WO2017030900A1 - Outil quantitatif faisant appel à la spectroscopie d'impédance pour surveiller la guérison d'une fracture - Google Patents

Outil quantitatif faisant appel à la spectroscopie d'impédance pour surveiller la guérison d'une fracture Download PDF

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Publication number
WO2017030900A1
WO2017030900A1 PCT/US2016/046568 US2016046568W WO2017030900A1 WO 2017030900 A1 WO2017030900 A1 WO 2017030900A1 US 2016046568 W US2016046568 W US 2016046568W WO 2017030900 A1 WO2017030900 A1 WO 2017030900A1
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Prior art keywords
bone
fracture
electrodes
impedance
healing
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PCT/US2016/046568
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English (en)
Inventor
Monica LIN
Michel MAHARBIZ
Safa HERFAT
Chelsea Bahney
Meir MARMOR
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The Regents Of The University Of California
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Publication of WO2017030900A1 publication Critical patent/WO2017030900A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/45—For evaluating or diagnosing the musculoskeletal system or teeth
    • A61B5/4504—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/053—Measuring electrical impedance or conductance of a portion of the body
    • A61B5/0538—Measuring electrical impedance or conductance of a portion of the body invasively, e.g. using a catheter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6867—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive specially adapted to be attached or implanted in a specific body part
    • A61B5/6878—Bone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/04—Arrangements of multiple sensors of the same type
    • A61B2562/046—Arrangements of multiple sensors of the same type in a matrix array

Definitions

  • the field of the currently claimed embodiments of this invention relates to monitoring fracture healing, and more particularly systems and methods for monitoring fracture healing using impedance spectroscopy.
  • a system for monitoring or observing a property or condition of a bone, a bone fracture, or a bone graft substrate of a subject includes a first electrode and a second electrode configured to be implanted into the bone, the bone fracture, or the bone graft substrate so as to be in electrical connection with each other through at least a portion of the bone or the bone fracture region.
  • the system also includes a variable frequency power supply electrically connected to the first and second electrodes to provide a source signal.
  • the system also includes a detection system electrically connected between the first and second electrodes and configured to detect phase-sensitive current and voltage of a circuit formed by the variable frequency power supply, the first and second electrodes and the bone, the bone fracture, or the bone graft substrate, and to provide detection signals for each of a plurality of frequencies.
  • the system also includes a signal processor arranged to communicate with the detection system to receive the detection signals, the signal processor being configured to process the detection signals to calculate a complex impedance of the bone, the bone fracture, or the bone graft substrate corresponding to each of the plurality of frequencies to provide an output impedance spectrum of the bone, the bone fracture, or the bone graft substrate.
  • a method of monitoring or characterizing a bone fracture region includes applying a first plurality of alternating electrical signals, each at a different frequency, to a pair of electrodes implanted into the bone fracture region on opposite sides of a bone fracture, and measuring a first set of complex impedances of the bone fracture region for each of the first plurality of alternating electrical signals to obtain a first impedance spectrum.
  • the method further includes applying a second plurality of alternating electrical signals, each at a different frequency, to the pair of electrodes implanted into the bone fracture region on opposite sides of the bone fracture, and measuring a second set of complex impedances of the bone fracture region for each of the second plurality of alternating electrical signals to obtain a second impedance spectrum.
  • the method further includes comparing the first and second impedance spectra to at least one of each other or to a reference spectrum to provide an indication of a degree of healing of the bone fracture.
  • Figure 1 is a schematic illustration of a system for monitoring or observing a property or condition of a bone, a bone fracture, or a bone graft substrate of a subject;
  • Figure 2 shows an overview of an impedance sensing system
  • Figure 3 shows an example of sensor needles used in a murine model
  • Figure 4A is a circuit model displaying the impedance measurement taken between two electrodes and what paths the signal may take;
  • Figure 4B shows the setup for taking measurements in a cadaveric model across
  • Figure 5 shows schematic representations of some embodiments of the invention involving a bone plate
  • Figure 6 shows an example of bone screws according to some embodiments
  • Figure 7 shows schematic representations of some embodiments of the invention involving a fixation rigid rod or plate disposed outside the body;
  • Figure 8 shows a schematic of an intramedullary nail according to some embodiments
  • Figure 9 illustrates how electrodes can be integrated into a hip acetabular cup, a hip femoral stem, a femoral condyle replacement, and a tibial insert;
  • Figure 10 illustrates the integration of a circuit and/or sensor arrays on the surface of a spine cage and on a posterior stabilization rod
  • Figure 11 is a schematic illustration of a system for diagnosing and/or monitoring bone healing according to some embodiments of the current invention
  • Figure 12 is a schematic of a control board according to some embodiments of the current invention
  • Figure 13 shows the layout of a control board used to perform the methods described herein;
  • Figure 14 shows a system for measuring intact fracture calluses dissected from mice
  • Figure 15 shows multiple printed circuit board (PCB) designs for in vivo sensors in mice;
  • Figure 16 shows CAD diagrams to UV laser cut sensors for in vivo mouse studies.
