be described more detail. in detail. in more

Then, aa method Then, methodfor characterizing tissue forcharacterizing tissue ininaccordance with some accordance with embodiments some embodiments of of thethe

disclosed disclosed technology, represented in technology, represented in figure figure 88and thatcan and that canbe be implemented by means implemented by means 20 of of 20 the the system system of figure 1 of1 figure 7, will 7, will be be presented, presented, as as as well wellexemplary as exemplary results results obtainedobtained by by means means of of thissystem this system or method or method (see figures (see figures 15 to 15 to 18). 18).

[0082] As already

[0082] As already specified, specified, the the probe probe 20the 20 of of the system system of figure 1 of 1 figure 7 comprises 7 comprises a a vibrator 12, such vibrator 12, suchasasananelectromechanical electromechanical vibrator vibrator or anor an acoustic acoustic speaker, speaker, to deliver to deliver

mechanical mechanical vibrations vibrations to to thethe tissue tissue 51 the 51 of of the subject. subject. ThisThis mechanical mechanical vibration vibration can be can be 25 delivered 25 delivered to the to the tissue tissue either either as aasforce a force exerted exerted upon upon the the subject's subject's body by body a tip by tip of athe of the probe,asasa adisplacement probe, displacementof aofportion a portion of the of the subject's subject's body body on contact on contact withenforced with tip, tip, enforced by the by the tip, tip, or or as a combination as a thereof. combination thereof.

[0083]In the Insystem

[0083] the system 1 of7, 1 of figure figure 7, the vibrator the vibrator 12 is rotationally 12 is rotationally symmetrical symmetrical

around vibratoraxis, around a avibrator axis,which which coincide coincide withwith the the probe probe axis axis z. When Z. When the vibrator the vibrator 12 12 30 vibrates, 30 vibrates, it itinduces induces displacements displacements thatmainly that are are mainly longitudinal, longitudinal, parallel parallel to its to its axis. axis.

21 2020207873 24 Jul 2020

[0084] In the

[0084] In the system system 1 of1 figure of figure 7, 7, thethe emitter and ultrasoundemitter ultrasound andthe theultrasound ultrasound receiver are receiver constituted by are constituted by aa same sameultrasound ultrasoundtransducer transducer11 11(for(for instancea instance a piezoelectric transducer). piezoelectric transducer). This ultrasound transducer This ultrasound transducer1111is isrotationally rotationallysymmetrical symmetrical around a atransducer around transduceraxis axis andand emits emits ultrasound ultrasound beamsbeams centered centered on this on thisThe axis. axis. The 5 transducer 5 transducer axisaxis coincides coincides with with the vibrator's the vibrator's axis. axis. The ultrasound The ultrasound transducer transducer 11 has for11 has for instancea acircular instance circularsection, section,the thevibrator's vibrator'saxis axispassing passing through through the center the center of this of this section. section.

In this In this system, system, the the transducer 11 is transducer 11 is part part of of the the probe 10. It probe 10. It is is mounted betweenthethe mounted between

vibrator 12 vibrator 12 and andthethe tiptipofof theprobe. the probe. The The tipthe tip of of the probeprobe is theispart the of part theofprobe the to probe be to be placedononcontact placed contact with with thethe subject's subject's body. body. Theistiprelatively The tip is relatively small: small: its contact its contact surface surface

10 isistypically 10 typically smaller than 11 square smaller than squarecentimeters. centimeters.The The tiptipmay may have have a diameter a diameter smaller smaller

than 11 centimeter, than centimeter,ororsmaller smaller than than or even 8 even 8 or 5 millimeters. 5 millimeters.

[0085] The probe

[0085] The probe 10 comprises 10 comprises manual trigger, a manuala trigger, such as such as a button a control control 13button or 13 or dial. dial. The system 1 1isisconfigured The system configuredtotoachieve achieve a transient a transient elastography elastography measurement measurement

whenthe when themanual manualtrigger trigger 13 13 is is actuated. actuated.

15 [0086] 15 [0086] The probe The probe may comprise may comprise a manual a manual adjustment adjustment control, control, such as as such a cursor, aa a cursor, slider, aa button slider, button or or aaknob, knob,totomanually manually adjust adjust the amplitude the amplitude of the of the periodic periodic mechanical mechanical

vibration, the vibration, amplitudeofofthe the amplitude thetransient transient mechanical mechanical pulse, pulse, or or both. both.

[0087] The system

[0087] The system may bemay be configured configured to automatically to automatically adjust adjust the amplitude the amplitude of the of the periodic periodic mechanical vibration (in mechanical vibration (in harmonic elastography)and/or harmonic elastography) and/orthe theamplitude amplitude of of the the

20 transient 20 transientmechanical mechanicalpulse pulse (in(intransient transientelastography). elastography). The Thesystem systemmaymay be configured be configured

to adjust to adjust automatically automatically the the amplitude of the amplitude of transient mechanical the transient pulse based mechanical pulse basedononthethe amplitude amplitude ofofthe theperiodic periodic mechanical mechanical vibration vibration previously previously adjusted. adjusted.

[0088] It will

[0088] It will be be appreciated appreciated that, that, in inother otherembodiments embodiments according according to the to the disclosed disclosed

technology, the technology, the ultrasound ultrasound emitter emitter and andreceiver receivercould couldbe be constituted constituted by by twotwo distinct distinct

25 transducers, 25 transducers, instead instead of of the the same sameone. one.InInaddition, addition, the the probe probe may maycomprise comprisean an additional additional vibrator, vibrator, like like an an electromechanical vibrator, an electromechanical vibrator, anacoustic acousticspeaker speaker or an or an

electric electric motor providedwith motor provided withan an eccentric eccentric cam.cam. This additional This additional vibrator vibrator may be may be

rotationally symmetrical rotationally symmetrical around the Z zaxis, around the axis, inin the the same same manner manner as vibrator as the the vibrator 12 12 described above, described above, or least or at at least configured configured to induce to induce vibrations vibrations parallel parallel to the Z to theInz axis. In axis.

30 such 30 suchembodiments, embodiments, the system the system could could be configured be configured to generate to generate periodic periodic mechanical mechanical

vibrations by vibrations by means means ofofthe theadditional additional vibrator, vibrator, while generating transient while generating transient mechanical mechanical vibrations by means vibrations by means of the of the vibrator vibrator 12. 12.

22 2020207873 24 Jul 2020

[0089] The system

[0089] The system 1 of figure 1 of figure 7 comprises 7 comprises also a unit also a central central unit 20 including 20 including the the control control module 21, an module 21, an ultrasound ultrasound front front end 22 with end 22 with an an ultrasonic ultrasonic transmitter transmittermodule module 27 27

and anultrasonic and an ultrasonic receiver receiver module module29,29,andand a motion a motion actuation actuation servo servo controller controller 23 to 23 to

control the control the vibrator vibrator 12. 12. The ultrasound front The ultrasound front end end 2222and andthethemotion motion actuation actuation servo servo

5 controller 5 controller 23 23 are are both both connected connectedtotothe thecontrol control module module2121(that (thatisis to to say say that that they they can can receive instructionsfrom receive instructions fromthethecontrol control module module 21 or21send or send data data to it).to it).

[0090] The The

[0090] motion motion actuation actuation servo servo controller controller 23 23 comprises comprises an electric an electric circuit circuit configured to configured to generate generateananelectric electric signal signal appropriate appropriate totodrive drivethe thevibrator vibrator 12, 12, when when instructed instructed to to by by the the control control module 21. This module 21. This electric electric circuit circuit may may comprise anelectric comprise an electric 10 current 10 current amplifier, amplifier, or or another another typetype of amplifier. of amplifier.

[0091] The The

[0091] ultrasound ultrasound front front end end 22 comprises, 22 comprises, a switch a switch 28 alternatively 28 for for alternatively transmitting and transmitting receiving ultrasonic and receiving ultrasonic signals. signals.The The ultrasonic ultrasonic transmitter transmittermodule 27 of module 27 of this front this front end 22comprises end 22 comprises an electric an electric circuit circuit configured configured to generate to generate an electric an electric

ultrasonic signal ultrasonic signal appropriate appropriate toto drive drive the theultrasound ultrasoundtransducer transducer 11 (such 11 (such as theas the 15 sequence 15 sequence of ultrasound of ultrasound shots shots described described further further below below withwith reference reference to step to step b), b), when when

instructed to bybythe instructed to thecontrol controlmodule module 21. This 21. This electric electric circuit circuit may comprise may comprise an amplifier an amplifier

and aa digital and digital totoanalog analog converter converter (DAC), (DAC), for for instance instance an 8 to an 8 to 16 16 bits bits DAC with aa 10 DAC with 10 to to 1000 Mega-sample 1000 Mega-sampleper per second second rate.rate. The The ultrasonic ultrasonic receiver receiver module module 29 comprises 29 comprises an an electric circuit electric circuitconfigured configuredtoto acquire acquire an electric ultrasonic an electric ultrasonic signal signal (an echo signal), (an echo signal), 20 previously 20 previouslyreceived receivedby by thethe ultrasound ultrasound transducer transducer 11 transmitted 11 (and (and transmitted to ultrasonic to ultrasonic

receiver module receiver module2929viaviathe theswitch switch28). 28).TheThe electriccircuit electric circuit ofof the the ultrasonic ultrasonic receiver receiver module 29may module 29 may comprise comprise a tension a tension amplifier, amplifier, filters and filters and anananalog analogtotodigital digital converter converter (ADC), for instance (ADC), for instance an an 88 to to 16 16 bits bits ADC ADCwith witha a1010toto1000 1000 Mega-sample Mega-sample per second per second

rate. rate.

25 [0092] 25 [0092]The control The control module module 21 is a 21 is a device device or system or system comprising comprising electricelectric circuitry circuitry for for processing data, such processing data, such as asa amicroprocessor microprocessorcoupled coupled to to a non-volatilememory a non-volatile memory comprising machine comprising machineexecutable executable instructionsand/or instructions and/oraa programmable programmable microcircuitlike microcircuit likeanan FPGA FPGA (fieldprogrammable (field programmable gate array) gate array) or (digital or a DSP a DSP (digital signal processor). signal processor).

[0093] As represented

[0093] As represented in figure in figure 7, the 7, the control control module module 21 comprises 21 comprises more more 30 specifically: 30 specifically:

processor 24, a processor a 24, for for instance instance aageneral general purpose purpose processor; processor;

23 2020207873 24 Jul 2020

signal processing aa signal processing circuit circuit 26, 26, for forinstance instance an an FPGA (FPGA FPGA (FPGA coprocessor), coprocessor), a DSP a DSP or or another programmable another programmable circuit; and circuit; and

aa physical physical non-transitory non-transitorymemory module25, memory module 25,comprising comprisinga anon-volatile non-volatile memory memory250250 forfor

storing machine storing executable machine executable instructionstotobebe instructions executed executed by processor by the the processor 24, 24, and, and, 5 optionaly, 5 optionaly, a aRAM RAM memory memory 251 for251 for storing storing signal signal data data and and instructions instructions during during the the system operation. system operation.

[0094]

[0094] The control The control module module2121cancan be be in the in the form form of FPGA of an an FPGA carrier carrier board,board, for for instance. instance. The processor 24 The processor 24 can canbebeeither either embedded embedded withinthe within thesignal signalprocessing processingcircuit circuit 26 (e.g. 26 (e.g. within within the the FPGA), FPGA),or or offoff thiscircuit this circuit (e.g.: (e.g.: off off the FPGA,thethe the FPGA, FPGA FPGA then then 10 executing 10 executing special special signal signal processing processing tasks, tasks, likesignals like echo echo correlation signals correlation calculations, calculations, to to offload the offload the processor processor 24). 24). TheThe signal signal processing processing circuit circuit 26 is 26 is configured configured to process to process the the echo signal echo signal received receivedby by thethe transducer transducer (once (once digitized digitized by ultrasonic by the the ultrasonic receiver receiver

module 29). module 29).

[0095]

[0095] As already As already mentioned, thecontrol mentioned,the control module module2121is isprogrammed programmed to make to make the the 15 system 15 system 1 executing 1 executing thethe steps steps a),a),b)b)and andc) c)presented presented above. above. TheThe control control module module 21 21 is is programmedto tomake programmed make the the system system executing executing thesethese stepssteps in that in that it contains it contains instructions, instructions,

which, when which, executedbybythe when executed thecontrol control module module21, 21,make makethethe controlmodule control module 21 21 to:to:

control the control the motion motionactuation actuation servo servo control control 23 so23 so itthat that it drives drives the vibrator the vibrator 12 to deliver 12 to deliver

the periodic the periodicmechanical mechanical vibration vibration to the to the tissue tissue (step (step a));a));

20 control 20 control thethe ultrasound ultrasound frontfront endso 22 end 22 soitthat that it drives drives the ultrasound the ultrasound transducer transducer 11 which 11 which in in return return emits emitsaasequence of ultrasound sequence of shots to ultrasound shots to track track how how the the tissue tissue is ismoved by the moved by the periodic periodic mechanical vibration, and mechanical vibration, so that and so that the the ultrasonic ultrasonic receiver receiver module 29 acquires module 29 acquires corresponding corresponding echo echo signals signals (step(step b)); b));

determine, from determine, at least from at least some some ofof the the echo echosignals signalsthus thusacquired, acquired, homogeneity homogeneity 25 information 25 information representative representative of theofability the ability of tissue of the the tissue to transmit to transmit elastic elastic waves, waves, that isthat to is to say toto let say let elastic elastic waves propagate waves propagate through through it, and it, and ofhomogeneity of the the homogeneity of thewith of the tissue tissue with respect to respect to the the propagation propagationof ofelastic elasticwaves, waves, andand providing providing this this information information to to the the operator, for operator, for instance instancebybytransmitting transmitting it ittotothe theoperator operator interface interface 30 30 (step (step c)).c)).

[0096] The instructions,

[0096] The instructions, whosewhose execution execution make make the the control control module module 21 21 to to control control 30 the 30 thesystem system 1 so 1 so that that it itexecutes executesanyany given given step, step, in in particularsteps particular stepsa), a), b)b) and andc), c), are are stored in stored in the the non-volatile non-volatilememory 250, in memory 250, in the the form form of of machine machineexecutable executableinstructions instructions

24 2020207873 24 Jul 2020

or code instructions, or code instructions, or or physically physically embedded embedded in inthe theprogrammable programmable circuit circuit 26, 26, in the in the

form ofofelectric form electric (reconfigurable) (reconfigurable) connections connectionsbetween between gatesgates of circuit, of this this circuit, or a or a combination thereof. combination thereof.

[0097] The control

[0097] The control module module 21 may21bemay morebespecifically more specifically programmed programmed in order into, order in to, in 55 stepc): step c):

cO) determine, c0) determine, from fromthe theecho echo signals signals acquired acquired in step in step b), b), datadata representative representative of aof a deformation ofof the deformation the tissue tissue 51, 51, atat different different depths within the depths dd within the tissue tissue and andatatdifferent different moments moments t2,t2, t1,t1, t3t3 ofof theperiodic the periodic mechanical mechanical vibration vibration delivered delivered to thetotissue; the tissue; and toand to

c1) determine the c1) determine the homogeneity information from homogeneity information from the thedata datarepresentative representative of of the the 10 deformation 10 deformationofofthe thetissue tissue 51 51 determined determinedininstep step c0). c).

