Ultrasound stimulation of musculoskeletal cellular structures

Abstract

A method for ultrasound stimulation of a musculoskeletal tissue structure includes generating a plurality of acoustic space-time modes consisting of a complex sine wave, the complex sine wave having a modulation envelope that improves space-time measurement accuracy at a region of the multi-layered biological tissue structure and a pulse repetition frequency and duty cycle that are osteogenic at the region of the multi-layered biological tissue structure; beamsteering the acoustic space-time modes to the region of the multi-layered biological tissue structure to promote tissue healing; and generating bimodal stress levels in the multi-layered biological tissue structure that are sufficient to induce fracture healing.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 797,009, filed in the U.S. Patent and Trademark Office on January 25, 2019, the entire contents of which are incorporated herein by reference.

[0002] Embodiments of the present disclosure relate to multi-modal acoustic spatial-temporal signals with predetermined characteristics that dynamically generate stimulation and characterization of deep biological tissue structures at frequencies that can efficiently trigger a cascade of cellular functions to accelerate tissue healing. [Background technology]

[0003] The use of ultrasound to therapeutically treat and evaluate tissue and bone injuries is known. Application of ultrasound pulses having suitable parameters, such as frequency, pulse repetition and amplitude, at suitable external locations adjacent to tissue or bone injuries for a suitable period of time has been shown to accelerate the natural healing of, for example, tissue tears, bone breaks and fractures.

[0004] Ultrasound propagation in tissue exerts bidirectional radiation forces on all absorbing and reflecting obstacles in its path, even at the microstructural level. The components of acoustic energy that can affect chemical changes can be thermal, mechanical (agitation) and cavitational in nature. The largest non-thermal effects are due to stable cavitation and mass transfer. As such, they can cause acoustic microstreaming, resulting in shear stresses on cell walls and boundary layers, and on the cytoskeleton. The latter effects, due to intracellular microstreaming, can result in increased metabolic function of cells.

[0005] Since the early 1960s, the specific physical and biological mechanisms behind the therapeutic effectiveness of low-intensity ultrasound have been extensively studied. Low-intensity ultrasound refers to those power levels that are just above the biological threshold that can trigger or evoke a whole-body biological regulatory response [1]. 0.1-0.5 W / cm 2 For spatially-averaged-temporal-averaged (SATA) intensities in the range, non-thermal high-stress mechanisms of acoustic streaming and cavitation can be generated. In vitro studies on isolated fibroblasts have shown that the effect of ultrasound on the cells is pressure-sensitive, suggesting a (stable) cavitation mechanism caused by the rapid expansion and collapse of microbubbles [2, 3]. The resulting bubble oscillations, which can cause acoustic microstreaming, can generate high shear stresses on cell membranes, which may affect the permeability of cells to sodium and calcium ions [4]. Increased cell permeability may result in increased calcium uptake [5], increased protein and DNA synthesis in fibroblasts, and may be the main cause of the observed macrophage activation. The production of fibroblasts and macrophages characterizes the normal fracture repair process. Hill [6] has determined that the cavitation threshold is 0.1 W / cm in aqueous media. 2 and ter Haar [7] determined that the in vivo 2 It was estimated that:

[0006] Low intensity ultrasound has been clinically demonstrated to promote the process of angiogenesis or increase blood flow around the fracture site, thereby further accelerating wound and fracture healing of superficial musculoskeletal tissues. Research studies have shown that there may be a set of one or more acoustic signal excitations that will maximally promote fracture healing by shortening healing time and / or improving the quality of regenerated tissue.

[0007] Duarte, U.S. Patent No. 4,530,360, describes a basic non-invasive treatment technique and device that applies ultrasonic pulses externally to the skin surface at a location adjacent to a bone injury. To apply the ultrasonic pulses during a procedure, the operator must manually hold the applicator in place until the procedure is completed. Duarte, like Winder et al., U.S. Patent No. 5,520,612, describes a range of RF signals that generate longitudinal ultrasonic waves, ultrasonic power density levels, a range of durations for each ultrasonic pulse, and a range of ultrasonic pulse frequencies.

[0008] Winder's U.S. Patent No. 6,213,958 B1 describes a diagnostic system that detects, localizes, and characterizes acoustic emissions produced by applying non-invasive mechanical stimuli to the musculoskeletal system. The mechanical stimuli can be either static or dynamic, but the Instron test machine shown in FIG. 1 of the cited patent implies that the excitation load is static. Winder's invention would facilitate clinical manipulation more easily if the static load could be replaced by an external dynamic means.

[0009] No. 7,429,248B1 to Winder et al. describes a method and apparatus for controlling acoustic modes in tissue healing applications. This patent provides the same ranges of RF signals for generating longitudinal ultrasound waves, ultrasound power density levels, ranges of duration for each ultrasound pulse, and ranges of ultrasound pulse frequencies as those provided in U.S. Patent No. 5,520,612. Summary of the Invention [Means for solving the problem]

[0010] Exemplary embodiments of the present disclosure relate to systems and methods that use an ultrasound transducer / transmitter system to generate acoustic space-time modes that propagate to sites in multi-layered biological tissue structures to promote tissue healing. These unique acoustic modes are generated by beam steering and their pulse repetition frequency, duty cycle, and bimodal stress (spatial-averaged time-averaged intensity; I SATA ) levels, which can significantly promote fracture healing.

