Fracture healing assessment of musculo-skeletal tissue structures

Abstract

A system for assessing fracture healing in real time using low intensity pulsed ultrasound (LIPUS) excitation includes a transducer that transmits a longitudinal fracture healing assessment diagnostic signal at an angle of 0º(> (normal) to the transducer or at an oblique angle up to a first critical angle of 20 degrees, or receives one or more FHA echo signatures, and a processor. The processor is configured to sum the received echo signatures, convert the received echo signatures to an analytic echo signal, normalize the analytic signal against healthy bone signatures, sum the set of normalized analytic signatures and create a data vector; generate a. real-time diagnostic fracture healing assessment metric by processing the data vector using one or more metrics; and identify a stage of bone fracture healing by using the real-time diagnostic fracture healing assessment metrics.

Description

[0001] FRACTURE HEALING ASSESSMENT OF MUSCULOSKELETAL TISSUE STRUCTURES

[0002] BACKGROUND

[0003] Technical Field:

[0004] Embodiments of the disclosure are directed to a method and system that produces longitudinal acoustic waves for real-time monitoring the quality of bone fracture healing achieved with primarily shear waves.

[0005] Discussion of the Related Art:

[0006] Bone fractures are one of the most common traumas that humans experience and are the main outcome of osteoporosis, a common chronic disease associated with aging. Skeletal tissue repair is currently assessed at several levels: at the tissue and whole organ level, via X-Ray, computed tomography (CT), micro-CT, and magnetic resonance imaging (MRI); at the cellular level, via micro-CT and histological analysis; and at. the molecular level, via immune-histological analysis, as well as analysis of messenger RNA (mRNA) and protein expression. These modalities all have significant limitations, notably including size, cost, complexity and the use of ionizing radiation, that a home use approach employing ultrasound excitation would overcome. Conversely, low intensity pulsed ultrasound (LIPUS) is a highly promising imaging modality that has been shown to be non-ionizing and capable of measuring the change in osseous tissue properties, based on the core principle that sonic propagation velocity' is directly correlated to a material's elastic modulus and Poisson’s ratio, and that spectrum and correlation technology allow estimation of bone mechanical strength and anisotropy [1-4],

[0007] SUMMARY

[0008] Embodiments of this disclosure provide a method that obtains and analyzes data in real- time. Embodiments disclose computing four metrics to increase accuracy of healing assessment: bone mineral density, speed-of-sound, ultrasound attenuation, and elastic modulus. Embodiments further disclose transmitting a longitudinal signal at an angle either normal to the long bone axis, or at the first critical angle of about 15 to 20 degrees relative to the long bone axis, thereby' producing a longitudinal signal that travels along the surface of the long bone axis (i.e.,, the periosteum). In an embodiment herein, “real-time” refers to each treatment session, wherein the data collected for assessment is made in one minute of a standalone FHA diagnostic device operation, or the first minute of an integrated FHA and bone growth stimulation (BGS) diagnostic / treatment cycle of 21 minutes. Real-time monitoring during the first two stages of bone fracture healing will substantially encourage patient compliance and may detect delayed or non-union fractures at an earlier point in time, which could possibly lead to earlier surgical intervention where necessary.

[0009] According to an embodiment of the disclosure, there is provided a system for assessing the real-time healing of a bone fracture in real time using low intensity pulsed ultrasound (L1.PUS) excitation. The system includes a transducer that transmits into a bone fracture a longitudinal fracture healing assessment (FHA) diagnostic signal, at an angle of 0° (normal) to the transducer or at an oblique angle up to a first critical angle of about 20 degrees, or receives one or more FHA echo signatures, and a processor. The processor is configured to: (a) sum the received echo signatures, convert the received echo signatures to an analytic echo signal, normalize the analytic signal against a bone standard and generate a set of normalized analytic signatures, sum the set of normalized analytic signatures, and create a data vector; (b) generate a real-time diagnostic fracture healing assessment metric by processing the data vector using one or more metrics, wherein the one or more metrics include bone mineral density, speed-of-sound, ultrasound atenuation, or elastic modulus; and (c) identify a stage of bone fracture healing by using one or more of the real- time diagnostic fracture healing assessment metrics.

[0010] According to a further embodiment of the disclosure, the FHA diagnostic signal includes a Gaussian structural waveform and is transmitted at a resonant carrier frequency between 0,5 MHz to 5,0 MHz, with a duty cycle of 0.4-20%, a period of 1 ms, a pulse width of 4-200 microseconds, a pulse repetition frequency (PRF) of about 1.0 kHz, and a spatial average-temporal average intensity (ISPTA) of about 30 mW / cni2.