  • Figure 17 shows Bode diagrams of impedance magnitude and phase versus frequency showing the effect of a bone plate and bone screws on impedance measurements
  • Figure 18 shows impedance measurements of cadaveric tissues
  • Figure 19 shows results from tracking impedance measurements of the fracture calluses in mice over time
  • Figure 20 shows Bode diagrams of impedance magnitude and phase versus frequency showing the progression of impedance of a fracture callus over healing time
  • Figure 21 shows Bode diagrams of impedance magnitude and phase versus frequency of muscle taken from multiple mice at the various timepoints
  • Figure 22 shows representative histologic sections of fracture calluses at each of days 7, 14, and 21;
  • Figure 23 shows a regression analysis of phase angle ( ⁇ ) correlated to % volume fractions of cartilage for fracture calluses
  • Figure 24 shows a regression analysis of phase angle ( ⁇ ) correlated to % volume fractions of cartilage for trabecular bone.
  • EIS Electrical impedance spectroscopy
  • Figure 1 shows a system for monitoring or observing a property or condition of a bone, a bone fracture, or a bone graft substrate of a subject according to some embodiments of the invention.
  • the system 100 includes a first electrode 102 and a second electrode 104 configured to be implanted into the bone, the bone fracture, or the bone graft substrate so as to be in electrical connection with each other through at least a portion of the bone or the bone fracture region.
  • the system 100 also includes a variable frequency power supply 106 electrically connected to the first and second electrodes 102, 104 to provide a source signal.
  • the system 100 also includes a detection system 108 electrically connected between the first and second electrodes 102, 104 and configured to detect phase-sensitive current and voltage of a circuit formed by the variable frequency power supply 106, the first and second electrodes 102, 104, and the bone, the bone fracture, or the bone graft substrate, and to provide detection signals for each of a plurality of frequencies.
  • the system 100 also includes a signal processor 110 arranged to communicate with the detection system 108 to receive the detection signals.
  • the signal processor 110 is configured to process the detection signals to calculate a complex impedance of the bone, the bone fracture, or the bone graft substrate corresponding to each of the plurality of frequencies to provide an output impedance spectrum of the bone, the bone fracture, or the bone graft substrate.
  • the system further includes a data storage device configured to communicate with the signal processor to receive and store the output impedance spectrum of the bone, the bone fracture, or the bone graft substrate for at least one of further processing or later retrieval.
  • the system includes an RF transmitter configured to communicate with at least one of the signal processor or the data storage device to transmit the output impedance spectrum of the bone, the bone fracture, or the bone graft substrate.
  • the system further includes a display device configured to communicate with at least one of the signal processor, the data storage device or the RF transmitter to receive and display the output impedance spectrum of the bone, the bone fracture, or the bone graft substrate.
  • the first and second electrodes have an electrically conducting tip structured to make electrical connection with bone marrow while being insulated with respect to surrounding regions.
  • the embodiments of the invention are not limited to the electrically conducting portion being located at the tip.
  • the electrically conductive part that acts as the exposed electrode could be, for example, a surface pad or the uninsulated center portion of a wire.
  • the first and second electrodes are incorporated into at least one of bone screws, a bone plate, or an intramedullary nail.
  • the variable frequency power supply is a type of power supply that is capable of providing a frequency of the source signal of at least 500 kHz.
  • variable frequency power supply is a type of power supply that is capable of providing a frequency of the source signal of at least 1 MHz. According to some embodiments, the variable frequency power supply is a type of power supply that is capable of providing a frequency of the source signal of about 1 KHz to about 1 MHz.