[0011] According to one embodiment of the present disclosure, there is provided a method of ultrasound stimulation of a musculoskeletal tissue structure comprising: generating a plurality of acoustic space-time modes of a composite sine wave having a modulation envelope with structural detail that improves space-time measurement accuracy at a site of the multi-layered biological tissue structure and a pulse repetition frequency and duty cycle that is osteogenic at the site of the multi-layered biological tissue structure; beam steering the plurality of acoustic space-time modes to the site of the multi-layered biological tissue structure to promote tissue healing; and generating a bi-modal stress level in the multi-layered biological tissue structure that is sufficient to induce fracture healing.

[0012] According to a further embodiment of the present disclosure, the acoustic space-time mode includes shear waves that promote integrin response in bone tissue extracellular matrix.

[0013] According to further embodiments of the present disclosure, beam steering utilizes a multi-element linear or planar phased array, or a single element driving a wedge block.

[0014] According to a further embodiment of the present disclosure, when the angle of the multiple acoustic space-time modes at the tissue layer boundary of the multi-layer biological tissue structure is less than a first critical angle, shear waves propagate along the fracture path and longitudinal waves propagate beneath the periosteal surface of the bone tissue at 30-60° to the tissue layer boundary.

[0015] According to a further embodiment of the present disclosure, when the angle of the multiple acoustic space-time modes at the tissue layer boundary of the multi-layer biological tissue structure is substantially equal to the first critical angle, a combination of shear waves propagates along the fracture path and longitudinal waves propagate below and parallel to the periosteal surface of the bone tissue at 60-90° to the tissue layer boundary.

[0016] According to a further embodiment of the present disclosure, when the angle of the multiple acoustic space-time modes at the tissue layer boundary of the multi-layered biological tissue structure is substantially equal to a second critical angle, only shear waves propagate along and beneath the periosteal surface of the bone tissue.

[0017] According to a further embodiment of the present disclosure, the acoustic intensity stress level per beam is between 30 and 70 milliwatts / cm 2 I SATA The range is.

[0018] According to a further embodiment of the present disclosure, the acoustic intensity stress level per beam is between 40 and 50 milliwatts / cm 2 I SATA The range is.

[0019] According to a further embodiment of the present disclosure, the low frequencies of the acoustic spatial-temporal modes are osteogenic.

[0020] According to a further embodiment of the present disclosure, the low frequency is in the range of 300 kHz to 3.0 MHz.

[0021] According to a further embodiment of the present disclosure, the low frequency for long bone healing is 1.0 MHz.

[0022] According to a further embodiment of the present disclosure, the low frequency for cervical and lumbar fusion healing is 0.5 MHz.

[0023] According to a further embodiment of the present disclosure, the modulation envelope is constant.

[0024] According to a further embodiment of the present disclosure, the modulation envelope is a Gaussian function.

[0025] According to a further embodiment of the present disclosure, the low frequency of the modulation envelope is generated by an amplitude modulation technique, and the composite sine wave is s(t) AM =(1+msinω m t)sinω c t =sinω c t-(m / 2)cos(ω c +ω m )t+(m / 2)cos(ω c -ω m ) where ω c is the carrier frequency, m is the modulation index that controls the degree of amplitude modulation, and ω m is the modulation frequency.

[0026] According to a further embodiment of the present disclosure, a lower sideband of the composite sine wave is utilized between 500 kHz and 1.0 MHz for bone tissue osteogenic repair, and an upper sideband of the composite sine wave is utilized between 2.0 and 2.5 MHz for bone tissue imaging.

[0027] According to a further embodiment of the present disclosure, the pulse repetition frequency (PRF) is less than or equal to 10 kHz.

[0028] According to a further embodiment of the present disclosure, the pulse repetition frequency is about 1 kHz.

[0029] According to a further embodiment of the present disclosure, the duty cycle is in the range of 10-50%.

[0030] According to another embodiment of the present disclosure, the duty cycle is about 20%.

[0031] According to a further embodiment of the present disclosure, there is provided an ultrasound transducer / transmitter system comprising a source of an acoustic space-time mode consisting of a complex sine wave propagating to a site in a multi-layered biological tissue structure to promote tissue healing, the source comprising a single transducer combined with a wedge block and a multi-element linear or planar phased array for beam steering the acoustic space-time mode.

[0032] According to a further embodiment of the present disclosure, the wedge block is constructed from a low viscous loss material including a thermoplastic, a thermoset, an elastomer, or a mixture thereof.