[0098] StepStep

[0098] canexecuted cO) be c0) can be executed using using a a correlation correlation technique technique or another or another patterning matching patterning algorithm, to matching algorithm, to determine howportions determine how portionsofof the the tissue tissue 51 51 move moveunder under the influence the influence of of the the elastic elastic wave that isis passing wave that passingthrough throughit it(the (theelastic elastic wave wavebeing being generated bybythe generated the periodic periodic mechanical mechanicalvibration vibration delivered delivered by the system). For example, system). For example, 15 the 15 thetissue tissueinin aasmall smallzone zoneofofthe theregion regionofofinterest interestmay maymove move slightly slightly away away fromfrom the the transducer 11 transducer 11 and andthen thenslightly slightlytoward towardthe thetransducer transducer 11 11 asspatial as a a spatial period period of the of the

elastic elastic wave passes through wave passes through this this zone. zone. Step Stepc0) cO)is istypically typically executed executed bybythe the programmable programmable circuit circuit 26, 26, to offload to offload the the processor processor 24. 24.

The control

[0099] The control

[0099] module module 21 may21be may be further further programmed programmed to, interto, intermake alia, alia,the make the 20 system 20 system1 execute 1 execute the the differentsteps different steps of of the the method method for characterizing for characterizing tissue tissue representedin infigure represented figure8.8.

[00100] As represented

[00100] As represented in figure in figure 7, the 7, the system system 1 for 1 for tissuecomprises characterizingtissue characterizing comprises the operator the operatorinterface interface3030 mentioned mentioned above. above. Still,Still, in other in other embodiments embodiments accordingaccording to the to the disclosed technology, the disclosed technology, theoperator operatorinterface interfacecould couldbe be distinctfrom distinct from the the system system for for

25 characterizing 25 characterizingtissue. tissue. TheThe operator operator interface interface may may for instance for instance be embedded be embedded in a in a smartphone smartphone orora acomputer computer communicating communicating withwith the the system system for characterizing for characterizing tissue. tissue. In In

such case,to toprovide such a acase, provide thethe homogeneity homogeneity information information to thetooperator, the operator, the control the control

module2121transmits module transmitsthis this information information to to the the external external operator operator interface interface by by means means ofofaa

communication module communication module of the of the system system for characterizing for characterizing tissue. tissue. The communication The communication

30 module 30 module maymay beelectric be an an electric circuitconfigured circuit configuredtotoexchange exchange data data using using a wire a wire or or wireless wireless

25 2020207873 24 Jul 2020

link, for link, instance for according instance accordingtoto ananUSB, USB,aaFirewire, Firewire,a aBluetooth, a 6LoWPAN, Bluetooth, ZigBee, a 6LoWPAN, aa ZigBee,

Z-Wave, aa Z-Wave, or or a Sigfox a Sigfox protocol. protocol.

[00101] WithWith

[00101] the the system system of figure of figure 7, the 7, the homogeneity homogeneity information information determined determined by by the the control module control 21 is module 21 is provided provided to to the the operator operator by by means ofthe means of the display display screen screen 31 31 of of the the 55 operator operator interface interface 30, 30, for for instance instance in form in the the form of theofgraphs the graphs 808, 808, 809 and 809 and indicator indicator 810 810 of figure of 15. The figure 15. Theoperator operator interface interface 30 30 may may comprise comprise also a also light emitting lighta emitting diode diode or otheror other light light emitting emitting device 14,arranged device 14, arrangedon on the the probe probe 10,visually 10, for for visually indicating indicating to operator to the the operator 40 whether 40 whether the the tissue tissue is is homogeneous homogeneous oror not not by by means meansof ofa change a change of of colororor color luminousintensity luminous intensityofofthe thelight lightemitted. emitted.

10 [00102] 10 [00102] In some In some embodiments, embodiments, according according to which to which thethe system system is isa apocket pocket system, system, the operator the operator interface interface comprises comprisesthe thelight light emitting emitting device devicementioned mentioned above, above, but but no no display screen. display screen.

[00103] Still

[00103] Stillin inanother anotherembodiment, embodiment, the the operator operator interface interface comprises comprises a speaker a speaker for for

indicating toto the indicating theoperator operator whether the tissue whether the tissue is is homogeneous homogeneous or or notnot by by means means of of an an 15 audible 15 audiblesignal. signal. Such Suchhomogeneity homogeneity information information could could also also be be provided provided to to theoperator the operatorbyby means means ofofa ahaptic haptic indication indication such such as as aa change changeofoftype typeororamplitude amplitudeofofthe themechanical mechanical vibration. vibration.

[00104] Though

[00104] Though the central the central unit unit 20 the 20 and and probe the probe 10 are10represented are represented as separate as separate

parts in parts in figure figure 7, 7, all all or part of or part of the the modules modules21, 21, 22, 22, 23the 23 of of central the central unitpresented unit 20 20 presented 20 above 20 above could could be be arranged arranged within within thethe probe. probe.

[00105] It Itwill

[00105] will be be appreciated appreciated that that aa number of variations number of variations may may be made inin the be made the system for system for characterizing characterizing tissue tissue presented abovewithout presented above withoutdeparting departingfrom fromthe thescope scope of of

the disclosed the disclosedtechnology. technology. For For instance, instance, some electric some electric functionalities functionalities could could be be distributed differently within distributed differently the central within the central unit unit than than what whathashas been been described described above.above. As an As an

25 example, 25 example,the theDAC DAC andand ADC ADC couldcould be located be located in control in the the control unit unit instead instead of the of the ultrasonic transmitter ultrasonic transmitterand and receiver receiver modules. Someofofthe modules. Some themodules modules 23 29 23 to to could 29 could be be mergedtogether, merged together,orordistributed. distributed. Moreover, Moreover,thethe controlunit control unitmaymay comprise comprise just just one one processor, instead processor, instead of of one oneprocessor processorandand a signal a signal processing processing unit.unit. Alternatively,thethe Alternatively,

control unit may control unit maycomprise comprise a greater a greater number number of processing of processing units units than in than figurein7. figure 7.

30 [00106] 30 [00106]A flowA chart flow chart of a method of a method for characterizing for characterizing tissue tissue in accordance in accordance with with some some embodiments embodiments of of the the disclosed disclosed technology technology is represented is represented in figure in figure 8. As already 8. As already

26 2020207873 24 Jul 2020

mentioned, the mentioned, the control module2121of ofthe control module thesystem system 1 of 1 of figure7 can figure 7 can be be programmed programmed to to make thesystem make the system1 1totoexecute executethis this method. method.

[00107] This

[00107] Thismethod method comprises comprises the the followingmain following main steps:S0,SO, steps: detecting detecting homogeneous homogeneous tissue, tissue, S1, measuring S1,measuring tissue tissue stiffnessbybytransient stiffness transient elastography, elastography, and andS2, S2, 55 providingananultrasound providing ultrasoundattenuation attenuationvalue value to to thethe operator. operator. In In step step S0,SO, the the system system 1 1 delivers the delivers continuousperiodic the continuous periodicmechanical mechanical vibration vibration to to thethe subject subject to test to test tissue tissue

homogeneity and homogeneity andprovides provides the thehomogeneity homogeneityinformation information mentioned mentionedabove above to to thethe operator 40. operator 40. This Thisinformation informationis iscontinuously continuously refreshed, refreshed, so that so that the the operator operator can can monitor in real monitor in real time timethe thetissue tissuehomogeneity homogeneity to test to test different different probe's probe's positions. positions. Once the Once the

10 homogeneity 10 homogeneityinformation informationindicates indicatesthat thatthethe tissue tissue 51 under 51 under examination examination is is homogeneous, homogeneous, thethe operator operator 40 40 actuates actuates thethe manual manual trigger trigger (e.g.:the (e.g.: theoperator operatorpresses presses the control the control button button 13). 13).The The execution execution of of step step SO S0 then then stops stops and the execution and the execution of of steps steps S1 and S2S2starts. S1 and starts. Once Oncethe thetissue tissuestiffness stiffness measurement measurement hashas beenbeen made made in step in step S1, S1,

the execution the executionof ofstep step S0 SO restarts restarts so that so that the operator the operator can becan be assured assured that the that probethe is probe is 15 still 15 still placed in front placed in front of of homogenous homogenous tissue. tissue. TheThe process process of alternating of alternating between between the the emission ofof the emission thecontinuous continuous periodic periodic mechanical mechanical vibration vibration (for (for homogeneity homogeneity assessment)and assessment) and thethe measurement measurement of tissue of tissue stiffness stiffness by transient by transient elastography elastography can can continue until continue until a arequired requirednumber number of of tissue tissuestiffness stiffnessmeasurements measurements have been obtained. have been obtained.

[00108] Steps

[00108] Steps So, So, andare S1 S2 S1 and S2now aredescribed now described in detail, in more more detail, one after one after the the other. other.

20 [00109] 20 [00109] StepStep S0: SO: detectinghomogeneous detecting homogeneous tissue tissue

[00110] As represented

[00110] As represented in figure in figure 8, step 8, step So So comprises comprises steps steps a), a), b) b) andand c) c) presented presented

above. StepSoSostarts above. Step startswith withstep stepa), a), during duringwhich thecontrol whichthe controlmodule module 21 controls 21 controls the the

vibrator 12 vibrator 12 (via (via the the motion motionactuation actuation servo servo control control 23)that 23) so so the thatvibrator the vibrator 12 delivers 12 delivers a a continuous andperiodic continuous and periodic mechanical mechanicalvibration vibrationPMV PMVto to thethe tissue tissue 51 51 of of thethe subject subject 50. 50.

25 This 25 Thisperiodic periodicmechanical mechanical vibrationPMVPMV vibration is continuously is continuously delivered delivered all all along along step step S0 SO (it(it

lasts all lasts allalong alongstep stepSO). S0).Once Once the the emission of this emission of this periodic periodic mechanical vibration PMV mechanical vibration PMV

has begun, has begun,the thecontrol controlmodule module executes executes step step b), during b), during whichwhich the control the control modulemodule

controls the ultrasound controls the ultrasoundtransducer transducer 11 (via 11 (via the ultrasonic the ultrasonic transmitter transmitter modulemodule 27) so that 27) so that

it emits it emits aa sequence sequence of of ultrasound ultrasound shots shots to track to track howtissue how the the tissue is moved is moved by the periodic by the periodic

30 mechanical 30 mechanical vibration,andand vibration, acquires acquires corresponding corresponding echo signals echo signals (via the(via the ultrasonic ultrasonic

receiver module receiver 29). Then, module 29). Then, inin step step c), c), the controlmodule the control module determines the homogeneity determines the homogeneity information from information from the the echo echosignals signalsacquired acquired in step in step b) and b) and then then provides provides it to it theto the

27 2020207873 24 Jul 2020

operator. operator. Then, the control Then, the control module executesagain module executes againsteps steps b) b) and and c),c),while whilethe theperiodic periodic mechanical vibration mechanical vibration PMV continues totobebedelivered, PMV continues delivered,totoprovide providenew, new,updated updated homogeneityinformation homogeneity informationtotothe the operator. operator. The Theset set of of steps steps comprising comprising step stepb)b) and andc)c) is is thus continuously thus continuously executed, executed, several several timestimes successively, successively, untilS0step until step SO is stopped is stopped by the by the 5 operator 5 operatoractuating actuatingthe themanual manual triggermentioned trigger mentioned above. above. For example, For example, in theincase the of case of figure 9, figure 9, the the set set of ofsteps comprising step stepscomprising step b) b) and c) isisrepeated and c) repeated every every 50 milliseconds 50 milliseconds

(with aa repetition (with repetition rate rate of of 20 hertz). So, 20 hertz). So,inin this this case, case,ifif itittakes takes 33 seconds forthe seconds for theoperator operator to find to find aa proper proper probe location and probe location and to to actuate the manual actuate the manualtrigger trigger(for example), then (for example), then step So will step So will last lastfor forapproximately approximately 33 seconds and the seconds and the set set of of steps steps comprising stepb)b) comprisingstep 10 and 10 andc)c)will will be be repeated repeated approximately approximately6060times. times.

[00111] In the

[00111] In the embodiments embodiments of figure of figure 8, the 8, the setset of of steps steps comprising comprising step step b) b) and and c) c)isis

executed executed in in real-time, real-time, that that is to is to saysay withwith a repetition a repetition rate higher rate higher than orthan equalortoequal 10 to 10 hertz, or hertz, or even higher than even higher than or or equal equal toto 2020hertz, hertz, and andwith witha alag lagtime timesmaller smallerthan thanor or equal to 11 second, equal to second, or or even evensmaller smallerthan thanororequal equaltoto0.1 0.1 second, second,ororsmaller smallerthan than0.03 0.03 15 seconds. 15 seconds. The The laglag time time is isthe thetime timeinterval interval between betweenthe thebeginning beginningofofthe the emission emissionofofthe the sequence sequence of of ultrasound ultrasound shots, shots, in step in step b), the b), and and instant the instant at which at which the updated the updated

homogeneityinformation, homogeneity information,determined determined from from the the echoecho signals signals acquired acquired in b), in step stepisb), is providedtotothe provided theoperator. operator.

[00112] In the

[00112] In the method method of figure of figure 8, step 8, step c) comprises c) comprises the sub-steps the sub-steps c1) and c0) and cO) c1) 20 described 20 describedabove. above. In step In step the the c0),cO), control control module module determines, determines, from from the signals the echo echo signals acquired acquired ininstep stepb),b),data data representative representative of a of a deformation deformation of the 51, of the tissue tissue 51, at different at different

depths withinthe depths d dwithin thetissue tissue and and at different at different moments moments t1,t3t2,oft3theofperiodic t1, t2, the periodic mechanical mechanical

vibration delivered vibration deliveredtotothe thetissue. tissue.In Instep step the the c1),c1), homogeneity homogeneity information information provided provided to to the operator the operator comprises comprisesa agraph graph representing, representing, both both as as a function a function of time of time t and t and as aas a 25 function 25 functionofofdepth depthd, d, thethe deformation deformation of tissue of tissue caused caused by theby the periodic periodic mechanical mechanical

vibration (this vibration (this deformation has deformation has been been determined determined in stepinc0)), step like like graphs cO)),graphs 808 of 808 of figures figures and 15, 99 and 15, graphs graphs168 168and and 178178 of of figures1616 figures and and 17,17, or or graphs graphs 188a 188a to 188e to 188e of figure of figure

18. 18.

[00113] Steps

[00113] Steps a), and a), b) b) and c) are c) are nownow described described in more in more detail. detail.