[0011] According to a further embodiment of the disclosure, the FHA diagnostic signal is transmitted at a resonant carrier frequency between 2.0 MHz and 3.0 MHz, and wherein the resonant carrier frequency is modulated by linear frequency modulation so that spatial resolution, dynamic range, signal-to-noise ratio (SNR) are increased, and clutter interference is reduced.

[0012] According to a further embodiment of the disclosure, the FHA signal is transmitted by one or two acoustic transducers in a range of 0.5 to 5.0 MHz, that provide the longitudinal FHA transmission at 0 degrees along the MKA or at an oblique angle up to the first critical angle, According to a further embodiment of the disclosure, the one or two acoustic transducers focus the FHA, signal at an ISATA intensity level of about 30 mW / on2into the bone fracture. According to a further embodtnient of the disclosure, two acoustic transducers are positioned on each side of the bone fracture, and wherein a propagation velocity of the FHA signal across the bone fracture is another metric that establishes the stage of bone fracture healing by comparing the received echo of the bone fracture to that of an intact bone.

[0013] According to a further embodiment of the disclosure, multiplied outputs of two transducers are sent to a low-pass filter that removes high-frequency outputs by doubling a directivity of the multiplicative array and a system dynamic range (in dB). According to a further embodiment of the disclosure, the one or two transducers are positioned within or alongside a larger AMCbembedded transducer resonant at 1 .0 MHz.

[0014] According to a further embodiment of the disclosure, the transducer is a multi-element transducer and uses a beamformer that electronically sweeps the FHA diagnostic signal through a series of angular direction steps from a first angle to a second angle via adjustments to a phase of a signal that drives each transducer array element of the multi -element transducer,, selects a signal with a maximum amplitude or signal-to-noise ratio from a set of signals received at each angle, and transmits the selected signal into the bone fracture.

[0015] According to a further embodiment of the disclosure, the transducer is a multi-element transducer and uses a beamformer that electronically sweeps the FHA diagnostic signal through a series of angular direction steps from a first angle to a second angle via adjustments to a phase of a signal that drives each transducer array element of the multi-element transducer, processes signals received at each of the angles, and transmits a desired signal from the processed signals into the bone fracture. According to a further embodiment of the disclosure, the FHA signal is transmitted by one or more circular ring transducers in a range of 0.5 to 5,0 MHz and that form a concaved or focused dedicated annular array, wherein an AMC-embedded transducer is pos itioned at the center of the annular array, wherein each circular ring of the annular array has a thickness of about 1.5 to 2 mm, and wherein each circular ring of the annular array is separated from an adjacent ring by about 100 microns. According to a further embodiment of the disclosure, the transducer is a time modulated array (TMA) implemented as a multi-element planar array.

[0016] According to a further embodiment of the disclosure, the processor estimates state variables of the transducer by suboptimal filtering, wherein the state variables include radiated pressure, acceleration, input current to the transducer, and efficiency.

[0017] A ccording to a farther embodiment of (he disclosure, the processor con verts the data vector from analog to digital format, stores the digital data vector in persistent memory, and transmits the digital data vector to another system for data analysis puiposes. According to a further embodiment of the disclosure, farther comprising a therapeutic bone growth stimulation (BGS) device.

[0018] BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 depicts the diagnostic FHA and. therapeutic BGS signals, according to an embodiment of the disclosure [P- 1 ]. FIG. 2 is a functional block diagram of echo reception, echo signature conditioning, and digital subsystem, according to an embodiment of the disclosure.

[0020] FI.G. 3 is functional block diagram format of data acquisition and processing operations, according to an embodiment of the disclosure.

[0021] FIG. 4 illustrates one or two dedicated FHA transducers alongside or embedded in an acoustic model converter (AMC) of a BGS transducer, according to an embodiment of the disclosure [P-3].

[0022] FIG. 5 illustrates one or more annular ring arrays around the embedded AMC circular transducer, according to an embodiment of the disclosure.

[0023] FIG. 6 illustrates a standalone FHA transducer configuration with two transducers in a biaxial transmission configuration according to embodiments of the disclosures, and used to measure the elastic properties of the bone tissue.

[0024] FIG 7. illustrates a standalone FHA transducer configuration of two transducers in a multiplicative array according to embodiments of the disclosures, and used to measure the elastic properties of the bone tissue.

[0025] DETAILED DESCRIPTION

[0026] The term “about" as used herein is inclusive of the stated value and means within an acceptable range of deviation for the particular value as determined by one of ordinary skill in the art, considering the measurement in question and the error associated with measurement of the particular quantity, such as the limitations of the measurement system. For example, “about” may mean within one or more standard deviations as understood by one of ordinary skill in the art Further, it is to be understood that while parameters may be described herein as having “about” a certain value, according to embodiments, the parameter may be exactly the certain value or approximately the certain value within a measurement error as would be understood by a person skilled in the art.