[0033] According to further embodiments of the present disclosure, the wedge block has an acoustic impedance of 1.6±6% MRayl, is non-toxic to humans, and is impermeable to human blood. [Brief description of the drawings]

[0034] [Figure 1] 13 shows multimode transmission of tilted NEWSIG into rabbit tissue for a beam steering angle of 10.5° of the transducer face relative to the skin surface in accordance with an embodiment of the present disclosure. [Diagram 2] 1 shows multimode transmission of tilted NEWSIG into rabbit tissue for a 13.5° beam steering angle of the transducer face relative to the skin surface (first critical angle (CA1)) in accordance with an embodiment of the present disclosure. [Diagram 3] 13 shows multimode transmission of tilted NEWSIG into rabbit tissue for a beam steering angle of 31.5° of the transducer face relative to the skin surface (second critical angle (CA2)) in accordance with an embodiment of the present disclosure. [Figure 4] 1 is a flow chart of a method for ultrasound stimulation of musculoskeletal tissue structures, according to one embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Exemplary embodiments of the present disclosure described herein generally provide a method for generating multimodal acoustic signals at several stress levels and frequencies that stimulate and characterize deep biological tissue structures at frequencies that can accelerate tissue healing. While the embodiments are susceptible to various modifications and alternative forms, specific embodiments thereof are shown by way of example in the drawings and are described in detail herein. It is to be understood, however, that the disclosure is not intended to be limited to the particular forms disclosed, but on the contrary, the disclosure encompasses all modifications, equivalents and alternatives falling within the spirit and scope of the present disclosure.

[0036] The disclosed embodiments relate to the design and generation of novel shear wave rich, multimodal signals that optimize integrin response for low frequency stimulation of biological tissue structures. This is highly beneficial for both bone and wound healing, as well as (potentially) spinal fusion healing. Biomechanical principles are applied to limb fracture treatment procedures and benchmark metrics are proposed to characterize the healing process. The disclosed embodiments provide radiation pressure and measured target response properties for, but not limited to, acoustic emission monitoring, bone tissue growth, fracture healing, lumbar and cervical fusion, muscle re-education and tissue wound healing.

[0037] The exogenous use of acoustic waves to effectively facilitate diagnosis, therapy and surgery of biological systems relies on a detailed understanding of the physical properties of the system, such as particle displacement, particle velocity, stress, strain and elasticity. In particular, when properly stimulated, bone tissue can support remodeling and remineralization during the final healing phase.

[0038] LIPUS stimulation induces physiological responses in bone healing Animal connective tissue consists of an extracellular matrix composed primarily of collagen, the main protein in bone that cells secrete around themselves. It is the collagen in this matrix that gives supporting tissues their tensile strength. Low-intensity pulsed ultrasound (LIPUS) stimulation of the extracellular matrix outside the cell is transmitted across the fragile plasma membrane to the cytoskeleton inside the animal cell via molecular protein bonds called integrins. Research has shown that ultrasound enhances the cellular integrin response that initiates a cascade of intracellular pathway events. These events include (1) increasing the permeability of the cell wall membrane of the extracellular matrix, (2) affecting several cytoplasmic growth factors such as TGF-β, PDGF, EGF, (a,b) FGF, IGF-I, II, and NGF, which result in the transcription of specific genes, and (3) utilizing mRNA to translate the specific gene transcripts to the cell nucleus to activate protein synthesis. Specifically, studies have shown that LIPUS promotes soft callus mineralization (endochondral ossification) during the second stage of healing and further increases fracture hard callus strength during the remineralization and remodeling phase that occurs during the third (and final) stage of healing.

[0039] Therefore, integrin molecular protein response is important to generate the cellular function of protein synthesis and, as a result, the physiological response of clinical bone healing. In vivo experiments have shown that integrins respond optimally to shear wave radiation pressure. Therefore, signals that stimulate bone tissue repair should be rich in shear waves and match the relaxation time of the biological response of bone tissue. This maximizes the callus index, defined as the ratio of callus diameter to bone diameter, and bone density in the fracture path.

[0040] Shear wave generation According to one embodiment of the present disclosure, shear waves can be generated by a specially designed coupling wedge that acts as an acoustic mode converter (AMC) that can spatially control acoustic longitudinal waves transmitted perpendicular to the bone by a piezoelectric transducer to generate both shear and longitudinal waves within the bone surface, as described in more detail below.

[0041] The particle direction of the shear wave is perpendicular to the propagation direction, allowing two types of shear waves to exist depending on the direction of particle vibration relative to the propagation direction: horizontal shear wave (SH) and vertical shear wave (SV). Generally, random shear waves incident on the boundary between two different solid media contain both SH and SV components. Furthermore, SV waves can also undergo mode conversion according to the boundary conditions established by Snell's law, which also governs the interaction of longitudinal waves at the interface between medium 1 and medium 2, as follows: (sinθ s / C s )1=(sinθ L / C L )1=(sinθ L / C L )2=(sinθ s / C2)2(1) In the formula, θ s is the angle of the shear wave, and θ L is the angle of the longitudinal wave, and C s is the shear wave velocity, and C L is the longitudinal wave velocity. Note that the shear wave angle and longitudinal wave angle are measured relative to the shear wave velocity and longitudinal wave velocity, respectively, relative to the normal to the bone tissue. In contrast, SH waves cannot undergo mode conversion. Instead, they maintain motion relative to the boundary. An acoustic waveguide, such as a fracture path, can support pure SH waves.

[0042] Equation (1) demonstrates that when a wave travels from a slower material to a faster material, there is an angle of incidence known as the first critical angle that creates a 90 degree refraction angle for longitudinal waves. If the angle of incidence is greater than the first critical angle, only shear waves propagate within the material. In most materials, there is also an angle of incidence that creates a 90 degree refraction angle for shear waves. This is called the second critical angle.