30 [00114] 30 [00114]In step In a), stepthe a), periodic the periodic mechanical mechanical vibration vibration delivered delivered to tissue to the the tissue has ahas a base frequency, base frequency,that that is is to to say fundamentalfrequency, a fundamental say a frequency,comprised comprised between between 10 hertz 10 hertz

and 200hertz. and 200 hertz. It It may haveaa base may have basefrequency frequency comprised comprised moremore specifically specifically between between 10 10

28 2020207873 24 Jul 2020

hertz and hertz 60 hertz. and 60 hertz. Such frequencyvalues Such frequency valuesare arefavorable favorablefor foraa deep deeppenetration penetrationofofthe the vibration within vibration within the the tissue, tissue,while whilestill fastfast still enough to to enough determine determineupdated updated homogeneity homogeneity

informationwith information witha arefresh refreshrate rate higher higher thanthan or equal or equal to 10tohertz, 10 hertz, thus enabling thus enabling real-time real-time

monitoring of monitoring of the the tissue tissue homogeneity. Theperiodic homogeneity. The periodic mechanical mechanicalvibration vibrationPMV PMVmaymay for for

5 instance 5 instancehave havea abase base frequency frequency of of 40 40 hertz hertz (and (and thus thus a period a period of of 2525 milliseconds),like milliseconds), like in figures in and10, 9 and figures 9 10,ororofof25 25 hertz hertz (and (and thusthus a period a period of 40 of 40 milliseconds), milliseconds), like in like in figure figure 11. As 11. represented in As represented in figures figures 9, 9, 10 10 and and 11, 11, the the periodic mechanical vibration periodicmechanical vibration PMV is aa PMV is

sinusoidal vibration. Still, sinusoidal vibration. Still, other otherperiodic periodicwaveforms, waveforms, such astriangular such as triangular waveforms, waveforms, could be employed. could be employed.TheThe periodic periodic mechanical mechanical vibration vibration PMV PMV is is continuous continuous in thatinitthat it

10 comprises 10 comprises a same a same vibration vibration pattern pattern VP (here VP (here sine period) a sinea wave wave period) repeated repeated several several times successively times successively over overtime, time,cyclically, cyclically, one immediatelyafter one immediately afterthe theother. other. Each Eachnewnew instanceofofthe instance thevibration vibrationpattern patternstarts startsimmediately immediately after after the the previous previous one, one, with with no no delay delay in between. in Thevibration between. The vibration pattern pattern isis repeated repeatedwith witha arepetition repetition rate rate that that is is the the base base frequency mentioned frequency mentionedabove. above. As already As already mentioned, mentioned, the periodic the periodic mechanical mechanical vibration vibration

15 lasts 15 lastscontinuously continuously all all along along stepstep SO. the S0. So, So,periodic the periodic mechanical vibrationvibration mechanical lasts typically lasts typically

secondorormore. 1 second 1 more.TheThe part part of of thethe subject's subject's tissue tissue 51 51 in contact in contact with with thethe probe probe 20 20 oscillates with oscillates withan an amplitude comprisedtypically amplitude comprised typically between between0.1 0.1and and2 millimeters, 2 millimeters,asasa a result of result of the the periodic mechanical periodic mechanical vibration vibration delivered delivered by the by the probe. probe.

[00115] In step

[00115] In step b), b), thethe controlmodule control module 21 21 instructsthe instructs theultrasonic ultrasonic transmitter transmitter module module 20 2727to togenerate 20 generate a sequence a sequence of ultrasound of ultrasound electric electric pulsespulses thatconverted that are are converted by the by the ultrasoundtransducer ultrasound transducer 11 which, 11 which, in return, in return, emits emits a sequence a sequence of shortofultrasound short ultrasound pulses, pulses, namedultrasound named ultrasoundshots, shots, to to track,ororininother track, otherwords words to to probe, probe, how how the tissue the tissue 51 51 is is movedbybythethe moved periodic periodic mechanical mechanical vibration vibration PMV.PMV. Figure Figure 9 shows 9 shows a representative a representative

sequence sequence 8080ofofultrasound ultrasoundshots shots81, 81,8282,... . The central The central frequency frequency of eachofultrasound each ultrasound 25 shot 25 shotisiscomprised comprisedfor forinstance instancebetween between 1 and 1 and 5 megahertz. 5 megahertz. The The duration duration of each of each shot, shot,

for instance for instanceequal equalto to100100 microseconds, microseconds, is typically is typically smaller smaller than a than a millisecond. millisecond. In step In step b), b), the the control control module 20also module 20 alsoacquires acquiresa sequence a sequence of corresponding of corresponding echo echo signals, signals,

received by received by the the ultrasound ultrasoundtransducer transducer11.11.Each Each echoecho signal signal is corresponding is corresponding to anto an ultrasoundshot ultrasound shotemitted emitted by the by the transducer transducer in the in that thatecho the signal echo signal is an ultrasound is an ultrasound wave wave 30 back 30 back scattered scattered by the by the tissue tissue in response in response to thetoemission the emission of the ultrasound of the ultrasound shot shot considered(or(oratatleast considered leastisisrepresentative representative of this of this back back scattered scattered wave). wave). Eachsignal Each echo echo signal is is representative ofback representative of backscattering scattering properties properties of the of the tissue, tissue, as aas a function function of depth of the the depth di d within the within the tissue tissue(as (aseach each instant, instant, within within one one of these of these short short echo signals, echo signals, corresponds corresponds

29 2020207873 24 Jul 2020

to aa given to given depth depth in in the the tissue, tissue, since since the the round-trip round-trip travel traveltime timeofofananultrasound ultrasound wave wave

betweenthe between thetransducer transducerand anda point a pointlocated locatedatatthe thedepth depthconsidered considered depends depends directly directly

on that depth). on that depth).

[00116] As already

[00116] As already mentioned, mentioned, these these successive successive echo signals echo signals are acquired are acquired to be to be 55 compared compared one one withwith eacheach other, other, for instance for instance using using a correlation a correlation technique technique or another or another

patterning matching patterning algorithm, to matching algorithm, to determine howportions determine how portionsofof the the tissue tissue 51 51 move moveunder under the influence the influenceofofthe theelastic elasticwave wave that that is is passing passing through through the tissue the tissue (this(this determination determination is is carried on inin step carried on stepc)). c)). Thus, Thus,to toprevent prevent decorrelation decorrelation between between two signals two echo echo signals successively acquired, the successively acquired, the ultrasound ultrasoundshots shotsareareemitted emitted with with a pulse a pulse repetitionrate repetition rate 10 higher 10 higher than than or equal or equal to Hertz, to 500 500 Hertz, or higher or even even higher than or than equalor toequal to 1 kilohertz, 1 kilohertz, in in step b) step b) (indeed, such (indeed, decorrelation could such decorrelation could occur, occur, due to global due to global tissue tissuedisplacements causedbyby displacements caused

respiration, for respiration, forinstance, instance,when when the the duration duration between thetwo between the twosuccessive successive shots shots is is too too

long). Typically, long). Typically, the the pulse pulse repetition repetition rate rate isiscomprised between1 kilohertz comprised between 1 kilohertzand and 10 10 kilohertz (depending kilohertz (depending ononthe thecontrol controlmodule module calculation calculation capacities). capacities). So, So, within within the the 15 sequence 15 sequence of ultrasound of ultrasound shots shots emitted emitted in step in step b), b), thethe duration duration between between any any shot,shot, and and the shot the shotimmediately immediately following following it, is it, is smaller smaller or equal or equal to 2 to 2 milliseconds, milliseconds, or smaller or even even smaller to to or or equal to 11 millisecond. equal to millisecond.

[00117] In the

[00117] In the method method of figure of figure 8, the 8, the sequence sequence of ultrasound of ultrasound shots shots emitted emitted in step in step

b) spans b) spansatatleast leastover over oneone half, half, or even or even over over at least at least three three fourth fourth of aperiod of a same sameof period of 20 the 20 theperiodic periodicmechanical mechanical vibration vibration PMVPMV delivered delivered to tissue to the the tissue (for instance (for instance over aover a whole period whole period ofofthe theperiodic periodicmechanical mechanicalvibration). vibration). And Andthis thissequence sequence comprises comprises at at least 10, least 10, or or even 50 ultrasound even 50 ultrasound shots shots per per period period ofof the the periodic periodic mechanical mechanicalvibration. vibration. As aaresult, As result, inin this this case, case,a asame same period, period, orleast or at at least the major the major part part of of aperiod a same sameofperiod of the periodic the periodic mechanical mechanicalvibration vibration PMV PMVis is sampled, sampled, all all at once, at once, as aas a whole, whole, by by the the 25 sequence 25 sequence of of shots shots emitted emitted in in step step b).AsAsalready b). alreadyexplained, explained,this this enables enablesa amuch muchbetter better monitoringofofthe monitoring thepropagation propagation of the of the periodic periodic elastic elastic deformation deformation thanstroboscopic than with with stroboscopic like sampling like sampling methods. methods.

[00118] In step

[00118] In step b), control b), the the control module module may in may in particular particular control control the ultrasonic the ultrasonic

transmitter module transmitter module2727so so thatthat it generates it generates the the sequence sequence of ultrasound of ultrasound shots asshots as 30 represented 30 represented in figure in figure 9, or1011. 9, 10 or 11.

[00119] In the

[00119] In the examples examples of figure of figure and the 9 10, 9 and 10, sequence the sequence 80 of ultrasound 80 of ultrasound shots shots emitted in step emitted in step b) b) spans spansmore moreprecisely preciselyover over oneone period period of the of the periodic periodic mechanical mechanical

30 2020207873 24 Jul 2020

vibration PMV. vibration In these PMV. In theseexamples, examples,thethe ultrasound ultrasound shots shots repetitionrate repetition rateis isequal equalto to2 2 Therefore,the kilohertz. Therefore, kilohertz. thesequence of ultrasound sequence of shots comprises ultrasound shots comprises5050shots shotsperper period period

of of the periodic mechanical the periodic mechanical vibration vibration (the(the frequency frequency of theofperiodic the periodic mechanical vibrationvibration mechanical being equal being equaltoto4040hertz, hertz,ininthese these examples). examples).

55 [00120]In theIn example

[00120] the example of figure of figure 11,sequence 11, the the sequence of ultrasound of ultrasound shots emitted shots emitted in in step b) spans step b) over more spans over morethan thana aperiod. period.The The ultrasound ultrasound shots shots repetitionrate repetition ratemay may also also

be equal be equal toto 22 kilohertz, kilohertz, corresponding corresponding toto8080shots shotsperper period period (the (the frequency frequency of the of the

periodic mechanical periodic mechanical vibration vibration being being equal equal to 25tohertz, 25 hertz, in this in this case). case).

[00121] The The

[00121] sequence sequence of ultrasound of ultrasound shots shots 80, 80" 80, 80', 80',emitted 80" emitted in step in step b) could b) could be be 10 emitted 10 emittedinina asynchronized synchronized manner manner with with respect respect to periodic to the the periodic mechanical mechanical vibration, vibration,

starting starting from from an instant io an instant io which, which, within within aa cycle cycle of of the the periodic periodic mechanical vibration mechanical vibration

PMVdelivered PMV delivered to the to the tissue tissue 51, 51, is the is the samesame for execution for each each execution of step of step b). b). As As shown in shown in figure 9, figure 9, this thisenable enable to to obtain obtain aa stable stable propagation graph 808n propagation graph 808nwith withno no rolling(time rolling (time shifting) shifting) effect effect from oneexecution from one executionof of steps steps b) and b) and c) the c) to to the other. other.

15 [00122] 15 [00122]In such In asuch case, a the case, the absolute absolute time to,time to',to, to"to', at to" at the which which the sequence sequence of of ultrasoundshots ultrasound shots starts starts is is differentfrom different from one one execution execution of stepofb)step b) to to the the But other. other. the But the time at time at which whichthethesequence sequence starts starts relative relative to beginning to the the beginning of theofcycle of the cycle of the periodic the periodic

mechanical mechanical vibration vibration is is thethe same same for each for each execution execution of stepofb)step b) precisely, (more (more precisely, the time the time at at which the sequence which the sequence starts,relative starts, relativetoto the thebeginning beginningofofthethecycle cycleof of thethe periodic periodic

20 mechanical 20 mechanical vibration vibration that that is theisclosest the closest to thistostarting this starting time - time - that that is is relative to say to say relative to to the beginning the beginningof of thethe instance instance of the of the vibration vibration pattern pattern that that is theisclosest the closest tostarting to this this starting time -- is time is the the same same foreach for each execution execution of step of step b). b).

[00123] In the

[00123] In the casecase of figure of figure 9 and 9 and 10, 10, for for instance, instance, forfor each each execution execution of of step step b),b),

the sequence the sequenceof ofultrasound ultrasoundshots shots startsalmost starts almost at the at the beginning beginning of aofperiod a period of of the the 25 periodic 25 periodicmechanical mechanical vibration,when vibration, whenthethevibration vibrationpasses passesthrough throughzero zero whileincreasing while increasing (the (the sequence sequence ofofultrasound ultrasoundshots shotscould couldalso alsostart startaagiven, given,fixed fixed delay delay time time after after the the beginningofofa aperiod beginning periodof of the the periodic periodic mechanical mechanical vibration). vibration).

[00124] Thanks

[00124] Thanks to synchronization, to this this synchronization, the propagation the propagation graph representing graph representing the the deformationof of deformation the the tissue tissue (that (that is deduced is deduced from from the emitted the shots shots emitted in step in step b)) both b)) as aboth as a 30 function 30 functionofofdepth depthand andasasa function a functionofoftime, time,starts, starts, for for each each new executionofofsteps new execution steps b)b) and c), and c), from fromthe thesame same instant instant io within io within a cycle a cycle of periodic of the the periodic mechanical mechanical vibration vibration (like (like

31 2020207873 24 2020

the different the different propagation propagation graphs graphs 808, 808, 808',808', 808" 808" of of figure figure 9, displayed 9, displayed successively successively to to the operator). the operator). This This graph graphthus thusremains remains stable stable from from one one execution execution to thetoother, the other, is is Jul aligned temporally,instead aligned temporally, instead of rolling.Thanks of rolling. Thanks to this to this stabilization, stabilization, the the graph graph is easier is easier to to understandforforthethe understand operator operator (as (as the the deformation deformation monitoring monitoring is not disturbed is not disturbed by temporal by temporal

5 rolling, 5 rolling,shifting shifting of of the the graph). graph).The The operator operator can can thus thus determine determine morewhether more easily easily the whether the probe is placed probe is placed in in front frontofof a homogeneous tissue, in a homogeneous tissue, in aa situation situationadequate adequate to tomeasure measure a a

physical parameter physical parameter of of thethe tissue, tissue, or or not. not.

[00125] Step

[00125] Step b) b) cancan be be repeated repeated with with a rate a rate such such thateach that each newnew sequence sequence of of ultrasound shots ultrasound shots is is emitted immediately after emitted immediately after the the other, other, with with no interruptionsbetween no interruptions between

10 them, 10 them,like likeinin figure figure 10. 10. In In the the example of figure example of figure 10, 10, aa sequence ofultrasound sequence of ultrasound shots shotsisis thus emitted thus emitted(to(totrack trackthethe tissue tissue deformation) deformation) for period for each each period of the of the periodic periodic mechanicalvibration mechanical vibration PMV. PMV. Step Step b) also b) can can be alsorepeated be repeated with a rate, with a slower slower forrate, for instance by instance by emitting emitting aa sequence sequence ofofultrasound ultrasoundshots shotsevery everytwo twoperiods periodsofofthe theperiodic periodic mechanicalvibration mechanical vibration PMV, PMV,like like in in the the case case of of figure figure9,9,when when the thecontrol controlmodule module 21 21 has has

15 a amore 15 more limitedprocessing limited processingspeed. speed. In Inthe thecase caseofoffigure figure 9, 9, aa new, new, updated updatedversion versionofofthe the homogeneityinformation homogeneity informationis is provided provided to operator to the the operator after after each emission each emission of the of the sequenceofofultrasound sequence ultrasoundshots, shots, before before the the next next sequence sequenceofofultrasound ultrasoundshots shotsisis emitted. emitted. In other In other words, words, inin this this case, case, the theexecution executionof of step step c) c) is is completed completed before before a newa new execution execution ofofstep stepb).b).