[0027] Overview

[0028] The method disclosed herein provides a method for real-time monitoring of bone fracture healing and assessment using LIPUS excitation. In one embodiment, this capability may be built into a stand-alone diagnostic device. In another embodiment, this capability may be packaged with an external bone growth stimulation device, to provide feedback on therapeutic treatment.

[0029] FHA provides patients with feedback on the progression of their healing via an integrated mobile application. At the patient’s discretion, this information will also be available to the orthopedic care professional who presented the device via a HlPAA-compliaut web space. The choice of a proper transmit signal’s PRF depends on the biology. When treating a specific anatomical bone structure of interest, the signal waveform should support the relaxation time (1 / PRF) of the insonified tissue. A long bone can be considered an acoustic waveguide; thus, insonifying a fractured long bone with a specific repetitive sequence of pulses not only will result in echo signatures at the transmitted frequency, but also in a demodulation to the PRF. Thus, depending on the tissue relaxation time in the fracture channel, it is estimated that the demodulatedfrequency can be between 500 Hz and 2 kHz, detectable in the early stages of healing, such as the first two stages as defined in the Data Analysis section below. Embodiments of this disclosure utilize a single-element transducer with an embedded acoustic modal converter (AMC) that transmits the FHA diagnostic signal at 0 degrees along the maximum response axis (MRA) or at an oblique angle with respect to the MRA up to the first critical angle.

[0030] Other embodiments of this disclosure utilize a multi-element linear or planar array providing azimuthal steering of the transmitted ultrasound beam by adjusting the relative phase of the individual elements, in a manner known to those skilled in the art. The steering is done from a starting angle through to an ending angle, in convenient steps with a step size such as I angular degree. The received signals for each step are sent for further processing. Alternatively, the set of received signals is analyzed in the receiver apparatus to ascertain the received signal with the highest desired characteristic such as amplitude or signal-to-noise ratio, after which this signal is transferred to a remote processor for further algorithmic processing.

[0031] FHA, Signal Cha ract eristics

[0032] An acoustic waveguide, such as a bone fracture channel, can support both shear and longitudinal waves. When an acoustic wave moves from a slower to a faster material, there is an incident angle known as the “first critical angle” that makes the angle of refraction for a longitudinal wave 90 degrees (as measured from the normal to the interface between the two materials). In most materials, there is also an incident angle that makes the angle of refraction for a shear wave 90 degrees. This is referred to as the “second critical angle.”

[0033] A L1PUS FHA diagnostic operational frequency band according to an embodiment for diagnostic treatment (FHA mode) is from 0.5 MHz to 5.0 MHz, with a duty cycle of 0.4-20%, a period of 1 ms, and a spatial average-temporal average intensity (ISPTA) of about 30 mW / cmf For a total transmission time of one (1) minute prior to the start of the bone healing treatment, an FHA signal is transmited normal to the transducer along the maximum response axis (MRA) or at an angle oblique io the axis of the long bone up to the first critical angle (15-20 degrees).

[0034] In an embodiment, the diagnostic signal is interleaved with a therapeutic signal. The diagnostic signal has a much shorter duration than the therapeutic signal, by about an order of magnitude. For example, FIG. 1 shows 1 minute of an FHA diagnostic signal followed by 20 minutes of a BGS therapeutic signal for a single daily treatment. As shown in FIG. I, the FHA diagnostic longitudinal signal has a Gaussian structural waveform with a pulse width of 4 microseconds, while the BGS therapeutic signal has a rectangular structural waveform with a pulse width of 200 microseconds, and both modes for a pulse temporal period of 1 ms. However, embodiments are not necessarily limited thereto, and a more intimate interleaving also works, in which several cycles of diagnostic signal generation and capture are followed by several cycles of therapeutic signal generation.

[0035] There are several differences between the BGS diagnostic signal and the FHA therapeutic signal, including but not limited to the signal envelope, the spatial, average-temporal average intensity (ISATA), and the transmit carrier frequency :

[0036] The signal envelope is typically Gaussian for the diagnostic signal and rectangular for the therapeutic signal, as shown in FIG. 1, although other envelopes, such as but not limited, to Flamming or Hanning envelopes also work. * The BGS therapeutic ISATA for bone fracture healing is about 50 mW / cnr (40-60 mW / cm2) and the ISAYA for FHA diagnostic imaging and fracture healing assessment is about 30 mW / cn?.

[0037] * The therapeutic transmit earner frequency is 1.0 MHz, but for FHA diagnostic operation the transmit carrier frequency may be 2.0 - 3.0 MHz and may also be modulated, such as via linear frequency modulation (LFM), to significantly increase spatial resolution, dynamic range, and signal-to-noise ratio (SNR) and to reduce clutter interference.

