Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
  • A61B8/08—Clinical applications
  • A61B8/0833—Clinical applications involving detecting or locating foreign bodies or organic structures
  • A61B8/085—Clinical applications involving detecting or locating foreign bodies or organic structures for locating body or organic structures, e.g. tumours, calculi, blood vessels, nodules
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N2007/0004—Applications of ultrasound therapy
  • A61N2007/0013—Fracture healing
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N2007/0039—Ultrasound therapy using microbubbles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N2007/0052—Ultrasound therapy using the same transducer for therapy and imaging
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N2007/0073—Ultrasound therapy using multiple frequencies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N2007/0086—Beam steering
  • A61N2007/0095—Beam steering by modifying an excitation signal

Definitions

• Embodiments of the disclosure are directed to a multi-modal acoustic spatial-temporal signal with specific properties for dynamically generating the stimulation and characterization of deep biological tissue structures at frequencies that can efficiently invoke a cascade of cellular functions to accelerate tissue healing.
• Ultrasound wave propagation in tissue exerts a unidirectional radiation force on all absorbing and reflecting obstacles in its path, even at the microstmctural level
• the components of acoustic energy that can affect chemical change can be thermal, mechanical (agitational) and cavitational in nature.
• the largest non-thermal effects are those attributed to stable cavitation and mass transfer. These, in turn, can induce acoustic microstreaming, producing shear stresses on the cellular wall and boundary layer, and on the cytoskeleton.
• the latter effect due to intracellular microstreaming, can produce an increase in the metabolic functions of the cell.
• Low- intensity ultrasound refers to those power levels that just exceed biological thresholds which can trigger or evoke general biological regulatory reactions [1].
• SATA spatial average-temporal average
• the resulting bubble oscillations can generate high shear stress on the cell membrane, which can affect the cell’s permeability to sodium and calcium ions [4].
• the increase in cell permeability may result in an increase in calcium uptake
• U.S Patent No. 4,530,360 to Duarte describes a basic non-invasive therapeutic technique and apparatus for applying ultrasonic pulses externally to the skin surface at a location adjacent to the bone injury.
• To apply the ultrasound pulses during treatment an operator must manually hold the applicator in place until the treatment is complete.
• the Duarte patent as well as U.S. Patent No. 5,520,612 to Winder, et al describe ranges of RF signal for creating the longitudinal ultrasound waves, ultrasound power density levels, ranges of duration for each ultrasonic pulse, and ranges of ultrasonic pulse frequencies,
• U.S. Patent No. 6,213,958 B1 to Winder describes a diagnostic system to detect, localize, and characterize the acoustic emissions produced by applying noninvasive mechanical stimulation to the musculoskeletal system.
• the mechanical stimulation can either be static or dynamic
• the Instron testing machine shown in Figure 1 of the referenced patent implies that the excitation loading is static, The Winder invention would more readily facilitate clinical operation if the static loading could be replaced with external dynamic means.
• U.S. Patent No 7,429,248 B1 to Winder, et al describes a method and apparatus for controlling acoustic modes in tissue healing applications.
• the patent gives the same ranges of RF signal for creating the longitudinal ultrasound waves, ultrasound power density levels, ranges of duration for each ultrasonic pulse, and ranges of ultrasonic- pulse frequencies as given in U.S. Patent No. 5,520,612.
• Exemplary embodiments of the present disclosure are directed to a system and method of using an ultrasonic transducer/transraitter system to generate acoustic spatial-temporal modes that propagate to the site of a multi-layered biological tissue structure to promote tissue healing.
• These specific acoustic modes produced by beam steering and characterized by their pulse repetition frequency, duty cycle, and bi-modal stress (intensity spatial-average temporal-average; I SATA ) levels, can significantly enhance bone fracture healing.