20 [00126] 20 [00126] In b), In step steptheb),sequence the sequence of ultrasound of ultrasound shots shots 110, 110,110" 110', 110', 110" could could also also start from start instantsio, from instants io, io', io', io" io" which, withina acycle which, within cycleof ofthethe periodic periodic mechanical mechanical vibration vibration

PMVdelivered PMV delivered to the to the tissue tissue 51, 51, are are different different fromfrom one execution one execution of step of b) step b) other, to the to the other, as represented as representedin in figure figure 11. 11. In this In this such such a case, a case, if a propagation if a raw raw propagation graph graph like graphlike graph 118, 118 118, 118 oror 118" 118"ofoffigure figure 11 11 were wereprovided providedto tothetheoperator, operator,ininstep stepc), c), the the operator operator 25 would 25 would perceive perceive thethe disturbing disturbing rolling, time rolling, timeshifting shifting effect effect mentioned above mentioned above when when thisthis

raw graph raw graphwould wouldbe be refreshed refreshed (a "raw (a "raw propagation propagation graph" graph" is understood is understood to amean to mean a graph showing graph showingthethe tissue tissue deformation deformation both both as a as a function function ofand of time time and the depth, depth, the deformation being deformation being displayed displayedover overtime timeinin the the order order it it was sampled; ; inin other was sampled other words, words, in in such aa raw such rawgraph, graph,the the temporal temporalcoordinate coordinateisisthe the actual actual time time at at which which the the deformation deformation 30 was 30 wasmeasured). measured).

[00127] So, So,

[00127] in this in this case, case, to prevent to prevent such such a a rolling rolling effect, effect, the deformation the deformation data data determined from determined fromthetheecho echo signals signals is post-processed is post-processed (in step (in step c)) order c)) in in order to re- to be be re-

32 2020207873 24 Jul 2020

aligned temporallybefore aligned temporally before being being displayed, displayed, the form in form in the of re-aligned of re-aligned propagation propagation graphs graphs

that start that start all allfrom from aa same, fixed instant, same, fixed instant, within cycle of within aa cycle of the the periodic periodic mechanical mechanical vibration, like vibration, likegraphs graphs118a, 118a, 118a', 118a', 118a" of figure 118a" of figure 12. In other 12. In other words, words, the the re-aligned re-aligned propagationgraph propagation graph provided provided to operator to the the operator in stepin c) step c) starts starts from a from reference instant iRinstant a reference iR

5 which, 5 which, within within a period a period of the of the periodic periodic mechanical mechanical vibration vibration delivered delivered to the tissue, to the tissue, is the is the same eachtime same each time thethe graph graph is updated is updated on base on the the base of newly of newly determined determined deformation deformation

data. Thetemporal data. The temporalre-alignment re-alignment cancan be achieved be achieved as follow: as follow: the deformation the deformation data data obtained for times obtained for times (actual, (actual, absolute measurement absolute measurement times) times) that that precede precede the the reference reference

instant iR instant iRare movedas as are moved a block a block to placed to be be placed at theatend theofend the of the deformation deformation data, data, from a from a 10 temporal 10 temporal point point of of view view (as (as if if they they had been measured had been measuredjust justafter after the the end end ofof the the sequence of ultrasound sequence of shots), as ultrasound shots), as represented represented schematically schematically in in figure figure 12. 12. The The reference instant reference instant iR iR is is aa given, given, fixed fixed moment withinthe moment within thevibration vibration pattern pattern VP VPthat thatisis repeatedseveral repeated several times times successively, successively, for instance for instance the beginning the beginning of thisof this vibration vibration pattern, pattern,

whenthe when thevibration vibration passes passesthrough through zero zero while while increasing. increasing. This This re-aligning re-aligning technique technique

15 stabilizes 15 stabilizes well well the the display display of of the the propagation propagationgraph, graph,from from a temporal a temporal point point of view. of view.

Though, the Though, the re-aligned re-aligned propagation propagation graph graphobtained obtainedin inthis thiswayway comprises comprises a a discontinuity, atat the discontinuity, the junction junction with the cut-and-paste with the cut-and-pasteblock blockof of data data thatthat has has been been

temporally shifted temporally shifted (this (this discontinuity discontinuity isisidentified identifiedbybyanan arrow, arrow, in in the the graphs 118a, graphs 118a,

118a', 118a" 118a', 118a" of of figure figure 12). 12). ItItwill willbebeappreciated appreciatedthat propagation that propagationgraphs graphs obtained obtained by by

20 directly 20 directly synchronizing synchronizingthetheemission emission of the of the sequence sequence of ultrasound of ultrasound shotsthewith shots with the periodic mechanical periodic vibration, asas inin figures mechanical vibration, figures9 9 and 10, do and 10, do not notcomprise comprisesuch such discontinuities. discontinuities.

[00128] Step

[00128] Step c).c).

[00129] As As

[00129] already already mentioned, mentioned, in step in step cO),thethe c0), controlmodule control module21 21 determines determines 25 deformation 25 deformationdata data representative representative of of thethe deformation deformation of the of the tissue, tissue, forfor differentdepths different depths within the within the tissue tissue and andat at differentmoments different moments of periodic of the the periodic mechanical mechanical vibration vibration

delivered to the delivered to the tissue, tissue, by by comparing comparingsuccessive successive ultrasound ultrasound echo echo signals signals using using a a correlation techniqueororanother correlation technique another patterning patterning matching matching algorithm. algorithm.

[00130] The The

[00130] term term deformation deformation is considered is considered in a broad in a broad sense sense in thisindocument. this document. It It 30 encompasses 30 encompassesanyany movement movement parameter parameter such such as displacement, as the the displacement, the speed, the speed, the the deformation, the deformation deformation, the deformationrate, rate,the thespeed speed of of deformation deformation and and any mathematical any mathematical

transformation applied transformation applied to to these these parameters. parameters.

33 2020207873 24 Jul 2020

[00131] In Instep

[00131] step c1),c1), the the homogeneity homogeneity information information is determined is determined from from the the deformation data determined deformation data determinedininstep stepc0). Thehomogeneity cO). The homogeneity information information may may comprise comprise

one ofthe one of thefollowings: followings:

propagationgraph, aa propagation graph, like like thethe ones ones 808,808, 168, 168, 178, 178, . . presented ... presented above; above;

55 a agraph graphrepresenting representing a phase a phase delay delay of (p of periodic the the periodic deformation deformation oftissue, of the the tissue, as a as a function of function of depth depthd,d,like likegraph graph809809 of of figure figure 15;15;

graph representing aa graph representing an anamplitude amplitudeAmp Amp of of an an envelope envelope of the of the periodic periodic deformation deformation of of

the tissue, the tissue, as as aa function functionofofdepth depthd, d,like likegraph graph811811 of figure of figure 15; 15;

an homogeneityindicator an homogeneity indicator810. 810.

10 [00132] 10 [00132]FigureFigure 15 shows 15 shows an example an example of the elements of the elements that can that can be displayed be displayed to the to the operator by means operator by meansof of thethe operator operator interface interface screen screen 31, 31, to provide to provide him/her him/her with with the the

homogeneityinformation. homogeneity information.In Inthethe casecase of figure of figure 15, homogeneity 15, the the homogeneity information information

comprises all the comprises all the elements listed above. elements listed Still, in in above. Still, other embodiments, other embodiments, the the homogeneity homogeneity

information could information comprisejust could comprise just one, one, or or just just some some ofofthese theseelements. elements.These These different different

15 elements, 15 elements,and and theway the way to to determine determine them, them, areare nownow described described in more in more detail. detail.

[00133] The The

[00133] propagation propagation graph,graph, that represents that represents the deformation the deformation of the at of the tissue tissue at different different depths depths within withinthe thetissue tissueand and at atdifferent differentmoments moments of of the the periodic periodicmechanical mechanical

vibration vibration can can be be aa two-dimensional image808 two-dimensional image 808compounded compounded by control by the the control module module 21, 21,

whosepixels whose pixels row rowindex indexrepresents representsdepth depthd dand and whose whose pixels pixels column column index index represents represents

20 time 20 timet t(or (or conversely), conversely), each eachpixel pixel having having aa pixel pixel value value representing representing the the deformation deformation ofof the tissue the tissue at at the the depth and time depth and time associated associatedtotothe thepixel pixel considered. considered.The Thepixel pixelvalue, value, that represents that the deformation represents the deformation value valueatatthe thepoint pointand andinstant instantconsidered, considered,cancan be be a a luminosityvalue, luminosity value,like likein infigure figure15 15 (the(the pixelpixel luminosity luminosity being being all theall the than higher higher the than the algebraic deformation value algebraic deformation valueis is high), high), or or a color a color valuevalue (like(like hue value), a huea value), or a or a 25 combination 25 combination thereof. thereof.

[00134] As As

[00134] already already mentioned,when mentioned, when thethe tissueisis homogeneous tissue homogeneousandand suitablefor suitable for elastic wavepropagation elastic wave propagation (no orairliquid (no air or liquid interposition), interposition), such asuch a periodic periodic elastic wave elastic wave

propagation image propagation image808 808isiscomprised comprisedofofone oneorormore more diagonal diagonal stripes.These stripes. Thesestripes stripesare are diagonalininthat diagonal thatthey theyare areslanted, slanted,in inthethet-dt-dcoordinate coordinate system. system. TheirTheir inclination inclination is to is due due to 30 the 30 thepropagation propagationtime time of of thethe periodicelastic periodic elasticwave, wave,from fromthethe skinof ofthethesubject skin subjecttotothe the

34 2020207873 24 Jul 2020

depth considered. The depth considered. Theslope slope of of these these stripesisisthus stripes thussomehow somehow representative representative of the of the

speed speed atatwhich which these these elastic elastic waves waves propagate propagate in the in the tissue. tissue.

[00135] As explained

[00135] As explained in detail in detail aboveabove with with reference reference to figures to figures 16 to 16 18 to 18 the (see (see the section section presenting presenting the the summary summary ofofthe the disclosed disclosed technology), technology), such suchpropagation propagationgraphs graphs 55 enable enable the the operator operator to to readily readily determine determine whether whether the the tissue tissueisishomogeneous and homogeneous and suitable for elastic suitable for elastic wave propagation wave propagation or not. or not.

[00136] When

[00136] When the tissue the tissue 51 is51homogeneous is homogeneous and suitable and suitable for elastic for elastic wave wave propagation (for propagation (for example there isis no example there no air air or or liquid liquid interposition interpositionbetween betweenthe the probe probe and and

the targeted the targeted tissue), tissue), the the phase phasedelay delay varies p varies substantially substantially linearlyover linearly over depth, depth, as as 10 shown 10 shownby by thethe graph graph 809809 of of figure15. figure 15.

[00137] TheThe

[00137] phase phase delay delay canp be canexpressed be expressed as a duration as a duration or asoranasangle an angle (in (in degrees or radians). degrees or radians). At At aa given given depth depth d, d, the the phase phasedelay delay prepresents represents thethe dephasing dephasing

betweenthe between theperiodic periodic deformation deformationofofthe thetissue tissue at at that that depth, depth, and reference periodic and aa reference periodic oscillation, oscillation,such such as as the the periodic periodic mechanical vibration delivered mechanical vibration delivered to to the the tissue, tissue, or or the the 15 periodic 15 periodic deformation deformation of tissue of the the tissue in an in an upper upper portionportion of the tissue. of the tissue. The module The control control module 21 may bebeprogrammed 21 may programmedto to determinethethephase determine phase delayfrom delay p from a frequency-domain a frequency-domain representationofofthe representation thedeformation deformation data, data, as represented as represented in figure in figure 14. In 14. suchIna such case, a case, the the measurement measurement of of thethe deformation deformation of of thethe tissue tissue over over time time 141, 141, at at a particulardepth, a particular depth,isis transformed into transformed into aafrequency-domain frequency-domain representation representation of this of this variation variation 142,142, (using (using a a 20 Fourier 20 Fourier transform transform or or other other time time domain domainto tofrequency frequency domain domain conversion). conversion). This This frequency-domainrepresentation frequency-domain representationshows shows a peak a peak at a frequency at a frequency fq thatfqisthat the is the base base frequencyofofthetheperiodic frequency periodic mechanical mechanical vibration vibration delivered delivered to the to the tissue. tissue. Theofvalue The value the of the Fourier transform Fourier 142 ofof the transform 142 the deformation deformationatatthis this particular particular frequency fq is frequency fq is aa complex complex

number whose number whoseargument argumentisisthe the phase phase delay delay p(in (in radians). radians). The The phase delay phase delay p may may 25 then 25 thenbebe converted converted into into a time,before a time, before being being plottedagainst plotted againstdepth depth d. d. A linearcurve A linear curve fit fit

144 may 144 maybebesuperimposed superimposed to the to the phase phase delay delay graph graph 143 obtained 143 obtained in this in this way,way, so that so that

the operator the operator can can more moreeasily easilyassess assesstissue tissuehomogeneity homogeneity (by (by checking checking thatthat the the phase phase

delay doesnotnotdepart delay does depart significantly significantly from from a linear a linear variation). variation).

[00138] The amplitude

[00138] The amplitude Amp of Amp of the variation the variation of the deformation of the tissue tissue deformation over over time time 30 (that 30 (that is istoto say say thethe amplitude amplitude ofenvelope of the the envelope of this of this variation), variation), at adepth at a given givend, depth can d, can be determinedinin the be determined the same samewayway as as forfor thephase the phase delay, delay, butbut considering considering thethe amplitude amplitude

of the of Fourier transform the Fourier at the transform at the peak peak frequency frequencyfq, fq,instead insteadofofits its phase, phase, for for example. example.

35 2020207873 24 Jul 2020

The amplitude The amplitude Amp Ampcould could also also be be determined determined using using another another kindkind of amplitude of amplitude envelope estimation envelope estimation or detection or detection technique. technique.

[00139] When

[00139] When the tissue the tissue 51 is51homogeneous is homogeneous and suitable and suitable for elastic for elastic wave wave propagation, the propagation, the amplitude amplitude Amp Ampis isexpected expectedto to varywith vary withdepth depthd daccording according to to a given a given

55 theoretical model, theoretical model,for for instance instance proportionally proportionally to to 1/dn, 1/dn,where is an where nn is an integer integer comprised comprised

between1 1and between and3.3.ToToenable enable thethe operator operator to to easilycheck easily check whether whether the the amplitude amplitude Amp Amp varies with varies with depth depth in inthis thismanner, manner,the theamplitude amplitudeAmp can be Amp can be plotted plotted against against depth using depth using

log-linear scale. aa log-linear scale. Indeed, whensuch Indeed, when such a scale a scale is used, is used, the the graph graph representing representing the the

variations of variations ofthe the amplitude amplitude over over depth is linear, depth is linear,which whichcan can be be readily readilyassessed assessed from a from a

10 visual 10 visualpoint point of of view, view, should should the the amplitude amplitude vary proportionally vary proportionally to to 1/dn. 1/dn.

[00140] The The

[00140] homogeneity homogeneity indicator indicator 810 810 can be can be displayed displayed in the in the form of form of a a binary binary indicator, like aa green/red indicator, like orgreen/black green/red or green/black one, one, or ainmore or in a more gradual gradual manner,manner, in the form in the form

of aa needle of needledial, dial,a percentage a percentage value, value, or a bar or a level level bara (like (like a kind kind of of progress progress bar), for bar), for instance. instance.