[0038] Transducer Planar Array Subsystem

[0039] The position of the active planar array transducer is distal to the fracture and oblique to the MRA at either the first critical angle for the diagnostic phase, wherein the transducer propagates longi tudinal waves along the axis of the bone, or at the sec ond critical angle for the treatment phase wherein the transducer propagates shear waves along the axis of the bone. The first critical angle is about 15-20 degrees, and the second critical angle is about 31.5 degrees, wherein both angles are relative to the long bone axis.

[0040] Thus, there are many possible FHA transducer configuration embodiments, including but not limited to:

[0041] 1. A. single standalone acoustic transducer having a diameter of about ,15mm to 25 mm, and a resonant frequency from 0.5 to 5.0 MHz, that can provide the longitudinal FHA transmission at. 0 degrees along the MRA or at an oblique angle up to the first critical angle, noting that embodiments of the disclosure are not necessarily limited to those dimensions. 2. A single acoustic transducer having a resonant frequency from 0.5 to 5.0 'MHz, that can provide the FHA transmission at 0 degrees along the MRA or at an oblique angle up to the first critical angle, that can be embedded within or positioned alongside a larger AMC-embedded BGS therapeutic transducer resonant at I MHz, where the diameter of the smaller transducer is- less than about 15mm and that of the larger transducer is about 20mm, noting that embodiments of the disclosure are not necessarily limited to those dimensions. For example, a smaller (<15 mm) concave FHA transducer can focus the acoustic beam at the desired ISAIA intensity' level into the fracture gap. The smaller FHA transducer can be used for general bone quality assessment of cortical long bone, properties, such as cortical thickness, anisotropic stiffness, and porosity [5], This embodiment is illustrated in FIG. 4.

[0042] 3. Adding one or more FHA ring transducers comprising an annular array around the embedded AMC transducer described in the second embodiment above, in which the AMC transducer is at the center of the annular array, where each circular ring of the annular array has a thickness of about 1.5-2 mm, and where each ring is separated from the adjacent ring by about 100 microns, noting that embodiments of the disclosure are not necessarily limited to those dimensions.

[0043] This embodiment is illustrated in FIG. 5, which illustrates a sample embodiment with one circular ring, which may or may not be focused.

[0044] 4. As an extension of the first embodiment above, similar (< I5 mm) transducers may be placed on each side of the fracture gap, referred to as “bi-axial transmission,” so that the propagation velocity across the fracture gap may be used as another metric in establishing the state of bone healing by comparing it to intact bone [6-7] . This embodiment is illustrated in FIG. 6. 5. As an additional extension of the fourth embodiment above, the signals captured by the transducers on each side of the fracture gap may be multiplied on recei ve, often referred to as a “multiplicative array,” with a low-pass filter to remove the high-frequency output, as a way of doubling both the two-way directivity of the array and the receiver dynamic range (in dB) [8]. Tliis embodiment is illustrated in FIG. 7.

[0045] 6. A time modulated array (TMA) approach, either sequentially or simultaneously, as disclosed in co-pending application PCT / US20 / 62877 [P-2], the contents of which are herein incorporated by reference in their entirety, would use a multi-element planar array for both FHA and BGS transmissions. In an embodiment, a 3-element array is used, although embodiments are not necessarily' limited thereto.

[0046] 7. Electronically sweeping the transmited FHA signal from a first angle through a second angle using a beamformer to adjust the phase of the signal that drives each element, selecting a signal from the sei of signals received at each of the angles and select the angle with a maximum signal-to-noise ratio, and further processing the selected signal for fracture assessment. 8. Electronically sweeping the transmited FHA signal from a first angle through a second angle using a beamformer to adjust the phase of the signa! that drives each element, processing the signals received at each of the angles as desired in accordance with the chosen detection threshold, and selecting a signal from the set of processed signals for fracture assessment.

[0047] 9. Control theory'- can be used for parameter estimation on receive to retransmit the desired modified signal. For example, offline processing can provide suboptimal Kalman-Bucy filtering to estimate the state variables of a typical transducer, such as the radiated pressure, the acceleration, the input current to the transducer, or the efficiency, to achieve a desired signal-to-noise ratio and probability of false alarm [9-11],

[0048] The FDA requires the mechanical index (M l) and beam nonuniformity ratio (BNR.) of the FHA transducer to be mea sured. In the previous testing of the BGS transducer, it was found that the error sources and uncertainties include hydrophone sensitivity, A-to-D converter, temperature, beam alignment with the fracture site gives an uncertainty of about + / - 17%, not including the uncertainty in the scaling factor for the obliquity (phi) which is usually taken as cos phi. Thus, in this case, “about” is taken to be + / - 20%, which is within a measurement error as would be understood by a person having ordinary skill in the art.