• a method for ultrasound stimulation of musculo-skeletal tissue structures including generating a plurality of acoustic spatial-temporal modes comprised of a sinusoidal-complex, wherein the sinusoidal-complex has a modulation envelope with structural details such that it enhances spatial-temporal measurement accuracy at a site of a multi-layered biological tissue structure, and a pulse repetition frequency and duty cycle that are osteogenic at the site of the multi-layered biological tissue structure, beam steering the acoustic spatial-temporal modes to the site of the multi-layered biological tissue structure to promote tissue healing, and producing bi-modal stress levels in the multi- layered biological tissue structure that are sufficient to generate bone fracture healing.
• the acoustic spatial-temporal modes include shear waves that promote integrin response of bone tissue extracellular matrix.
• the beam steering utilizes multi- element linear or planar phased arrays or a single element that drives a wedge block.
• an angle of the acoustic spatial-temporal modes at a tissue layer boundary in the multi-layered biological tissue structure is less than a first critical angle, shear waves propagate along a fracture channel and longitudinal waves propagate at 30-60° with respect to the tissue layer boundary below a periosteal surface of bone tissue.
• an angle of the acoustic spatial -temporal modes at a tissue layer boundary in the multi-layered biological tissue structure is substantially equal to the first critical angle
• a combination of shear waves propagate along the fracture channel and longitudinal waves propagate at 60-90° with respect to the tissue layer boundary below and parallel to the periosteal surface of bone tissue.
• an angle of the acoustic spatial- temporal modes at a ti ssue layer boundary in the multi -layered biological tissue structure is substantially equal to a second critical angle, only shear wa ves propagate along and just below the periosteal surface of bone tissue.
• an acoustic intensity stress level per beam ranges from 30 to 70 milliwatts/cm 2 I SATA .
• the acoustic intensity stress level per beam ranges from 40 to 50 milllwatls/cm I SATA .
• low frequencies of the acoustic spatial-temporal modes are osteogenic.
• the low frequencies range from 300 kHz to 3.0 MHz.
• the low frequency for long bone healing is 1.0 MHz.
• the low frequency for healing of cervical and lumbar fusions is 0.5 MHz.
• the modulation envelope is constant.
• the modulation envelope is a
• low frequencies of the modulation envelope are produced by amplitude-modulation techniques wherein the sinusoidal-complex is represented as:
• w c is the carrier frequency
• m is a modulation index that controls a degree of amplitude modulation
• w m is a modulation frequency.
• a lower sideband of the sinusoidal- complex utilizes 500 kHz- 1.0 MHz for bone tissue osteogenic repair and the upper sideband of the sinusoidal-complex utilizes 2.0-2.5 MHz for bone tissue imaging.
• the pulse repetition frequency (PRF) is equal to or less than 10 kHz.
• the pulse repetition frequency is about 1 kHz
• the duty cycle ranges from 10-50%
• the duty cycle is about 20%.
• an ultrasonic teansducer/transmitter system that includes a source of acoustic spatial-temporal modes comprised of a sinusoidal-complex that propagates to a site of a multi-layered biological tissue structure to promote tissue healing, wherein the source comprises a single transducer combined with a wedge block, and a multi-element linear or planar phased array that beam steers the acoustic spatial-temporal modes.
• the wedge block is composed of low viscous loss materials that include thermoplastics, thermosets, elastomers, or mixtures thereof
• the wedge block has an acoustic impedance of 1.6 +/- 6% MRayls, is nontoxic in humans, and impermeable to human blood.
• FIG. 1 illustrates the multi-modal transmission of an oblique NEWSIG into rabbit tissue for a beam-steering angle of 10.5 of the transducer face relative to the skin surface, according to embodiments of the disclosure.
• FIG. 2 illustrates the multi-modal transmission of an oblique NEWSIG into rabbit tissue for a beam-steering angle of 13.5° (the first critical angle (CA1)) of the transducer face relative to the skin surface, according to embodiments of the disclosure.
• CA1 first critical angle
• FIG. 3 illustrates the multi-modal transmission of an oblique NEWSIG into rabbit tissue for a beam-steering angle of 31.5° (the second critical angle (CA2)) of the transducer face relative to the skin surface, according to embodiments of the disclosure.