  • the system further includes a third electrode configured to be implanted into bone, and a multiplexer arranged in electrical connection with the variable frequency power supply and with the first, second and third electrodes.
  • the multiplexer is configured to select pairs of electrodes between the first, second and third electrodes to provide position-sensitive impedance spectra.
  • a method of monitoring or characterizing a bone fracture region includes applying a first plurality of alternating electrical signals, each at a different frequency, to a pair of electrodes implanted into the bone fracture region on opposite sides of a bone fracture, and measuring a first set of complex impedances of the bone fracture region for each of the first plurality of alternating electrical signals to obtain a first impedance spectrum.
  • the method further includes applying a second plurality of alternating electrical signals, each at a different frequency, to the pair of electrodes implanted into the bone fracture region on opposite sides of the bone fracture, and measuring a second set of complex impedances of the bone fracture region for each of the second plurality of alternating electrical signals to obtain a second impedance spectrum.
  • the method further includes comparing the first and second impedance spectra to at least one of each other or to a reference spectrum to provide an indication of a degree of healing of the bone fracture.
  • the pair of electrodes penetrate into bone marrow on each side of the bone fracture.
  • the pair of electrodes are incorporated into at least one of bone screws, a bone plate, or an intramedullary nail.
  • comparing comprises comparing at least one of the first and second impedance spectra to a reference spectrum to provide an indication of a stage of healing of the bone fracture.
  • the stage of healing is one of a predefined number of healing stages.
  • each of the first plurality of alternating electrical signals and the second plurality of alternating electrical signals has a frequency between 20 Hz and 1 MHz. According to some embodiments, each of the first plurality of alternating electrical signals and the second plurality of alternating electrical signals has a frequency between 1 kHz and 500 kHz.
  • At least one of the first set of complex impedances and the second set of complex impedances is measured in a marrow canal or cortical bone of the bone fracture region. According to some embodiments, at least one of the first set of complex impedances and the second set of complex impedances is measured in a fracture gap of the bone fracture region.
  • impedance spectroscopy is utilized to understand bone tissue health and to distinguish between different tissue types present in fracture healing.
  • the system consists of electrodes to contact the tissue of interest, which are routed to control hardware that interfaces with an LCR meter and laptop, allowing for automatic collection of impedance measurements across a range of frequencies.
  • Sensors are placed at or near a fracture injury to gather as much information as possible about the tissues in the fracture gap.
  • Multiple electrodes can be arrayed to probe the area at multiple locations to both spatially and temporally resolve the healing process.
  • impedance spectroscopy may detect subtle changes in the tissue, enabling objective assessment and providing a unique insight into the condition of an injury.
  • Measurements can be taken across electrodes in a 2-point or 4-point measurement configuration, for example.
  • a microcontroller sends commands to multiplexers to determine which electrodes to measure between at any given time.
  • the drive signal can be provided from an impedance analyzer or LCZ meter, which then calculates the complex impedance of the tissue of interest.
  • the frequency response can be analyzed, in particular for any dispersions.
  • Arrayed electrodes can allow for spatial information of tissue health in a given area of interest. According to some embodiments, for each pair of electrodes, 5 measurements are taken in about 2-3 seconds for each frequency.
  • these impedance sensors can ultimately be integrated into the existing management techniques of surgically-treated fractures. In other embodiments, this could be used to monitor progression of de novo bone formation either through intramembranous bone or endochondral bone regeneration.
  • Target cases would include fractures stabilized by either internal or external fixation.
  • FIG 2 shows an overview of an impedance sensing system according to some embodiments.
  • Figure 3 show an example of sensor needles comprising electrodes that are used for a murine model.
  • the electrodes can be made as a bone screw so the electrodes are exposed at the end or edge of the screw, and the traces (metal conducting lines) lead out the top of the screw for connection to another module to read out the signal.
  • the electrodes can lie either embedded in the center of the bone (in the marrow canal or the surrounding cortical bone) or within the fracture gap itself (centered in the cross-sectional area of the bone). In other embodiments, there can be an array of electrodes.
  • the electrodes are arrayed, it is possible that in one sensor there are some electrodes in the marrow canal and some in the cortical bone, for example.
