Bone healing system and method

Abstract

There is provided the use of ultrasound for treating a calcified or ossified tissue by creating cavities into the calcified or ossified tissue and / or by inducing erosion, thinning, weakening, or structural modification of the tissue, such as a subchondral bone. Such use provides an improvement in the treatment of bone diseases such as subchondral bone disease, by enabling a particularly less invasive treatment.

Description

BONE HEALING SYSTEM AND METHODCROSS-REFERENCE TO A RELATED APPLICATION

[0001] This disclosure claims priority from U.S. provisional application number 63 / 753,585 filed February 4, 2025, which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] This disclosure relates to the field of bone treatment, particularly systems and methods of inducing structural-morphological changes that facilitate vascular infiltration, allowing blood vessels to access necrotic bone, restore blood circulation, and stimulate bone repair processes, thereby promoting bone tissue formation.BACKGROUND OF THE ART

[0003] Subchondral bone diseases represent a diverse group of conditions affecting the layer of bone beneath joint cartilage. The subchondral bone plays a pivotal role in joint health, providing structural support and participating in the dynamic processes of load-bearing and shock absorption. Various pathologies can disrupt the delicate balance within the subchondral bone, leading to functional impairment and pain. These pathologies affect both pediatrics and adult patients, and unfortunately, no effective curative treatment exists today. For example, osteoarthritis, the most common degenerative joint disease, involves changes in the subchondral bone known as bone marrow lesion (BML) (excess fluid accumulation in the bone marrow). The natural history of BML is to progress in symptomatic osteoarthritis with cartilage degeneration. Currently, the only available treatment for BML is subchondroplasty (injection of cement in the BML) and no long-term efficacy data is available for this invasive procedure. BML could be treated with microfracturing to offer targeted approaches to alleviate symptoms, promote bone healing and prevent cartilage degeneration. Osteonecrosis, characterized by the loss of blood supply to bone tissue, can lead to subchondral bone collapse. Microfracture or drilling interventions are employed to promote blood flow and stimulate the formation of reparative tissue. These procedures aim to create controlled micro injuries, triggering the release of growth factors, and stimulating the migration of cells for optimal tissue repair. Microfracture and drilling are the only available procedures in the management of subchondral disease conditions, and treatment decisions are tailored to the specific characteristics of each patient's condition, guided by medical professionals for optimal outcomes. This treatment is invasive, requires a significant number of resources to perform (operating room setup) and its efficacy is low. Accordingly, improvementsare desired in the treatment of subchondral bone disease, particularly less invasive treatment would be advantageous.SUMMARY

[0004] In one aspect, there is provided the use of ultrasound for treating a calcified or ossified tissue by creating cavities and / or eroding into the calcified or ossified tissue. In some embodiments, the ultrasound is used for inducing erosion, thinning, weakening, or structural disruption of the calcified or ossified tissue. The calcified or ossified tissue is, for example, in a subchondral bone, such as a bone marrow lesion, or can be osteochondritis dissecans, subchondral insufficiency fractures, or avascular necrosis. The ultrasound is preferably a high-intensity focused ultrasound (HIFU). Generally, the ultrasound can operate at a frequency between 0.1 MHz and 100 MHz. In some embodiments, the cavities have a size between 1 nm and 2 mm.

[0005] Accordingly, in one aspect, there is also provided a method of treating a calcified or ossified tissue in a subject in need thereof, the method comprising: applying ultrasound on the ossified or calcified tissue to create erosion or cavities in the ossified or calcified tissue; to promote healing of the ossified or calcified tissue by increasing or restoring blood flow. In some embodiments, the ultrasound is a high-intensity focused ultrasound (HIFU). The ultrasound can operate at a frequency between 0.1 MHz and 2 MHz and at a duty cycle above 10%, at a frequency between 0.1 MHz and 2.5 MHz and at a duty cycle below 10%, and preferably below 1%, or at a frequency between 1 MHz and 10 MHz and at a duty cycle above 10%, and preferably between 10% and 50%. The method can be a non-invasive method. The ossified or calcified tissue is for example in a subchondral bone. In some embodiments, the cavities have a size between 1 nm and 2 mm.

[0006] In a further aspect, there is provided an ultrasound system comprising an ultrasound transducer comprising a radiating surface formed by one or a plurality of radiating elements, a transducer power output comprising a plurality of radiofrequency drive amplifiers, the plurality of radiofrequency drive amplifiers configured to generate power for driving the plurality of radiating elements to generate a plurality of ultrasound waves, and a coupling member configured to apply the plurality of ultrasound waves to a calcified or ossified tissue to create a plurality of cavities therein.

[0007] In some embodiments, the radiating surface is flat, and the plurality of radiating elements generate unfocused ultrasound waves.

[0008] In some embodiments, the radiating surface is concave, and the plurality of radiating elements generate focused ultrasound waves. In some embodiments, the plurality of radiating elements comprise a plurality of piezoelectric elements arranged in a vertical stack. In some embodiments, the plurality of radiating elements comprise a plurality of piezoelectric elements arranged in at least one two-dimensional array. In some embodiments, the plurality of piezoelectric elements resonates at a frequency between 0.02 MHz and 5.0 MHz, preferably between 0.1 MHz and 2.0 MHz.

[0009] In some embodiments, the radiating surface has a radius of curvature between 10 millimeters and 1000 millimeters, preferably between 100 millimeters and 300 millimeters.

[0010] In some embodiments, the ultrasound transducer has a geometric focus spaced from the radiating surface by a distance between 10 millimeters and 100 millimeters. In some embodiments, the geometric focus has a focal width ranging from below 1 millimeter to 10 millimeters, preferably from 0.3 millimeters to 5 millimeters, and a focal length ranging from 1 millimeter to 50 millimeters, preferably from 3 millimeters to 20 millimeters.

