WO2023002227A1

WO2023002227A1 - Methods and systems for modifying elasticity properties of a target in a soft material

Info

Publication number: WO2023002227A1
Application number: PCT/IB2021/000503
Authority: WO
Inventors: Cyril Lafon; Stefan Catheline; Gilles Thuret; Maxime LAFOND; Philippe Gain
Original assignee: Institut National De La Sante Et De La Recherche Medicale (Inserm); Centre Leo Berard; Universite Claude Bernard Lyon 1 (Ucbl); Universite Jean Monnet Saint Etienne; Centre Hospitalier Universitaire De Saint Etienne
Priority date: 2021-07-19
Filing date: 2021-07-19
Publication date: 2023-01-26

Abstract

The invention relates to a method for modifying elasticity properties of a soft material using ultrasound waves. The invention is particularly applicable to the human eye for the treatment of presbyopia by non-invasively modifying the stiffness of the crystalline lens. Ultrasound pulses generated with an ultrasonic transducer, such as a HIFU transducer, are focused on a target region of the material. The ultrasound pulses create cavitation bubbles in the target region, thus reducing the stiffness of the material.

Description

METHODS AND SYSTEMS FOR MODIFYING ELASTICITY PROPERTIES OF A

TARGET IN A SOFT MATERIAL

TECHNICAL FIELD

The present invention relates to a method for modifying elasticity properties of a target in a soft material.

BACKGROUND

Presbyopia is a condition resulting from a deterioration of the crystalline lens of the eye due to ageing, resulting in decreased visual abilities and especially a decrease in accommodation abilities. Essentially, presbyopia can be attributed to changes in mechanical properties of the crystalline lens, such as decreased elasticity and increased stiffness. More specifically, presbyopia is caused by an increase in the stiffness of the lens nucleus.

Due to the prevalence of presbyopia in the population, there is a considerable interest in identifying solutions for treating or mitigating the effect of presbyopia in the human eye.

Some current solutions involve modifying mechanical properties of the lens of the eye by surgery, such as refractive surgery or laser-based surgery. However, these surgeries are invasive and may have adverse side effects.

Furthermore, these methods only compensate for the consequences of presbyopia and do not cure the underlying condition. Thus, these solutions may have a limited efficiency as the crystalline lens deteriorates further due to continuous ageing of the subject.

There is therefore a need for a non-invasive solution for mitigating the effects of presbyopia and more particularly for modifying the elasticity of the crystalline lens-and more specifically its nucleus.

More generally, there is a need for non-invasive systems and methods for modifying elasticity properties of a target in a soft material.

SUMMARY

An object of the present invention is therefore to provide a method for modifying elasticity properties of a target in a soft material, wherein the method comprises: identifying, using an elasticity measurement device, at least one target region in a material, such as a soft material, said target having an elasticity higher than a predefined threshold, delivering at least one focused ultrasound pulse on said target region of the soft material, using at least one ultrasonic transducer, in order to generate cavitation bubbles in said target region.

According to advantageous optional aspects, alternative embodiments of the invention may comprise one or more of the following features, taken alone or according to all possible technical combinations:

- A plurality of focused ultrasound pulses are emitted and the pulses are repeated with a pulse repetition frequency comprised between 1 Hz and 1000 Hz

- The ultrasound pulses are emitted in the soft material with a peak negative pressure comprised between 6 MPa and 30 MPa.

The ultrasound pulses have a frequency comprised between 0.1 MHz and 3 MHz.

- The pulses are grouped in a plurality of emission cycles.

- The emission cycles have a duration between 2me and 10Ome.

- The ultrasonic transducer is a therapeutic ultrasonic transducer or an apparatus that focuses ultrasonic waves.

- The method further comprises, during and/or after delivering the sequence of ultrasound pulses, a step of measuring at least one elasticity value of said at least one target region, using an elasticity measurement device.

- The elasticity measurement device is either an acoustical or an optical elastography measurement device.

According to another aspect, the invention relates to a method for treating presbyopia in at least one eye of a subject. The method is as previously described. The material is a crystalline lens of a subject. The target is a region of the soft material having a stiffness higher than a specified threshold.

According to another aspect, the invention relates to a system comprising an ultrasonic transducer and an elasticity measurement device, wherein the system is configured to: identify, using an elasticity measurement device, at least one target region in a material, such a soft material, said target having an elasticity higher than a predefined threshold, deliver at least one focused ultrasound pulse on said target region of the soft material, using at least one ultrasonic transducer, in order to generate cavitation bubbles in said target region.

BRIEF DESCRIPTION OF THE DRAWINGS The invention will be understood upon reading the following description, provided solely as an example, and made in reference to the appended drawings, in which:

Fig. 1 is a schematic diagram of an ultrasound emission system comprising an ultrasound transducer according to embodiments of the invention.