[0043] Embodiments of the present disclosure can optimize the longitudinal and shear components of interacting acoustic waves to enhance the physiological response of bone healing and promote integrin response in bone tissue extracellular matrix.

[0044] Design and construction of acoustic mode transducers. Beam steering can control the relative amounts of longitudinal and shear energy propagating in bone tissue, and the amount of thermal energy generated. Control of the beam steering angle is known in underwater sonar, radar, and medical applications and is accomplished in several different ways using: (1) multi-element linear or planar phased arrays of transducer elements, and (2) a single transducer embedded in an intermediate wedge of different material that controls the relative refractive index between the transducer / wedge and the intervening biological material layer. Signal steering is achieved by adjusting the relative phase (timing) of the waveform emitted by each element, effectively negating the wave propagation in one or more directions and enhancing it in other directions. A linear array is an array of rectangular transducer elements, which due to their shape produce non-hemispherical propagating waves. The elements of a linear array can also be phased to further steer the beam.

[0045] According to one embodiment, a specially designed coupling wedge acting as an acoustic mode converter (AMC) is a simple approach in medical ultrasound research to generate both normal and oblique longitudinal modes to propagate to the fracture. The coupling wedge is generally considered to be a viscoelastic material. The AMC according to one embodiment comprises a suitable low viscous loss material including, but not limited to, thermoplastics, thermosets, elastomers or mixtures thereof. AMC design considerations include sound speed, acoustic attenuation, acoustic impedance, toxicity in humans, transparency to human blood, and ability to generate an acoustic free field from an implanted emitting transducer. The AMC according to one embodiment has an acoustic impedance of 1.6±6% MRayl, is non-toxic to humans, and is opaque to human blood.

[0046] Biological System Model According to one embodiment of the present disclosure, to establish a balance between shear and longitudinal modes, the insonified structure is modeled as a parallel four-layer system, where the outermost three layers (skin, fat, and muscle) behave as viscous fluids and the innermost fourth layer (bone) behaves as a viscoelastic solid. Bone tissue should feature both viscous and elastic components to meaningfully affect fracture repair.

[0047] According to one embodiment, a propagating longitudinal acoustic signal incident on a tissue layer boundary at an oblique angle has three components: (1) a reflected longitudinal signal, where the angle of reflection is equal to the angle of incidence, and a bimodal signal transmitted inside the bone, propagating as both (2) a shear wave and (3) a longitudinal wave. The bimodal signal incident on the muscle / bone tissue interface, which is rich in both longitudinal and shear wave content, is hereinafter referred to as a new acoustic signal ("NEWSIG").

[0048] According to one embodiment, the effectiveness of NEWSIG depends on providing sufficient energy to acoustic modes that match the unique characteristics of each mode, i.e., whether it is longitudinal or shear. However, shear waves are more lossy than longitudinal waves, and in order to utilize shear waves, their intensity levels should be increased relative to that of longitudinal waves.

[0049] According to one embodiment, the increase in shear strength in bone tissue is based on empirical research studies. The longitudinal attenuation coefficient α for acoustic waves at normal incidence to bone in the low therapeutic frequency band of 1-4 MHz is L teeth, α L =4.2dB / MHz-cm (2) The shear attenuation coefficient α that generates acoustic shear waves via the mode conversion method is s teeth, α s =7.0dB / MHz-cm (3) It is.

[0050] Therefore, according to one embodiment, in the case of multimode excitation, the intensity spatial average temperature average (I SATA ) is the I SATA Therefore, I for longitudinal excitation should be about 0.6. SATA is about 30mW / cm 2 If I for shear excitation is SATA is about 50mW / cm 2 It should be.

[0051] According to one embodiment, intensity tuning can provide effective shear modes for multimodal tissue healing. These tunings compensate for the fact that shear waves travel slower than longitudinal waves and dissipate more thermal energy as they propagate through bone tissue.

[0052] Acoustic stimulation of new signals According to one embodiment, the new signal, NEWSIG, can accelerate the process of fracture healing in long bones as well as promote healing in lumbar and cervical spinal fusions. NEWSIG, according to one embodiment, has sufficient spectral energy in a predefined low frequency range to have several biological bone formation effects: (1) increased permeability of cell wall membranes, enhancing diffusion processes for calcium uptake and protein synthesis, (2) increased hemoglobin released, and (3) gene expression in tissues exposed to ultrasound.

[0053] 4 is a flow chart of a method for ultrasound stimulation of a musculoskeletal tissue structure according to one embodiment of the present disclosure. Referring to the figure, the method begins at step 41 by generating a plurality of acoustic space-time modes. The acoustic space-time modes include composite sine waves having a modulation envelope that enhances space-time measurement accuracy at a site of the multi-layered biological tissue structure where structural details are present, and a pulse repetition frequency and duty cycle that are osteogenic at the site of the multi-layered biological tissue structure. The acoustic space-time modes are beam steered at step 43 to the site of the multi-layered biological tissue structure to promote tissue healing, and at step 45 generate a bimodal stress level sufficient to generate fracture healing in the multi-layered biological tissue structure. The acoustic space-time modes include shear waves that promote integrin response of bone tissue extracellular matrix.