15 [00141] 15 [00141] The The homogeneity homogeneity indicator indicator 810 specifies 810 specifies whether whether the tissue the tissue 51 is 51 is homogeneous,more homogeneous, moreprecisely precisely homogeneous homogeneousover overthe thegiven givendepth depthrange rangementioned mentioned above, andsuitable above, and suitablefor forthe thepropagation propagation of of elasticwave, elastic wave, or not. or not. The The homogeneity homogeneity

indicator 810 indicator 810may may specify specify this this information information either either in ainbinary, a binary, all-or-nothing all-or-nothing manner, manner, or in or in more gradual a more a gradual way, way,asasaa continuous continuousvalue. value.

20 [00142] 20 [00142] By way By of wayillustration, of illustration,when when the the homogeneity homogeneity indicator indicator provides provides thisthis information in aa binary information in binary manner, manner,ifif the the tip tip of of the the probe probe isis placed placedinin contact contactwith with the the surface of surface of aa phantom (thatis phantom (that is aa test test sample madeof ofa asynthetic sample made syntheticviscoelastic viscoelastic material) material) that is that is homogeneous, deprived homogeneous, deprived of airoforair or liquid liquid inclusions inclusions or interpositions, or interpositions, large large enoughenough

(at least (at least 10 10 cm wideand cm wide and1010cm cm deep), deep), and and thatthat has has a Young's a Young's modulus modulus comprised comprised

25 between 25 between1 and 1 and 100 100 kilopascals kilopascals (or,alternatively, (or, alternatively, comprised between 5 5and comprised between and 75 75 kilopascals), then, kilopascals), then,thetheindicator indicator specifies specifies (for (for instance instance by turning by turning to that to green) green) the that the mediumisishomogeneous medium homogeneous and suitable and suitable for the for the propagation propagation of elastic of elastic waves. waves. And And if the if the

phantomisis not phantom not homogeneous homogeneous (for (for instance,includes instance, includeshard hardbeads), beads),ororcomprises comprises a water a water

layer aa few layer fewcentimeters centimeters below below its surface, its surface, then then the indicator the indicator specifies specifies that that the the medium medium 30 isisnot 30 nothomogeneous homogeneous or suitable or not not suitable for for thethe propagation propagation of elastic of elastic waves waves (for(for instance instance

by turning by turning to to black). black).

36 2020207873 24 Jul 2020

[00143] TheThe

[00143] controlmodule control module2121can canbebeprogrammed programmed to to determinethe determine thehomogeneity homogeneity indicator by indicator by processing the periodic processing the periodic elastic elastic wave propagationimage wave propagation image 808808 in order in order to to detect detect the the presence of one presence of or more one or homogeneous more homogeneous diagonal diagonal stripes stripes in in thisimage. this image.When When such stripes are such stripes are detected, detected, the thehomogeneity homogeneity indicator indicator 810810 indicates, indicates, forfor instance instance by by

5 switching 5 switchingfrom fromblack blacktotogreen, green,that thatthe the tissue tissue 51 51 is is homogeneous homogeneous andand suitable suitable forfor thethe

propagationofofelastic propagation elasticwave. wave.

[00144] The

[00144] Thecontrol control module module 2121 can canalso alsobebeprogrammed programmed to to determinethe determine the homogeneityindicator homogeneity indicator bybyprocessing processingthe theperiodic periodicelastic elastic wave propagationimage wave propagation image 808808

to detect to anedge detect an edgeor or an an average average line line of such of such a stripe, a stripe, and toand to determine, determine, bycurve by linear linear curve 10 fitting, 10 fitting, whether whether thisedge this edge or line or line is is substantially substantially linear linear over over thethe range range of depth of depth of interest of interest

and/or hasa aslope and/or has slopecomprised comprised in ain given a given interval interval of of likelyvalues. likely values.TheThe substantially substantially

linear nature linear ofthis nature of this line line or or edge edgecancan be be assessed assessed based based on a fitting on a fitting qualityquality parameter, parameter,

like the like coefficient of the coefficient of determination 2, the determinationR²,R the standard standard deviation deviation or other or other tools tools giving giving the the adequacy between adequacy between the fitted the fitted line aand line and a strictly strictly linearlinear variation variation over depth. over depth. The control The control

15 module 15 module maymay be programmed be programmed to determine to determine thatline that this thisorline or is edge edge is substantially substantially linear linear

whenthethe when coefficient coefficient of of determination determination 2 is higher R² isRhigher than than or or to equal equal 0.8, to or 0.8, even or even higher higher than or than or equal equal to to 0.9, 0.9, for for example. The homogeneity example. The homogeneity indicatorcould indicator couldbebedetermined determined as as being equal, being equal,ororproportional proportionalto to thisfitting this fitting quality quality parameter. parameter.

[00145] The

[00145] Thecontrol control module module 2121 can canalso alsobebeprogrammed programmed to to determinethe determine the 20 homogeneity 20 homogeneity indicator indicator by by determining determining whether whether the phase the phase delay delay P varies varies substantially substantially

linearly with linearly with depth overthe depth over therange range of of depth depth of interest of interest and/or and/or has ahas a slope slope comprised comprised in a in a given interval of given interval of likely likelyvalues. values.This Thisdetermination determination can be carried can be carried on on bybylinear linear curve curve fitting, asasexplained fitting, above. explained above.

[00146] The

[00146] Thecontrol control module module 2121 can canalso alsobebeprogrammed programmed to to determinethe determine the 25 homogeneity 25 homogeneity indicator indicator by by determining determining whether whether the phase the phase delay delay P varies varies substantially substantially

linearly with linearly with depth overthe depth over therange range of of depth depth of interest of interest and/or and/or has ahas a slope slope comprised comprised in a in a given interval of given interval of likely likelyvalues. values.This Thisdetermination determination can be carried can be carried on on bybylinear linear curve curve fitting, asasdescribed fitting, above. described above.

[00147] The

[00147] Thecontrol control module module 2121 can canalso alsobebeprogrammed programmed to to determinethe determine the 30 homogeneity 30 homogeneity indicator indicator by by determining determining whether whether the amplitude the amplitude Amp with Amp varies varies with depth depth according according to to a given model a given model orornot, in particular not, in particular whether whether the the amplitude amplitude Amp Amp isis proportionally toto 1/dn proportionally 1/d"orornot. not.This Thisdetermination determination cancarried can be be carried on byfitting. on by curve curve fitting. The The

37 2020207873 24 Jul 2020

fact the fact the amplitude Ampvaries amplitude Amp varieswith withdepth depth according according to the to the model model canassessed can be be assessed based onona afitting based fitting quality quality parameter, like the parameter, like the determination determination coefficient R 2 giving coefficient R² giving the the adequation between adequation between thethe variationsof of variations theamplitude the amplitude over over depth depth and and the model. the model. The The

homogeneity homogeneity indicator indicator could could be determined be determined asequal, as being beingorequal, or proportional proportional to this to this fitting fitting 5 quality 5 quality parameter. parameter.

[00148] TheThe

[00148] controlmodule control module 21 21 cancan alsoalso be programmed be programmed to determine to determine different different intermediary homogeneity intermediary homogeneity indicators,based indicators, based on different on the the different the criteria the criteria describes describes

above (so, determined above (so, determinedeither eitherfrom fromthetheperiodic periodicelastic elasticwave wavepropagation propagation image image 808,808,

from the from the variations variations of of the the phase delay, or phase delay, or from from the the variations variations of of the the amplitude Amp), amplitude Amp),

10 and 10 andtotodetermine determinethen then a finalhomogeneity a final homogeneity indicatorbased indicator based on these on these different different intermediary homogeneity intermediary homogeneityindicators, indicators,for forinstance instancebyby averaging averaging theses theses intermediary intermediary

homogeneityindicators. homogeneity indicators.

[00149] The The

[00149] control control module module 21 also 21 can can be also be programmed programmed to estimate, to estimate, in step inc1), stepa c1), a preliminary value preliminary value ofof a amechanical mechanical property property of tissue of the the tissue related related to wave to shear shear wave 15 propagation, 15 propagation, such such asasits its Young's Young'smodulus, modulus,orora range a range of values of values in which in which thisthis mechanicalproperty mechanical propertyisis likely likely to to be be found. found. This This value or range value or range of of value value is is determined determined from the from the data data representative representative ofofthe theperiodic periodic deformation deformationofofthe thetissue tissuedetermined determinedin in step Thisvalue cO). This step c0). valueororrange range of of value value is then is then provided provided tooperator, to the the operator, by of by means means the of the display screenofofthe display screen theoperator operator interface interface 30, 30, for for instance. instance.

20 [00150] 20 [00150] To end, To this this end, the control the control module module 21 derive 21 may may derive a preliminary a preliminary estimate estimate of theof the propagation speed propagation speedofofshear shearwaves wavesin in thetissue, the tissue,from fromthe theslope slopeofof the the diagonal stripes diagonal stripes of of the the periodic periodicelastic elasticwave wavepropagation propagation image 808 described image 808 describedabove, above,ororfrom fromthe theslope slope of of the line 404 the line representing the 404 representing the variations variations of of the the phase phasedelay delayover (p over depth depth d. The d. The

control control module 21 may module 21 maythen thendetermine determine a preliminaryestimate a preliminary estimate ofof theYoung's the Young's modulus, modulus,

25 from 25 fromthis thisvalue valueofofthe the propagation propagationspeed speedofofshear shearwaves. waves. As As mentioned mentioned in preamble, in preamble, a a value of value of the the propagation speedofofshear propagation speed shearwaves waves determined determined in this in this wayway is usually is usually less less

accurate than aa value accurate than value determined determinedbyby transientelastography transient elastography(due (due to to compression compression and and

shear wave shear wave superposition, superposition, interinter alia). alia). But But it isstill it is still useful usefulfor for the theoperator operatortotobebe provided provided

with such with such aapreliminary preliminaryvalue, value,ororrange rangeof of values values in which in which the the actual actual value value of of the the 30 Young's 30 Young's modulus modulus (or other (or other mechanical mechanical property property of theistissue) of the tissue) likely is to likely to be be found. found.

[00151] StepStep

[00151] S1: Si: measuring measuring tissue tissue stiffness stiffness by transient by transient elastography elastography

38 2020207873 24 Jul 2020

[00152] In step

[00152] In step S1, S1, to determine to determine the the mechanical mechanical property property of the of the tissue tissue 51 51 related related to to

shear wavepropagation shear wave propagation(e.g.: (e.g.: shear shearmodulus, modulus,Young's Young's modulus modulus E, shear E, shear wavewave speed, speed,

. . ) by ...) by transient transient elastography, the control elastography, the control module module2121is isprogrammed programmed to the to make make the system executing system 1 1executing thethe following following steps: steps:

55 d)d)stopping stoppingthe thecontinuous continuous andand periodic periodic mechanical mechanical vibration vibration PMV,PMV, then then delivering delivering a a transient low transient lowfrequency frequency mechanical mechanical pulsepulse to thetotissue the tissue of theof the subject; subject;

e) e) emitting emitting aa sequence of ultrasound sequence of ultrasound shots shots by by means meansof of theultrasound the ultrasoundemitter emitter1111and and acquiring acquiring corresponding echosignals corresponding echo signalsreceived receivedbybythe the ultrasound ultrasound receiver receiver 11, 11, while while the the low frequency low frequencymechanical mechanical pulsepulse travels travels through through the tissue the tissue 51; 51;

10 f)f) determining 10 determining said said mechanical mechanicalproperty propertyofofthethetissue tissuerelated relatedto toshear shear wave wave propagation,from propagation, from at at least least some some of the of the echo echo signals signals acquired acquired in step inf). step f).

[00153] The The

[00153] control control module module 21 be 21 may may be specifically more more specifically programmed programmed in orderin to, order in to, in step f): step f):

fO) determine, f0) from the determine, from theecho echo signals signals acquired acquired in step in step e), e), datadata representative representative of a of a 15 transient 15 transient deformation deformation of tissue, of the the tissue, at different at different depths depths within within the tissue the tissue and at different and at different

times after times after the the low lowfrequency frequency mechanical mechanical pulse pulse was delivered was delivered to the tissue; to the tissue; and to and to

f1) determine f1) the mechanical determine the mechanicalproperty property of of the the tissue tissue related related to toshear wave propagation, shearwave

from the from the data data representative representative of of the the transient transient deformation deformation ofof the the tissue tissue determined determinedinin step fO). step f0).

20 InInstep 20 stepd),d),the thecontrol module controlmodule 21 21 the the controls controls 12 12 vibrator vibrator thethe (via(via motion motion actuation actuation

servo controller servo controller 23) so that 23) so that it it delivers delivers to to the the tissue tissue the the transient transientmechanical pulse, mechanical pulse,

whoseduration whose duration is typically is typically smaller smaller than than 0.2 0.2 second second (the pulse (the pulse duration duration is understood is understood to to mean thetime mean the timelaps, laps, outside outside of of which whichthe the pulse pulseamplitude amplitudeisissmaller smallerthan thanone onetenth tenthofof the peak, the peak, maximum maximum amplitude amplitude of the of the pulse).This pulse). This mechanical mechanical pulse pulse is ais low a low frequency frequency

25 oneone 25 in that in that itsits spectral spectral content content (its(its spectral spectral density) density) is mostly is mostly locate locate belowbelow 500 or 500 hertz, hertz, or evenbelow even below100100 hertz. hertz. The The pulsepulse duration duration is typically is typically smaller smaller thanor10/f, than 10/f, evenor even smaller smaller than 2/f, than 2/f, where is the where f fis the central central frequency frequencyof of thethe pulse pulse spectrum. spectrum.

[00154] In step

[00154] In step e), e), thethe controlmodule control module 21 may 21 may control control the the ultrasound ultrasound transducer transducer 11 11 (via (via the the ultrasonic ultrasonictransmitter transmittermodule module 27) 27) so so that that ititemits emitsthe thesequence of ultrasound sequence of ultrasound

30 shots 30 shots atpulse at a a pulse repetition repetition raterate higher higher than than or equal or equal to 2 kilohertz. to 2 kilohertz. The ultrasound The ultrasound shots shots

39 2020207873 24 Jul 2020

emitted aresimilar emitted are similartotothe theones ones emitted emitted in step in step b) ofb)step of step SO.they S0. But Butare they are emitted emitted at a at a higher pulse higher repetition rate, pulse repetition rate, as step S1 as step S1isisfor precisely measuring for precisely measuringthethe mechanical mechanical

propertyofofthe property thetissue, notjust tissue, not just for visualizing, monitoring for visualizing, tissuehomogeneity. monitoringtissue homogeneity.

[00155] ForFor

[00155] example, example, the the transient transient mechanical mechanical pulse pulse may may last last for for 20 40or 20 or 40 55 milliseconds,the milliseconds, the sequence sequenceof of ultrasoundshots ultrasound shotslast last8080milliseconds millisecondsand andthe theultrasound ultrasound shots be emitted shots be emittedatata apulse pulserepetition repetition rate rate of of 66 kilohertz, kilohertz, thus enabling to thus enabling to track track the the deformation of the deformation of the tissue tissue as as aa function function ofof depth depthatat 480 480different different successive successiveinstants instants distributed distributed during during this this 80 milliseconds period 80 milliseconds period (that (that starts starts when theemission when the emissionof ofthethe transient mechanical transient mechanical pulse pulse starts). starts). In other In other words,words, in this in thisthe case, case, the transient transient elastic elastic 10 wave 10 wave propagation propagation image image 805 805 would would comprise comprise 480 columns. 480 columns.

[00156]In step

[00156] In step the data fO), data f0), the representative representative of the transient of the transient deformation deformation of the of the tissue tissue are determined by are determined bycomparing comparingthetheecho echo signalsacquired signals acquiredin instep stepe)e)one onewith witheach eachother, other, for instance for usinga acorrelation instance using correlationtechnique technique or another or another patterning patterning matching matching algorithm, algorithm, like like in step in of step cO) of step c0) step SO. SO.