[0011] In some embodiments, the ultrasound transducer operates at a frequency between 0.1 MHz and 2 MHz and at a duty cycle above 10%.

[0012] In some embodiments, the ultrasound transducer operates at a frequency between 0.1 MHz and 2.5 MHz and at a duty cycle below 10%, and preferably below 1%.

[0013] In some embodiments, the ultrasound transducer operates at a frequency between 1 MHz and 10 MHz and at a duty cycle above 10%, and preferably between 10% and 50%.

[0014] In some embodiments, the ultrasound transducer is a high-intensity focused ultrasound (HIFU) transducer.

[0015] In some embodiments, the transducer power output is configured to control a focal steering of the plurality of radiating elements, further wherein the focal steering is at least one of radial and axial.

[0016] In some embodiments, the plurality of radiofrequency drive amplifiers is configured to generate electrical power ranging from 0 W to 50,000 W, preferably from 10 W to 500 W for a duty cycle above 10%, and from 500 W to 20,000 W for a duty cycle below 10%. In some embodiments, an ultrasound burst has a duration defined by the duty cycle and is followed by a silent time and the sum of the duration of the ultrasound burst and the silent time is between 2 nanoseconds to 30 seconds, preferably between 1 millisecond and 1 second. In some embodiments, the plurality of radiofrequency drive amplifiers is configured to generate one of continuous power and pulsed power up to a frequency of 10 MHz. In some embodiments, the plurality of radiating elements generates the plurality of ultrasound waves having an intensity level between 0 Wcnr2and 100 W cm2when the plurality of radiofrequency drive amplifiers generates the continuous power, and the intensity level of the plurality of ultrasound waves reaches 2000 W cm-2when the plurality of radiofrequency drive amplifiers generates the pulsed power at the duty cycle below 10%.

[0017] In some embodiments, the plurality of radiating elements generates the plurality of ultrasound waves to cause a pressure to be applied on the calcified or ossified tissue, the pressure ranging between 0 MPa and 200 MPa, preferably between 0.01 MPa and 50 MPa.

[0018] Many further features and combinations thereof concerning the present improvements will appear to those skilled in the art following a reading of the instant disclosure.DESCRIPTION OF THE DRAWINGS

[0019] In the figures,

[0020] FIG. 1A is a block diagram of a system for treating ossified or calcified tissue, in accordance with one embodiment.

[0021] FIG. 1B, FIG. 1C, and FIG. 1D are schematic diagrams of the ultrasound transducer of FIG. 1A, in accordance with one embodiment.

[0022] FIG. 2 is a microscopy image showing the main bone parameters measured.

[0023] FIG. 3 is a graph showing the bone surface density measurements in rat models.

[0024] FIG. 4 is a graph showing the trabecular number for the rat models.

[0025] FIG. 5 is a graph showing the trabecular thickness measurements for the rat models.

[0026] FIG.6 is a graph showing the trabecular separation measurements for the rat models.

[0027] FIG. 7 is a graph showing measurements of the ratio of bone surface volume (BS) to total volume of tissue (BS / TV) for femoral head blocks of pork bone models (***: p-value <0.001).

[0028] FIG. 8 is a graph showing trabecular thickness (Tb.Th) measurements for femoral head blocks of pork bone models (***: p-value <0.001).

[0029] FIG. 9 is a graph showing trabecular number (Tb.N) measurements for femoral head blocks of pork bone models (***: p-value <0.001).

[0030] FIG. 10 is a graph showing trabecular separation (Tb.Sp) measurements for femoral head blocks of pork bone models (***: p-value <0.001).

[0031] FIG. 11 is a graph showing connectivity density (Conn.Dn) measurements for femoral head blocks of pork bone models (***: p-value <0.001).

[0032] FIG. 12A and FIG. 12B show graphs of focused ultrasound (FU) remodels SB without thermal effects. Temperature monitoring at 0.1 and 5% duty cycle in water respectively.

[0033] It will be noted that throughout the appended drawings that like features are identified by like reference numerals.DETAILED DESCRIPTION

[0034] There is provided a method and system for treating ossified or calcified tissue by creating cavities in a non-invasive manner or minimally invasive manner. Specifically, ultrasound is used to create cavities, fractures, channels, holes or defects which may have any geometric shape, including but not limited to circular, elliptical, rectangular or irregular configurations with dimensions ranging from nanometers to millimeters. For example, the ultrasound can create cavities having a size ranging from 1 nm to 2 mm in the tissue or tissue erosion. The cavities created can also be considered micro or nano fractures, and they restore blood flow, stimulate the bone marrow , which in turn improves tissue healing. The ultrasound method is therefore a non-invasive, single-stage bone marrow focused stimulation. Microfracturing with ultrasound is intended to induce bleeding, activate marrow, trigger the migration of progenitor cells and growth factors to the subchondral bone while ultimately filling the bone defect. The approach creates erosion / thinning and cavities which can be pores, fractures, holes, defects or channels in thetissue. These facilitate vascular infiltration, allowing blood vessels to reach necrotic bone, restore circulation, and trigger natural bone repair processes. The purpose of this methodology is to stimulate repair of ossified or calcified tissue, which can be necrotic before chondral damage occurs.

[0035] The ultrasound waves are generally applied in an intermittent fashion. The total energy delivered by ultrasound waves has to be enough to create the cavities in the targeted tissue. The adoption of ultrasound waves enacts a series of mechanisms to fracture from ex vivo a target in vivo tissue. Accordingly, in some embodiments, the methods used herein do not require any surgical access to the ossified or calcified tissue. It should be understood, however, that, in certain embodiments, the present methods and uses can be applied during surgery. The surgery could be prescribed for a different reason and the fact that invasive access was created can be leveraged to provide the ultrasound waves according to the present disclosure. In such embodiments, although the overall treatment may be invasive, the specific method applied herein is non-invasive or minimally invasive. If access to the ossified or calcified tissue is available (e.g. through surgery for a different cause), then the ultrasound system may be applied directly and in contact with the tissue. Applying ultrasound at pre-determined frequencies, powers, duty cycles, half cycle duties (HCD), pulse repletion period, and geometric focus, creates cavities on the tissue to facilitate blood bone flow and trigger the migration of progenitor cells and growth factors to the subchondral bone while ultimately removing necrotic bone and stimulating the formation of new bone.