• CA2 the second critical angle
• FIG. 4 is a flowchart of a method for ultrasound stimulation of musculo-skeletal tissue structures, according to an embodiment of the disclosure.
• Exemplary embodiments of the disclosure as described herein generally provide a method for generating a multi-modal acoustic signal at certain stress levels and frequencies that stimulates and characterizes deep biological tissue structures at frequencies that can accelerate tissue healing. While embodiments are susceptible to various modifications and alternative forms, specific embodiments thereof are shown by way of example in the drawings and will herein be described in detail. It should be understood, however, that there is no intent to limit the disclosure to the particular forms disclosed, but on the contrary, the disclosure is to cover all Modificatio s, equivalents, and alternatives failing within the spirit and scope of the disclosure.
• Embodiments of the disclosure are directed to the design and generation of a new multi- modal signal, rich in shear waves, to optimize the integrin response for the low frequency stimulation of biological tissue structures. This would be highly beneficial to both bone and wound healing, as well as (potentially) spinal fusion healing. Biomechanical principles are applied to the therapeutic treatment of fractures of the extremities, and metric measures are proposed to characterize the healing process.
• Embodiments of the disclosure provide radiation pressure and measured target response properties for, but not limited to, acoustic emission monitoring, bone tissue growth, bone fracture heating, spinal lumbar and cervical fusion, muscle reeducation, and tissue wound healing.
• acoustic waves to efficiently enhance the diagnosis, therapy, and surgery of a biological system depends on a detailed understanding of the system’s physical properties, such as particle displacement, particle velocity, stress, strain, and elasticity.
• physical properties such as particle displacement, particle velocity, stress, strain, and elasticity.
• bone tissue can support remodeling and remineralization in the final healing phase.
• Animal connective tissues consist largely of an extracellular matrix comprised mainly of collagen, the chief protein in bone that cells secrete around themselves. It is the collagen in this matrix that gives supportive tissues their tensile strength.
• Low-intensity pulsed ultrasound (LIPUS) stimulation of the extracellular matrix outside a cell is transferred across a weak plasma membrane to the cytoskeleton in an animal cell via molecular protein linkages called mtegrins.
• LIPUS Low-intensity pulsed ultrasound
• LIPUS enhances soft callus mineralization (endochondral ossification) in the second stage of healing and further increases the fracture hard callus strength in the rermneralization and remodeling phases that occur in the third (and last) stage of heal ing.
• the integrin molecular protein response is key to generating the cellular function of protein synthesis, resulting in a clinical bone healing physiological response.
• integrals respond best to shear wave radiation pressure.
• a signal that stimulates bone tissue repair should be rich in shear waves and be matched to the biological response relaxation times of bone tissue. This will maximize the callus index, defined as the ratio of the callus diameter to bone diameter, and the bone density in the fracture channel.
• shear waves can he generated by a specially designed coupling wedge serving as an acoustic modal converter (AMC) that can spatially control the acoustic longitudinal waves transmitted normal to the bone by a piezoelectric transducer to produce both shear and longitudinal waves interior to the bone surface.
• AMC acoustic modal converter
• the particle direction of shear waves is normal to the propagation direction, permitting two types of shear waves to exist, namely, shear horizontal (SH) and shear vertical (SV), depending upon the direction of particle oscillation with respect to the propagation direction.
• SH shear horizontal
• SV shear vertical
• a random shear wave incident at a boundary between two different solid media contains both SH and S V components.
• SV waves can undergo modal conversion according to the boundary condition established by Snell's Law that also governs the interaction of the longitudinal wave at the interlace between a medium 1 and a medi um 2:
• EQ ( 1 ) demonstrates that when a wave moves from a slower to a faster material, there is an incident angle, known as the first critical angle, which makes the angle of refraction for the longitudinal wave 90 degrees. If the angle of incidence becomes greater than the first critical angle, only the shear wave propagates into the material In most materials, there is also an incident angle that makes the angle of refraction for the shear wave 90 degrees. This is referred to as the second critical angle.
