Multimodal electrode array for electrochemical sensing and electrical stimulation with a medical implant

Abstract

To provide an implant device that can be implanted in a patient's body.SOLUTION: The implant device includes a set of electrodes in an array spaced apart on the implant device, a measurement circuit configured to perform a measurement mode on signals from the electrodes, a multiplexer interconnecting different pairs of electrodes in the array to the measurement circuit, and a controller. The controller controls the multiplexer to selectively connect different electrode pairs in the array over time to perform a measurement mode, wherein the measurement mode includes at least two of an open circuit potential (OCP) measurement, an amperometry measurement, and an electrochemical impedance measurement.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates to medical implants that house electronic circuitry. [Background technology]

[0002] Smart implants are traditional orthopedic implants that have been augmented with electronics to enable sensing, therapeutic, and connectivity capabilities.

[0003] Typically, electrochemical sensing systems require a dedicated electrochemical cell (i.e., a set of two or three electrodes) for each sensor measurement and analyte (e.g., pH or dissolved oxygen). In some scenarios, counter and reference electrodes may be shared, while a unique working electrode (i.e., sensing electrode) is functionalized specifically for each analyte. These existing configurations are not suitable for smart implant applications requiring measurement of multiple biomarkers in a form factor with very limited space constraints (e.g., interbody spacers). Summary of the Invention

[0004] Embodiments of the present disclosure are directed to smart musculoskeletal implants that can provide physicians / clinicians and their patients with the ability to monitor, detect, and treat different characteristics.

[0005] Some embodiments of the present disclosure are directed to an implant device implantable within a patient's body, the implant device including: a set of electrodes in an array spaced apart on the implant device; measurement circuitry configured to perform a measurement mode on signals from the electrodes; a multiplexer interconnecting different pairs of electrodes in the array to the measurement circuitry; and a controller. The controller controls the multiplexer to selectively connect different pairs of electrodes in the array over time to perform the measurement mode, the measurement mode including at least two of open circuit potential (OCP) measurements, amperometric measurements, and electrochemical impedance (EIS) measurements.

[0006] OCP measurements involve the measurement circuit measuring the free potential across a first electrode pair while the controller applies no current between the electrode pairs. Amperometry measurements involve the controller applying power to one of the electrodes in a second electrode pair while the measurement circuit measures the resulting current at the other electrode in the second electrode pair. EIS measurements involve the controller applying an alternating current to one of the electrodes in a third electrode pair while the measurement circuit measures the resulting current at the other electrode in the third electrode pair.

[0007] Some other embodiments of the present disclosure are directed to methods executed by a controller of an implantable device within a patient's body. The method includes controlling a multiplexer to selectively connect different electrode pairs of a set of spaced electrodes on the implant device to a measurement circuit over time to perform measurement modes. The measurement modes include at least two of: an open-circuit potential (OPC) measurement, in which the measurement circuit of the implant device measures a free potential across a first electrode pair while the controller applies no current between the electrode pair; an amperometric measurement, in which the controller applies power to one of the electrodes in a second electrode pair while the measurement circuit measures the resulting current at the other electrode in the second electrode pair; and an electrochemical impedance spectroscopy (EIS) measurement, in which the controller applies an alternating current to one of the electrodes in a third electrode pair while the measurement circuit measures the resulting current at the other electrode in the third electrode pair. [Brief explanation of the drawings]