[0036] As used herein, the “size” of the cavities created can be defined by the greatest distance between two points in the cavity. The cavity is for example a pore which can be spherical in which case the size is the diameter of the pores. The cavity can also be a defect, a fracture or a channel, for example a channel having a tubular shape. The size can vary for example from 1 nm to 2 mm, from 1 nm to 1 mm, from 1 nm to 100 pm, from 1 nm to 10 pm, from 100 pm to 500 pm, or from 200 to 300 pm, and this can optionally refer to a diameter of a pore or a channel. In some embodiments, the application of ultrasound energy results not only in the formation of cavities but also, or alternatively, in the erosion or thinning of a bone surface. The erosion may extend into underlying trabecular bone and lead to thinning, weakening, or breaking of trabeculae. The modifications created promote healing of the ossified or calcified tissue by increasing or facilitating restoration of blood flow and stimulating biological healing processes.

[0037] In some embodiments, the ultrasound parameters (e.g. frequency, power, duty cycle, pulse repetition period (PRP), etc.) are not pre-determined. Instead, the ultrasound parameters may be determined and optimized during a preliminary (or testing) phase (e.g., during which ultrasound is applied to test tissue to cause a breakdown thereof without damaging healthy surrounding tissue).

[0038] In the present disclosure, the concept of leaving a surrounding tissue as “healthy” means that the effect of the ultrasound on that tissue does not cause damage that would prevent the functioning of the surrounding tissue or cause necrosis or cell death. In some embodiments, partial or minimal damage or heating happens on the surrounding tissues which does not lead to any permanent tissue damage (e.g. damage to the function of the tissue or structure of the tissue). To determine how to avoid or reduce damage on the surrounding tissues, the method can comprise a step of measuring an acoustic signal from the ossified or calcified tissue and / or from the tissue surrounding it to determine a focused ultrasound regimen that targets specifically the ossified or calcified tissue.

[0039] The target tissue to be treated has a specific density, and consistency. It therefore has a distinct acoustic impedance, and this can be leveraged to prevent any damage to other surrounding tissues by specifically targeting the characteristics of the target tissue. The different density and consistency of adjacent tissues means that ultrasound parameters that do not affect adjacent tissues can still affect the target tissue. Preferably, the target tissue is a mineralized calcified body tissue, such as bone tissue (e.g. subchondral bone), dentine, enamel, cementum, cartilage and the like. Preferably, the target tissue is a subchondral bone.

[0040] Based on the characteristics of the target tissue, the ultrasound can be varied, to provide different shapes and sizes of cavities and / or to induce erosion, thinning, weakening, or structural modification of the target tissue, including modification of trabecular bone. In some embodiments, the cavity formation can be characterized by a total volume of bone tissue that is lost by creating the porosity without collapsing the cartilage, for example the volume is from 0.1 mm3to 500 mm3, more typically from 1 mm3to 100 mm3.

[0041] Osteoarthritis is the disease associated with the most years spent on disability, affecting workers' autonomy and productivity, not to mention their psychological health. Long regarded as a disease originating in cartilage, it is now recognized that idiopathic osteoarthritis is a disease of the subchondral bone. Cartilage degeneration occurs secondary to damage to thebone beneath the cartilage. To date, treatments for osteoarthritis have focused on cartilage replacement or regeneration, and the current state of knowledge means that there is no way to regenerate cartilage. The present disclosure provides a method that acts upstream, before the cartilage is affected, and thus treats the bone before the cartilage is damaged. The only treatment currently available that targets the bone is subchondroplasty. Subchondroplasty is an invasive procedure, requiring access to the operating theatre and all associated resources, and involves the injection of cement into the area of bone oedema. This procedure is a potentially effective one for short-term pain relief, but there is no demonstrated long-term efficacy. The present method which non-invasively leverages ultrasound overcomes the disadvantages of these prior methods.

[0042] Osteochondrosis is a broad category of pathologies affecting bone and eventually cartilage. Osteochondrosis can affect any bone in the human body, including the spinal column (Scheurmann disease). One of the sub-categories is traction pathology, the best-known of which is Osgood Schlatter disease of the knee. There was no proven effective treatment for this problem other than observation (waiting for growth to finish by reducing participation in sporting activities). This can take several years into adolescence, with disastrous consequences for young people (sedentary lifestyle, isolation, depression, suicide, etc.). Another sub-category of osteochondrosis is osteochondritis dissecans (OCD). This is an area of necrosis that forms under the cartilage, most often seen in the knee, elbow or ankle, but can be found in many other joints. There is great difficulty in treating this condition. Similar to traction apophysitis, OCD is first treated with rest and cessation of sport for several months. Periodic magnetic resonance imaging (MRI) scans are performed to monitor progression. In the case of progressive disease, in an attempt to halt progression and heal the ossified or calcified tissue (e.g. necrotic bone), surgical intervention may be prescribed. The aim of the surgical procedure is to stimulate the bone marrow and its cells by mechanically damaging the bone (drilling). This procedure requires access to the operating theatre, including general anesthesia and all associated resources. Drilling is done freehand, with no guarantee of reaching the diseased area, and effectiveness is doubtful. The ineffectiveness of this surgical treatment alone, and the need to perform it in an operating room setting (invasive), certainly explains why it is not recommended from the very beginning of diagnosis. The present method allows to introduce a porosity to induce bone healing non-invasively and address the issues with the prior methods.