Fig. 2 is a simplified flow chart of a method for modifying the stiffness of a target material in a soft material according to embodiments of the invention.

Fig. 3 illustrates an exemplary excitation signal for driving the ultrasound transducer of Figure 1 during the method of Figure 2.

Fig. 4 illustrates a comparison of the image produced by a B-mode ultrasound scanner of a soft material (porcine ocular globe) (A) before application of the ultrasound signal and (B) during application of the ultrasound signal.

DESCRIPTION OF SOME EMBODIMENTS

Figure 1 illustrates a system 2 for modifying at least one elasticity property of a target in a material 4, 6, such as a soft material, although the invention is applicable to non-soft materials.

In some embodiments, the soft material 4, 6 may be a biological tissue.

In the illustrated example, the soft material may be a crystalline lens 6 of an eye 4, such as an eye of a living subject, for example a human eye. In that case, the target may correspond to a specific region of the lens 6.

For example, the target region comprises the nucleus of the crystalline lens, or at least part of the nucleus.

The system 2 is thus capable of modifying at least one elasticity property, such as a stiffness property or elasticity property, of the crystalline lens 6 at the target location.

Of course, many other alternative embodiments are possible. For example, the material may be a food item, or a synthetic soft material, these examples being not limiting.

In the illustrated embodiment, the system 2 comprises an ultrasound emission system and, optionally, a measurement system for measuring at least one elasticity property of a material, such as stiffness or elasticity.

The ultrasound emission system comprises an ultrasonic probe 10, driving circuitry 12 connected the ultrasonic probe 10, and an electronic control unit 14 connected to the driving circuitry 12.

The ultrasonic probe 10 comprises one or more ultrasonic transducers, for example configured to generate ultrasound waves upon receiving an excitation electrical signal from the driving circuitry 12. In some embodiments, the ultrasonic transducers comprise at least one therapeutic ultrasonic transducer or an apparatus that focuses ultrasonic waves.

The ultrasonic transducer(s) can be housed inside a probe body, for example inside a casing made of a plastic material.

The driving circuitry 12 is configured to generate excitation signals to activate one or several ultrasonic transducers.

For example, the driving circuitry 12 may comprise signal processing circuitry such as amplifiers, or signal generators, or the like. The driving circuitry 12 may also comprise a power supply unit and/or power conversion devices.

The driving circuitry 12 may be connected to the ultrasonic probe 10 by means of one or more cables. In some embodiments, the driving circuitry 12 can be housed inside the probe body. In that case, the ultrasound probe can be directly connected to the electronic control unit 14.

The electronic control unit 14 is configured to control the operation of the ultrasound emission system. For example, the electronic control unit 14 may comprise a processor and a computer memory.

In many embodiments, the computer memory stores computer code and/or executable instructions for causing the processor and the electronic control unit 14 to execute a method for controlling the ultrasound transducer 10 when such computer code and/or executable instructions are executed by the processor.

As used herein, the term "processor" refers not only to electronic controller devices including a processor or a microprocessor, but also to other equivalent elements such as programmable logic controllers (PLC), application-specific integrated (ASIC) circuits, field- programmable gate array (FGPA) circuits, logic circuits, analog circuitry, equivalents thereof, and any other circuit or processor capable of executing the functions described herein.

The electronic control unit 14 may further include a user interface. The user interface may comprise one or more interface elements, such as a graphical display, a wireless interface to allow remote control and/or exchange of data with a mobile terminal, data input means such as a keyboard, a mouse, a pointer device, a touch-sensitive screen, or any equivalent interface element, or any combination of such interface elements.

In the illustrated embodiment, the electronic control unit 14 is a computer.

The electronic control unit 14 also comprises a first input/output interface for connecting the driving circuitry 12. The electronic control unit 14 may be connected to the driving circuitry 12 by means of one or more cables, or through a wireless link, such as a radiofrequency link.

In the illustrated embodiment, the elasticity measurement device comprises a measurement probe 20 and processing circuitry 22.

The measurement probe 20 is configured to measure at least one elasticity property of the soft material at the target location, preferably in a non-invasive way.

In preferred embodiments, the elasticity measurement device is an elastography measurement device, such as an optical elastography measurement device. For example, the measurement system is an optical coherence tomography measurement system.

In some alternative embodiments, the elasticity measurement device may be an acoustic elastography device configured to use an ultrasound elastography technique.

The processing circuitry 22 is configured to process measurement signals received from one or more sensing portions of the measurement probe 20. The processing circuitry 22 is connected to an output port of the probe 20.

In this example, the processing circuitry 22 is also connected to a second input/output interface of the electronic control unit 14, in order to be controlled by the electronic control unit 14.

The elasticity measurement device is more particularly able to identify at least one target region in a soft material, said target having an elasticity higher than a predefined threshold.