[0008] Aspects of the present disclosure are illustrated by way of example and not limitation in the accompanying figures. [Figure 1] 1 illustrates an example of a smart implant system configured to alert a clinician to biofilm growth and treat the biofilm to help prevent infection, according to some embodiments of the present disclosure. [Figure 2] 1 illustrates an example of a smart implant system for total knee arthroplasty (TKA), according to some embodiments of the present disclosure. [Figure 3] 1 illustrates multiple electrodes in an electrode array, according to some embodiments of the present disclosure. [Figure 4A] 10 illustrates different locations where a set of electrodes in an array may be located on a smart implant system for TKA, according to some embodiments of the present disclosure. [Figure 4B]10 illustrates different locations where a set of electrodes in an array may be located on a smart implant system for TKA, according to some embodiments of the present disclosure. [Figure 4C] 10 illustrates different locations where a set of electrodes in an array may be located on a smart implant system for TKA, according to some embodiments of the present disclosure. [Figure 4D] 10 illustrates different locations where a set of electrodes in an array may be located on a smart implant system for TKA, according to some embodiments of the present disclosure. [Figure 5] 1 illustrates an embodiment of a smart musculoskeletal implant that includes a control and communication module that is assembled to, integrated with, or part of a conventional musculoskeletal implant, according to some embodiments of the present disclosure. [Figure 6] 1 illustrates an example of a control and communication module, according to some embodiments of the present disclosure. [Figure 7] 1 illustrates three-electrode and two-electrode configurations according to some embodiments of the present disclosure. [Figure 8] 1 illustrates an example of a smart implant having a three-electrode configuration with a functionalized working electrode, according to some embodiments of the present disclosure. [Figure 9] 1 illustrates an example of a smart implant having a three-electrode configuration with a functionalized working electrode, according to some embodiments of the present disclosure. [Figure 10] 1 illustrates an example of a smart implant having a multimodal working electrode and separate electrode arrays for sensing and stimulation, according to some embodiments of the present disclosure. [Figure 11] 1 illustrates an example of a smart implant having a multimodal working electrode and separate electrode arrays for sensing and stimulation, according to some embodiments of the present disclosure. [Figure 12] 1 illustrates an example of a smart implant with a multimodal working electrode and separate electrode arrays for measurement / sensing and stimulation, according to some embodiments of the present disclosure. [Figure 13]1 illustrates an example of a smart implant with a multimodal working electrode and separate electrode arrays for measurement / sensing and stimulation, according to some embodiments of the present disclosure. [Figure 14] 1 illustrates a smart implant having multiple multimodal working electrodes and the same electrode array for measurement / sensing and stimulation, according to some embodiments of the present disclosure. [Figure 15] 1 illustrates a smart implant having multiple multimodal working electrodes and the same electrode array for measurement / sensing and stimulation, according to some embodiments of the present disclosure. [Figure 16] 1 illustrates an electrode array being controlled to sequentially execute measurement modes, according to some embodiments of the present disclosure. [Figure 17] 1 illustrates an example of an electrode array that sequentially performs open circuit potential (OCP), amperometry, and electrochemical impedance spectroscopy (EIS), according to some embodiments of the present disclosure. [Figure 18] 1 illustrates an example of an electrode array performing two electrochemical techniques in parallel, according to some embodiments of the present disclosure. [Figure 19] 1 illustrates an example of an electrode array performing EIS and OCP in parallel, according to some embodiments of the present disclosure. [Figure 20] 1 illustrates an example of a controller controlling a multiplexer to select a new working electrode for performing a series of electrochemical techniques, according to some embodiments of the present disclosure. [Figure 21] 10 illustrates a flowchart of a measurement process in which electrodes in an electrode array are cycled, according to some embodiments of the present disclosure. [Figure 22] 22 illustrates electrodes in an electrode array being cycled during the measurement process of FIG. 21 according to some embodiments of the present disclosure. [Figure 23] 10 illustrates a flowchart of a stimulation sequence used in conjunction with a measurement sequence, according to some embodiments of the present disclosure. [Figure 24A]1 illustrates a smart interbody spacer according to some embodiments of the present disclosure. [Figure 24B] 1 illustrates a smart interbody spacer according to some embodiments of the present disclosure. [Figure 24C] 1 illustrates a smart interbody spacer according to some embodiments of the present disclosure. [Figure 24D] 1 illustrates a smart interbody spacer according to some embodiments of the present disclosure. [Figure 24E] 1 illustrates a smart interbody spacer according to some embodiments of the present disclosure. [Figure 24F] 1 illustrates a smart interbody spacer according to some embodiments of the present disclosure. [Figure 24G] 1 illustrates a smart interbody spacer according to some embodiments of the present disclosure. [Figure 24H] 1 illustrates a smart interbody spacer according to some embodiments of the present disclosure. [Figure 24I] 1 illustrates a smart interbody spacer according to some embodiments of the present disclosure. [Figure 25] 10 illustrates a flowchart of a stimulation sequence used in conjunction with a bone growth measurement sequence, according to some embodiments of the present disclosure. [Figure 26] 1 illustrates a flow chart of a combined osteogenic and microbial application system according to some embodiments of the present disclosure. [Figure 27] 1 illustrates an example of an implant device according to some embodiments of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0009] The following discussion is presented to enable those skilled in the art to make and use embodiments of the present disclosure. Various modifications to the illustrated embodiments will be readily apparent to those skilled in the art, and the principles herein may be applied to other embodiments and applications without departing from the embodiments of the present disclosure. Thus, the embodiments are not intended to be limited to the embodiments shown, but are to be accorded the widest scope consistent with the principles and features disclosed herein. The following detailed description should be read with reference to the drawings, in which like elements in different drawings have like reference numerals. The figures, which are not necessarily to scale, depict selected embodiments and are not intended to limit the scope of the embodiments. Those skilled in the art will recognize that the examples provided herein have many useful alternatives and are within the scope of the embodiments.