• Embodiments of the disclosure can optimize the longitudinal and shear content of interacting acoustic waves to enhance a bone healing physiological response, and promote integrin response of bone tissue ex tracellular matrix.
• Beam steering can control the relative amount of propagating longitudinal and shear energy in hone tissue, and the amount of heat energy generated.
• the control of beam steering angles is known in underwater sonar, radar, and medical applications, and is achieved in several different ways utilizing: (1) multi-element linear or planar phased arrays of transducer elements; and (2) single transducers embedded in intermediate wedges of various materials that control the relative indices of refraction between transducer/wedge and intervening biological material layers.
• Signal steering is done by adjusting the relative phase (timing) of the waveform emitted by each element, which effectively cancels the wave propagation in one or more directions and reinforces it in other directions.
• Linear arrays are arrays of rectangular transducer elements which by their shape produce a non-hem ispherical propagating wa ve. The elements of a linear array can also be phased to further steer the beam.
• a specially designed coupling wedge acting as an acoustic modal converter is a simple approach in medical ultrasound research to producing both normal and oblique longitudinal modes to be propagated to the bone fracture.
• the coupling wedge is generally considered to be a viscoelastic material.
• An AMC according to an embodiment includes suitable low viscous loss materials that include, but are not limited to, thermoplastics, thermosets, elastomers, or mixtures thereof.
• AMC design considerations include the velocity of sound, acoustic attenuation, acoustic impedance, toxicity in humans, permeability to human blood, and ability to produce an acoustic free-field from the embedded radiating transducer.
• An AMC according to an embodiment has an acoustic impedance of 1.6 +/- 6%
• MRayls is nontoxic in humans, and impermeable to human blood.
• an 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 be characterized with both viscous and elastic components to meaningfully affect bone fracture repair.
• a propagating longitudinal acoustic signal that is incident on a tissue layer boundary at an oblique angle has three components: (1) a reflected longitudinal signal where the reflection angle equals the incident angle; and a bi-modal signal transmitted into the interior of the bone, propagating as both (2) shear and (3) longitudinal waves.
• the bi -modal signal incident at the muscle/bone tissue interface, rich in both longitudinal and shear wave content, is referred to herein below as a new acoustic signal (“NEWSIG”).
• the effectiveness of the NEWSIG depends on providing sufficient energy to the acoustic modes, matched to the unique character of each mode, that is, whether it is longitudinal or shear.
• shear waves are more lossy than longitudinal waves, and to utilize them, their intensity levels should be increased relative to that of the longitudinal waves.
• the increase in shear intensity in bone tissue is based on empirical research studies.
• the intensity spatial- average temporal-average (ISATA) for the longitudinal modal component should be about 0.6 the intensity spatial- average temporal-average (ISATA) for the longitudinal modal component.
• the I SATA for longitudinal excitation is about 30 mW/cm 2
• the I SATA for shear excitation should be about 50 mW/cm 2 .
• adjusting the intensity can produce an effective shear mode for multi-modal tissue healing. These adjustments compensate for the fact that the shear waves travel slower than longitudinal waves and dissipate more heat energy in propagating through bone tissue.
• the new signal can accelerate both the treatment of long bone fracture healing and promote the healing of lumbar and cervical spine fusions.
• a NEWSIG according to an embodiment has sufficient spectral energy in a specific range of low frequencies, such that there will he several biological osteogenic effects; (1) an increase in the permeability of the cellular wall membrane, which enhances the diffusion process for calcium uptake and protein synthesis; (2) an increase in the hemoglobin released; and (3) effect the gene expression within the insonated tissue.
• FIG. 4 is a flowchart of a method for ultrasound stimulation of musculo-skeletal tissue structures, according to an embodiment of the disclosure.
• the method begins at step 41 by generating a plurality of acoustic spatial-temporal modes.