  • a small RF chip can be placed at the top of the screw or on the corresponding bone plate and the system can be passively powered from outside the body to take a measurement and collect data.
  • the general concepts of the current invention are not limited to this particular example.
  • the system could be powered by some form of piezoelectric mechanism (converting mechanical stress experienced by the bone/joint/etc. to an electric charge.
  • batteries and/or other energy storage devices could be used.
  • This system also has the capability of providing electrical stimulation across the fracture gap to potentially increase the rate of healing.
  • the signal will travel through biological tissue at and around the fracture site so the impedance measurement will reflect the changing tissues as the fracture heals.
  • Figure 4a is a circuit model displaying the impedance measurement taken between two electrodes and possible paths the signal may take.
  • Two Kirschner wires and a Syntheses 245.16 bone plate (stainless steel) were used in this study. Measurements were taken in intact cortical bone.
  • Figure 4B shows the setup for taking measurements in a cadaveric model across Kirschner wires in a tibia with a bone plate.
  • This technology has the potential to fit a wide range of applications.
  • Impedance spectroscopy can also be applied widely to monitoring surface injuries as well as internal injuries.
  • Electrodes can be directly integrated into the bone screws and drilled in at the site of the fracture. This would allow for readings that reflect what tissue is in the gap, and thus what stage of healing the injury has progressed to.
  • Figure 5 shows schematic representations of some embodiments of the invention. According to some embodiments, electrodes can be disposed on the underside of the bone plate. According to some embodiments, the electrodes can be disposed on sensor screws at or flanking the fracture site.
  • a flexible array of electrodes is wrapped around the fracture beneath the bone plate. These embodiments can also be combined. Circuitry to collect the data/make measurements and send data can be integrated on the bone plate hardware.
  • the underside of the bone plate can be coated with an insulating material, separating it from the bone.
  • Figure 6 shows an example of bone screws according to some embodiments.
  • An array of electrodes can be instrumented on a single screw, and the screw can include circuitry to collects and send data.
  • the electrodes can be dispose along the side of the screw or at the tip of the screw. Any pairwise combination of electrodes can be measured.
  • the electrodes may be disposed on the same screw or on different screws.
  • the electrodes may also be included in a dedicated sensor screw that is not designed to secure sections of bone like a bone screw is.
  • the sensor screw may have multiple electrodes at its tip that are design to be placed at the fracture cite.
  • the electrodes can go into an empty fracture gap, a closed juncture between the reduced bone, or into bone grafts or other substrates.
  • the bone screws can be coated with an insulating coating, as can the underside of the bone plate, separating it from the bone.
  • External fixators utilize a rigid rod or plate outside of the body with bone screws piercing the skin and going through the bone to stabilize a fracture in place. As illustrated in Figure 7, these bone screws can be utilized to take impedance measurements across the fracture gap. Circuitry to collect and send data can be included on the rigid rod or plate outside the body. In some embodiments, they could also be used to monitor healing progression for bone lengthening procedures that use external fixators for distraction osteogenesis, for example.
  • FIG. 8 A schematic of an intramedullary nail is shown in Figure 8.
  • the nail comprises an electrode array long its length, and can include circuitry disposed, for example, at an end of the nail. This nail allows for readings directly through the center of the bone and fracture gap, revealing information about tissue health at and around the site of the injury. This method produces a map of electrical impedance that can reveal spatial information about the tissue health.
  • Electrode arrays can also be integrated into joint replacements.
  • Figure 9 illustrates how electrodes can be integrated into a hip acetabular cup, a hip femoral stem, a femoral condyle replacement, and a tibial insert.
  • Figure 10 illustrates the integration of a circuit and/or sensor arrays on the surface of a spine cage and on a posterior stabilization rod. The embodiments of the invention are not limited to these examples. Electrode arrays can be implemented into many types of replacement joints and other devices inserted into the body, as will be appreciated by one of ordinary skill in the art.
  • Some embodiments describe two-electrode systems.
  • the general concepts of the current invention are not limited to only two-electrode systems.
  • some embodiments can take 3 -point measurements using 3 electrodes at one time or 4-point measurements using 4 electrodes.
  • electrode arrays could be used in some embodiments of the current invention.