[0010] Embodiments of the present disclosure are directed to electrochemical sensors and smart implant sensing systems that enable the measurement of multiple analytes using multiple electrochemical techniques using multimodal electrode arrays where each electrode can perform multiple sensing functions.

[0011] Embodiments herein include multimodal electrode arrays and smart implant systems that may offer the following advantages: multiple electrochemical techniques from a single, non-functionalized working electrode in an array to avoid the need for multiple dedicated working electrodes; any electrode in the array can be configured as a working electrode, reference electrode, or counter electrode to enable spatial sensing in a compact form factor; any electrode in the array can be configured as an anode or cathode to enable spatial stimulation in a compact form factor; clinical applications for electrochemical sensing of biofilms (e.g., infection) and tissues (e.g., bone growth); and clinical applications for electrical stimulation of biofilms (e.g., infection treatment) and tissues (e.g., bone growth promotion).

[0012] Electrochemical sensing technologies are preferred for smart implant applications due to their ability to measure a wide variety of in vivo electrical, chemical, and biological analytes.

[0013] Electrical stimulation is a preferred treatment mechanism for smart implant applications. Smart implants can use electrical stimulation for the treatment of infection, bone healing, pain, and cancer. Using electrical stimulation in tandem with electrochemical sensing may require separate sets of electrodes for stimulation and sensing functions; however, embodiments herein may use the same set of electrodes for stimulation and sensing functions, as it may be advantageous to minimize the number of electrodes that must be integrated into a smart implant due to space limitations. Some embodiments of the present disclosure describe smart implant systems that enable the measurement of multiple analytes using multiple electrochemical techniques and the delivery of electrical stimulation using multimodal electrode arrays, where each electrode can perform multiple sensing and stimulation functions.

[0014] This disclosure is organized in three sections: microbial applications, osteogenic applications, and composite applications. However, it should be noted that embodiments from each application may be applied to the other applications.

[0015] Microbial is a term used to describe microorganisms, particularly disease-causing bacteria. In the context of this disclosure, microbial applications include the detection and treatment of bacterial cells, bacterial biofilms, and bacterial infections. The major clinical manifestations of infections associated with musculoskeletal surgery include periprosthetic joint infections (PJIs) in joint arthroplasty and surgical site infections (SSIs) in trauma and spine surgery. Both infection types are caused by implant biofilms.

[0016] Periprosthetic joint infection (PJI) is a devastating complication of total joint arthroplasty caused by the development of bacterial biofilms on the surfaces of biologically inert implant components. PJI affects approximately 30,000 patients annually in the United States and is the leading cause of revision knee arthroplasty (TKA). Often, PJI is not detected until patients report acute symptoms such as fever, inflammation, or fistulas, prompting detailed follow-up and synovial fluid cultures. Alternatively, chronic infections may develop more slowly and be detected only after symptoms of pain or instability caused by infected loosening of implant components. In either case, a mature biofilm is typically well established before PJI is diagnosed. At this stage, antibiotic treatment is typically ineffective at eradicating bacteria, which are protected by the extracellular polymeric substance (EPS) matrix. Standard treatment for PJI consists of surgical debridement and / or component revision, accompanied by 6–12 weeks of intravenous antibiotics. Some embodiments of the present disclosure include means for detecting and treating infection-causing biofilms, eliminating the need for invasive and costly surgical intervention.

[0017] Surgical site infection (SSI) is a type of infection that occurs after surgery in any part of the body where surgery has been performed. Similar to PJI, implant-associated SSI is often caused by the formation of bacterial biofilms on implant components. In trauma and spine surgery, the incidence of SSI is generally greater in longer and more invasive procedures, such as femoral nailing and deformity correction. In lumbar fusion surgery, the incidence of infection is 2-4%, but studies have shown that infection is an underdetected and underreported cause of fusion failure (i.e., nonunion). In fact, one study found positive intraoperative bacterial cultures in 10% of lumbar nonunion revision surgeries where infection was not suspected.

[0018] One way smart implants can treat infections is by utilizing electrical stimulation to eliminate bacterial biofilm at its source, for example through the use of low-dose controlled current therapy, as described in more detail below.

[0019] Electrochemical sensing is described in more detail below.

[0020] The basic operating principle of an electrochemical sensor involves the reaction of a target substance with the surface of an electrode, which generates an electrical signal proportional to the substance's concentration. Electrochemical sensors may contain three electrodes, including a working electrode, a counter electrode, and a reference electrode, which are connected to a data acquisition system called a potentiostat. Some techniques require only a two-electrode configuration, where the reference electrode may be coupled to the counter electrode or eliminated entirely. A variety of electrochemical techniques exist that differ in the method of excitation and interpretation of the electrochemical reaction. Three of the most common electrochemical sensing techniques include open-circuit potential, amperometry, and electrochemical impedance spectroscopy.