[0043] In addition to traction apophysitis and OCD, there is another major category of osteochondrosis, avascular necrosis. In pediatric patients, these are idiopathic conditions and can occur in various bones (femoral head known as Legg-Calve-Perthes, or navicular known asKohler's disease, etc). As with other osteochondroses, no effective treatment is currently available. The present method allows a non-invasive approach to treat these conditions as soon as the diagnosis is made and prevent or significantly reduce catastrophic articular damage.

[0044] Calcified tendinosis is a condition characterized by the deposition of calcium salts in a tendon, leading to pain and inflammation. The most common site affected is the shoulder tendon (particularly supraspinatus). Current treatments include physical therapy, corticosteroid injections and in severe cases surgery to remove the calcium deposits. The present method allows a non-invasive approach to treat that condition.

[0045] To perform the method of the present disclosure, an ultrasound system is used. It can include an emitter and all the related electronic components capable of inducing structural-morphological changes of nano to millimeter size (1 nm to 2 mm) to any ossified or calcified tissue exposed to it. The exposition can be both intra- or extra-corporeal.

[0046] Referring now to FIGs. 1A, 1B, 1C, and 1D, there is shown an ultrasound system 100 comprising an ultrasound transducer 102 and a transducer power output (TPO) 104. The ultrasound system 100 is coupled with the target body or volume 105 to be treated (e.g., the calcified or ossified tissue, shown as a block in FIGs. 1 B, 1C, and 1 D for illustrative purposes only). The ultrasound system 100 is coupled to the target volume 105 by means of a coupling medium (e.g. gel or water), not shown, and optionally a coupling member 106 (e.g., a coupling cone or a bladder coupling system comprising an acoustically transparent membrane).

[0047] As understood by those skilled in the art, the ultrasound transducer 102 is a device configured for transforming electrical energy, in the form of an electrical signal, into mechanical energy. The electrical signal may be an alternating current signal or a direct current signal, depending on the implementation. The ultrasound transducer 102 described herein thus operates as a transmitter of ultrasound waves (illustrated as 107 in FIGs. 1 B and 1 C), which are conveyed towards (i.e. applied to) the calcified or ossified tissue of the subject to create the cavities.

[0048] The ultrasound transducer 102 includes a radiating surface 108 (also referred to herein as an emitting surface) formed by one or more radiating elements 110. In one embodiment, the radiating elements 110 are arranged as a multi-element array (reference 109 in Figs. 1B, 1C, and 1 D) to form the radiating surface 108. The radiating surface 108 can be a flat (or linear) surface (as illustrated in FIG. 1 B) with the radiating elements 110 generating unfocused ultrasound waves, a concave (or curvilinear) surface (as illustrated in FIG. 1C) with the radiating elements 110generating focused ultrasound waves, ora combination thereof. The unfocused ultrasound waves cause acoustic cavitation and acoustic streaming as main mechanisms for generating cavities in ossified or calcified tissue. It will be appreciated that various types of ultrasound transducers 102 may apply depending on the application, including, but not limited to, capacitive transducers. In some cases, an acoustic lens (not shown) may be placed between the elements 110 and the target volume 105 to create a desired focus effect.

[0049] In unfocused ultrasound systems, the radiating (e.g., piezoelectric) elements 110 are stacked vertically to generate a piezo-driven longitudinal resonator. For instance, the radiating elements 110 may be positioned on top of one another, e.g. using multiple piezoelectric layers stacked vertically (along the “z” direction of FIG. 1 B). In focused ultrasound systems, the radiating elements 110 are arranged in at least one two-dimensional array (reference 109 in FIGs. 1 B, 1C, and 1 D) disposed along the (x, y) plane (see FIG. 1 D). The array 109 may comprise any suitable number of radiating elements 110. As an example, the array 109 may comprise between 1 and 3000 radiating elements 110 (e.g., over-the-counter transducers can typically have up to 774 radiating elements as in 110). The array 109, preferably comprises between 20 and 1000 radiating elements 110, more preferably between 50 and 700 radiating elements 110, and even more preferably between 64 and 512 radiating elements 110. In the focused ultrasound systems, the radiating elements 110 of a given array 109 are typically oriented towards a single point or a region that the ultrasound waves 107 are directed to. Although the radiating elements 110 are illustrated in FIGs. 1A to 1D as being arranged in a 2D rectangular array 109, it should be understood that the radiating elements 110 may be arranged in different configurations to form the radiating surface 108. For example, the radiating elements 110 may be arranged in a spiral, packed, or random array configuration. Additionally, although the radiating elements 110 are illustrated in FIG. 1D as being arranged so as to form an array 109 having a generally circular shape (or contour), it should be understood that any other suitable shape may apply, depending on the configuration (e.g. shape and size) of the ultrasound transducer 102.

[0050] The generation of cavities in the ossified or calcified tissue, and / or the induction of erosion, thinning, weakening, or disruption of the ossified or calcified tissue, can be enacted by different mechanisms that either act individually or in combination. These possible mechanisms include: cavitation, mechanical damage by a shockwave, or histotripsy which can be created with a frequency of 0.1 to 2.5 MHz at duty cycles above 10%, where thermal effects likely prevail, or at duty cycles below 10% (preferably below 1%), where non-thermal effects likely prevail. The term “duty cycle” refers to the ratio of ultrasound on-time to total on and off time. This on and offtime can be repeated, resulting in several “pulses” delivered. When the duty cycle is above 10% (preferably between 10% and 50% for a frequency between 1 MHz and 10 MHz), ultrasound is usually referred to as “high-intensity”. If the ultrasound is delivered as a focused ultrasound, it is referred to as high-intensity focused ultrasound (HIFU). Generally, the frequency and duty cycle at which the ultrasound transducer 102 operates are selected based on the hardness of the targeted ossified or calcified tissue. The harder the tissue, the greater the frequency required for creating the cavities. However, to avoid any damage to the tissue, the more the frequency is increased, generally, the more the duty cycle is decreased. The frequency and duty cycle will also vary based on the distance of the tissue to the device (i.e. to the ultrasound system 100).