  • Micromotion at the site of internal fixation often leads to failure of a surgical implant used to stabilize a fracture. This motion would move the electrodes further apart, changing the distance between the electrodes and thus change how far the signal has to travel. These differences would manifest themselves in changes in impedance, which could be recorded to detect whether or not micromotion exists at a surgical site.
  • Compartment syndrome occurs as a result of increased pressure within a compartment of tissue that leads to insufficient blood supply to the muscles and nerves in the area. This may be detectable by impedance, so integrating sensors around the area that has suffered from a traumatic injury would enable objective data collection about the tissue health and reflect pressure in the area.
  • Wireless capability can be utilized for this device to function within the framework of internal monitoring. This can allow for remote monitoring, one of the major advantages of some embodiments of the invention. This would allow patient data to be collected on a more frequent basis and sent to the physician for analysis.
  • the electrodes would be placed inside the body at or in the bone, and a control unit can be placed beside it using the bone plate or other surgical implant as a platform. This use case addresses a huge unmet clinical need, as there is no adequate alternative for monitoring internal healing.
  • Figure 11 is a schematic illustration of a system for diagnosing and/or monitoring bone healing according to some embodiments of the current invention.
  • Figure 12 is a schematic of a control board according to some embodiments of the current invention.
  • Figure 13 shows the layout of a control board used to perform the methods described herein.
  • Figure 14 shows a system for measuring intact fracture calluses dissected from mice.
  • Figure 15 shows multiple printed circuit board (PCB) designs for in vivo sensors in mice.
  • Figure 16 shows CAD diagrams to UV laser cut sensors for in vivo mouse studies.
  • PCB printed circuit board
  • variable frequency power supply is intended to have a broad meaning to include at least all types of power supplies discussed in relation to specific embodiments of the current invention. This is intended to include, but is not limited to, a white noise signal generator. It is intended to also include, but is not limited to, a power supply in which one can either manually or electronically select specific frequencies.
  • Example 1 Impedance Spectroscopy to Monitor Fracture healing
  • EIS Electrical impedance spectroscopy
  • Sensors will be placed at or near a fracture injury to gather as much information as possible about the tissues in the fracture gap.
  • Multiple electrodes can be arrayed to probe the area at multiple locations to both spatially and temporally resolve the healing process.
  • these impedance sensors will ultimately be integrated into the existing management techniques of surgically-treated fractures.
  • Target cases would include fractures stabilized by either internal or external fixation.
  • Internally stabilized fractures involve a metal bone plate in which bone screws are drilled into healthy bone on either side of the fracture site to secure a plate in place and stabilize the fracture.
  • Our sensors would be designed to mimic a bone screw and then drilled into the bone tissue at or immediately flanking the fracture site to measure impedance in or across the injury.
  • Fig. 1 shows how the sensors fit within this treatment regime and how the signal will travel between the electrodes.
  • External fixation is similar, except the metal plate is left outside the body and only the bone screws pierce the skin and are fixed to the uninjured areas of bone.
  • the signal will travel through biological tissue at and around the fracture site so the impedance measurement will reflect the changing tissues as the fracture heals.
  • the impedance measurement will reflect the changing tissues as the fracture heals.
  • there is a metal bone plate pressed up against the bone there is a possibility that the current will short through this highly conductive path rather than travel through the bone tissue.
  • Two Kirschner wires and a Syntheses 245.16 bone plate were used in this study. Measurements were taken in intact cortical bone.
  • the experimental setup is shown in Figure 4B.
  • the setup includes a bone plate secured by two bone screws in between electrodes.
  • Figure 4A is a fracture model depicting sensor integrated within the treatment scheme. The model shows how the signal can travel within the fracture environment.
  • Figure 17 shows Bode diagrams of impedance magnitude and phase versus frequency showing the effect of a bone plate and bone screws on impedance measurements.
  • the distance listed in the legend corresponds to the distance between the electrodes.
  • the electrodes were placed 36mm apart and bone was measured first without screws, and then with two bone screws inserted in between the electrodes.
  • the impedance magnitude dropped after the screws were inserted. This result indicates that the bone screw is making good electrical contact to the bone, so current could travel through the bone screws and create a short circuit through the plate. This will only be an issue if the bone screws are placed too close to the sensors at the fracture site.