[0021] FIG. 3 illustrates multiple electrodes in an electrode array according to some embodiments of the present disclosure.

[0022] A working electrode (e.g., working electrodes 310a-n) comprises an electrode that acts as an anode in an electrode array and is the location where sensor measurements are taken. For example, a working electrode may be utilized for spatial mapping of a single parameter, such as impedance measurements, to obtain impedance measurements at each working electrode on the electrode array. Using multiple electrochemical techniques, such as potentiometry, electrochemical impedance spectroscopy, and cyclic voltammetry, in series, an array of working electrodes may also be used to sequentially capture multiple property readings, such as impedance, conductivity, and pH. However, in some embodiments, different electrochemical techniques may be performed in parallel on individual working electrodes. For example, cyclic voltammetry may be performed on a first working electrode, amperometry may be performed on a second working electrode (different from the first electrode), and impedance spectroscopy may be performed on a third electrode (different from the first and second electrodes).

[0023] Counter electrodes (eg, counter electrode 330) include electrodes that act as cathodes in an electrode array system.

[0024] A reference electrode (e.g., reference electrode 320) includes an electrode to which a fixed reference voltage (e.g., 1.7 volts) is supplied for sensing measurements. The reference electrode may provide a baseline against which changes in potential at the working electrode may be interpreted. By maintaining a stable and reproducible reference potential through the reference electrode, the electrode array may obtain more consistent electrical signal response measurements, making it easier to analyze and interpret the electrical and / or chemical properties measured by the working electrode.

[0025] In some embodiments, a reference electrode is not used (or is not present) on the electrode array. In still other embodiments, the reference electrode is connected to the counter electrode, thereby causing them both to act as counter electrodes. How the reference electrode is used may depend on the type of electrical and / or chemical property being measured by the working electrode or the measurement process used (e.g., amperometry).

[0026] However, as described herein, any of the electrodes in the array can be selected as a working electrode, a counter electrode, or a reference electrode by the multiplexer during measurement mode.

[0027] FIG. 27 illustrates an example of an implant device 100 (also referred to herein as an implant or a smart implant) according to some embodiments of the present disclosure. The implant device 100 is implantable within a patient's body and may include a set of electrodes 110 in an array spaced apart on the implant device 100. The implant device 100 may further include a measurement circuit 120 configured to perform a measurement mode on signals from the electrodes 110. The implant device may further include a multiplexer 150 interconnecting different pairs of electrodes 110 in the array to the measurement circuit 120. The implant device 100 may also optionally include a controller 130, which may include a processing circuit 140. Alternatively, the processing circuit 140 is physically separate but communicatively coupled to the controller 130. The control unit 130 may control the multiplexer 150 to selectively connect different pairs of electrodes 110 in the array over time to perform the measurement mode. The measurement mode may include one or more of an open circuit potential (OCP) measurement, an amperometric measurement, and an electrochemical impedance spectroscopy (EIS) measurement.

[0028] The measurement circuit 120 may include a signal generator 122 that generates signals to provide selected electrodes to the controller 130 .

[0029] The implant device 100 may further include a transmitter / receiver antenna 160 configured to transmit measurements (e.g., in a measurement report) to a patient device or a clinician device to report the detection of infection, bone growth (or lack thereof), etc. The transmitter / receiver antenna 160 may further be configured to receive instructions from the patient device or the clinician device, the instructions including instructions regarding the measurement mode the implant device is to perform or the level / duration of electrical stimulation the implant device is to perform.

[0030] Open-circuit potential (OCP) involves passive measurement of the free potential of an electrochemical system when no current flows between the reference electrode and the working electrode. A common application of OCP is pH sensing, where increasing pH results in a decrease in potential due to a decrease in hydrogen ion concentration. In addition, ions such as proton / hydroxonium, sodium, potassium, calcium, and chloride can be detected using potentiometry. For example, if the potentiostat is in potentiometry or open-circuit potential mode, the cations sodium and potassium can be measured on the ion-selective electrodes. For example, the measurement circuit 120 of the implant device 100 can measure the free potential through the first electrode pair (of the electrodes 110), while the controller 130 of the implant device 100 does not apply a current between the first electrode pair.