• the acoustic spatial-temporal modes include a sinusoidal-complex that has a modulation envelope whose structural details enhance spatial-temporal measurement accuracy at a site of a multi-layered biological tissue structure, and a pulse repetition frequency and duty cycle that are osteogenic at the site of the multi-layered biological tissue structure.
• the acoustic spatial-temporal modes are beam-steered at step 41 to the site of the multi-layered biological tissue structure to promote tissue healing, and at step 45 produce bi-modal stress levels in said multi-layered biological tissue structure that are sufficient to generate bone fracture healing.
• the acoustic spatial- temporal modes include shear waves that promote integrin response of bone tissue extracellular matrix.
• the Duarte Signal is the only FDA-approved acoustic signature for accelerating the healing of long bone fractures
• a Duarte signal has a nominal frequency of the ultrasound is 1.5 MHz, the width of each pulse varies between 10 and 2,000 microseconds, the pulse repetition rate varies between 100 and 1,000 Hz, and the power level of the ultrasound is maintained below 100 milliwatts per square centimeter.
• the primary difference between the Duarte Signal and a NEWSIG according to an embodiment is that the Duarte Signal is a higher frequency longitudinal wave while a NEWSIG is a lower frequency longitudinal shear wave that results in greater healing osteogenic action at deeper penetration of biological bone tissue.
• the primary spectral energy content of a NEWSIG lies in the frequency band from 3 Hz to 3 MHz, has a pulse repetition frequency (PRF ⁇ less than 10 kHz, a duty cycle from 10-50%, an I SATA from 3-400 mW/c , a modulating envelope from constant to Gaussian and a dosage time less than 60 minutes.
• a NEWSIG for musculo-skeletal hone 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, a constant or Gaussian envelope, a maximum PRF of 1 kHz, a duty cycle £ 20%, an I SATA from 30 to 150 mW/cm at the skin interface, and a daily dosage time equal to or less than 20 minutes. Due to signal demodulation that occurs in the fracture channel, a PRF of 1 kHz is better matched to the relaxation time of bone tissue, in the low 1 millisecond region.
• the low frequencies of the acoustic spatial-temporal modes are osteogenic, and range from 300 kHz to 3.0 MHz.
• the low frequency for long bone healing is 1.0 MHz
• the low frequency for healing of cervical and lumbar fusions is 0.5 MHz.
• an acoustic intensity stress level per beam ranges from 30 to 70 milliwatts/cm 2 I SATA
• the acoustic intensity stress level per beam ranges from 40 to 50 milliwatts/cm 2 I SATA .
• an osteogenic spectral envelope can be obtained by utilizing well known amplitude and frequency modulation technology.
• the simplest amplitude modulation method utilizes the phased linear sura of transmitted sinusoidal waves in the focal zone represented by the following trigonometric identity:
• s(i) is the transmitting signal
• A is the carrier frequency
• D is the desired low osteogenic frequency
• another low spectral frequency envelope is produced by varying the magnitude of the carrier in accordance with the amplitude and frequency of the modulating source.
• this can be represented as: s( t) AM — (1 + m sin w m t) sin w) c t
• osteogenic stimulation may be optimized.
• the spatial array directivity and range resolution increases with frequency, with the result that finer pathology details can be discerned in tissue images.
• the higher sideband of 2.0 to 2,3 MHz provides more spatial and range resolution and higher SNR for increased detectability and is therefore used for hone tissue diagnostic imaging, but is limited by the associated energy absorption that increases with increasing frequency, making it. tissue- depth-limited.
• the lower sideband of 500 kHz to 1.0 MHz is primarily useful for bone tissue osteogenic repair at deeper depths, but is limited by cavitation effects that increase with decreasing frequency.
• a randomized, double-blind POC study has shown that the clinical potential of a multimodal transmission according to an embodiment is that such treatment initially enhances critical revascularization in the initial inflammatory phase and again at the end of the soft callus phase, just before bone tissue remodeling adapts to mechanical requirements id the final hard callus phase.
