FIELD OF THE INVENTION

The present invention pertains to methods for focusing ultrasonic wave fields.

The wave field in question can consist of a wave pulse focused at one or more points of the medium, or it may involve a more complex spatio-temporal field.

More particularly, the invention relates to a method for focusing an ultrasonic wave field in a medium by an array of several transducers, said method including at least :

(a) an emission step in which a first ultrasonic wave field is transmitted in the medium and scattered by scatterers in said medium, which transmit a scattered wave to said transducer array,

(b) a capture step in which the transducers i of the transducer array capture respective scattered signals S ₁ (t) generated by said scattered wave; (c) a focusing step in which each transducer i of the transducer array emits an emission signal e _x (t) which corresponds to a time reversal of a signature signal S ₁ (t) obtained from the scattered signal S ₁ (t) received by said transducer i, to create a focused ultrasonic wave field in the medium. It should be noted that the time reversal mentioned above my consist in a direct computation of S ₁ (- t) in the time domain, or in a more narrow-band treatment such as phase conjugation or delay modification applied to S ₁ U) . This technique of time reversal enables to focus precisely the second ultrasonic wave on the scatterers in the medium. Of course, the method may involve repeating steps (b) and (c) , in which case the focused ultrasonic wave field of step (c) is backscattered to the transducers so that a new scattered signal S ₁ (t) is captured and used to generate the subsequent signals e _x (t) at the next step (c) to build a more and more precisely focused ultrasonic wave field.

BACKGROUND OF THE INVENTION Pernot at al . [Applied Physics Letters 88, 034102,

2006] disclosed an example of such a method, m which a bubble is generated m the medium by cavitation in order to voluntarily create a scatterer in the medium at a place where the ultrasonic wave field should be focused during the focusing step (c) , thus enabling an efficient focusing of the second ultrasonic wave on said position.

However, the technique proposed by Pernot et al . supposes that one knows m advance at what position (s) the second ultrasonic wave field should be focused, which is not always the case. As a matter of fact, m some cases, the ideal position of the focusing zone(s) is determined by intrinsic parameters of the medium (such as local chemical composition, local biological parameters, etc.) which are not known m advance . OBJECTS AND SUMMARY OF THE INVENTION

The present invention is aimed in particular at proposing a new focusing method in which one could efficiently focus the second ultrasonic wave field on focal zones which are not necessarily known in advance and which are determined by intrinsic parameters of the medium.

To this end, according to the invention, a method of the type in question is characterized m that, at least before said emission step (a) , a targeted ultrasonic contrast agent is added to the medium, said targeted ultrasonic contrast agent being adapted to concentrate in areas of the medium having predetermined intrinsic characteristics (i.e. which contain particular molecules and / or have a particular physiology) .

Thanks to these dispositions, it may be possible to focus the second ultrasonic field very precisely on an area of interest which is not necessarily known in advance.

The focused ultrasonic field can then be used for instance for imaging purposes, or for treatment purposes, or else. In preferred embodiments of the invention, recourse may possibly be had moreover to one and/or other of the following arrangements: the signature signal Si (t) is equal to the scattered signal si(t) ; - the signature signal Si (t) is obtained by combining several scattered signals si(t) received by the transducer i from the medium, using any kind of linear or non linear combination of the signals; the method further includes: (a') an additional emission step in which said first ultrasonic wave field is transmitted in the medium without targeted ultrasonic contrast agent present in the medium, said first ultrasonic wave field being scattered by scatterers in said medium, which transmit a reference scattered wave to said transducer array,

(b' ) an additional capture step in which the transducers i of the transducer array capture respective reference scattered signals sθi(t) generated by said reference scattered wave, and during the focusing step (c) , the signature signal Si(t) is based on a difference between said scattered signal Sj _. (t) and said reference scattered signal sθi(t) ; the targeted ultrasonic contrast agent present in the medium is eliminated after said capture step (b) (for instance, the ultrasonic contrast agent may be disrupted by an ultrasonic pulse, or else) and wherein said additional emission step (a' ) is carried out after said capture step (b) ; the signature signal Sj _. (t) is obtained by a detection method chosen in the group consisting of harmonics filtering, pulse inversion sequences, disruption sequences, amplitude modulation, radial modulation and other methods using nonlinear behavior of the ultrasonic contrast agent ; - the capturing and focusing steps (b) and (c) are repeated iteratively, the scattered signals Si(t) which are captured at said capture step being generated by ultrasonic waves scattered from the focused ultrasonic wave field obtained at step (c) ; - the targeted ultrasonic contrast agent which is added to the medium comprises a linking material adapted to enable retention by a specific chemical or physiological environment ; said linking material is chosen in the group consisting of ligands, antibodies, toxins or passive targeting materials; the ultrasonic contrast agent which is not retained in the medium by said linking material is eliminated before the emission step (a) ; - the targeted ultrasonic contrast agent which is added to the medium is chosen in the group consisting of: encapsulated microbubbles including a shell filled with gas, the shell including said linking material , - liquid droplets, and solid particles; the focused ultrasonic wave field is used in a medical treatment to perform hyperthermia, cavitation, sonoporation or sonothrombolysis; - the targeted ultrasonic contrast agent is imaged