[0031] Amperometry, including chronoamperometry (CA), is an active technique that consists of applying a voltage step and measuring the resulting current response at the working electrode. Amperometry techniques are used to detect small molecules through electrochemical reduction. One application of CA is dissolved oxygen (DO) sensing, where the measured current response increases as the percentage of dissolved oxygen decreases. Another application is found in blood glucose test strips and newer continuous glucose monitors that rely on CA technology to quantify glucose concentrations in blood or interstitial fluid. For example, the controller 130 of the implant device 100 can apply power to one electrode in the second electrode pair, while the measurement circuit 120 of the implant device 100 measures the resulting current at the other electrode in the second electrode pair. In these embodiments, direct current (DC) can be used.

[0032] Electrochemical impedance spectroscopy (EIS) is one of the most complex and powerful methods in analytical electrochemistry. EIS involves applying a sinusoidal (AC) potential over a range of frequencies and measuring the magnitude and phase angle of the resulting current. Equivalent circuit models of electrochemical systems are often constructed using EIS data and used to isolate and investigate changes in individual components of the system (e.g., biochemical layers) over time. One application of EIS is in medical diagnostics, where the impedance of cancerous tissue structures can be distinguished from that of healthy soft tissue. For example, controller 130 can apply an AC current to one of the electrodes in a third electrode pair, while measurement circuit 120 measures the resulting current at the other electrode in the third electrode pair.

[0033] Infection detection via electrochemical sensing is discussed in more detail below.

[0034] Electrochemical sensing methods hold promise for the development of implantable biofilm sensors because they can provide insight into the electrochemical activity of the microenvironment on the sensor surface and the macroenvironment surrounding the sensor.

[0035] OCP, CA, and EIS may be of interest for measuring changes in biofilm physiology similar to pH, dissolved oxygen, and impedance, respectively. Metabolic waste products such as lactate and citric acid are thought to accumulate within the EPS as biofilms grow, causing the biofilm to become more acidic (lower pH) over time. Similarly, metabolic oxygen is thought to be consumed as biofilms develop, and oxygen depletion may be most pronounced at the greatest depth (i.e., at the biofilm-electrode interface). Finally, biofilm impedance (i.e., resistance) is thought to increase as biofilms thicken over time due to increasing obstruction to current flow across the EPS.

[0036] Treatment of infection via electrical stimulation is discussed in more detail below.

[0037] The electrical stimulation can be precisely controlled and steered by a controller within the implant device to target only the biofilm on the surface of the implant, without harming the surrounding tissue.

[0038] For example, 0.1 mA DC current applied for 21 days can prevent signs of clinical infection around percutaneous pins implanted in the tibia. Electrical stimulation can enhance antibiotic effectiveness and significantly reduce the concentration required to eradicate biofilms. For example, a continuous current of 0-10 mA for 15 minutes can achieve a 2-log (approximately 99%) reduction in E. coli biofilms attached to dental implants. This short treatment period may allow stimulation to be used during physician procedures within the clinic.

[0039] Infection detection and treatment via smart implant systems is discussed in more detail below.

[0040] The smart implant system described herein can detect and eradicate biofilm growth, thereby enabling early detection and treatment of implant-associated infections such as PJI and SSI.

[0041] Figure 1 illustrates an example of a smart implant system configured to alert a clinician to biofilm growth and treat the biofilm to help prevent infection, according to some embodiments of the present disclosure. Figure 2 illustrates an example of a smart implant system for total knee arthroplasty (TKA), according to some embodiments of the present disclosure. Figures 4A-4D illustrate different locations where a set of electrodes in an array may be located on a smart implant system for TKA, according to some embodiments of the present disclosure.

[0042] One embodiment of this system includes a TKA implant component (e.g., a tibial insert) with electrodes integrated along different portions of its surface. In this concept, the array of electrodes is controlled by an embedded smart module (also referred to herein as a controller (e.g., controller 130 in FIG. 27 )) that functions as an electrochemical sensing and stimulation system. The location and surface topology of these electrodes can be optimized to bias biofilm formation on the electrodes ahead of other areas of the implant. Once the patient recovers from surgery, measurement data (captured by the measurement circuitry via the electrodes) is transmitted (via a transmitter / receiver) to the patient's device (e.g., the patient's laptop, smartphone, etc.) and forwarded to the clinic for review. If the system detects early stages of biofilm formation, the clinic is alerted to prompt closer follow-up, earlier diagnosis, and / or treatment. For example, measurements captured by the measurement circuitry can be stored locally on the implant device or a device external to the patient and mapped over time to detect changes over time that indicate threshold shifts or potential infection.

[0043] Using this information, clinicians can choose to remotely administer non-invasive stimulation therapy to eradicate the biofilm. In combination with a standard antibiotic regimen, this therapy can prevent infection from occurring and eliminate the need for surgical intervention. Artificial intelligence can be added to this system to form a closed-loop system that autonomously and continuously identifies and eradicates early-stage biofilms before the onset of infectious symptoms.