[0054] To date, the Duarte signal is the only FDA-approved acoustic signature to accelerate healing of long bone fractures. The Duarte signal has a nominal frequency of ultrasound of 1.5 MHz, the width of each pulse varies from 10 to 2,000 milliseconds, the pulse repetition rate varies from 100 to 1,000 Hz, and the ultrasound power level is maintained at less than 100 milliwatts per square centimeter. The main difference between the Duarte signal and NEWSIG according to one embodiment is that the Duarte signal is a higher frequency longitudinal wave, while NEWSIG is a lower frequency longitudinal + shear wave, resulting in greater healing bone formation at greater depths in living bone tissue.

[0055] Spectral energy of the new signal The primary spectral energy content of the NEWSIG according to one embodiment is located in the frequency band between 3 Hz and 3 MHz, with a pulse repetition frequency (PRF) of less than 10 kHz, a duty cycle of 10-50%, and an energy density of 3-400 mW / cm. 2 I SATA , with a constant to Gaussian modulation envelope and an administration time of less than 60 minutes.

[0056] According to one embodiment, NEWSIG for musculoskeletal bone healing of short and long bone fractures and for promoting spinal fusion has the following characteristics: spectral energy of 300 kHz to 3.0 MHz, constant or Gaussian envelope, maximum PRF of 1 kHz, duty cycle of 20% or less, and 30 to 150 mW / cm at the skin interface. 2 I SATA and routine administration times of 20 minutes or less. Due to signal demodulation occurring in the fracture pathway, a PRF of 1 kHz is a better match to the relaxation time of bone tissue in the low 1 ms region.

[0057] In one embodiment, the low frequency of the acoustic space-time mode is osteogenic and ranges from 300 kHz to 3.0 MHz. According to one embodiment, the low frequency for long bone healing is 1.0 MHz and for cervical and lumbar fusion healing is 0.5 MHz. In some embodiments, the acoustic intensity stress level per beam is between 30 and 70 milliwatts / cm. 2 I SATA and in other embodiments, the acoustic intensity stress level per beam is in the range of 40-50 milliwatts / cm 2 I SATA The range is.

[0058] Amplitude Modulation Stimulus According to one embodiment, the bone formation spectral envelope can be obtained by utilizing well-known amplitude and frequency modulation techniques. The simplest amplitude modulation method utilizes a phase-adjusted linear sum of transmitted sine waves in the focal region, represented by the trigonometric formula: s(t) AM =sinA+sinB=2cos((AB) / 2)sin((A+B) / 2)=2cos(Δt)sin(ω c +Δ)t (4) where s(t) is the transmitted signal, A=B+2Δ t, B=ω c t and ω c is the carrier frequency and Δ is the desired low bone formation frequency.

[0059] According to one embodiment, a different low spectral frequency envelope is generated by varying the magnitude of the carrier according to the amplitude and frequency of the modulation source. For a sinusoidal source, this can be expressed as: s(t) AM =(1+msinω m t)sinω c t =sinω c t-(m / 2)cos(ω c +ω m )t+(m / 2)cos(ω c -ω m )t (5) where the signal spectrum can be characterized as the sum of the upper and lower sidebands of the carrier, (m) is commonly referred to as the modulation index and controls the degree of amplitude modulation, and ω m is the modulation frequency.

[0060] According to one embodiment, the carrier frequency ω c and modulation frequency ω mBy suppressing the carrier through appropriate selection of , osteogenic stimulation can be optimized. Spatial array directivity and axial resolution increase with frequency, resulting in finer pathological details being discerned in tissue images. According to one embodiment, the upper sideband of 2.0-2.5 MHz provides higher spatial and axial resolution and higher SNR for improved detectability, and is therefore used for bone tissue diagnostic imaging, but is limited by associated energy absorption, which increases with increasing frequency, resulting in limited tissue depth. On the other hand, the lower sideband of 500 kHz-1.0 MHz is primarily useful for bone tissue osteogenic repair at deeper depths, but is limited by cavitation effects, which increase with decreasing frequency.

[0061] Proof of Concept (POC) Studies A randomized, double-blind, POC study demonstrated the clinical potential of multimodal delivery in one embodiment, where such treatment would facilitate clinical revascularization, first during the early inflammatory phase, and again at the end of the soft callus phase, immediately prior to bone tissue remodeling, to meet the mechanical requirements in the final hard callus phase.

[0062] The POC study, according to one embodiment, is modeled after the work of Pilla at Mount Sinai, NYC, and relies on published research over the past 40 years measuring shear wave properties in biological tissue.

[0063] A POC study according to one embodiment used an AMC generating tilted NEWSIGSIG at 10.5°, NEWSIGSIG at 13.5°, and NEWSIGSIG at 31.5°. These angles are the oblique angles of the measured signal at the AMC / skin interface shown in Figures 1-3, respectively. The AMC was positioned to support systemic blood flow (distal to proximal). The signal transmission power level was adjusted to compensate for absorption through the AMC. The spatial-averaged-temporal-averaged intensity (I) at the wedge / skin interface was measured. SATA ) is 30mW / cm for the transmitted vertical longitudinal wave. 2 , 40mW / cm for oblique longitudinal waves2 was adjusted to be.