[0051] Focused transducers and HIFU transducers can both initiate the three mechanisms described herein above which are responsible for the generation of bone fractures. However, HIFU offers more flexibility as it can be designed to have a specific geometric focus, i.e. a volume (e.g., ellipsoidal) to which the ultrasound wave collides and delivers the desired effects. This geometric focus is defined by the size and curvature of the transducer (i.e. the transducer’s geometry), which also defines frequency, while the number of the piezoelectric elements in the array 109 defines the power.

[0052] The effective frequencies for the ultrasound range from 0.1 to 100 MHz, preferably delivered by HIFU transducers. The HIFU transducers can deliver ultrasound waves that have an external diameter up to 2 m, and a focal width and a length up to 40 cm each. The focus can also be steered to hit a different treatment volume. The steering can be lateral and axial and reach 12 x 103mm3. The higher the voltage applied, the higher the volume of the focus will be.

[0053] In one embodiment, each ultrasound pulse (or burst) has a given duration (defined by the duty cycle) which is followed by a silent (or listening) time before the next ultrasound pulse. The PRP (i.e. the total time from the start of one ultrasound pulse to the start of the next ultrasound pulse) is defined as the sum of the ultrasound pulse’s duration and the silent time. In one embodiment, the PRP is between 2 nanoseconds and 30 seconds, preferably between 1 millisecond and 1 second.

[0054] In focused ultrasound, the geometric focus is a volume at a certain distance from the radiating surface 108 where the effects of ultrasound take place. The radius of curvature (labelled “R” in FIG. 1C, not to scale) of the radiating surface 108 in focused emitters can vary from about 10 mm to about 1000 mm, most typically from about 100 mm to about 300 mm. The distance ofthe geometric focus from the radiating surface 108 can vary from 10 mm to 100 mm. The geometric focus differs in size according to the frequency and geometry of the emitting radiating elements 110 and radiating surface 108. The geometric focus can be characterized by a first dimension (referred to herein as a “focal width” of the geometric focus) defined in a plane orthogonal to the direction of propagation, and a second dimension (referred to herein as a “focal length” of the geometric focus) parallel to the direction of propagation. The focal width can range from below 1 mm to 10 mm, preferably from 0.3 mm to 5 mm. The focal length can range from 1 mm to 50 mm, preferably from 3 mm to 20 mm. The shape of the geometric focus may vary depending on the configuration of the ultrasound system 100.

[0055] In operation, the frequencies at which the radiating elements 110 resonate vary from 0.02 MHz to 5.0 MHz, preferably between 0.1 MHz to 2.0 MHz.

[0056] The ultrasound transducer 102 is powered (e.g. via cabling 111) by the TPO 104, which is configured to provide a modulated electrical signal to the ultrasound transducer 102. The TPO 104 is a device configured to generate an output signal based on electrical parameters such as current, voltage, power, frequency and power factor. The TPO parameters may be set manually by a user, or be predetermined (e.g., based on a given procedure to be performed and / or the body characteristics of the subject).

[0057] In some embodiments, the TPO 104 drives all the radiofrequency (RF) channels of the ultrasound transducer 102. In particular, the TPO 104 comprises a plurality of RF drive amplifiers 112 which are configured to generate power (e.g., up to a frequency of 10 MHz), which can be continuous or pulsed, fordriving the radiating elements 110 of the ultrasound transducer 102 to generate ultrasound waves.

[0058] The RF drive amplifiers 112 are configured to generate electric power having a value which can vary from 0 to several thousand Watts, in continuous power (100% duty cycle) or through power pulses (below 100 % duty cycle). Possible values of nominal electrical power generated by the RF drive amplifiers 112 range between 0 Wand 50000 W, preferably 10 Wto 500 W for duty cycles above 10%, and 500 Wto 20000 W for duty cycles below 10%. The duty cycle can be varied from 0 to 100%.

[0059] Typical powers delivered through radiating surfaces 108 of different geometries and areas result in different surface intensities, typically ranging from above 0 W cm-2to 100 W cm-2on a continuous basis, and up to 2000 W cm2on a few seconds duty cycle below 10% (e.g., for pulsed power).

[0060] Typical powers delivered through radiating surfaces 108 of different geometries and areas result in different pressure levels focused on the volume to treat (e.g., the calcified or ossified tissue), typically from 0 to 200 MPa, preferably from 0.01 to 50 MPa.

[0061] The TPO 104 allows control of a focal steering of the radiating elements 110 (i.e. the ability of the radiating elements 110 to shift the focal spot of the ultrasound beam without moving the ultrasonic transducer 102). In one embodiment, the focal steering is controlled through the TPO 104 to sweep the entirety of the volume to treat with no or minimal movement of the ultrasound transducer 102. Such focal steering can be radial (i.e. the angle of the ultrasound beam can be varied along the lateral, or left / right, directions), axial (i.e. the focal distance can be controlled along the ultrasound beam axis, allowing to move the focal spot closer or further from the radiating surface 108), or both and achieved using any suited algorithm. For instance, a computing device running the algorithm can be coupled to a controller that performs the focal steering. The computing device may be configured to control the radial and axial focal steering individually, or to control both the radial and axial focal steering using multichannel communication.

[0062] Referring back to FIG. 1A and 1B, the coupling member 106 may be provided as coupling cones or bladder coupling systems, which are configured to facilitate the transmission of the ultrasound waves generated by the ultrasound transducer 102 to the volume to be treated. The coupling member 106 may also facilitate the containment of coupling gel. The coupling member 106 comprises any suitable device configured to enable optimal transmission of the ultrasound waves from the ultrasound transducer 102 to the target volume. As such, it will be appreciated that coupling members 106 otherthan cones or bladder coupling systems (e.g., pads and specialized devices such as acoustic standoffs) may apply.