Operation of the system 2 will now be explained in reference to figures 2, 3 and 4.

Figure 2 illustrates an exemplary method for modifying at least one elasticity property in the material 4, 6, such as stiffness.

This method is illustrated with an example when the soft material a lens 6 of an eye 4. The description that follows will be made in reference to a lens 6 of an eye 4, but the steps could be generalized to any other material or soft material in alternative embodiments.

Initially, the material 4, 6 is provided and the system 2 is set up and positioned to be able to target the material 4, 6. In the case of an eye 4, the probe 10 may be aligned with a front facing region of the eye 4.

First, at a step 100, the measurement probe 20 of the measurement system is used to identify at least one target region in the target soft material 4, 6.

For example, the target region is defined as a region or volume of the material in which the material has a mechanical property, such as the Young modulus, higher than a predefined threshold. In other words, the regions of the lens 6 of the eye 4 having excessive stiffness are identified and marked for treatment. In what follows, the target region and the material comprised in the target region may be simply referred to as “target”.

At step 102, an excitation signal is generated by the driving circuitry 12.

For example, the excitation signal is an electrical signal.

In some embodiments, the excitation signal may be generated by the driving circuitry 12 based on measured properties of the target material.

Then, at step 104, ultrasound waves are emitted by the emission system 2 and one or more ultrasound pulses focused on said target region of the soft material are emitted.

For example, a suitable excitation signal is generated by the driving circuitry 12 and sent to the ultrasound probe 10. Then, ultrasound waves focused on the target region are generated by the transducers of the ultrasound probe 10.

In some examples, if several ultrasound pulses are emitted, then the ultrasound pulses can be grouped in a plurality of emission cycles. The emission cycles can have a predefined duration and periodicity. Two immediately consecutive emission cycles being separated by a time period during which no ultrasound pulse is emitted.

The steps 102 and 104 may be repeated for each target region identified during step

100.

In some embodiments, if the configuration of the ultrasound probe 10 allows it, several zones may be treated simultaneously, for example if their elasticity properties are similar and/or if the estimated ultrasound dose required to reduce their stiffness is similar or identical.

In practice, during and/or after step 104, the ultrasound waves interact with the target material and create mechanical vibrations, resulting in the creation of inertial cavitation bubbles. This in turn reduces the stiffness and increase the elasticity of the material by destroying or at least altering at least some of the material by cavitation.

For example, in the case of presbyopia, the hardening of the crystalline lens can be attributed to the accumulation of clusters of certain proteins (so-called crystalline proteins). The mechanical vibrations caused by the ultrasound pulses in the target material, and especially the microscopic cavitation bubbles resulting from these interactions, disrupt and/or dissolve the accumulated clusters or proteins, thus at least partially restoring some of the original elasticity of the crystalline lens.

Additionally, in at least some cases, the cavitation may lead to the diffusion of antioxidant agent that can contribute to restore at least in part the elasticity of the crystalline lens.

Thus, presbyopia can be treated, or at least mitigated, by non-invasive means, without requiring invasive interventions such as surgery. The method preferentially targets only the regions of the soft material having an excessive stiffness, leaving other regions untouched, thus avoiding unnecessary damage to other regions having an acceptable elasticity or stiffness value.

Optionally, during a step 106, during and/or after delivering the sequence of ultrasound pulses, at least one elasticity value of said at least one target region is measured using the elasticity measurement device 20, 22.

This allows to detect if the stiffness of the target regions has been successfully modified after steps 102 and 104. This also allows to identify if damage has been accidentally caused outside of the target regions.

Preferably, step 106 is implemented by the measurement system 20, 22. However, in some embodiments, another measurement system could be used, such as a passive ultrasound elastography measurement device.

It is to be noted that, in many alternative embodiments, the method steps described above could be executed in a different order. One or more method steps could be omitted or replaced by equivalent steps. One or more method steps could be combined or dissociated into different method steps. The disclosed exemplary embodiment is not intended to be limiting and does not prevent other methods steps to be executed without departing from the scope of the claimed subject matter.

Figure 3 illustrates an example of the excitation signal used to generate the ultrasound pulses during steps 102 and 104, plotting the amplitude of the pulses (on the y-axis, said amplitude being expressed in arbitrary units for illustrative purposes) as a function of time (x-axis).

In the illustrated example, the excitation signal 30 comprises a plurality of pulses 32, such as electrical voltage pulses.

Preferably, the ultrasound pulses are identical or at least similar (for example in terms of amplitude or duration).

In some preferred embodiments, the ultrasound pulses are emitted periodically (e.g., emitted periodically at least during each emission cycle). For example, the ultrasound pulses may be repeated with a repetition frequency comprised between 1 Hz and 1000 Hz, although other values are nonetheless possible.