  • bone screws are typically placed far from the site of injury to ensure they are secured in strong, healthy bone so the bone plate is adequately held in place against the fracture. Therefore, this is not a major concern, although this potential issue still needs to be considered in determining best use cases for our device.
  • Stage one the inflammatory phase, commences immediately after the injury with the formation of a hematoma.
  • the hematoma is formed to stop the bleeding and contain the fracture debris after the bone break.
  • the hematoma is a critical step in initiating healing and the tissue composition begins largely as coagulated blood that is remodeled into a fibrous scaffold.
  • Stage two is characterized by a soft callus that bridges the fracture gap and is primarily composed of cartilage.
  • blood vessels invade the cartilage so the tissue becomes calcified and eventually converts into cancellous bone.
  • Figure 19 shows Bode diagrams of impedance magnitude and phase for measurements across a simulated fracture plotted as a function of frequency. Analysis of the data, shown in Figure 19, shows clear differences between the impedance across a fracture gap filled with cartilage and one filled with cancellous bone, with the graph for the mixture falling in between the two tissues as expected.
  • Cartilage and cancellous bone placed in a gap created in cortical bone represent stage two and stage three of the fracture healing process, respectively. Since cortical bone is of higher impedance than the other tissues present in the fracture gap, it is critical that impedance measurements taken across the fracture reflect the tissues in the gap and are not completely dominated by the cortical bone around the fracture. Data collected from this simulated fracture indicate that our system can at least distinguish between injuries at stage two versus stage three of the healing process. This will enable tracking of fracture healing over time, and allow physicians to spot when a fracture does not progress through the different stages of healing at the anticipated rate. This will allow for early intervention to prevent high risk fractures from failing to heal in an acceptable time frame.
  • Example 2 Impedance Sensor to Monitor Fracture Healing
  • Intramembranous ossification features healing through direct osteogenesis, where mesenchymal cells directly differentiate into bone-forming osteoblasts.
  • Endochondral ossification is a biphasic process involving chondrogenesis followed by osteogenesis. It occurs through four overlapping phases of repair, beginning with an inflammatory phase, followed by formation of an early callus that matures into a hard callus, and finally remodeling into healthy bone.
  • the inflammatory phase begins with hematoma in response to the trauma, and inflammatory cells debride the wound while skeletal progenitor cells are recruited.
  • the fracture enters the soft callus phase which is primarily made up of cartilage.
  • the soft callus becomes a hard callus in the third stage as the matrix is vascularized and cancellous bone replaces the callus.
  • the cancellous bone undergoes remodeling via organized osteoblast and osteoclast activity to form cortical bone.
  • EIS Electrical impedance spectroscopy
  • the electrodes can be integrated in or flanking the fracture site with a bone plate over the fracture gap.
  • the measurement path of interest goes from one electrode through bone to the fracture gap, then through bone again to the other electrode.
  • Bone plates are typically made of titanium, stainless steel, or cobalt chrome, so this provides a highly conductive path through which the signal can travel.
  • An experiment is conducted to determine the effect of this parallel path on the impedance of the system. This study tests the sensitivity of the impedance measurement system in a simulated fracture environment and to inform device design for translation.
  • the system consists of electrodes to contact the tissue of interest, which are routed to control hardware that interfaces with an LCR meter and laptop, allowing for automatic collection of impedance measurements across a range of frequencies.
  • the control hardware currently runs off of four AA batteries, and a set of measurements between two electrodes that incorporates a frequency sweep takes a little over one minute.
  • Table 1 Device specifications of electrodes to measure impedance in bone.
  • Cadaveric samples of blood, coagulated blood, cartilage, cancellous bone, cortical bone, muscle, and fat are obtained and two point measurements taken across each of these tissues in a frequency sweep from 20 Hz - 1 MHz. For each set of measurements for a given tissue type, five readings are collected at each frequency, and then the electrodes are removed, cleaned, and reapplied five times for repeated measurements. To analyze the data, the five readings per trial are first averaged, then these five numbers are averaged across trials to produce graphs of impedance magnitude and phase as functions of frequency.
  • Two Kirschner wires are first drilled into a healthy, cadaveric long bone to use as electrodes, and impedance is measured. Then a Syntheses 245.16 bone plate (stainless steel) is screwed into the set-up and impedance is measured again. The spacing between the electrodes and the placement of the bone screws are adjusted to isolate their effects.