[0049] FIG. 4 illustrates this architecture 40 positioned with respect to a bone 411. The architecture 40 includes a coaxial cable 401 connected to a power source, the AMC 409, a larger AMC-embedded BGS therapeutic transducer 405 that is about 20 mm in diameter and has a spectral -6dB bandwidth from 0,8- 1.2 MHz, and a smaller FHA transducer 407 that is less than about 15 mm in diameter, can be unfocused or focused, has a resonant frequency from 0.5 to 5.0 MHz, and a housing 403 that accommodates the AMC 409 and the transducers 405 and 407. Another significant difference between the BGS and FHA transducers is in the backing of the two transducers: the BGS backing is air-backed for greater sensitivity, but the FHA requires a loaded acoustic back impedance for greater spatial resolution.

[0050] FIG. 5 illustrates a cross sectional view and a front view of an ultrasound transducer assembly 500 that includes a piezoelectric transducer 510, one annular ring 520, and a housing 522, according to this embodiment. The housing 522 contains the piezoelectric transducer 510 with a uniform or an elliptical electroded ground plane covered with a 1 / 4-wave matching layer 51 1 on a front surface thereof, on which is attached an embedded AMC 530.

[0051] The transducer element is slanted with respect to a front side of the housing fixture by an angle of 31.50 degrees, which matches the wedge angle of the embedded AMC 530. The front view shows the transducer 510 with the AMC 530 removed, which also reveals the upper inner surface 521 of the housing 520. The indicator 580 on the housing indicates the direction of beam steering by the embedded AMC. The bousing dimensions permit transmission at the desired oblique angle with minimal back-scattering interference.

[0052] A space 525 behind a back surface 512 of the transducer 510 is filled with air, but it is also well-known in the transducer design art that controlling the acoustic impedance of backing material can significantly affect detection and measurement parameter sensitivity. Exemplary, non-limiting piezoelectric elements include but are not limited to PZT-4, PZT-5I1, PZT-7H, and PZT-8. The piezoelectric transducer 510 also includes a tuned electric circuit 570.

[0053] The back of the housing 520 includes the transducer array cable 550 and a tuned electric circuit 570 connected to the cable housing 550 and to the transducer 510. The back surface 512 of the piezoelectric transducer 510 may be uniformly covered with an electrode pattern 512 or may be covered by an elliptical electrode pattern 513. The tuned circuit as shown in FIG 5 is a series RLC network to transform the complex impedance of the transducer to a 50 ohms resistance tha t loads the previous output stage of the high-power switching amplifier in the driving transmitter. It is well-known in the electronics design art that the series-RLC shown can be replaced with equivalent pi (-tr) and T networks to facilitate specific operational considerations (i.e., balanced, unbalanced, heat dissipation, Q-value, etc.). FIG. 6 illustrates a functional flow diagram of acoustic signal transmission and reception, wherein a transmitting transducer 61 generates and transmits an acoustic signal that traverses the soft tissue 63 and bone 64, slightly distal to a bone fracture 65, which is received by the receiving transducer 62.

[0054] FIG, 7 illustrates a functional flow diagram of acoustic signal transmission and reception, wherein a transmiting and receiving transducer 71 generates and transmits an acoustic signal that traverses the soft tissue 73 and bone 74, slightly distal to a bone fracture 75, which is received by one or more of the transmitting and receiving transducer 71 and / or a receiving transducer 72. The received signal is combined as necessary by a multiplier 76, and sent to a lowpass filter 77 for additional signal processing. and Digital Subsystem

[0055] FIG. 2 illustrates an echo reception, conditioning, and digital subsystem 20 according to embodiments of the disclosure, and includes a transducer 200, an optional bea.mfbrmer 205, an echo transmit / receive (T / R) switch with transformer (a T / R. circuit) 210, a preamplifier (a preamplification circuit) 220, an anti-aliasing filter (a filtering circuit) 230, an analog-to-digita! (A-to-D) converter (a data conversion circuit) 240, a persistent memory' (a memory circuit) 250, and an optional signal processor (260), The T / R switch 210 controls whether the transducer 200 functions in a transmiting mode or a receiving mode, and the beamformer 205 in some embodiments controls the electronic sweeping of the transducer 200 on transmission. The echo reception, conditioning, and digital subsystem match the impedance to minimize electromagnetic noise pickup in the cable and to significantly reduce the power requirements of the cable driver, thereby reducing internal heating. When the transducer 200 is functioning as a receiver, all FHA echoes received by the transducer 200 are signal condi doned by the T / R switch 210, the preamplifier 220, and the anti-aliasing filter 230, digitized by the analog-to-digital (A-to- D) converter 240, and stored in persistent memory 250. In some embodiments a signal processor 260 analyzes the signal digitized by the A-to-D converter 240, including selecting a signal with a maximum amplitude or signal-to-noise ratio from a set of signals received at each angle, or processing the signals received at each of the angles and selecting a desired signal, and providing transmission instructions to the beamformer 205.