15 [00157] 15 [00157]In step In f1), step the the mechanical f1l), mechanical property property of the of the tissue, tissue, related related to shear to shear wave wave propagation,isisdetermined propagation, determined according according to techniques to techniques known known in in the the art. art.

[00158] The The

[00158] control control module module 21 bemay 21 may be programmed programmed in order into, order to, inf1), in step stepprovide f1), provide aa transient transient elastic elasticwave propagation image, wave propagation image, like like the the image image 805 805of offigure figure15, 15, representing the representing the deformation deformation ofof the the tissue tissue caused causedbybythe thetransient transientmechanical pulse, mechanicalpulse, 20 both 20 both asfunction as a a function of depth of depth and asand as a function a function of time,of sotime, so that that the the can operator operator can visually visually check the quality check the quality ofofthe thetransient elastography transient measurement. elastography measurement.

[00159] TheThe

[00159] controlmodule control module 21 21 maymay also also be be programmed programmed to provide to provide thethe operator operator with the with the value value of of the the mechanical property of mechanical property of the the tissue, tissue, once determined, for once determined, for instance instance in the in the form of the form of the stiffness stiffness results results display display106 106shown shown in figure in figure 1. 1.

25 [00160] 25 [00160] Stepproviding Step S2: S2: providing an ultrasound an ultrasound attenuation attenuation valuevalue to operator to the the operator

[00161] In step

[00161] In step S2, S2, the the control control module module 12 provides 12 provides the operator the operator 40 with 40 with a value a value of of the ultrasound the ultrasound attenuation attenuation parameter parametermentioned mentionedabove, above, forfor instance instance by by displayingthis displaying this value on value on the the screen screen3131ofofthe theoperator operatorinterface interface (e.g. (e.g. in : inthe theform formofofthe theattenuation attenuation results display results display 107 107ofoffigure figure1). 1).

40 2020207873 24 Jul 2020

[00162] The The

[00162] ultrasound ultrasound attenuation attenuation parameter parameter is determined is determined by thebycontrol the control modulemodule 21 from some 21 from someororall all of of the the echo echo signals signals acquired acquired in in step step b) b) of of step step SO, S0, more precisely more precisely

during the last during the last execution execution of of step stepb), b), just just before before SoSostops. stops.This calculationcancan Thiscalculation be be

achieved either in achieved either in step step S0, SO, or or only only once onceexecuting executingstep step S2,S2, that that is is totosay say once once the the

5 operator 5 operatorhas hasactuated actuatedthe themanual manual trigger. trigger.

[00163] OneOne

[00163] may may remark remark thatthat a number a number of variations may of variations maybebemade madein inthe themethod method for characterizing for characterizing tissue presented above tissue presented abovewithout without departing departing from from the the scope scope of theof the disclosed technology. disclosed technology.

[00164] ForFor

[00164] instance,step instance, stepS2 S2could could be besuppressed suppressed(the methodthen (the method then comprising comprising 10 step 10 stepS0SOand and stepS1, step S1,butbutnot notS2). Similarly, step S2). Similarly, S1 could step S1 could be suppressed. be suppressed.

[00165] Besides,

[00165] Besides, thethe transition from transition from Step Step S0, SO, toto step step S1 and/orS2, S1 and/or S2,could couldbebe triggered automatically, triggered automatically, by by the the control control module itself, when module itself, the homogeneity when the homogeneityindicator indicator described above described aboveindicates indicatesthat thatthethe tissue tissue under under examination examination is homogeneous is homogeneous and and suitable for suitable for elastic elastic wave propagation. wave propagation.

15 [00166] 15 [00166] The The method method couldcould also also comprise comprise stepstep SO only, S0 only, thethe step step of of providing the providing the ultrasound attenuation ultrasound attenuation parameter parameterto to thethe operator operator beingbeing executed executed within within step step S0, SO, regardless of regardless of the the more or less more or less homogeneous homogeneous nature nature of the of the tissue tissue under under examination. examination.

Still, Still, in insuch sucha acase, case,the the control controlmodule maybebeprogrammed module may programmed to determine to determine a quality a quality

coefficient associated coefficient associatedto to thethe ultrasound ultrasound attenuation attenuation parameter, parameter, this coefficient this quality quality coefficient 20 being 20 beingallallthe thehigher higherasasthe thetissue tissueisis homogeneous homogeneouswithwith respect respect to the to the propagation propagation of of the periodic the periodicmechanical mechanical vibration vibration delivered delivered to thetotissue. the tissue. This quality This quality coefficient coefficient could could be determinedononthe be determined thebasis basisofof the the homogeneity homogeneityindicator indicatordescribed describedabove, above,for forinstance instance as being as beingequal equalor orproportional proportional to to thethe value value of this of this indicator. indicator.

[00167] The The

[00167] different different operations operations executed executed during during the the method method couldcould be organized be organized in in 25 steps 25 steps according according to a to a different different distribution distribution thanonethe than the one presented presented above (in above (in particular, particular,

the method the couldthus method could thus comprise comprisea agreater greaternumber numberof of stepsororsub-steps). steps sub-steps).

[00168] The The

[00168] disclosed disclosed technology technology provides provides also also a non-transitory a non-transitory computer computer readable readable

medium comprising medium comprising a computer a computer program program comprising comprising machine machine executable executable instructions instructions

whoseexecution whose executionbybya acontrol control module moduleofofaa system systemcomprising comprising

30 a probe, 30 a probe, to to be be holdhold against against the the bodybody of a of a subject subject and comprises and that that comprises a vibrator a vibrator to to deliver mechanical deliver mechanical vibrations vibrations to to a tissue a tissue of the of the subject subject

41 2020207873 24 Jul 2020

an emitter configured ultrasound emitter an ultrasound configured to emita asequence to emit sequence of ultrasound shots of ultrasound shots and and

an ultrasound receiver an ultrasound receiver configured configured to to receive receivecorresponding corresponding echo signals echo signals

makesthethe makes control control module module to execute to execute the following the following steps: steps:

a) controlling a) controlling the the probe probeso so that that it itdelivers deliversa continuous a continuous and periodic and periodic mechanical mechanical

55 vibrationtotothe vibration thetissue tissue of of thethe subject; subject;

b) b) controlling controlling the the ultrasound ultrasound emitter emitter so so that that ititemits emitsa asequence of ultrasound sequence of ultrasound shots and shots and acquiring acquiring corresponding corresponding echo echosignals signalsreceived receivedbybythe theultrasound ultrasoundreceiver, receiver, to to track how track how the thetissue tissueisis moved movedby by thethe periodic periodic mechanical mechanical vibration vibration delivered delivered to the to the

tissue; tissue;

10 10 c) providing c) providing homogeneity information to homogeneity information to an an operator operator ofof the the system, system,the the homogeneityinformation homogeneity informationthe thehomogeneity homogeneity information information being being determined determined from from at least at least

some some ofofthe theecho echo signals signals acquired acquired in step in step b), homogeneity b), the the homogeneity information information being being

representative of representative of the theability ability ofof the thetissue tissueto totransmit transmit elastic elastic waves waves andtheof and of the homogeneity homogeneity of the of the tissue tissue withwith respect respect to propagation to the the propagation of elastic of elastic waves;waves;

15 steps 15 stepsb)b)and andc)c)being beingexecuted executedcontinuously, continuously,several severaltimes timessuccessively. successively.

[00169] Embodiments

[00169] Embodiments of the of the subject subject mattermatter and and the the operations operations or described or steps steps described in in this this specification specification (e.g. (e.g.the the elements of the elements of the central central unit unit 20 20 ofofFigure Figure7)7)cancan be be

implemented implemented in in digitalelectronic digital electroniccircuitry, circuitry, or or inin computer computer software, software, firmware, firmware, or or

hardware, including hardware, including the the structures structures disclosed disclosed in this inspecification this specification and theirand their structural structural

20 equivalents, 20 equivalents,ororinin combinations combinationsofofone oneorormore more of of them. them. Embodiments Embodiments of the of the subject subject

matter described inin this matter described this specification specification can can be implementedasas be implemented oneone or more or more computer computer

programs, i.e., one programs, i.e., or more one or moremodules of of modules computer computer program program instructions, instructions, encoded encoded on on computerstorage computer storagemedium medium for execution for execution by, orby, or to control to control the operation the operation of, data of, data processing apparatus. processing apparatus.

25 [00170] 25 [00170]A computer A computer storage storage medium medium can orbe,can can be, or be canincluded be included in, in, a computer a computer- readable storage readable storagedevice, device,a acomputer-readable computer-readable storage storage substrate, substrate, a random a random or serial or serial

access memory access memory array array or or device, device, or or a a combination combination of of oneone or or more more of them. of them. Moreover, Moreover,

while aa computer while computerstorage storage medium medium is anot is not signal,signal, a propagated propagated a computer a computer storage storage medium can medium can be be a source a source or destination or destination of of computer computer program program instructions instructions encoded encoded in in 30 ananartificially-generated 30 artificially-generated propagated signal. The propagated signal. computerstorage The computer storagemedium medium also also cancan be,be,

or can or can bebeincluded includedin,in,one oneor or more more separate separate physical physical components components or (e.g., or media media (e.g., multiple CDs, disks, multiple CDs, disks, ororother otherstorage storagedevices). The operations devices).The operations described described in thisin this

42 2020207873 24 Jul 2020

specification specificationcan canbe be implemented implemented as operations performed as operations by aa data performed by data processing processing apparatus on data apparatus on data stored stored on on one oneorormore morecomputer-readable computer-readablestorage storagedevices devicesoror received from received from other other sources. sources.

[00171] The The

[00171] term term "control "control module" module" encompasses encompasses all kindsallofkinds of apparatus, apparatus, devices, devices,

55 andmachines and machines for for processing processing data, data, including including by way by way of example of example a microprocessor, a microprocessor, a a digital signal digital signalprocessor processor (DSP), computer, aasystem a computer, (DSP), a systemon on a chip, a chip, or or multipleones, multiple ones, or or

combinations ofofthe combinations the foregoing. foregoing. The Thecontrol controlmodule modulecancan include include special special purpose purpose logic logic

circuitry (like circuitry (like in in the the case case ofoffigure figure1)1)e.g., e.g.,an an FPGA FPGA or an(application-specific or an ASIC ASIC (application-specific integrated circuit). integrated circuit).

10 [00172] 10 [00172] A computer A computer program program (alsoknown (also known as as a program, a program, software, software software, software application, script, application, script,ororcode) code) can be written can be written inin any anyform formof of programming programming language, language,

including compiled including or interpreted compiled or interpreted languages, declarative or languages, declarative or procedural procedural languages, and languages, and

ititcan can be be deployed in any deployed in anyform, form, including including as asa astand-alone stand-aloneprogram program or or as as a module, a module,

component, subroutine, component, subroutine, object, object, or or other other unit unit suitable suitable for for use in aa computing use in computing 15 environment. 15 environment.A computer A computer program program may, may, but butnot, need need not, correspond correspond to a filetoina afile in file a file system. A Aprogram system. program can can be stored be stored in a inportion a portion of aoffile a file thatholds that holdsother otherprograms programs or or data (e.g., data (e.g., one oneorormore more scripts scripts stored stored in ainmarkup a markup language language document), document), in a singleinfile a single file dedicatedto tothethe dedicated program program in question, in question, or in multiple or in multiple coordinated coordinated files files (e.g., (e.g., files thatfiles that store one store or more one or moremodules, modules,sub-programs, sub-programs, or portions or portions of of code). code). A computer A computer program program

20 can 20 canbe be deployed deployed to executed to be be executed on computer on one one computer or on multiple or on multiple computers computers that are that are located at one located at onesite siteorordistributed distributedacross across multiple multiple sites sites and and interconnected by a by a interconnected communicationnetwork. communication network.

[00173] TheThe

[00173] processes processes and and logiclogic flows flows described described in this in this specification can specification canbebe performed byone performed by oneorormore moreprogrammable programmable processors processors executing executing one one or or computer more more computer 25 programs 25 programs to to perform perform actions actions by operating by operating on input on input data data and generating and generating output.output. The The processes and logic processes and logic flows flows can can also also be be performed by, and performed by, apparatus can and apparatus can also also be be implemented as,special implemented as, specialpurpose purpose logic logic circuitry, e.g., circuitry, e.g., an an FPGA FPGA (fieldprogrammable (field programmable gate array) gate array) ororananASIC ASIC (application-specific (application-specific integrated integrated circuit). circuit).

[00174] Processors

[00174] Processors suitable suitable for execution for the the execution of a of a computer computer program program include,include, by by 30 way 30 way of of example, example, bothboth general general and and special special purpose purpose microprocessors, microprocessors, and and any oneany or one or more processorsofofanyany more processors kind kind of of digitalcomputer. digital computer.Generally, Generally,a processor a processor willreceive will receive instructions instructions and and data data from read-only memory from aa read-only memoryor or a random-access a random-access memory memory or both. or both.

43 17 Sep 2020 2020207873 17 Sep 2020

The essential The essentialelements elementsof of a computer a computer are a are a processor processor for performing for performing actions actions in in accordance withinstructions accordance with instructions and and one oneorormore morememory memory devices devices for storing for storing instructions instructions

and data.Generally, and data. Generally, a computer a computer will also will also include, include, or be or be operatively operatively coupled coupled to receive to receive

data from or data from or transfer transfer data data to, to, or or both, both, one or more one or moremass mass storage storage devices devices forfor storing storing

5 data,e.g., 5 data, e.g., magnetic, magnetic,magneto-optical magneto-optical disks, disks, or or opticaldisks. optical disks.However, However, a computer a computer

need not have need not havesuch such devices. devices. Devices Devices suitable suitable for for storing storing computer computer program program 2020207873

instructions instructions and data include and data include all all forms forms of of non-volatile non-volatile memory, memory,media media and and memory memory

devices, including by devices, including by way of example way of examplesemiconductor semiconductor memory memory devices, devices, e.g., e.g., EPROM, EPROM,

EEPROM, EEPROM, and and flashflash memory memory devices; devices; magnetic magnetic disks,internal disks, e.g., e.g., internal hardordisks or hard disks

10 removabledisks; 10 removable disks; magneto-optical magneto-optical disks; disks; and CD-ROM and CD-ROM andand DVD-ROM DVD-ROM disks.disks. The The processor processor and the memory and the memorycancan be be supplemented supplemented by, by, or incorporated or incorporated in,in, special special purpose logiccircuitry. purpose logic circuitry.

[00175] To provide

[00175] To provide for interaction for interaction withwith a user, a user, embodiments embodiments of theofsubject the subject matter matter

described in this described in this specification specification can can be implemented be implemented on on a computer a computer having having a display a display

15 device,e.g., 15 device, e.g.,ananLCDLCD (liquid (liquid crystal crystal display), display), LEDLED (light (light emitting emitting diode), diode), or OLED or OLED

(organic light emitting (organic light emitting diode) diode) monitor, for displaying monitor, for displaying information to the information to the user user and anda a keyboard anda apointing keyboard and pointingdevice, device,e.g., e.g.,aamouse mouseor or a trackball,bybywhich a trackball, which thethe user user cancan

provide input to provide input to the the computer. In some computer. In someimplementations, implementations, a touch a touch screen screen cancan be used be used

to display to display information information and and to to receive receive input inputfrom fromaauser. user. Other Other kinds kinds of of devices devices can can be be

20 used 20 used to to provide provide forforinteraction interactionwith with aa user useras aswell; well; for for example, feedbackprovided example, feedback provided toto

the user the user can can be beany anyform form of of sensory sensory feedback, feedback, e.g.,visual e.g., visualfeedback, feedback,auditory auditory feedback, or feedback, or tactile tactile feedback; and input feedback; and input from fromthe theuser usercan can be be received received in in anyany form, form,

including acoustic,speech, including acoustic, speech,or or tactileinput. tactile input.