  • the samples are fixed immediately and processed for histology by the Laboratory for Skeletal Regeneration. After sectioning, they are stained by classic Trichrome or Direct Red histology techniques for visualization, and the amount of each tissue type (i.e. cartilage, cancellous bone, etc.) is quantified.
  • tissue type i.e. cartilage, cancellous bone, etc.
  • Measurements of different types of fracture tissues produced impedance magnitude measurements that trend as expected, with readings steadily increasing from stage one through stage four, as plotted in Figure 18.
  • the largest spread in the data is found at frequencies between 5 and 15 kHz.
  • the shapes of these plots as a function of frequency vary amongst the tissues, with the dominant pole shifting to the right (higher frequency) as the tissues progress through the healing phases.
  • the poles and zeros that describe the frequency responses of impedance of these tissues fall out of transfer function fits to their respective Bode plots.
  • a parameter used to distinguish between the different tissue types may be a combination of information gathered from impedance magnitude and phase, as well as from transfer function fits. This will allow us to objectively classify a fracture within one of the four stages of healing, and track the progression of recovery over time.
  • the electrodes were placed 36mm apart and bone was measured first without screws, and then with two bone screws inserted in between the electrodes.
  • the impedance magnitude dropped after the screws were inserted. This result indicates that the bone screw is making good electrical contact to the bone, so current could travel through the bone screws and create a short circuit through the plate. This will only be an issue if the bone screws are placed too close to the sensors at the fracture site.
  • bone screws are typically placed far from the site of injury to ensure they are secured in strong, healthy bone so the bone plate is adequately held in place against the fracture. Therefore, this is not a major concern, although this potential issue still needs to be considered in determining use cases for the device.
  • Cartilage and cancellous bone placed in a gap created in cortical bone represent stage two and stage three of the fracture healing process, respectively. Since cortical bone is of higher impedance than the other tissues present in the fracture gap, it is critical that impedance measurements taken across the fracture reflect the tissues in the gap and are not completely dominated by the cortical bone around the fracture. Data collected from this simulated fracture, shown in Figure 19, indicate that our system can at least distinguish between injuries at stage two versus stage three of the healing process. This will enable tracking of fracture healing over time, and allow physicians to spot when a fracture does not progress through the different stages of healing at the anticipated rate. This will allow for early intervention to prevent high risk fractures from failing to heal in an acceptable time frame.
  • FIG. 20 shows Bode diagrams of impedance magnitude and phase versus frequency showing the progression of impedance of a fracture callus over healing time.
  • the magnitude of impedance is clearly distinguishable between days 8, 14, and 21, particularly between 10 3 and 10 4 Hz.
  • the impedance values trend upward as expected as the mouse is healing over time. This is due to the fact that cartilage prevalent in the early stages of healing is of lower impedance than cancellous bone prevalent in the later stages, as we found in Figure 18.
  • muscle measurements were also taken in mice, plotted in Figure 21.
  • Figure 21 shows Bode diagrams of impedance magnitude and phase versus frequency of muscle taken from multiple mice at the various timepoints. It is clear that the muscle measurements do not change across mice and between the different timepoints, so they serve as a good reference point for measurement.
  • the Skeletal Regeneration Laboratory is currently processing the samples for histology, and will have quantitative volume fraction analysis for each of the timepoints in a few weeks. These can then be correlated with the impedance measurements to determine if the impedance measurement is sensitive enough to detect differences at a single timepoint depending on volume fraction of various tissues of the callus. This is important because there can be variation between mice at the same timepoint; some mice inherently heal faster than others. For example, one mouse may have significantly more cancellous bone in its callus at day 21 than another mouse that has a slower healing response and thus has a callus with proportionally more cartilage at the same timepoint. More rigorous statistical tests need to be performed on the study data as well as correlations made between the impedance measurements and the individual tissue make up of each callus.
  • Example 3 Impedance Spectroscopy Device Detects Fracture Progression in Mice
  • Radiography remains the standard technique to monitor healing, but because it relies on detection of mineralized tissue, it can only diagnose delayed healing at the late stages of fracture repair.
  • impedance spectroscopy can distinguish non- mineralized tissues, such as fibrous and cartilage tissues, from the mineralized bone tissue, which enables us to monitor the process of fracture repair.