[0044] It should be noted that while this disclosure describes embodiments of smart implants designed to detect and treat infection, this disclosure is not limited thereto, but rather includes other clinical applications such as oncology and pain management. Additionally, smart implants refer to the integration of electronics with any implant used for musculoskeletal surgery, including spinal implants (e.g., interbody spacers, rods, screws), joint implants (e.g., total hip replacements, total knee replacements, total shoulder replacements), and trauma implants (e.g., plates, nails, screws, external fixators).

[0045] A smart musculoskeletal implant is an implantable medical device with control and communication capabilities designed to promote healing, prevent complications, and / or monitor surgical outcomes in patients with musculoskeletal disorders. Embodiments of a smart musculoskeletal implant (i.e., smart implant) include a control and communication module that is assembled to, integrated with, or part of a conventional musculoskeletal implant, which is further defined below.

[0046] FIG. 5 illustrates an embodiment of a smart musculoskeletal implant that includes a control and communication module that is assembled to, integrated with, or part of a conventional musculoskeletal implant, according to some embodiments of the present disclosure.

[0047] A conventional musculoskeletal implant includes any implant designed for musculoskeletal surgery, including spinal, trauma, and joint procedures, which can be made "smart" through the addition of electronic modules (e.g., control and communication modules).

[0048] FIG. 6 illustrates an example of a control and communication module according to some embodiments of the present disclosure.

[0049] The control and communication module may be what makes the system "smart." The control and communication module includes at least a control subsystem, a communication subsystem, and a power subsystem. In some optional embodiments, the smart implant further includes an electrochemical sensing subsystem, an electrical stimulation subsystem, or both.

[0050] Some embodiments of smart implants may have a primary function of stabilizing and restoring musculoskeletal structures and a secondary function of sensing and acting on its surroundings using electrochemical means.

[0051] Infection can be caused by pathogens, including bacteria, that thrive in biofilms on the implant surface and affect the microenvironment of the implant surface as well as the macroenvironment surrounding the implant, including pH levels, oxygen concentration, and electrical impedance. Additionally, such biofilms and the pathogens present therein can be eradicated with low levels of electrical stimulation.

[0052] Generally, an electrochemical sensing system may include a dedicated electrochemical cell (i.e., a set of two or three electrodes) for each sensor measurement and analyte (e.g., pH and dissolved oxygen). The working electrode may be functionalized to enable a sensitive and specific reaction with the target analyte.

[0053] Figure 7 illustrates a three-electrode and two-electrode configuration according to some embodiments of the present disclosure. Figures 8-9 illustrate an example of a smart implant having a three-electrode configuration with a functionalized working electrode according to some embodiments of the present disclosure.

[0054] Electrochemical measurements of oxygen concentration, pH level, and impedance may include dedicated sets of electrodes for each measurement. Additionally, electrical stimulation may be facilitated through separate, dedicated sets of anodic (+) and cathodic (-) electrode pairs. As shown in Figures 8-9, a three-electrode configuration may require nine electrodes to perform all three electrochemical measurements, plus one or more additional electrode pairs for stimulation.

[0055] 10-11 illustrate an example of a smart implant having a working electrode in a shared cell and separate electrode arrays for measurement / sensing and stimulation, according to some embodiments of the present disclosure.

[0056] To reduce the system's space requirements and total number of electrodes, counter and reference electrodes may be shared by different working electrodes, but a unique working electrode (i.e., sensing electrode) is generally required for each analyte. Thus, electrochemical measurements of oxygen concentration, pH level, and impedance may require a dedicated working electrode (i.e., sensing electrode) for each measurement. Additionally, shared electrode arrays may be utilized so that each electrode can function as an anode or cathode on demand via programming (i.e., multiplexer control), depending on the usage scenario. This electrode configuration allows for precise control and steering of stimulation.

[0057] 12-13 illustrate examples of smart implants with multimodal working electrodes and separate electrode arrays for measurement / sensing and stimulation, according to some embodiments of the present disclosure.

[0058] In these examples, the smart implant includes a sensing electrode array and another electrode array used as a stimulating electrode array. The other electrode array may be separate from the sensing electrode array on the implant device and may include a set of electrodes that are physically separate and electrically isolated from the set of sensing electrodes in the sensing electrode array. In some of these embodiments, the controller controls the multiplexer to selectively connect different electrode pairs in the other array over time to sequentially perform measurement modes and / or perform electrical stimulation.