• a POC study according to an embodiment was modeled after Pilla’s work at Ml Park, N.Y.C., and depends on published research over the past forty years measuring the properties of shear waves in biological tissue.
• a POC study according to an embodiment used AMCs that produced an oblique NEWSIG at 105°, a NEWSIG at 13.5°, and a NEWSIG at 31.5°. These angles are oblique angles of the measured signal at the AMC/skm interface as shown in FIGS. 1-3, respectively.
• the AMCs were positioned to support systemic blood flow (from distal to proximal).
• the signal transmission power levels were adjusted to compensate for absorption through the AMC.
• the spatial average-temporal average intensity ( I SATA ) at. the wedge/skhi interface was adjusted to be 30 mW/cm 2 for transmitted normal longitudinal waves and 40 mW/cm 2 for oblique longitudinal waves.
• FIGS. 1-3 illustrate the multi-modal transmission of an oblique NEW .1G into rabbit tissue for various angles of the transducer lace relative to the skin surface, according to embodiments of the disclosure.
• q is the oblique angle of the transducer face relative to the skin surface, with 0° representing the transducer face parallel to the skin for normal transmission;
• f is the refracted angle of the ultrasound wave propagating from the AMC into the tissue, measured relative to the perpendicular (normal);
• a 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);
• b is the refracted angle of the longitudinal portion of the ultrasound wave propagating from the overlyin1 tissue into the bone, measured relative to the perpendicular (normal); and the triangle is the acoustic wedge AMC, and XDR is the transducer.
• the estimated thickness of the muscle tissue between the skin surface to the hone fibula is 1.5 cm
• the measured longitudinal velocity of the acoustic wave for the AMC material is 921 m/s
• the phase velocity through the muscle tissue is from 1560 to 1580 m/s.
• the phase velocity of the longitudinal components is 3500-3900 m/s along the surface of the bone tissue and 3100 m/s along the fracture channel
• the phase velocity of the shear components is 1700-1750 m/s along the surface of the bone tissue and 1600-1650 m/s along the fracture channel.
• FIGS. 1 -3 show that when an angle of the acoustic spatial-temporal modes at a tissue layer boundary in the multi-layered biological tissue structure is 10.5°, less than the first critical angle of 13.5°, comprised of shear waves that propagate along a fracture channel at about 19° and longitudinal waves that propagate at 30-60° with respect to the tissue layer boundary below a periosteal surface of bone tissue.
• an angle of the acoustic spatial-temporal modes at a tissue layer boundary hi the multi-layered biological tissue structure is substantially equal to the first critical angle
• a combination of shear waves propagate along the fracture channel at about 24° and longitudinal waves propagate at 60-90° with respect to the tissue layer boundary below and parallel to the periosteal surface of bone tissue.
• an angle of the acoustic spatial-temporal modes at a tissue layerboundary in the multi-layered biological tissue structure is substantially equal to 31.5°, which is the second critical angle, only shear waves propagate along and just below the periosteal surface of bone tissue.
• design of a BGS signal should consider the linear and nonlinear characteristics of the propagating medium.
• the dynamics of living tissue are generally nonlinear; however, to facilitate the understanding and visualization of physical phenomena, the response to various stimuli is linearized, both natutaUy-oceurring in nature and man-made.
• This linearization process is well-known and is often termed the small-amplitude case.
• the small- amplitude or low intensity case is considered nan-thermal and therefore produces biological effects through mechanical stimulation, only, which can be either static or dynamic.
• the two most well-known non-themal nonlinear effects are cavitation and acoustic streaming.
• Common measures of noo-!hermai nonlinear ultrasound behavior in biological tissue are the mechanical index (MI) and the beam nonuniformity ratio (BNR).
• MI mechanical index
• BNR beam nonuniformity ratio
• TI thermal index
• the MI is a measure of the destructive behavior of ultrasound induced in biological tissue due to cavitation effects, and is intended for B-niode short-pulse, low duty cycle ( ⁇ 2%) diagnostic imaging where high peak pressures are often obtained.