[00176]

[00176] FromFrom the foregoing, the foregoing, it will it will be be appreciated appreciated that that specificembodiments specific embodiments of the of the

25 inventionhave 25 invention have been been described described herein herein for purposes for purposes of illustration, of illustration, but that but that various various

modifications modifications may be made may be made withoutdeviating without deviatingfrom fromthe thescope scopeofofthe theinvention. invention.

[00177] Throughout

[00177] Throughout thisthis specification and specification andthe theclaims claimswhich whichfollow, follow, unless unless the the context requires otherwise, context requires otherwise, the the word word"comprise", "comprise",and andvariations variationssuch suchas as "comprises" "comprises"

and "comprising", and "comprising", willbebe will understood understood to imply to imply the inclusion the inclusion of a stated of a stated integer integer or stepororstep or

30 group 30 group of integers of integers or steps or steps butthe but not notexclusion the exclusion of any of anyinteger other other integer or group or step or step or of group of

integers or steps. integers or steps.

44 17 Sep 2020 2020207873 17 Sep 2020

[00178]

[00178] The The reference reference to prior to any any prior art art in in thisspecification this specification is is not, not, and and should should not not be be

takenas, taken as,ananacknowledgement acknowledgementor any or any form of form of suggestion suggestion that the that the prior art prior forms art forms part of part of the common the general common general knowledge knowledge in Australia. in Australia.

45 18 Sep 2025 2020207873 18 2025

CLAIMS CLAIMS Sep

1. 1. A system A system forcharacterizing for characterizing tissue, tissue, comprising: comprising:

a probe,totobe a probe, behold holdagainst against thethe body body of aof a subject subject and comprises and that that comprises a vibrator a vibrator to to deliver mechanical vibrations to to a tissue of of thethe subject; 2020207873

deliver mechanical vibrations a tissue subject;

an ultrasound emitter an ultrasound emitter that that is isconfigured configured to toemit emitaasequence of ultrasound sequence of ultrasound shots shots and an ultrasound and an ultrasound receiver receiver configured configured to to receive receive corresponding corresponding echo signals; and echo signals; and

a a control control module programmed module programmed to to make make thethe system system executing executing the the following following steps: steps:

a) delivering aacontinuous a) delivering continuousandand periodic periodic mechanical mechanical vibration vibration (PMV) (PMV) to to the tissue the tissue

of of the subject, the the subject, theperiodic periodicmechanical mechanical vibration vibration comprising comprising of avibration of a same same vibration pattern pattern

(VP) repeated (VP) repeated several several times times successively successively over time; over time;

b) b) emitting emitting aa sequence of ultrasound sequence of ultrasoundshots shotsbybymeans meansof of thethe ultrasound ultrasound emitter emitter

and acquiring corresponding and acquiring correspondingecho echosignals signalsreceived receivedbyby theultrasound the ultrasound receivertototrack receiver track how thetissue how the tissue is is moved movedbybythetheperiodic periodicmechanical mechanical vibration vibration (PMV) (PMV) delivered delivered to the to the

tissue; tissue;

c) providing homogeneity c) providing information to homogeneity information to an an operator operator ofof the thesystem, system,the the homogeneity informationbeing homogeneity information being determined determined fromfrom at least at least some some of the of thesignals echo echo signals acquired in step acquired in step b) b) and and by by carrying carrying out out aa comparison betweensaid comparison between saidatatleast least some someecho echo signals signals acquired in step acquired in step b), b), the homogeneityinformation the homogeneity informationbeing being representative representative of of thethe

ability ability of of the the tissue tissue to to transmit elastic waves transmit elastic wavesandand of the of the homogeneity homogeneity of the of the with tissue tissue with respect to the respect to the propagation of elastic propagation of elastic waves, andsaid waves, and saidhomogeneity homogeneity information information being being

determined independentlyofofa astiffness determined independently stiffnessmeasurement measurement of said of said tissue tissue such such thatthat the the at at

least least some of the some of theecho echosignals signalsthat thatare areprocessed processed by by the the control control module module to provide to provide

homogeneity information homogeneity information of of said said tissue tissue are are different different from from echo signals echo signals that are that are

processed processed forfor making making the the stiffness stiffness measurement measurement of said of said tissue; tissue;

wherein the wherein the control control module is programmed module is programmed soso that: that:

- steps - steps b) b) and andc)c)areare executed executed by system by the the system continuously, continuously, severalseveral times times successively and so successively and so that that - the - the sequence sequence of of ultrasound ultrasound shots shots emitted emitted in step in step b) spans b) spans at over at least leastone over one half half of of a sameperiod a same period(VP) (VP) of of thethe periodic periodic mechanical mechanical vibration vibration (PMV) (PMV) delivered delivered to theto the

46 18 Sep 2025 2020207873 18 Sep 2025

tissue, and tissue, comprisesatatleast and comprises least1010 ultrasound ultrasound shots shots per per period period of said of said mechanical mechanical

vibration. vibration.

2. 2. The systemofofclaim The system claim1, 1, wherein whereinthe the control control module is further module is further programmed programmed

to determine to determine atatleast leastone one physical physical property property of the of the tissue tissue comprising comprising one one of: of: 2020207873

an ultrasound parameter an ultrasound (BUA, ,α,CAP), parameter (BUA, CAP),relative relative to to ultrasound ultrasound wave wave propagation within propagation within the the tissue; tissue;

a mechanical property a mechanical property (Vs, (Vs, E) E) of of the the tissue tissue related related to to shear shear wave wave propagation, propagation, determined bytransient determined by transient elastography. elastography.

3. 3. The systemofofclaim The system claim2,2, wherein whereinthe thecontrol control module modulebeing beingprogrammed programmed to to

determine saidmechanical determine said mechanical property property E)s, of (Vs,(V E)the of tissue the tissue related related to wave to shear shear wave propagation, by transient propagation, by transient elastography, elastography, the the control control module moduleisisfurther further programmed programmedto to

make thesystem make the systemexecuting executingthe thefollowing following steps: steps: d) stopping the d) stopping thecontinuous continuous andand periodic periodic mechanical mechanical vibration vibration (PMV),(PMV), then then delivering delivering aa transient transientlow lowfrequency frequency mechanical mechanical pulse pulse to theto the tissue tissue of the of the subject; subject;

e) e) emitting emitting aa sequence of ultrasound sequence of ultrasoundshots shotsbybymeans meansof of thethe ultrasound ultrasound emitter emitter

and acquiringcorresponding and acquiring corresponding echo echo signals signals received received by the by the ultrasound ultrasound receiver,receiver, while the while the

low frequency low frequency mechanical mechanical pulsepulse travels travels through through the tissue; the tissue;

f) determining f) said mechanical determining said mechanicalproperty property(Vs, (Vs,E)E)ofofthe thetissue tissuerelated relatedtotoshear shear wavepropagation, wave propagation, fromfrom at least at least somesome of theofecho the signals echo signals acquired acquired in step in step e). e).

4. TheThe 4. system system of claim of claim 3, wherein 3, wherein thethe controlmodule control module is isprogrammed programmed to to trigger the trigger executionofofsteps the execution stepsd),d),e)e)and andf):f):

whena amanual when manual trigger trigger is actuated is actuated by operator by the the operator of theof the system; system; or or automatically, automatically, when saidhomogeneity when said homogeneity information information indicates indicates that that thethe tissue tissue is is

homogeneous with homogeneous with respect respect to to thepropagation the propagationofofelastic elastic waves. waves.

5. System 5. System according according to claim to claim 3 or 34,orwherein 4, wherein the control the control modulemodule is is programmed programmed so so that,ininstep that, stepe), e), the the ultrasound ultrasoundshots shotsare areemitted emittedatataapulse pulserepetition repetition rate rate higher thanororequal higher than equaltoto2 2kilohertz. kilohertz.

47 18 Sep 2025 2020207873 18 Sep 2025

6. 6. System accordingtotoany System according anyone oneofofclaims claims2 2toto5,5,wherein whereinthe thecontrol controlmodule moduleisis

further programmed further programmed totodetermine determine said said ultrasound ultrasound parameter parameter (BUA, (BUA, α, CAP) a, CAP) provided provided

that the that the homogeneity information indicates homogeneity information indicates that that the thetissue tissueis is homogeneous with respect homogeneous with respect to the to the propagation propagation of of elastic elastic waves, waves, and wherein said and wherein said ultrasound ultrasound parameter parameter isis determined from determined from oneone or more or more ofecho of the the signals echo signals acquired acquired in step in b).step b). 2020207873

7. 7. System accordingtotoany System according anyone oneofofclaims claims22toto 6, 6, wherein wherein the the control control module module

is is programmed to determine programmed to determine said said ultrasound ultrasoundparameter parameter(BUA, (BUA, α, , CAP) from one CAP) from one or or more more ofofthe theecho echo signals signals acquired acquired in step in step b), to b), and and to determine determine a quality a quality coefficient coefficient (R²) (R²) associated associated toto said said ultrasound ultrasound parameter, parameter, the quality the quality coefficient coefficient being being all the all the as higher higher as the tissue the tissue is is homogeneous homogeneous with with respect respect to thetopropagation the propagation of elastic of elastic waves. waves.

8. 8. System System according according to one to any anyof one of claims claims 1 to 1 7,towherein 7, wherein the control the control module module

is is programmed to determine, programmed to determine, from from at least at least some some of of the the echo echo acquired signals signals acquired in step b), in step b),

data representative data representative of of a periodic a periodic deformation deformation of tissue, of the the tissue, at different at different depths depths (d) within (d) within

the tissue the tissue and andatatdifferent different moments moments (t)(t)ofofthe theperiodic periodicmechanical mechanical vibration vibration (PMV) (PMV)

delivered to delivered to the thetissue, and tissue, andwherein whereinsaid saidhomogeneity homogeneity information information comprises oneof comprises one of the the following: following:

a graph representing a graph representing the the variation variation over over depth depth of of atat least least one onetemporal temporal characteristic of characteristic of the the temporal, temporal,periodic periodic variation variation of of the the deformation deformation of the of the tissue; tissue; or or an indicationspecifying an indication specifyingwhether whether saidsaid characteristic characteristic varies varies with with depthdepth (d) as(d) if as theif the

tissue were tissue were homogeneous over homogeneous over a given a given range range of of depth depth (ROI), (ROI), oror not. not.

9. 9. System accordingtotoclaim System according claim 8, 8, wherein: wherein:

said graphrepresents said graph represents the the deformation deformation of theoftissue the tissue at different at different depthsdepths (d) within (d) within

the tissue the tissue and andatatdifferent different moments moments (t)(t)ofofthe theperiodic periodicmechanical mechanical vibration vibration (PMV) (PMV)

delivered delivered to to the the tissue, tissue, said said graph graph being being aa two-dimensional two-dimensionalimage image whose whose pixels pixels row row

index represents depth index represents depth and andwhose whose pixelscolumn pixels column index index represents represents time, time, or or conversely, conversely,

each pixelhaving each pixel having a pixel a pixel value value representing representing the deformation the deformation of theattissue of the tissue at the depth the depth

and timeassociated and time associatedto to thethe pixel pixel considered; considered; or wherein or wherein

said indication specifies said indication specifieswhether whether said said graph, graph, which which represents represents the deformation the deformation of of the tissue the tissueatatdifferent differentdepths depths(d)(d) within within the the tissue tissue and and at at different different moments moments (t) (t) of the of the

48 18 Sep 2025 2020207873 18 Sep 2025

periodic periodic mechanical vibration (PMV) mechanical vibration (PMV)delivered deliveredtotothe thetissue, tissue, said said graph graphbeing beinga atwo- two- dimensional imagewhose dimensional image whose pixels pixels row row index index represents represents depth depth andand whose whose pixels pixels column column

index represents time index represents time or or conversely, conversely, each eachpixel pixel having havinga apixel pixel value valuerepresenting representingthe the deformation of the deformation of the tissue tissue at at the the depth and time depth and time associated associatedtotothe thepixel pixel considered, considered, is is comprised comprised of of diagonal diagonal stripes stripes overover saidsaid range range of depth of depth (ROI),(ROI), or not.or not. 2020207873

10. 10. System System according according to claim to claim 8 or 89,orwherein 9, wherein the homogeneity the homogeneity information information

comprises comprises at at leastoneone least of:of:

a graphrepresenting a graph representing a phase a phase delaydelay () of (φ) the of the periodic periodic deformation deformation of the tissue, of the tissue,

as as aa function functionofofdepth depth(d); (d);ororwherein wherein an indication specifying an indication specifyingwhether whether the the phase delay () phase delay (φ)of of the the periodic periodic deformation deformation

of of the tissue varies the tissue variessubstantially substantiallylinearly linearlywith withdepth depth (d)(d) over over saidsaid range range of depth of depth (ROI), (ROI),

or not. or not.

11. System 11. System according according to any to any one one of of claims claims 1 towherein 1 to 10, 10, wherein the control the control module is module is

programmed programmed so so that: that:

a basefrequency a base frequencyofofthe theperiodic periodicmechanical mechanical vibration vibration (PMV) (PMV) delivered delivered to the to the

tissue of tissue of the the subject subjectisis comprised comprised between between 10 hertz 10 hertz and and 200 200 and hertz, hertz, and in in step b), the step b), ultrasoundshots the ultrasound shots areare emitted emitted at aat a pulse pulse repetition repetition rate rate higher higher than than

or or equal to 500 equal to 500hertz. hertz.

12. System 12. System according according to any to any one one of of claims claims 1 towherein 1 to 11, 11, wherein the control the control module is module is

programmed programmed so so thatthe that thesystem system executes executes thethe setset ofof stepscomprising steps comprising steps steps b)b) and and c)c)inin

real real time. time.

13. System 13. System according according to any to any oneclaims one of of claims 1 towherein: 1 to 12, 12, wherein: the homogeneity the homogeneity information information provided provided to to the the operator operator comprises comprises aagraph graph representing representing a a deformation deformation of the of the tissue, tissue, at different at different depths depths (d) within (d) within the tissue the tissue and atand at

different moments different moments (t) (t) of of thethe periodic periodic mechanical mechanical vibration vibration delivered delivered to the and to the tissue, tissue, and wherein wherein

the control the control module moduleisisprogrammed programmed so that so that the emission the emission of theofsequence the sequence of of ultrasound shots ofofstep ultrasound shots stepb)b)isissynchronized synchronized with with the the periodic periodic mechanical mechanical vibration vibration

49 18 Sep 2025 2020207873 18 Sep 2025

(PMV), the sequence (PMV), the sequenceof of ultrasound ultrasound shots shots startingfrom starting from an an instant instant (io)which, (io) which,within withinaa cycle (VP)ofofthe cycle (VP) theperiodic periodic mechanical mechanical vibration vibration delivered delivered to the to the tissue, tissue, is theforsame for is the same

each execution each execution of of step step b).b).