  • Non-unions fail to progress to mineralized tissue and the composition of the fracture callus in these cases is critical in directing clinical management of the fracture.
  • Our novel sensor system that utilizes impedance spectroscopy will allow clinicians to monitor fracture healing and detect delays in union at a very early stage, thus enabling earlier intervention in poor bone healing.
  • Impedance measurements of cadaveric tissues are shown in Figure 18, demonstrating that the various tissue types are distinguishable between 10 3 and 10 5 Hz.
  • Results from tracking impedance measurements of the fracture calluses in mice over time are shown in Figure 19.
  • the magnitude of impedance trends upward as healing time increases, and values between days 8, 14, and 21 are particularly spread out between 10 3 and 10 5 Hz.
  • muscle measurements were also taken in mice at each time point, and there were no discernable differences across mice and between the various time points, as expected.
  • EIS Electrical impedance spectroscopy
  • tissue volume fractions To quantify tissue volume fractions, histomorphometric analyses of total callus, cartilage, trabecular bone, cortical bone, muscle, fibrous tissue, and bone marrow space volumes were performed using an Olympus CAST system and Visiopharm software. The total tissue volumes were calculated in cubic millimeters (mm 3 ) using the equation for a conical frustum and Cavalieri's principle. Univariate linear regression analysis was performed to assess correlative relationships between impedance measurements and volume fraction percentages of the various tissues present in the fracture calluses, and two- tailed t-tests were used to determine whether regression slopes were significantly different than zero. Significance was set at p ⁇ 0.05 and trends were defined as 0.05 ⁇ p ⁇ 0.1.
  • Figure 23 shows a regression analysis of phase angle ( ⁇ ) correlated to % volume fractions of cartilage for fracture calluses.
  • Figure 24 shows a regression analysis of phase angle ( ⁇ ) correlated to % volume fractions of cartilage for trabecular bone.
  • Linear regression analyses indicated negative relationships between impedance magnitude (
  • Impedance magnitude and phase angle have significant correlations with volume fractions of cartilage, trabecular bone, fibrous tissue, and marrow space at multiple frequencies, particularly below 5 kHz and above 500 kHz. These findings support use of electrical impedance spectroscopy for monitoring fracture healing.

Abstract

L'invention concerne un système permettant de surveiller ou d'observer une propriété ou un état d'un os comprenant une première électrode et une seconde électrode conçues pour être implantées dans l'os de manière à être en connexion électrique l'une avec l'autre par l'intermédiaire d'au moins une partie de la région osseuse ou de la région de fracture osseuse, et une alimentation électrique à fréquence variable raccordée électriquement aux première et seconde électrodes pour fournir un signal source. Le système comprend un système de détection raccordé électriquement entre les première et seconde électrodes et conçu pour détecter le courant et la tension sensibles à la phase d'un circuit formé par l'alimentation électrique à fréquence variable, les première et seconde électrodes et l'os, et pour fournir des signaux de détection pour chaque fréquence d'une pluralité de fréquences. Le système comprend également un processeur de signal agencé pour communiquer avec le système de détection afin de recevoir les signaux de détection, le processeur de signal étant conçu pour traiter les signaux de détection afin de calculer une impédance complexe du substrat osseux correspondant à chaque fréquence de la pluralité de fréquences, pour fournir un spectre d'impédance de sortie.
PCT/US2016/046568 2015-08-14 2016-08-11 Outil quantitatif faisant appel à la spectroscopie d'impédance pour surveiller la guérison d'une fracture WO2017030900A1 (fr)

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WO2018229463A1 (fr) * 2017-06-16 2018-12-20 Ucl Business Plc Détection d'une activité dans les nerfs périphériques
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WO2018009911A1 (fr) 2016-07-07 2018-01-11 The Regents Of The University Of California Implants utilisant une rétrodiffusion à ultrasons pour détecter l'impédance électrique d'un tissu.
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WO2018229463A1 (fr) * 2017-06-16 2018-12-20 Ucl Business Plc Détection d'une activité dans les nerfs périphériques
CN109692037A (zh) * 2017-10-24 2019-04-30 白惠善 骨愈合确认装置
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JP2019076726A (ja) * 2017-10-24 2019-05-23 ベク ヘソンPAIK, Hae Sun 骨癒合確認装置

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