[0064] 1-3 show multi-mode transmission of tilted NEWSIG into rabbit skin for various angles of the transducer face relative to the skin interface, according to an embodiment of the present disclosure. θ is the oblique angle of the transducer face with respect to the skin surface, with 0° representing the transducer face parallel to the skin for normal transmission; φ is the refracted angle of the ultrasound propagating from the AMC into the tissue, measured relative to the perpendicular (normal) line; α is the refracted angle of the shear portion of the ultrasound wave propagating from the overlying tissue into the bone, measured relative to the perpendicular (normal) line; β is the angle of refraction of the longitudinal portion of the ultrasound wave propagating from the overlying tissue into the bone, measured relative to the perpendicular (normal); The triangle is the acoustic wedge AMC and the XDR is the transducer.

[0065] The estimated thickness of the muscle tissue between the skin surface and the fibula is 1.5 cm, the measured longitudinal velocity of the acoustic wave for the AMC material is 921 m / s, and the phase velocity through the muscle tissue is 1560-1580 m / s. Assuming that the bone propagates in the x-axis and the fracture propagates along the y-axis, the phase velocity of the longitudinal component is 3500-3900 m / s along the bone tissue surface and 3100 m / s along the fracture path, and the phase velocity of the shear component is 1700-1750 m / s along the bone tissue surface and 1600-1650 m / s along the fracture path.

[0066] Figure 1 shows the case where θ=10.5°, φ=18.1°, α=18.8±0.4° and β=47°. Figure 2 shows the case where θ=13.5°, φ=23.7±0.1°, α=24.4±0.1° and β is in the range of 62.4 to 90°. Figure 3 shows the case where θ=31.5°, φ=63° and α is in the range of 73.5 to 88.2°.

[0067] The POC study results shown in Figures 1-3 show that when the angle of the acoustic space-time modes at the tissue layer boundaries of the multi-layered biological tissue structure is 10.5°, i.e., less than the first critical angle of 13.5°, the combination of shear waves propagating along the fracture path at about 19° and longitudinal waves propagating below the periosteal surface of the bone tissue at 30-60° to the tissue layer boundaries. Furthermore, when the angle of the acoustic space-time modes at the tissue layer boundaries of the multi-layered biological tissue structure is substantially equal to the first critical angle, a combination of shear waves propagating along the fracture path at about 24° and longitudinal waves propagating below and parallel to the periosteal surface of the bone tissue at 60-90° to the tissue layer boundaries. Furthermore, when the angle of the acoustic space-time modes at the tissue layer boundaries of the multi-layered biological tissue structure is substantially equal to the second critical angle of 31.5°, only shear waves propagate along and beneath the periosteal surface of the bone tissue.

[0068] POC torsion testing in 17 rabbits with surgically induced bilateral fibular osteotomies showed that after 18 days (POD1-POD18, POD = post-op days) of treatment, including euthanasia on POD21, the test device with NEWSIG excitation was superior to the current FDA-approved device with Duarte signal excitation. Statistical analysis showed that maximum torque was increased by 25.3% (p=0.0215) and stiffness was increased by 25.7% (p=0.0501) relative to the Duarte signal. Of the two AMCs tested, the shear wave mode for 31.5° was found to be superior for bone growth stimulation (BGS) applications.

[0069] Biological Media Considerations According to one embodiment, the design of the BGS signal should take into account the linear and nonlinear characteristics of the propagation medium. Although the dynamics of biological tissues are generally nonlinear, in order to facilitate understanding and visualization of physical phenomena, their responses to various stimuli, both natural and artificial in nature, are linearized. This linearization process is well known and is often referred to as the small amplitude case. The small amplitude or low intensity case is considered to be non-thermal and therefore only results in biological effects that can be either static or dynamic through mechanical stimuli.

[0070] The two most well-known non-thermal non-linear effects are cavitation and acoustic streaming. Common measures of non-thermal non-linear ultrasonic behavior in biological tissue are the Mechanical Index (MI) and the Beam Non-Uniformity Ratio (BNR). The measure of the non-linear thermal effect resulting from acoustic power that increases tissue temperature by 1°C is called the Thermal Index (TI).

[0071] MI is a measure of the destructive behavior of ultrasound waves caused in biological tissue by cavitation effects and is intended for low duty cycle (<2%) diagnostic imaging, B-mode short pulses that often result in high peak pressures.

[0072] The 1992 AIUM-NEMA standard suggests an acceptable value for MI of less than 0.7 in ultrasound mode (page 144, section 7.1), below which cavitation (theoretically) does not occur. It was assumed that in vivo there existed stabilizing pockets of gas or free bubbles (which remains uncertain clinically, except for contrast agents). The FDA-approved devices tested were rated at 20 V. p-p and 1.5MHz, MI<0.1. The test equipment is 25V p-p and resulted in MI<0.2 for 1.0 MHz.