14. 14. System accordingtotoany System according any oneone of of claims claims 1 13, 1 to to 13, wherein wherein the the homogeneity homogeneity 2020207873

information provided toto the information provided theoperator operatorininstep step c) c) comprises comprises a graph a graph representing representing a a deformation deformation of of the the tissue, tissue, both both as aas a function function of depth of depth (d)asand (d) and as a function a function of time (t), of time (t),

the graph the graphstarting starting from from an instant an instant (io, (io, iR) which, iR) which, withinwithin a period a period (VP) of (VP) of the the periodic periodic mechanical vibration (PMV) mechanical vibration (PMV)delivered deliveredtoto the the tissue, tissue, isisthe thesame same each time the each time the graph graph is is updated onthe updated on the base baseof of newly newlydetermined determineddeformation deformationdata. data.

15. System 15. System according according to to any any oneone of of claims claims 1 to 1 to 14,14, wherein wherein theprobe's the probe’s vibrator is vibrator is rotationally rotationally symmetrical arounda vibrator symmetrical around a vibrator axisaxis (z),(z), and and wherein wherein the the ultrasound emitter and ultrasound emitter the ultrasound and the transmitter are ultrasound transmitter are constituted constitutedby bya asame same ultrasound ultrasound

transducerthat transducer thatisisrotationally rotationallysymmetrical symmetrical around around a transducer a transducer axis axis that that coincide coincide with with the vibrator axis (z). the vibrator axis (z).

16. System 16. System according according to any to any one one of of claims claims 1 towherein 1 to 15, 15, wherein the control the control module is module is

programmed programmed to:to:

determine, fromatatleast determine, from least some someof of thethe echo echo signals signals acquired acquired in step in step b), data b), data

representative representative ofofa a periodic periodic deformation deformation of tissue, of the the tissue, at different at different depths depths (d) within (d) within the the tissue and tissue andatatdifferent differentmoments moments (t) the (t) of of the periodic periodic mechanical mechanical vibration vibration delivered delivered to the to the tissue; and tissue; to and to

estimate estimate a avalue value of of a mechanical a mechanical property property (Vs, E)(V ofs, the E) of the related tissue tissue related to shear to shear

wavepropagation, wave propagation,orora arange rangeofofvalues valuesininwhich whicha amechanical mechanical property property (VE) (Vs, s, E) of of thethe

tissue related tissue relatedto to shear shearwave wave propagation propagation is likely is likely to found, to be be found, basedbased ondata. on said said data.

17. System 17. System according according to any to any oneclaims one of of claims 1 to 16: 1 to 16:

- further - furthercomprising comprising a a manual adjustmentcontrol manual adjustment controlfor foradjusting adjusting an anamplitude amplitudeofof the periodic the periodic mechanical vibration (PMV), mechanical vibration the control (PMV), the control module being further module being further programmed programmed

to provide to provide to to the the operator operator an information representative an information representative of of an amplitude of an amplitude of aa periodic periodic deformation deformation of of the the tissue, tissue, caused caused byperiodic by the the periodic mechanical mechanical vibrationvibration delivereddelivered to the to the

50 18 Sep 2025 2020207873 18 Sep 2025

tissue, the tissue, the amplitude of periodic amplitude of periodic deformation of the deformation of the tissue tissue being being determined determinedfrom from at at

least least some some ofofthe theecho echo signals signals acquired acquired in step in step b), or b), or

-- wherein wherein the the control control module module isis programmed programmedto to adjust adjust automaticallythe automatically the amplitude of the amplitude of the periodic periodic mechanical vibration (PMV) mechanical vibration delivered to (PMV) delivered to the the subject subjectbased based on on

the amplitude the amplitudeofofthe theperiodic periodic deformation deformation of the of the tissue. tissue. 2020207873

18. Method for 18. Method for characterizing characterizing tissue, tissue, carried carriedon on by meansofofa asystem by means system comprising: comprising:

a probe,totobebehold a probe, holdagainst against thethe skin skin of of a subject a subject and and that that comprises comprises a vibrator a vibrator to to deliver mechanical deliver mechanical vibrations vibrations to to a tissue a tissue of of a subject; a subject;

an ultrasound emitter an ultrasound emitter that that is isconfigured configured to toemit emitaasequence of ultrasound sequence of ultrasound shots shots and anultrasound and an ultrasoundreceiver receiverthat thatisis configured configuredtoto receive receive corresponding correspondingecho echo signals; signals;

and and a a control control module programmed module programmed to to make make the the system system executing executing the following the following steps steps

of of the the method: method:

a) delivering aa continuous a) delivering continuousandand periodic periodic mechanical mechanical vibration vibration (PMV) (PMV) to to the tissue the tissue

of of the subject, the the subject, theperiodic periodicmechanical mechanical vibration vibration comprising comprising of avibration of a same same vibration pattern pattern

(VP) repeated (VP) repeated several several times times successively successively over time; over time;

b) b) emitting emitting aa sequence of ultrasound sequence of ultrasoundshots shotsbybymeans meansof of thethe ultrasound ultrasound emitter emitter

and acquiring corresponding and acquiring correspondingecho echosignals signalsreceived receivedbyby theultrasound the ultrasound receivertototrack receiver track how thetissue how the tissue is is moved movedbyby theperiodic the periodicmechanical mechanical vibration vibration (PMV) (PMV) delivered delivered to the to the

tissue; tissue;

c) providing homogeneity c) providing information to homogeneity information to an an operator operator ofof the thesystem, system,the the homogeneity informationbeing homogeneity information being determined determined fromfrom at least at least some some of the of thesignals echo echo signals acquired in step acquired in step b) b) and and by by carrying carrying out out aa comparison betweensaid comparison between saidatatleast least some someecho echo signals signals acquired in step acquired in b), the step b), the homogeneity homogeneity information information being being representative representative of of thethe

ability ability of of the the tissue tissue to to transmit elastic waves transmit elastic wavesandand of the of the homogeneity homogeneity of the of the with tissue tissue with respect to the respect to the propagation of elastic propagation of elastic waves, andsaid waves, and saidhomogeneity homogeneity information information being being

determined independentlyofofa astiffness determined independently stiffnessmeasurement measurement of said of said tissue tissue such such thatthat the the at at

least least some of the some of theecho echosignals signalsthat thatare areprocessed processed by by the the control control module module to provide to provide

homogeneity information homogeneity information of of said said tissue tissue are are different different from from echo signals echo signals that are that are

processed processed forfor making making the the stiffness stiffness measurement measurement of said of said tissue; tissue;

51 18 Sep 2025 2020207873 18 2025

wherein the wherein the control control module is programmed module is programmed soso that: that:

Sep -- steps steps b) b) and andc)c)areare executed executed by system by the the system continuously, continuously, severalseveral times times

successively, and successively, and so so that that

-- the the sequence sequence of of ultrasound ultrasound shots shots emitted emitted in step in step b) spans b) spans at over at least leastone over one half half

of of a sameperiod a same period(VP) (VP) of of thethe periodic periodic mechanical mechanical vibration vibration (PMV) (PMV) delivered delivered to theto the 2020207873

tissue, and tissue, comprisesatatleast and comprises least1010 ultrasound ultrasound shots shots per per period period of said of said mechanical mechanical

vibration. vibration.

2020207873 24 Jul 2020

UPONT an 107

Methotrexate d Dr WHO Liver

102 80 70 60 50 40 30 mm 20

IQR

18 2020207873

t d CAP (dB/m)

275 MEDIAN 101

m

mm MEDIAN E (kPa) . 80 70 60

d 50 40 30 20

10 5.7 20 105C 103

105S

40

t IQR/med.

60

IQR 0.1 2% 105

80

09/09/2018

09:06

106 image propagation wave results attenuation refreshed continuously refreshed continuously wave Shear : 105S results Stiffness : 106 indicator Force : 103 wave Compression : 105C graph, TM-mode : 102 elastic Transient : 105 107 : ultrasound 101 : A-mode graph,

Fig. 1

1 / 14

2020207873 24 Jul 2020

Fig. 2

d x x 2020207873

x t 3 X

202 Fig. 3 4

d x x

X 3 t X

302 Fig. 4 4

d * x x 2 / 14

t 3 X

402

2020207873 24 Jul 2020

502

Depth (mm) d 80 70 60 50 40 30 20 10

normal Fig. 5

t 2020207873

d interposition interposition 80 70 60 50 40 30 20 10

Liquid

t 602

80 70 60 50 d 40 30 20 10

Air

t 602'

80 70 60 50 d 40 30 20 10

Fig. 6

Edges

t 602"

80 70 60 50 d 40 30 20 10

Vessel

t 3 / 14

detect difficult to vessel, isoechoic

602"

2020207873 24 Jul 2020

Z subject of. the tissue

51

11

1 50 2020207873

13 10 12

14

28 22 frontend Ultrasound Motion actuation 23 servo controller

T/R Fig. 7

Operator interface 30

Central unit 20 RX circuits 27 TX circuits

29

purpose

Control module 21 Special Processor circuit screen 31

26 display

MEM 25

4/14

251 250

2020207873 24 Jul 2020

to the operator attenuation value ultrasound providing an

S2

CAP 2020207873

31

mechanical

vibration

Periodic

a) d) pulse mechanical transient f) b) Ultrasound c) shots

f1) Ultrasound

f0)

shots

c1) c0) actuation trigger manual e)

propagation image 805 wave elastic transient homogeneity indicator tissue homogeneous detecting so elastography transient by tissue the of property mechanical a determining S1 propagation graph

tissue stiffness

808, 809

810

buton 13 display display control

31 31 5 / 14

Operator

Fig. 8

2020207873 24 Jul 2020

a) compression waves + waves shear = waves Elastic vibration mechanical continuous periodic

Ultrasound shots

PMV ; 40 Hz

operator the to displayed Image 2020207873

Refreshed every 50 ms

t1 81

t2 82

25 ms

io to t3 808 50 ms

VP

80 d VP t io to 808 correlation

technique

VP

b) c0) 80'

c1) io to 808"

pattern VP vibration

b) c0) 80"

c1) 808

b) c0)

time t c1) Fig. 9 6 / 14

t

2020207873 24 Jul 2020

vibration mechanical a) continuous periodic

Ultrasound shots

PMV ; 40 Hz 2020207873

25 ms

user the to displayed Image ARM, etc...) (DSP, FPGA, Refreshed every 25 ms

processing

waves Elastic image 40 Hz

Fast

b) c0)

c1 b) c0)

c1 b) c0)

c1

Fig. 10

7/14 time t

t

2020207873 24 Jul 2020

vibration mechanical continuous periodic

Ultrasound shots

PMV ; 25 Hz

image waves Elastic Hz 25 displayed to the user. Refreshed every 50 ms 2020207873

40 ms

50 ms

VP 118

IO technique Correlation depth d (mm) 80 70 60 50 40 30 20 10

VP 0 t (ms)

20

VP io 110 Depth (mm) 80 70 60 50 40 30 20 10

0 Time (ms)

20 118'

VP

110'

io" Depth (mm) 80 70 60 50 40 30 20 10

0 Time (ms)

20 118"

110"

Fig. 11

8 / 14

time t

t

2020207873 24 Jul 2020

depth d (mm) 08 70 09 50 40 30 20 10 t (ms) 0

20

iR 2020207873

118'

Depth (mm) 80 70 09 50 40 30 20 10

0

iR 20

118"

Depth (mm) 08 70 09 50 40 30 20 10

0

Fig. 12 IR 07

Depth (mm) 80 70 09 50 40 30 20 10

0 Time (ms)

20 118a

Depth (mm) 80 70 09 50 40 30 20 10

0 Time (ms)

20 118a'

9 / 14

Depth (mm) 80 70 60 50 40 30 20 10

0 Time (ms)

20 118a"

2020207873 24 Jul 2020

d t 130 2020207873

t t t wave elastic Periodic mechanical Perioc propagation images

Ultrasound shot

vibration PMV

sequences

Screen 1

Screen 2

n Screen 3

Screen 4

10 / 14

Fig. 13

t t t d t 134 133 132 131

2020207873 24 Jul 2020

808

model linear a to fitted then is curve The indicating linear, is propagation wave elastic the means fit accurate An window measurement proper image propagation wave elastic the of slope the represents curve Phase Depth (mm) 80 70 60 50 40 30 20 10 Elastic wave

0 Time (ms)

image

20

40 2020207873

Amplitude (UA) -2.5 -1.5 -0.5

0.5 1.5 2.5 -2 1-

141 0 0 1 2 Elastic wave image

at a given depth

10

Time (ms)

20

30 to depth each at Repeated curve phase the draw 40

FFT

Fig. 14

Amp. (UA) 1500 2000 2500 1000

500

00 frequency vibration = fq fq at computation Phase 100 (Hz) Frequency 200

300

143 400

500

0 90 80 70 60 '50 40 d30 20 10 0 Phase curve

142 20 curve Fit curve Phase 144 40

11 / 14

Depth (mm) 80 70 60 50 40 30 20 10 phase curve Elastic wave

0 image +

Time (ms) curve Phase 20

ROI 24 Jul 2020 2020207873 24 Jul 2020

811 d Amp

80 70 60 50 40 30 20 10 2020207873

809 80 70 60 50

d 40 30 20 10

t 810 808

80 70 60 Depth (mm) 50 d 40 30 20 10

10

Fig. 15 20

30

Time (ms)

40

t 50

60

805 80

-50 -40 -30 -20 -10 10 20 30 40 50 0

811 = Amplitude 809 = phase delay 808 = elastic wave 805 = elastic wave indicator 810= homogeneity periodic propagation map ; transient propagation map ;

12 / 14

2020207873 24 Jul 2020

Depth (mm) 80 60 40 20 elastic waves the periodic propagation of

Good

Time (ms) 0 2020207873

20 168

Fig. 16

Depth (mm) 80 60 40 20

0 20 elastogram Correct Time (ms)

165 40

60

80

Depth (mm) 80 60 40 20 the periodic elastic waves propagation of Chaotic

Time (ms) 0 20 178

Depth (mm) Fig. 17 80 60 40 20

0 20 Time (ms)

elastogram Inoperable

40 175

13 / 14

60

2020207873 24 Jul 2020

validity; elastogram of prediction Good good detection of

untrained an for Transient elastography interpretation artifacts; easy Interpretation TM-mode :

Harmonic

Transient

operator

mode: difficult 2020207873

Depth (mm) Depth [mm] 80 70 60 50 40 20 10 Depth (mm) 30 80 70 60 50 40 30 20 10 80 60 50 30 20 70 40 10

Normal

185a

188a 182a OK OK OK

Depth (mm) 80 60 70 50 40 30 20 10 Depth (mm) 80 70 60 50 40 30 20 10

Depth (mm) 80 70 60 50 40 30 20 10

Vessel

185b

182b NOK NOK 188b

OK vessel vessel

Depth (mm) Depth (mm) Depth (mm) 80 60 40 10 70 50 30 20 80 70 60 50 40 30 20 10 80 70 60 50 40 30 20 10

Edges

185c

NOK 182c

188c NOK noise OK

Depth (mm) Depth (mm) Depth (mm) interposition Liquid 80 70 60 50 30 80 70 60 50 40 30 20 10 40 20 10 80 70 60 50 40 30 20 10

185d

NOK 182d

OK noise 188d NOK

185e Depth (mm) Depth (mm) Depth (mm) Air interposition 80 70 60 50 40 20 10 80 70 60 50 40 30 20 10 80 70 60 50 40 30 20 10 30

14 / 14

Fig. 18

NOK 182e artefact

188e NOK noise OK