[0063] When coupling cones are used as the coupling member 106, coupling cones with different heights per radius geometry can be used to fit different focused ultrasound (FU) probes with varying volumes to treat. Vacuum pump(s) and a temperature control system can be fitted on the coupling member 106 to mitigate temperature increase and ensure degassing of the coupling member 106 media. Vacuum can be applied to the coupling member 106 containing the coupling gel to vary amplitude and modulate the force of fracture. Pressure compresses a liquidwhile vacuum augments its vapor tension. This changes the density of the liquid and, as a consequence, the acoustic impedance (i.e. the manner in which the ultrasound wave propagates in the medium).EXAMPLES

[0064] In a first set of experiments, data was acquired using an animal model, specifically a cadaveric rodent model. Ten rats (numbered J1 to J11 , J4 was excluded because of bone damage in femur harvesting) were sacrificed for other studies and femurs were harvested to conduct ultrasound experiments. Samples were then stored in Phosphate Buffered Saline (PBS) at 4°C until HIFU treatment. In another set of experiments data was obtained from femoral head blocks of pork bones of about 8 mm x 8mm x 10 mm, stored in PBS at 4°C.

[0065] In the cadaveric rodent model, two groups were created to separate samples into an experimental treatment group and a control group. The control group was made up of all right femur samples of the rats and micro computed tomography (CT) scanning was executed before degassing procedure (baseline) as well as after degassing procedure (Control). Degassing procedure was conducted by putting all opened 15 mL falcon tubes, with samples in PBS, in a vacuum chamber for two (2) hours at room temperature to remove as much dissolved gas from samples and media.

[0066] In the cadaveric rodent model, for the experimental group of all left femur samples, a first microCT scan was done before degassing procedure then degassing was done with all the samples in a vacuum environment. Finally, ultrasound treatment was executed with Sonic Concepts™ H-101 probe at 1.1 MHz, 30W of power, 100% Duty Cycle (DC) at 10 ms burst of 10 ms length fora total treatment time of 6 minutes. Afterthe ultrasound treatment, microCT scanning was done again to assess changes made from the ultrasound treatment. The only difference in the handling of the tissues between the two groups was the ultrasound treatment done to the experimental group. Ultrasound was delivered in a water tank that was degassed and oxygen levels were recorded at 4 mg / L at the start of experiments and at 4.6 mg / L in the water tank at the end of all treatments.

[0067] In the cadaveric rodent model, ultrasound (US) data was collected with a focused 1.1 MHz transducer at 30W of power to the transducer, from Sonic Concepts™, model H-101 (Area of 34.55 cm2, diameter of probe of 64 mm and a radius of curvature of 63.2 mm) with focus dimensions of 1.37 mm of focal width and 10.21 mm of focal length.

[0068] In the femoral head blocks of pork bone model, a design of experiments (DOE) with 3 frequencies (200 kHz, 400 kHz, 600 kHz) and 3 duty cycles (0.1% ; 1% ; 5%) was organized in 9 different combinations. For every condition, triplicates of bone samples were done. The other relevant parameters of the TPO were selected and unchanged for all 9 conditions to allow the study of the effects of frequency and DC only on the bone morphology 3D parameters. PRP (Pulse Repetition period) was set at 10 ms, voltage setpoint of the TPO was set at 63 V, treatment time was set at 30 minutes (Table 1).Table 1. Ultrasound tests conditions done on the femoral head blocks of pork bone model.

[0069] Frequencies of 400 and 500 kHz were achieved using the H-437 probe from Sonic Concepts (diameter of probe of 64 mm, central opening of 28.7 mm diameter and a radius of curvature of 63.2 mm) with focus dimensions of about 2.75 mm of focal width and 51.74 mm of focal depth. For conditions with a frequency of 200 kHz, the H-436 transducer from Sonic Concepts was used (diameter of probe of 110 mm, central opening of 28.7 mm diameter and a radius of curvature of 70 mm) with focus dimensions of about 4.5 mm of focal width and 38.4 mm of focal depth.

[0070] MicroCT scanning (Bruker Skyscan 1172) yielded 3D images of bone structural architecture, at a resolution of 5.82 pm and can be fed into CT analysis software that renders 3Dparameters that can characterize bone morphology and structural integrity. Image analysis starts by establishing a binary color code by the intensity of registered signal for each pixel. Then a process of thresholding and shrink-wrapping of the images to the region of interest was performed and finally 3D parameters were calculated by the software.

[0071] The bone parameter results for main morphological values were obtained from CT Analysis software. Baseline calculations were done for both conditions (Baseline Degas and Baseline US) and then scans were done again following either degassing procedure (Degas) or following degassing and ultrasonic treatment (Post-US) with parameters mentioned before for both models. Bone surface density was calculated by the ratio of bone surface to total tissue volume analyzed in the region of interest set in the CT analysis software.

[0072] For the cadaveric rodent model, FIG. 3 (see plot 200) shows the results of the ratio of the bone surface volume (BS) to the total volume of tissue (TV) which demonstrate a relative increase in the available bone surface compared to the tissue volume resulting from exposing more bone surfaces. These additional bone surfaces increase the bone surface-to-tissue volume ratio, which can be the result of trabecular thinning, i.e. damage trabeculae, leaving behind a network of thinner trabeculae.