(e.g. by ultrasonic imaging or MRI imaging, or else) ; at the focusing step (c) , time-reversal is performed by modifying at least one of the phase and the delay of the signature signal; - the signature signal is decomposed in a set of elementary signature signals corresponding respectively to focusing beams in different areas of the medium containing said targeted ultrasonic contrast agent, to increase antenna gain. BRIEF DESCRIPTION OF THE DRAWINGS

Other characteristics and advantages of the invention will become apparent in the course of the following description of one of its embodiments, given by way of non limiting example, with regard to the appended drawings.

In the drawings :

Fig. 1 is a basic diagram representing an exemplary device allowing implementation of the invention;

Fig. 2 is a repartition of areas of microbubbles in a medium, in an example of use of the invention;

Fig. 3 is an image of the medium in the example of Fig. 2, showing the pressure distribution of the ultrasonic wave field emitted in the medium before performing the method of the invention; - Fig. 4 is a view similar to Fig. 3, showing the pressure distribution of the focused ultrasonic wave field emitted in the medium during the focusing step of the method of the invention.

MORE DETAILED DESCRIPTION Figure 1 shows a device for implementing the invention, for instance for the purpose of imaging or treatment of a specific target area 2 in a medium 1. The medium 1 can be part of a human or animal body, or can be any other biological or physico-chemical medium. The target area 2 may be for instance an area of the medium suffering from an illness in the case of he human or animal body, or any other singular area of the medium in the general case.

In the present method, the area 2 is evidenced by a targeted ultrasonic contrast agent which may be added to the medium 1 (e.g. by injection) before the method is performed. Such targeted ultrasonic contrast agents are known in the art [see for instance Dayton et al . , Frontiers in Bioscience 12, 5124-5142, September 1, 2007] , and may be chosen among : - encapsulated microbubbles including a shell filled with gas, liquid droplets (which may be encapsulated in a shell too) , and solid particles. The targeted ultrasonic contrast agent is adapted to concentrate in areas of the medium having predetermined intrinsic characteristics, i.e. which contain particular molecules and / or have a particular physiology. More specifically, the targeted ultrasonic contrast agent may comprise a linking material adapted to enable retention by a specific chemical or physiological environment.

This linking material may be adapted to perform active targeting, i.e. to create a chemical bond with specific molecules in the medium (then, the linking material may be for instance a ligand, an antibody or a toxin) , or the linking material may be a passive targeting material adapted to concentrate in specific areas of the medium by physiological effects.

In the present case, the targeted ultrasonic contrast agent may be in the form of encapsulated microbubbles 3 of a few micrometers in diameter, including said linking material on their outer shell.

The ultrasonic contrast agent which is not retained in the medium by said linking material may be eliminated before the method is performed, e.g. by a natural flow of liquid such as blood or lymph in the case of the human or natural body.

The device of Figure 1 comprises an array 4 of ultrasonic transducers 5, which may be for instance a linear echographic array including for instance a few tens of transducers (e.g. 128, or else) . The array 5 might also include several sub-arrays, and / or have a more complex form.

The transducers 5 of the array 4 may be controlled individually by a central processing unit 6 (CPU) , comprising for instance a micro-computer and / or specific electronic circuits, as already known m the art.

The focusing method of the invention is performed by this device, as follows: (a) in an initial emission step, a first ultrasonic wave field is transmitted in the medium and scattered by scatterers in said medium, which transmit a scattered wave to said transducer array (this first ultrasonic wave field may be either unfocused, or already focused) , (b) in a capture step, the transducers i of the transducer array capture respective scattered signals S ₁ (t) generated by said scattered wave;

(c) and in a focusing step, each transducer i of the transducer array emits an emission signal e _α (t) which is correspond to a time reversal of a signature signal S ₁ (t) obtained from the scattered signal S ₁ (t) received by said transducer i, to create a focused ultrasonic wave field in the medium (e _x (t) =S _X (-t) or may be proportional to S ₁ (-a. t) where a is a positive constant) . At the focusing step (c) , time-reversal may be performed for instance by a pressure-release mirror. More generally, the time reversal may be performed by directly computing S ₁ (-t) m the time domain or by more narrow-band methods such as by modifying the phase of the signature signal (m particular by phase conjugating the signature signal) and/or the delay of the signature signal, or else.