[0056] In an exemplary echo reception, conditioning, and digital subsystem 20 according to embodiments, the T / R switch 210 is at least 0 dB over the frequency band 100 kHz to 5.0 MHz, to protect the preamplifier 220 against excessive input voltage during transmission and to isolate the preamplifier 220 from transmitter noise. The transformer 210 output that is coupled to the preamplifier 220 is an unbalanced-to-balanced transformation, with optimum impedance matching, and low frequency noise isolation. Preamplification 22.0 minimizes effects of commonmode noise, such as with a balanced-ifobalanced-out circuit and operates linearly above the transmitter spectral noise. In an embodiment, anti-alias filtering 230 is an elliptical low ripple lowpass Cauer filter from 0 to 5 MHz, with stopband attenuation of at least -60 dB at 10 MHz. Analog-to-digital conversion 240 has at least an 8-bit resolution and a sampling rate of at least 20 MHz. The persistent, memory 250 is used to store the digitized Gaussian echo data captured during the first minute of each treatment cycle, and may be, for example, a solid-state drive (SSD) integrated into the device. However, embodiments are not necessarily limited to the above configuration and settings.

[0057] Data Aca uisition Subsystem FIG. 3 illustrates a data acquisition and processing system 30 according to an embodiment of the disclosure, and includes a memory device 300 that stores data in the persistent memory 250 and includes a sendee port 310, a cable connection 320 that connects to the service port 310, a wireless (radio / WiFi) connection 330 that is connected to the memory device 300, an intermediary device (wired / wireless) connection 340 that is connected to the memory 300, and a backend server infrastructure 350 that performs data analysis and includes an application programming interface (API) 355, and is connected to the cable connection 320, the wireless connection 330 and the intermediary device connection 340. The backend server infrastructure 350 is further connected via the API 355 to a web application 360 and a mobile application 370. At regular intervals, the data stored in persistent memory 250 on the device 300 will be extracted and moved to the back- end server infrastructure 350 for data analysis.

[0058] In an embodiment, the data is accessed via the service port 310, and manually downloaded from the device 300 via the cabled connection 320. In this case, the extracted data would be manually uploaded to the back-end server infrastructure 350, In another embodiment, the data is transmitted to the back-end server infrastructure 350 directly via the wireless network connection 330, such as a radio signal or WiFi connection.

[0059] In another embodiment, the data is transmitted to an intermediary device 340, such as a charging cradle, via a wired or wireless connection such as USB or Bluetooth. In this case the intermediary device transmits data to the back-end server infrastructure 350 via one of the mechanisms listed above. Once collected in a message queue on the back-end server infrastructure 350, the recei ved data will be decompressed (if necessary), analyzed, and the results of the analysis will be made available to an API 355 that can be used by front-end web applications 360 or mobile applications 370 to provide usage and healing information to patients and their treating orthopaedists.

[0060] Data Analysis Subsystem

[0061] Following standards in the literature, three overlapping bone fracture healing stages are considered: (1) early inflammatory stage; (2) soft callus / late inflammatory stage; and (3) hard callus / remodeling stage.

[0062] Stage I ••• Early Inflammatory, On the day after fracture, there is a hematoma, necrosis of soft tissue, and an inflammatory reaction phase. The acoustic channel (i.e. , the fracture) is initially filled with blood clot and cellular debris, such as macrophage cells. Within a week, there is ^differentiated cell proliferation of marrow cells in the periosteum. This allows Stage .1 healing to be presented as a linear viscoelastic model based on Hooke’s Law.

[0063] Stage 2 ~ Soft Callus / Late Inflammatory. In this stage the acoustic impedance is measured perpendicular to the fracture gap. at the entrance to the fracture channel. Here, the acoustic impedance is similar to that of soft connective tissue and fat, about 1.33 MRayls. As the callus develops more cartilage, the bone fibers grow firmer and the acoustic impedance increases.

[0064] Stage 3 ■ Hard Callus / Remodeling. In this stage, increased bone formed by endochondral ossification begins to appear on the periosteal surface, followed by woven bone and lamellar bone formation, where the acoustic impedance is now increasingly similar to that of intact bone, about 3.5 to 6.5 MRayls within one single osteon [I]. The attenuation loss in bone fibers in this stage is high, viz., 4.2 dB / cm longitudinal and 7.0 dB / cm shear at 1 .0 MHz.