[0073] Trabecular number (Tb.N) (see plot 300 of FIG. 4) represents the amount of trabeculae per unit of length throughout the volume of interest established in the software. Trabecular Thickness (Tb.Th) is the measurement of the average wall thickness of the trabeculae and is established directly by 3D calculations (see plot 400 of FIG. 5), whereas Trabecular Separation (Tb.Sp) is the average distance between trabeculae or the average diameter of the pores in trabecular bone morphology (see plot 500 of FIG. 6). FIGs. 4 to 6 show an observed changes in trabecular microarchitecture with an increase in trabecular number results from the breakdown of larger trabeculae into smaller segments, while trabecular thickness decreases due to the thinning of these structures. Concurrently, trabecular separation diminishes as the formation of additional segments reduces the spaces between trabeculae. These alterations collectively increase the bone surface-to-volume ratio.

[0074] Statistical tests conducted on the experiments are paired t-tests with a confidence level of 95% for both models.

[0075] The ultrasound data from the cadaveric rodent model are presented in Table 2.Table 2. Data from ultrasound experiment on cadaveric rodent model.

[0076] The ultrasound data from the femoral head blocks of pork bone model are presented in Table 3, Table 4, and Table 5 fortests 1 to 3, 4 to 6, and 7 to 9 in Table 2, respectively. In these Tables, BS / TV is defined as the ratio of bone volume on total tissue volume of the analysed sample and corresponds to the ace density of the sample. Trabecular thickness (Tb.Th) is defined as the average thickness of the wall structure of the trabeculae. Trabecular number (Tb.N) isdefined as the inverse of the average distance between the inside wall structure of trabeculae. Trabecular separation (Tb.Sp) is defined as the average diameter of trabeculae. Connectivity density (Conn.Dn) is defined as a representation of the connectivity between different trabeculae in the bone microstructure.Table 3. Data from ultrasound experiment on femoral head blocks of pork bone model at 600 kHz. (D.C. = duty cycle, BL = baseline, exp = experimental)Table 4. Data from ultrasound experiment on femoral head blocks of pork bone model at 400 kHz.Table 5. Data from ultrasound experiment on femoral head blocks of pork bone model at 200 kHz.

[0077] The results of the statistical tests for the femoral head blocks of pork bone model, the average % change, as well as the standard deviation for replicates in each condition are presented in Table 6. Following the t-test, a p-value is available for each test and if that value is inferior to 0.05, then the test is successful, and the change is statistically significant with a confidence interval of 95%.Table 6. Statistical analysis of data from ultrasound experiment on femoral head blocks of pork bone model.

[0078] For conditions 1 through 8 in Table 6, the p-value is over 0.05, meaning no significant difference is observed on femoral head blocks of pork. For condition 9, all parameters had statistically significant changes, where a confidence level of over 99.9% is present for Conn.Dn.

[0079] FIG. 7 shows that the measured BS / TV fraction decreased in test 9, suggesting that the surface mineral density decreased with the treatment and that the trabecular network has become less dense.

[0080] FIG. 8 suggests that Tb.Th, the average thickness of trabeculae, increases in test 9.

[0081] FIG. 9 shows the decrease of the average trabecular number (Tb.N) at condition 9, which indicates inversely proportional to the increase of the distance between two neighbouring trabeculae. This indicates that trabeculae became sparser following the treatment.

[0082] FIG. 10 shows the increased trabecular separation (Tb.Sp) at condition 9 following treatment, suggesting increased spaces of trabeculae.

[0083] FIG. 11 shows decreased interconnection of trabeculae (Conn.Dn) after treatment.

[0084] FIGs. 12A-12B were obtained by measuring the evolution of temperature during the ultrasound treatment. These figures generally show that at 0.1 % duty cycle (DC) no thermal effect was observed whereas at 5% DC a maximum of 5 degrees Celsius increase was observed. More specifically, FIG. 12A shows the measured temperature change of a surrounding aqueous medium during ultrasound exposure at a frequency of approximately 200 kHz using a low DC of 0.1 %. Temperature was monitored at two spatially distinct locations positioned approximately 39 mm and 64 mm from the ultrasound focal region. Over the duration of exposure, no measurable temperature increase beyond experimental variability was observed at either location, indicating the absence of detectable bulk heating under these operating conditions. FIG. 12B shows corresponding measurements obtained using a higher duty cycle of 5%, representative of energy dosing regimes commonly associated with thermal high-intensity focused ultrasound (HIFU) applications. Under these conditions, a progressive temperature increase of the surroundingmedium was observed at both measurement locations, with greater temperature elevation detected closer to the focal region.

[0085] The comparison between low and high duty cycle operation demonstrates that, at equivalent acoustic frequency and high acoustic power, thermal effects are strongly dependent on duty cycle. Specifically, the absence of measurable temperature elevation at 0.1% DC supports that the disclosed procedure achieves its physical objective — mechanical opening of bone to enable biological access, without inducing thermal damage. The observed effects under low duty cycle operation are therefore predominantly mechanical rather than thermal in nature.

[0086] The above description is meant to be exemplary only, and one skilled in the art will recognize that changes may be made to the embodiments described without departing from the scope of the invention disclosed. Still other modifications which fall within the scope of the present invention will be apparent to those skilled in the art, in light of a review of this disclosure.

[0087] Various aspects of the systems and methods described herein may be used alone, in combination, or in a variety of arrangements not specifically discussed in the embodiments described in the foregoing and is therefore not limited in its application to the details and arrangement of components set forth in the foregoing description or illustrated in the drawings. For example, aspects described in one embodiment may be combined in any manner with aspects described in other embodiments. Although particular embodiments have been shown and described, it will be apparent to those skilled in the art that changes and modifications may be made without departing from this invention in its broader aspects. The scope of the following claims should not be limited by the embodiments set forth in the examples, but should be given the broadest reasonable interpretation consistent with the description as a whole.

Claims

WHAT IS CLAIMED IS:

1. Use of ultrasound for treating a calcified or ossified tissue by creating cavities and / or eroding into the calcified or ossified tissue.