[0059] In some preferred embodiments, as illustrated by Figures 12-13, oxygen concentration, pH, and impedance / dielectric properties are measured on a single multimodal working electrode. It is possible to measure multiple analytes in a common multimodal working electrode (MMWE), thus reducing the size and complexity of the electrode array. For example, in Figure 12, the multimodal working electrode (MMWE) can be configured to measure multiple oxygen concentrations, pH, and impedance / dielectric properties. Additionally, each electrode E1-E6 in the stimulation electrode array can be used to generate an electric field between electrode pairs (at different times or all at once) to electrically stimulate the tissue around the implant.

[0060] 14-15 illustrate a smart implant having multiple multimodal working electrodes and the same electrode array for measurement / sensing and stimulation, according to some embodiments of the present disclosure.

[0061] 14-15, a multimodal electrode array is utilized by both the electrochemical sensing subsystem and the stimulation subsystem, and any electrode in the array can be designated for any function (e.g., WE, RE, CE, anode, cathode) via multiplexer control and programming (via the implant device's controller and multiplexer). This can further reduce the size and complexity of the sensing and stimulation system to a minimum, which can be preferable due to the miniaturization requirements of smart implant applications.

[0062] Additionally, the function of any electrode within an electrode array can change over time. For example, three different electrochemical measurements can be captured from a single multimodal working electrode with adjacent electrodes acting as counter and reference electrodes. Then, at a later time, the roles of each electrode can be swapped, allowing multiple electrochemical measurements to be performed at all electrodes within the array. For example, the first electrode in a set of three electrodes can act as a working electrode, while the second electrode acts as a counter electrode. Then, at a later time, the second electrode can act as a working electrode and the first electrode can act as a counter electrode. Similarly, each electrode within the array can be alternated as an anode or a cathode to enable electrical stimulation at all electrodes within the array. Enabling this functionality is discussed further below.

[0063] The sensing sequence is discussed in more detail below.

[0064] FIG. 16 illustrates an electrode array controlled to sequentially perform measurement modes according to some embodiments of the present disclosure.

[0065] In some embodiments, a multimodal electrode array includes three or more electrodes whose functions can change over time. For example, one electrode can be designated as a working electrode, another as a counter electrode, and a third as a reference electrode. Then, at another time, the electrode functions can be switched (e.g., from functioning as a working electrode to a reference electrode), or at least one electrode can be switched (e.g., a new working electrode is selected by the multiplexer via the controller, and the previously used working electrode is deselected by the controller). Figure 20 illustrates an example of a controller controlling a multiplexer to select a new working electrode for performing a sequence of electrochemical techniques, according to some embodiments of the present disclosure. In this example, after a first working electrode performs one or more techniques, a second electrode in the electrode array is selected by the controller to perform the sequence of techniques.

[0066] To facilitate measurement of different analytes at the same working electrode (i.e., performance of different measurement modes), various electrochemical techniques can be performed sequentially. For example, technique 1 can be performed during a first time window by a first electrode pair in an electrode array (e.g., the controller controls a multiplexer to select the first electrode in the electrode pair to act as the working electrode and the second electrode in the electrode pair to act as the counter electrode), followed by technique 2 during a second time window by a second electrode pair in the electrode array, technique 3 during a third time window by a third electrode pair in the electrode array, and so on. When performed sequentially, the different time windows are distinct and do not overlap in time with one another. Additionally, the first, second, and third electrode pairs can be the same or different electrode pairs in the electrode array.

[0067] In some embodiments, during a time window that does not overlap with the first time window, the controller controls the multiplexer to select a first electrode to operate as a counter electrode and select a third electrode, different from the second electrode that operated as the counter electrode, to operate as a working electrode.

[0068] Pauses may be incorporated between techniques (i.e., measurement modes and / or electrical stimulation) for various reasons, including to allow for charge distribution and balancing. For example, between two sequences of techniques, the controller may be configured to delay a period during which the implant device controller (e.g., via the measurement circuit 120) applies no current or applies a reverse bias current to the electrode pairs used during the previously completed technique (or one of the previous techniques). The reverse bias current may be a reverse bias of the current applied during the previously completed technique (or one of the previous techniques).

[0069] FIG. 17 illustrates an example of an electrode array that sequentially performs open circuit potential, amperometry, and electrochemical impedance spectroscopy, according to some embodiments of the present disclosure.

[0070] In the example of electrochemical sensing for biofilm and infection detection, the electrochemical measurement sequence may include open circuit potentiometry (i.e., pH), followed by amperometry (i.e., oxygen), followed by electrochemical impedance spectroscopy (i.e., biofilm impedance). Each technique may be performed with the same two or three electrodes, each technique may be performed with different two or three electrodes, or some of the electrodes may be reused for each technique.