In some examples, the emitted ultrasound pulses are grouped in a plurality of emission cycles. The emission cycles themselves may be repeated periodically.

For example, each ultrasound pulse may have a duration of at least 2 microsecond (ps), or more.

However, preferably, the duration of each cycle is lower than 100 microseconds. In some embodiments, the number of emission cycles used to treat a target region is higher than one, or higher than five, and preferably lower than 100.

Preferably, the ultrasound pulses are high intensity focused ultrasounds and have a frequency comprised between 0.1 MHz and 3 MHz and preferably comprised between 0.5 MHz and 3MHz.

In many embodiments, the ultrasound pulses are emitted in the soft material with a negative pressure comprised between 6MPa and 30 MPa and preferably between 10 MPa and 26 MPa.

The respective values of the parameters may be chosen differently for different target regions, depending on the stiffness level.

These specific parameter value and pulse properties are chosen to deliver enough energy to the target region in order to generate cavitation bubbles responsible for the stiffness reduction and restoration of elasticity in the target region of the material.

However, these values prevent ultrasound from creating thermal lesions in the target regions.

For example, in embodiments where the soft material is a lens 6 of an eye 4, as such thermal lesions could have adverse consequence on the optical properties of the lens 6, such as increasing its opacity.

In other words, the modification of the at least one elasticity property of the target material is essentially due to mechanical interactions between ultrasound and the target material, and not by thermal interactions, such as locally heating the target material with ultrasounds.

Figure 4 shows two ultrasound images (A) and (B) illustrating the occurrence of cavitation in a soft material.

For example, the ultrasound images are produced by a B-mode ultrasound scanner.

The ultrasound image recorded before the application of high intensity pulsed ultrasound does not show hyperechogenicity in the target (A). A bubble cloud can be generated in the target when applying described pulsed ultrasound (B).

In the illustrated example, the material 6 is a pig eye harvested less than 24 hours prior to the experiment immersed in room temperature degassed water.

The reference sign “40” designates the porcine eye lens corresponding to the targeted soft material. The reference sign “42” points to the ultrasound probe 10 used in this experiment.

On the inset B, a cavitation cloud comprising a plurality of microscopic cavitation bubbles appearing within the eye lens, illustrating that the cavitation bubbles can be generated at a deep enough focal depth, and stay spatially restricted within the lens. Many other embodiments are possible.

The embodiments and alternatives described above may be combined with each other in order to create new embodiments of the invention, within the scope of the claims.

Claims

1. A method for modifying elasticity properties of a target (6) in a soft material, wherein the method comprises:

Identifying (100), using an elasticity measurement device (20, 22), at least one target region (6) in a material (4), such as a soft material, said target having an elasticity higher than a predefined threshold, delivering (102) at least one focused ultrasound pulse on said target region of the soft material, using at least one ultrasonic transducer (10), in order to generate cavitation bubbles in said target region.

2. The method of claim 1 , wherein a plurality of focused ultrasound pulses are emitted and the ultrasound pulses (30) are repeated with a pulse repetition frequency comprised between 1 Hz and 1000 Hz.

3. The method according to any one of previous claims, wherein the ultrasound pulses are emitted in the soft material with a negative pressure comprised between 6 MPa and 30 MPa.

4. The method according to any one of previous claims, wherein the ultrasound pulses (30) have a frequency comprised between 0.1 MHz and 3 MHz.

5. The method according to any one of the previous claims, wherein the ultrasound pulses (30) are grouped in a plurality of emission cycles.

6. The method according to the previous claim, wherein the emission cycles have a duration between 2 microseconds and 100 microseconds.

7. The method according to any one of previous claims, wherein the ultrasonic transducer is a therapeutic ultrasonic transducer or an apparatus that focuses ultrasonic waves.

8. The method according to any one of the previous claims, wherein the method further comprises, during and/or after delivering the sequence of ultrasound pulses, measuring (106) at least one elasticity value of said at least one target region, using the elasticity measurement device. 9 The method according to any one of the previous claims, wherein the elasticity measurement device (20, 22) is an optical or acoustical elastography measurement device. 10. A method for treating presbyopia in at least one eye of a subject, wherein the method is according to anyone of the previous claims, and wherein the material is a lens (6) of an eye (4) of a subject, and wherein the target is a region of the soft material having a stiffness higher than a specified threshold. 11. A system (2) for modifying elasticity properties of a target (6) in a soft material, said system comprising an ultrasonic transducer (10) and an elasticity measurement device (20), wherein the system is configured to: identify (100), using an elasticity measurement device (20, 22), at least one target region (6) in a material (4), such as a soft material, said target having a stiffness higher than a predefined threshold, deliver (102) at least one focused ultrasound pulse on said target region of the soft material, using at least one ultrasonic transducer (10), in order to generate cavitation bubbles in said target region.