[0065] In an embodiment, FHA computation performed by system 30 includes capturing at least the first acoustic echo referred to herein as “the data,” which may be used to compute FHA metrics using techniques such as a fast Fourier transform (FFT).

[0066] In a further embodiment in the receiver, the collected acoustic echoes will be summed in a range gale that just includes the periosteum and fracture gap width (6 mm maximum). We will initially determine whether the received echo data is stationary or nonstationary, then use data transformation techniques to convert the summed data to an analytic signal and normalize the analytic signal to our proprietary format by applying temporal-frequency technology to the normalized analytic signal. Ultimately, the processed normalized signal will be the indicator of fracture healing progress, as independently verifiable through gold standard modalities (e.g., X- radiographs). Noting that the absorption cross-section is much greater than the backscattering cross-section in our 1 MHz frequency region (0.8 to 1.2 MHz), these signatures are expected to be primarily coherent in the inflammatory and soft callus stages of healing, i.e., when the acoustic impedance is less than 2 MRayls (i.e., soft tissue). As the bone tissue fibers harden into the remodel ing stage of healing, the acoustic impedance tends to increase.

[0067] Ultrasound A-niode data are extracted as amplitude and time arrays. Intermediate processing steps output arrays for graphical analysis and further processing. A functional algorithm according to an embodiment takes these arrays as input, performs all necessary digital signal processing, and returns a metric that identifies the stage of healing with the greatest possible level of granularity. In an embodiment, between one (1) and 512 acoustic interrogations of the fracture channel can be compiled to provide the acoustic information (data) for fracture assessment. In an embodiment, based on SNR, propagation variability, temporal constraints and depending on the degree of signal coherence and dispersion, at least 32 acoustic interrogations are expected to be summed.

[0068] In an embodiment, the collected acoustic echoes are further processed to generate a realtime diagnostic fracture healing assessment metric by processing the data vector using a set of four metrics: bone mineral density, speed-of-sound, ultrasound attenuation, and elastic modulus. The stage of bone fracture healing can be identified by using one or more of the real-time diagnostic fracture healing assessment metrics. As an example, as the bone tissue fibers harden into the remodeling stage of healing, the acoustic impedance tends to increase.

[0069] I n an embodiment, a key intensi ty metric is the acoustic strength of the tissue in the fracture gap. A linear -elastic fracture model with a closed hysteresis curve is considered, and a generic linear model is applied to compute at the outermost edge of the fracture site including the periosteum, as a consistent indicator of healing common at all stages.

[0070] Tissue strength is also affected by forward-and-back scattering cross-sections. However, the absorption cross section is much greater than forward-and-back scattering cross sections in the frequency range 0.1- 10 MHz

[0013] and therefore is dominant for the periosteum and bone fracture tip. Thus, in stage 1 healing, the tissue strength is essentially constant and linear in frequency; in stage 2 healing,, it will be nearer to the acoustic impedance intensity of fat and soft tissue / soft callus; and in stage 3 healing, it will increase during the hard callus / reinodeling phase. Assuming proper mechanical reduction and stabilization are applied, the tissue strength factor will primarily change with healing, approaching that of intact bone as healing progresses. Therefore, an acoustic signature is determined, based on measurable quantities, such that the echo signature is indicative of the healing stage at the periosteum tissue and fracture tip, particularly in the third stage of healing.

[0071] Design Considerations of a Low Frequency Transducer

[0072] According to an embodiment, the low osteogenic frequencies characterized by an FHA signal can be generated by a transducer having electromagnetic, piezoelectric, electrostrictive, or magnetostrictive active elements. The active elements can be in the form of a single or multilayer component made of one or combination of materials named above. In addition, the active elements can be made of composites of such materials with polymeric, void, and / or metallic components.

[0073] Moreover, active elements made of such materials can generate low frequency waves via flextensional effects attainable with unimorphs, monomorphs, bimorphs, cymbals, moonies. thunders, rainbows, cerambows, etc., all well known by those skilled in the art. In addition, 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. Furthermore, the low osteogenic frequencies disclosed here can also generated by transducers made of micro-electro-mechanical ultrasonic transducers (MUTs). Examples of such MUTs include a capacitive micro-electro-mechanical ultrasonic transducer (CMUT) and a piezoelectric micro-electro-mechanical ultrasonic transducer (PMUT). The CMUT and PMUT can be stand-alone transducers or be integrated on an electronic circuit board driving such MUTs.

[0074] 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 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 this disclosure.

[0075] REFERENCES

[0076] Patents and Patent Applications

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[0082] 1. Machado P, Li J, Blackman R, Liu J-B, Kepler CK. Fang T, Muratore R, Winder JH, Winder AA, Forsberg F. “Comparison between Clinically Available L1PUS and a Novel Bimodal Acoustic Signal System for Accelerating Fracture Healing,” IEEE UFFC, VoL69, No. 2, Feb. 2022, 629-636.