[0073] BNR is [max I SPTA / I SATA ], where [max I SPTA ] is the acoustic axial distance of maximum pressure, which for a non-focused transducer is approximately (transducer diameter) 2 / (4 × wavelength λ), and I SATA is the total acoustic power divided by the effective radiating area (ERA). ERA is the width of the beam intensity profile function at the -13 dB point at a distance of 5 mm along the transducer axis, and was measured to be about 130 mm in the in vivo POC study mentioned above. The ERA in that study was approximately 3.88 cm 2which corresponds to an electrode diameter of 0.875 inches or 22.22 mm. The maximum measured BNR for test devices in POC studies was less than 5.0. The FDA requires that the BNR for therapy devices be less than 8.0 and that the maximum measured value be indicated on the device label.

[0074] For musculoskeletal therapeutic applications, the key thermal index for the long bones, navicular, metatarsal and head is determined by the bone near the surface, the Thermal Index of the Skull (TICB). TICB=W o / 40D eq (6) where W (in mW) o is the time-averaged acoustic power at the radiating surface of the transducer, and D eq is the equivalent diameter (in cm) of the active (or electroded) transducer area.

[0075] Design Considerations for Low Frequency Transducer Projectors According to an embodiment, the low bone formation frequencies characterized by NEWSIG can be generated by a transducer with an electromagnetic, piezoelectric, electrostrictive or magnetostrictive active element. The active element can be in the form of a single or multi-layered part made of one or a combination of the above-mentioned materials. Furthermore, the active element can be made of a composite of such materials with polymer, hollow and / or metallic parts. Furthermore, active elements made of such materials can generate low frequency waves through the flextensional effect obtained by unimorphs, monomorphs, bimorphs, cymbals, moonies, thunders, rainbows, cerambows, etc., known to those skilled in the art. Furthermore, the frequencies mentioned in the embodiments can be generated by mechanical vibration of air molecules or molecules of a medium in contact with the human body using speakers, buzzers, tuning forks, and / or any non-active mechanical vibration element driven by the above-mentioned active elements. Additionally, the low bone formation frequencies disclosed herein can also be generated by transducers made from microelectromechanical ultrasonic transducers (MUTs). Examples of such MUTs include electrostatic microelectromechanical ultrasonic transducers (CMUTs) and piezoelectric microelectromechanical ultrasonic transducers (PMUTs). CMUTs and PMUTs can be stand-alone transducers or integrated into electronic circuit boards that drive such MUTs.

[0076] Unique Features of the Disclosure Embodiments of the present disclosure provide at least five unique features: 1. Optimizing acoustic space-time transmission signals to enhance integrin response in bone tissue electro-cyto-matrix. 2. When transmitting SATA Tailoring the intensity, carrier and pulse repetition frequency and tilt longitudinal angle of transmitted signal excitation is necessary to promote both endosteal and periosteal healing at the fracture site. 3. Controlling the biological response of bone healing through the transmitted beam steering angle to generate an appropriate mixture of longitudinal and shear waves in the fracture path. 4. Generating the required gradient longitudinal signals by use of multi-element linear or planar phased arrays, or by other means such as acoustic model transducers using thermoplastic and elastic silicone rubber materials. 5. Positioning the beam-steered transducer above the skin during the procedure to support vascularized systemic (oxygenated) blood flow.

[0077] From the foregoing, one of ordinary skill in the art will appreciate that the embodiments of the present disclosure provide effective methods and devices that overcome many of the limitations associated with mechanical stimulation of biological material. The use of the methods and devices of the embodiments of the present disclosure in other applications, such as in therapeutic ultrasound, for example, as associated with bone fracture and wound healing, will also be readily apparent to one of ordinary skill in the art.

[0078] Although certain exemplary embodiments of the present disclosure have been specifically described herein, it will be apparent to those skilled in the art to which the present disclosure pertains that variations and modifications of the exemplary embodiments shown and described herein may be made without departing from the spirit and scope of the present disclosure.

[0079] References 1. Sarvazyan AP, Some General Problems of Biological Action of Ultrasound, IEEE Trans SU, 30(1):2-12, 1983 2.Clarke PR and Hill CR, Physical and Chemical Aspects of Ultrasonic Disruption of Cell, JASA, 47(2):649-653, 1969 3.Webster DF,Harvey W,Dyson M,Pond JB,The Role of Ultrasound-Induced Cavitation in the‘In Vitro’Stimulation of Collagen Synthesis in Human Fibroblasts,Ultrasonics:33-37,1980 4.Dyson M,Therapeutic Applications of Ultrasound,In Biological Effects of Ultrasound,Nyborg WL and Ziskin MC,eds.,Churchill Livingstone Inc,New York,1985:Chapter 11 5.Berridge MJ,Elementary and Global Aspects of Calcium Signalling,Journal of Physiology,(1997),499,2:291-306 6.Hill CR,Ultrasonic Exposure Thresholds for Changes in Cells and Tissues,JASA,52(2):667-672,1972 7.Ter Haar G,Review of Therapeutic Ultrasound,European Journal of Ultrasound,9,(1999):3-9