2. The use of claim 1 , wherein the calcified or ossified tissue is in a subchondral bone.

3. The use of claim 1 or 2, wherein the calcified or ossified tissue is a bone marrow lesion, osteochondritis dissecans, subchondral insufficiency fractures, avascular necrosis.

4. The use of any one of claims 1 to 3, wherein the ultrasound is a high-intensity focused ultrasound (HIFU).

5. The use of any one of claims 1 to 4, wherein the ultrasound operates at a frequency between 0.1 MHz and 100 MHz.

6. The use of any one of claims 1 to 5, wherein the cavities have a size between 1 nm and 2 mm.

7. A method of treating a calcified or ossified tissue in a subject in need thereof, the method comprising: applying ultrasound on the ossified or calcified tissue to create erosion or cavities in the ossified or calcified tissue to promote healing of the ossified or calcified tissue by increasing or restoring blood flow.

8. The method of claim 7, wherein the ultrasound is a high-intensity focused ultrasound (HIFU).

9. The method of claim 7 or 8, wherein the ultrasound operates at a frequency between 0.1 MHz and 2 MHz and at a duty cycle above 10%.

10. The method of claim 7, wherein the ultrasound operates at a frequency between 0.1 MHz and 2.5 MHz and at a duty cycle below 10%, and preferably below 1%.

11. The method of claim 7 or 8, wherein the ultrasound operates at a frequency between 1 MHz and 10 MHz and at a duty cycle above 10%, and preferably between 10% and 50%.

12. The method of any one of claims 7 to 11 , wherein the method is non-invasive.

13. The method of any one of claims 7 to 12, wherein the ossified or calcified tissue is in a subchondral bone.

14. The method of any one of claims 7 to 13, wherein the cavities have a size between 1 nm and 2 mm.

15. An ultrasound system comprising:an ultrasound transducer comprising a radiating surface formed by one or a plurality of radiating elements;a transducer power output comprising a plurality of radiofrequency drive amplifiers, the plurality of radiofrequency drive amplifiers configured to generate power for driving the plurality of radiating elements to generate a plurality of ultrasound waves; anda coupling member configured to apply the plurality of ultrasound waves to a calcified or ossified tissue to create a plurality of cavities therein.

16. The ultrasound system of claim 15, wherein the radiating surface is flat and the plurality of radiating elements generate unfocused ultrasound waves.

17. The ultrasound system of claim 15, wherein the radiating surface is concave and the plurality of radiating elements generate focused ultrasound waves.

18. The ultrasound system of claim 16, wherein the plurality of radiating elements comprise a plurality of piezoelectric elements arranged in a vertical stack.

19. The ultrasound system of claim 17, wherein the plurality of radiating elements comprise a plurality of piezoelectric elements arranged in at least one two-dimensional array.

20. The ultrasound system of claim 18 or 19, wherein the plurality of piezoelectric elements resonates at a frequency between 0.02 MHz and 5.0 MHz, preferably between 0.1 MHz and 2.0 MHz.21 . The ultrasound system of claim 17, wherein the radiating surface has a radius of curvature between 10 millimeters and 1000 millimeters, preferably between 100 millimeters and 300 millimeters.

22. The ultrasound system of claim 17, wherein the ultrasound transducer has a geometric focus spaced from the radiating surface by a distance between 10 millimeters and 100 millimeters.

23. The ultrasound system of claim 22, wherein the geometric focus has a focal width ranging from below 1 millimeter to 10 millimeters, preferably from 0.3 millimeters to 5 millimeters, and a focal length ranging from 1 millimeter to 50 millimeters, preferably from 3 millimeters to 20 millimeters.

24. The ultrasound system of claim 15, wherein the ultrasound transducer operates at a frequency between 0.1 MHz and 2 MHz and at a duty cycle above 10%.

25. The ultrasound system of claim 15, wherein the ultrasound transducer operates at a frequency between 0.1 MHz and 2.5 MHz and at a duty cycle below 10%, and preferably below 1%.

26. The ultrasound system of claim 15, wherein the ultrasound transducer operates at a frequency between 1 MHz and 10 MHz and at a duty cycle above 10%, and preferably between 10% and 50%.

27. The ultrasound system of claim 15, wherein the ultrasound transducer is a high-intensity focused ultrasound (HIFU) transducer.

28. The ultrasound system of claim 15, wherein the transducer power output is configured to control a focal steering of the plurality of radiating elements, further wherein the focal steering is at least one of radial and axial.

29. The ultrasound system of claim 15, wherein the plurality of radiofrequency drive amplifiers is configured to generate electrical power ranging from 0 Wto 50,000 W, preferably from 10 Wto 500 W for a duty cycle above 10%, and from 500 Wto 20,000 Wfor a duty cycle below 10%.

30. The ultrasound system of claim 29, wherein an ultrasound burst has a duration defined by the duty cycle and followed by a silent time, further wherein the sum of the duration of the ultrasound burst and the silent time is between 2 nanoseconds to 30 seconds, preferably between 1 millisecond and 1 second.31 . The ultrasound system of claim 29, wherein the plurality of radiofrequency drive amplifiers is configured to generate one of continuous power and pulsed power up to a frequency of 10 MHz.

32. The ultrasound system of claim 31 , wherein the plurality of radiating elements generates the plurality of ultrasound waves having an intensity level ranging from above 0 W cm2to 100 W cm-2when the plurality of radiofrequency drive amplifiers generates the continuous power, and the intensity level of the plurality of ultrasound waves reaches 2000 W cm2when the plurality of radiofrequency drive amplifiers generates the pulsed power at the duty cycle below 10%.

33. The ultrasound system of claim 15, wherein the plurality of radiating elements generates the plurality of ultrasound waves to cause a pressure to be applied on the calcified or ossified tissue, the pressure ranging between 0 MPa and 200 MPa, preferably between 0.01 MPa and 50 MPa.

Images