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Claims

W'HAT, IS, CLAIMED. IS:

1. A system for assessing the real-time healing of a bone fracture in real time using low intensity pulsed ultrasound (LIPUS) excitation, comprising:. a transducer that transmits into a bone fracture a longitudinal fracture healing assessment(FHA) diagnostic signal at an angle of 0° (normal) to the transducer or at an oblique angle tip to a first critical angle of about 20 degrees, or receives one or more FHA echo signatures; and a processor, wherein the processor is configured to:(a) sum the received echo signatures, convert the recei ved echo signatures to an analytic echo signal, normalize the analytic signal against a bone standard and generate a set of normalized analytic signatures, sum the set of normalized analytic signatures, and create a data vector;(b) generate a real-time diagnostic .fracture healing assessment metric by processing the data vector using one or more metrics, wherein the one or more metrics include bone mineral density, speed-of-sound, ultrasound attenuation, or elastic modulus; and(c) identify a stage of bone fracture healing by using one or more of the real-time diagnostic fracture healing assessment metrics.2 The system of Claim I , wherein the FHA diagnostic signal includes a Gaussian structural waveform and is transmitted at a resonant carrier frequency between 0.5 MHz to 5.0MHz, a pulse width of about 4 microseconds, a pulse repetition frequency (PRE) of about 1.0 kHz, and a spatial average-temporal average intensity (ISPTA) of about 30 mW / cnr.

3. The system of Claim 2, wherein the FHA diagnostic signal is transmitted at a resonant carrier frequency between 2.0 MHz and about 3.0 MHz, and wherein the resonant carrier frequency is modulated by linear frequency modulation so that spatial resolution, dynamic range, signal-to-noise ratio (SNR) are increased, and clutter interference is reduced.

4. The system of Claim I, wherein the FHA signal is transmitted by one or two acoustic transducers in a frequency range of 2.0 to about 3.0 MHz, that provide the longitudinal FHA transmission at 0 degrees along the M.RA or at an oblique angle up to the first critical angle.

5. The system of Claim 4, wherein the one or two acoustic transducers focus the FHA signal at an ISATA intensity level of about 30 mW / cm2into the bone fracture.

6. The system of Claim 4, wherein two acoustic transducers are positioned on each side of the bone fracture, and wherein a propagation velocity of the FHA signal across the bone fracture is another metric that establishes the stage of bone fracture healing by comparing the received echo of the bone fracture to that of an in tact bone.

7. The system of Claim 4, wherein multiplied outputs of two transducers are sent to a low-pass filter that .removes high-frequency outputs by doubling a directivity of the multiplicative array and a system dynamic range (in dB).

8. The system of Claim 4, wherein the one or two transducers are positioned within or alongside a larger AMC-embedded transducer resonant at 1.0 MHz.

9. The system of Claim 1 , wherein the transducer is a multi-elenient transducer and uses a beamformer that electronically sweeps the FHA diagnostic signal through a series of angular direction steps from a first angle to a second angle via adjustments to a phase of a signal that drives each transducer array element of the multi-element transducer, selects a signal with a maximum amplitude or signal-to-noise ratio from a set of signals received at each angle, and transmits the selected signal into the bone fracture.

10. The system of Claim 1 , wherein the transducer is a multi-element transducer and uses a beamformer that electronically sweeps the FHA diagnostic signal through a series of angular direction steps from a first angle to a second angle via adjustments to a phase of a signal that drives each transducer array element of the multi-element transducer, processes signals received at each of the angles, and transmits a desired signal from the processed signals into the bone fracture.1 1 . The system of Claim I , wherein the FHA signal is transmitted by one or more circular ring transducers in a range of 0.5 to 5.0 MHz and that form a concaved or focused dedicated annular array, wherein an AMC-embedded transducer is positioned at the center of the annular array, wherein each circular ring of the annular array has a thickness of about 1 .5 to 2 mm, and wherein each circular ring of the annular array is separated from an adjacent ring by about 100 microns.

12. The system of Claim 1, wherein the transducer is a time modulated array (TMA) implemented as a multi-element planar array that transmits multiple acoustic beams, wherein the acoustic beams are transmited either sequentially or simultaneously by controlling the harmonic number.

13. The system of Claim I , wherein the processor estimates state variables of the transducer by suboptimal filtering, wherein the state variables include radiated pressure, acceleration, input, cun-ent to the transducer, or efficiency.

14. The system of Claim I , wherein the processor converts the data vector from analog to digital format, stores the digital data vector in persistent memory, and transmits the digital data vector to another system for data analysis purposes.

15. The system of Claim 1 , further comprising a therapeutic bone growth stimulation(BGS) device.

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