Claims

1. 1. An ultrasonic transducer / transmitter system comprising: a source of acoustic space-time mode consisting of a complex sine wave propagating to a site of a multi-layered biological tissue structure to promote bone tissue healing, the source comprising a single transducer combined with a wedge block; a multi-element linear or planar phased array for beam steering the acoustic space-time mode; the composite sine wave has a pulse repetition frequency and duty cycle that is osteogenic at the site of the multi-layered biological tissue healing structure; The system comprises: generating a plurality of acoustic spatio-temporal modes consisting of complex sine waves; beam steering the plurality of acoustic spatio-temporal modes to promote tissue healing, wherein particular acoustic spatio-temporal modes propagate to the site of the multi-layered biological tissue structure; generating a bimodal stress level in the multi-layered biological tissue structure that is sufficient to cause fracture healing; The composite sine wave is s(t) ＡＭ =(1+msinω ｍ t)sinω ｃ t =to sew ｃ t-(m / 2)cos(oh ｃ +oh ｍ )~+(m / 2)cos(oh ｃ -oh ｍ ) where ω ｃ is the carrier frequency, m is the modulation index that controls the degree of amplitude modulation, and ω ｍ is the modulation frequency, An ultrasound transducer / transmitter system, wherein a lower sideband of the composite sine wave utilizes 500 kHz to 1.0 MHz for bone tissue osteogenic repair and an upper sideband of the composite sine wave utilizes 2.0 to 2.5 MHz for bone tissue imaging.

2. 10. The ultrasound transducer / transmitter system of claim 1, wherein the composite sine wave includes a modulation envelope that improves space-time measurement accuracy at the site of a multi-layered biological tissue healing structure.

3. 10. The ultrasound transducer / transmitter system of claim 1, wherein the multiple acoustic space-time modes include shear waves that stimulate integrin responses in bone tissue extracellular matrix.

4. 2. The ultrasound transducer / transmitter system of claim 1, wherein when an angle of the plurality of acoustic space-time modes at a tissue layer boundary of the multi-layered biological tissue structure, which is an oblique angle of the transducer face relative to the skin surface, is less than a first critical angle, shear waves propagate along the fracture path and longitudinal waves propagate beneath the periosteal surface of bone tissue at 30-60 degrees to the tissue layer boundary.

5. 2. The ultrasound transducer / transmitter system of claim 1, wherein when an angle of the plurality of acoustic space-time modes at a tissue layer boundary of the multi-layered biological tissue structure, which is an oblique angle of the transducer face relative to the skin surface, is equal to a first critical angle, a combination of shear waves propagates along the fracture path and longitudinal waves propagate below and parallel to the periosteal surface of bone tissue at 60-90 degrees to the tissue layer boundary.

6. 2. The ultrasound transducer / transmitter system of claim 1, wherein when an angle of the plurality of acoustic space-time modes at a tissue layer boundary of the multi-layered biological tissue structure, which is an oblique angle of the transducer face relative to the skin surface, is equal to a second critical angle, only shear waves propagate along and beneath the periosteal surface of bone tissue.

7. Acoustic intensity stress levels per beam are between 30 and 70 milliwatts / cm ２ I ＳＡＴＡ 2. The ultrasonic transducer / transmitter system of claim 1, wherein the ultrasonic transducer / transmitter system has a frequency of 100 Hz to 100 Hz.

8. The acoustic intensity stress level per beam is between 40 and 50 milliwatts / cm ２ I ＳＡＴＡ 8. The ultrasonic transducer / transmitter system of claim 7, wherein the range is

9. The ultrasound transducer / transmitter system of claim 1 , wherein the low frequencies of the plurality of acoustic space-time modes are osteogenic.

10. 10. The ultrasonic transducer / transmitter system of claim 9, wherein the low frequency is in the range of 300 kHz to 3.0 MHz.

11. 11. The ultrasound transducer / transmitter system of claim 10, wherein the low frequency for long bone healing is 1.0 MHz.

12. 11. The ultrasound transducer / transmitter system of claim 10, wherein the low frequency for cervical and lumbar fusion healing is 0.5 MHz.

13. 3. The ultrasonic transducer / transmitter system of claim 2, wherein said modulation envelope is constant or is Gaussian to improve space-time measurement accuracy.

14. The ultrasonic transducer / transmitter system of claim 2 , wherein the low frequency of the modulation envelope is generated by an amplitude modulation technique.

15. 10. The ultrasonic transducer / transmitter system of claim 1, wherein the pulse repetition frequency is less than or equal to 10 kHz.

16. 16. The ultrasonic transducer / transmitter system of claim 15, wherein the pulse repetition frequency is 1 kHz for bone tissue repair.

17. 2. The ultrasonic transducer / transmitter system of claim 1, wherein the duty cycle is in the range of 10-50%.

18. 20. The ultrasonic transducer / transmitter system of claim 17, wherein the duty cycle is 20%.

19. 10. The ultrasonic transducer / transmitter system of claim 1, wherein the wedge block is constructed from a low viscous loss material including a thermoplastic, a thermoset, an elastomer, or a mixture thereof.

20. 10. The ultrasound transducer / transmitter system of claim 1, wherein said wedge block has an acoustic impedance of 1.6±6% MRayl, is non-toxic to humans, and is impermeable to human blood.

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