• the 1992 AIUM-NEMA Standard proposes an acceptable value for M1 of less than 0.7 (p. 144, Section 7.1) in the unscanned mode, below which cavitation (theoretically) will not occur. It was assumed that stabilized pockets of gas or free bubbles exist in vivo - which clinically, other than for contrast agents, is Still not certain.
• the tested FDA-approved device produces an M1 ⁇ .1 for 20 Vp-p and 1.5 MHz and the test device produces an MI ⁇ 0.2 for 25 Vp-p and 1.0 MHz.
• the BNR is defined as the [max I SPTA / I SATA [ I SPTA ] is at the acoustic axial distance of maximum pressure, which for unfocused transducers is at a point approximately the (transducer diameter) /(4 x wavelength l). and I SATA is the total acoustic power divided by the Effective Radiation Area (ERA),
• the ERA is the width of the beam intensi ty profile function at the -13 dB point, at a distance of 5 mm along the transducer axis; measured in the in vivo POC study referred to earlier to be about 130 mm.
• the ERA in the study is approximately equal to 3,88 cm 2 , corresponding to an electrode diameter of 0,875 inches or 22.22 mm.
• the maximum measured value of BNR for the test device in the POC study was less than 5.0.
• the FDA requires that the BNR for therapeutic devices be less than 8.0 and that the measured maximum value be indicated on the label of the device.
• the thermal index of importance for long bones, scaphoid, metatarsal and head depends on the bone near the surface and is designated the thermal index for cranial bone (TICB),
• TICB W o / 40 D eq (6)
• W o (in mW) Is the time average acoustic power at the radiated surface of the transducer and D eq is the equivalent diameter (in cm) o f the active (or electroded) transducer area.
• the low osteogenic frequencies characterized by a NEWSIG can be generated by a transducer having electromagnetic, piezoelectric, electrostrictive, or magnetostrictive active elements.
• the ac elements can be in the form of a single or multilayer component made of one or combination of materials named above.
• the active elements can be made of composites of such materials with polymeric, void and/or metallic components.
• active elements made of such materials can generate low frequency waves via flextensional effects attainable with unimorphs, monoinorphs, bimorphs, cymbals moonies, thunders, rainbows, cerambows, etc, known by those skilled in the art.
• the frequencies mentioned in the embodiment can be generated by mechanical vibrations of air molecules or molecules of a medium in contact with human body using speakers, buzzers, tuning forks, and/or any nonactive mechanical vibrating elements being driven by the active elements mentioned above.
• the low osteogenic frequencies disclosed here can also be generated by transducers made of micro-electro-mechanical ultrasonic transducers (MUTs), Examples of such MUTs include a capacitive micrbelectrornechanical ultrasonic transducer (CMUT) and a piezoelectric microelectromechanica ultrasonic transducer (PMUT).
• CMUT capacitive micrbelectrornechanical ultrasonic transducer
• PMUT piezoelectric microelectromechanica ultrasonic transducer
• the CMUT and PMUT can be stand-alone transducers or be integrated on an electronic circuit board driving such MUTs.
• Embodiments of the disclosure provide at least five (5) unique features, namely. 1. Optimizing the acoustic spatial-temporal transmitted signal to enhance the integrin response of the hone tissue electro-cellular matrix.
• embodiments of the present disclosure provides an effective method and apparatus for overcoming many limitations associated with the mechanical stimulation of biological materials it will also be readily appreciated by one with ordinary skill in the art to use the method and apparatus of embodiments of the present disclosure in other applications, such as in therapeutic ultrasound, as related to bone fracture and wound healing, for example.
• Dyson M Therapeutic Applications of Ultrasound. In Biological Effects of Ultrasound, Nyborg WL and Ziskin MC, eds., Churchill Livingstone Inc, New York, 1985; Chapter 1 1.

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