The signature signal S ₁ (t) may be equal to the scattered signal S ₁ (t) (m which case the emitted signal is βj. (t) =s _x ( -t) ) , or the signature signal S ₁ (t) may be obtained by filtering said scattered signal S ₁ (t) to select at least one harmonic of the central frequency of the transducers, which enables to efficiently select the scattered signals coming from the ultrasonic contrast agent .

In a variant, the signature signal may be obtained by combining (linearly or nonlmearly) several scattered signals S ₁ (t) received by the transducer i from the medium. In particular, the method may further include:

(a') an additional emission step in which said first ultrasonic wave field is transmitted in the medium without targeted ultrasonic contrast agent present in the medium, said first ultrasonic wave field being scattered by scatterers in said medium, which transmit a reference scattered wave to said transducer array,

(b' ) an additional capture step in which the transducers i of the transducer array capture respective reference scattered signals SO ₁ (t) generated by said reference scattered wave, and during the focusing step (c) , the signature signal S ₁ (t) is based on a difference between said scattered signal S ₁ (t) and said reference scattered signal SO ₁ (t) (the signature signal may be equal to this difference S ₁ Ct)- SO ₁ Ct), or be obtained by filtering this difference S ₁ Ct)- SO ₁ Ct) to select harmonics of the central emission frequency, as explained above) . The additional steps (a' ) and (b' ) may be performed before step (a) , and before the ultrasonic contrast agent is added to the medium. Alternately, these additional steps could be performed after elimination (e.g. after destruction) of the microbubbles, after steps (a) and (b) . More generally, the signature signal S ₁ Ct) can be obtained by any detection method known for detecting ultrasonic contrast agents in the field of ultrasound imaging, for instance harmonics filtering, pulse inversion sequences, disruption sequences, amplitude modulation, radial modulation and other methods using nonlinear behavior of the ultrasonic contrast agent.

In another variant, the capturing and focusing steps (b) and (c) are repeated iteratively, the scattered signals S ₁ (t) which are captured at said capture step being generated by ultrasonic waves scattered from the focused ultrasonic wave field obtained at step (c) : a more and more precise focusing can thus be obtained.

In still another variant, the signature signal may be decomposed in a set of elementary signature signals corresponding respectively to different areas of the medium containing said targeted ultrasonic contrast agent, to increase antenna gain.

After performing the above process, focused ultrasonic wave field may be used for instance in a medical treatment to perform hyperthermia, cavitation, sonoporation or sonothrombolysis , when the medium 1 is the human or animal body.

During and after the above focusing process, the targeted ultrasonic contrast agent may be followed by imaging (e.g. ultrasonic imaging or MRI imaging, or else) .

One example of use of the method of the invention will now be decribed. In this example, droplets of avidinated-microbubbles were deposited on an agar gel covered with biotinylated gelatin. Disks, 2.5 mm in diameter, with high surface density of microbubbles were obtained. The agar gel was then immersed in a water tank equipped with 80 "HIFU" [High Intensity Focused Ultrasound] transducers fully programmable in both emission and reception. The dots of microbubbles were placed within 2 cm of the geometrical focus of the transducer array. A low- amplitude pulse was sent through the medium and the echoes from the different structures in its path were recorded by the array in a first set of RF data (radio- frequency data, i.e. the raw temporal data captured by each transducer) . A high-intensity pulse was then emitted by the array to disrupt all the bubbles on the surface of the gel . A second low-amplitude acquisition was performed and this bubble- less signal was subtracted from the first set of RF data for all the elements of array. The resulting subtraction was considered to be the signal from the targeted microbubbles, which was then time-reversed, amplified, elongated (to lOOus) and reemitted by the transducer array. The resulting increase in temperature at each point was observed using a thermosensitive gel . Pressure at each point was also measured by scanning a hydrophone. The pattern of thermal therapy was then compared to the distribution of microbubbles on the surface as observed by an optical camera.

Figure 2 shows the two dots of microbubbles on the gelatin surface. They were slightly off the geometric center of the HIFU array. On a typical low-amplitude RF acquisition, the signal from the microbubbles represented 14% of the total signal from the surface of the gel and could easily be segmented. When the time-reversed HIFU pulses were emitted, the thermosensitive paper showed a temperature- increase corresponding to the original pattern formed by the microbubbles. As a control, when simultaneous pulses were sent through all the transducers, the pattern of the geometric focus of the array was obtained on the thermosensitive paper. The resulting pressure distributions for the control and the time-reversal experiment as measured by the hydrophone are shown in Fig.3 and Fig.4, respectively. In Fig.4, the two dots representing the higher pressures are concomitant with the placement of the microbubbles dots.