[0071] 18 illustrates an example of an electrode array performing two electrochemical techniques in parallel, according to some embodiments of the present disclosure. FIG. 19 illustrates an example of an electrode array performing EIS and OCP in parallel, according to some embodiments of the present disclosure.

[0072] Not all of the techniques in the measurement process need be sequential. For example, technique 1 and technique 2 can be performed in parallel, followed by technique 3. In the example of infection detection, EIS and OCP can be measured in parallel, followed by a pause, and then amperometry.

[0073] Because they are considered in parallel, the techniques can be performed during at least partially overlapping time windows. For example, a first measurement mode of a plurality of measurement modes is performed during at least partially overlapping time windows, while a second measurement mode of at least two measurement modes is performed simultaneously, with the electrode pair used in the first measurement mode being different from the electrode pair used in the second measurement mode. However, the electrode pairs may share at least one electrode (e.g., a shared counter electrode).

[0074] However, it should be noted that although two techniques are run in parallel in Figures 18 and 19, more than two electrochemical techniques may be run in parallel.

[0075] This system also allows each electrode to function as a working electrode. The sequential measurements detailed above can be performed on a different electrode designated as the working electrode. This is discussed in more detail below.

[0076] 21 illustrates a flowchart of a measurement process in which electrodes in an electrode array are cycled, according to some embodiments of the present disclosure. FIG. 22 illustrates electrodes in an electrode array being cycled during the measurement process of FIG. 21, according to some embodiments of the present disclosure.

[0077] By cycling through the sequence of electrochemical measurements at each electrode, a map of the electrochemical environment surrounding the electrode array can be constructed. The map can be generated by the implant device (e.g., via a controller) and / or the measurements can be reported to an external device (e.g., a patient's phone or a clinician's device) in a measurement report for generation in the external device. This allows for a spatial understanding of when a biofilm or infection is present and when it is not.

[0078] In some of these embodiments, the controller generates a measurement report indicating the results of the measurement modes performed and controls the transmission of the report to a device external to the patient's body.

[0079] In the example of FIGS. 21-22, the measurement process is designed to determine whether infection is present on or around the area of ​​the implant. The measurement process may be performed automatically and / or repeatedly by the smart implant system at electronically configurable time intervals within the implant device's memory. The memory may be physically separate but electrically connected to the implant device's controller. Alternatively, the implant device's memory may be part of the controller. For example, once per day or once per week. However, shorter or longer time intervals may be used, and the length of the time interval may vary over time depending on the measurement (e.g., when an infection is detected) or the time since implantation of the implant device into the patient. A shorter interval may be desired to enable early detection of infection in the subacute phase, when the patient may be susceptible to infection. For example, the implant may perform the measurement process every two hours for the first 14 days after surgery. A longer interval may be desired later in the recovery period to conserve battery life or avoid patient compliance issues with wirelessly powering the device. For example, from day 14 to day 90, the implant may perform the measurement process once per day or once per week. After 90 days, the incidence of infection decreases significantly, and measurements may not need to be collected automatically. In situations where the patient remains at high risk of infection after 90 days, such as in the case of dental work, other surgery, or frequent urinary tract infections, the measurement process and protocol can be restarted by the patient or clinician. In addition to automatically performing the measurement process, measurements can also be manually initiated at any time by the patient or clinician using the connected system.

[0080] The measurement process may begin by the implant device's controller determining or controlling a multiplexer to select a set of electrodes that can function as working electrodes (e.g., the shared electrode array of FIG. 22). For example, the controller controls the multiplexer to sequentially select each electrode in the set of electrodes in the array to operate as the working electrode during different time windows while the controller sequentially performs at least two measurement modes.

[0081] The controller may then select (via a multiplexer) an electrode pair (or more) within the set of electrodes to perform an electrochemical measurement sequence. The electrochemical measurement sequence may include one measurement mode or multiple measurement modes (e.g., electrochemical techniques 1 through N). The controller may measure signals received by the electrodes using measurement circuitry connected through a multiplexer that interconnects different electrode pairs within the array to the measurement circuitry. After an electrode pair within the set of electrodes performs an electrochemical measurement sequence (cycle 1), the controller may determine whether there is another electrode pair (or more) within the array that is available to perform cycle 2 (or is not performing a measurement sequence). If there are no available electrodes, the measurement process ends. If there are available electrodes, the controller starts the measurement process from the beginning (cycle 2) and selects a different electrode pair (or more) to perform an electrochemical measurement sequence. This may continue until all electrodes within the electrode array have performed an electrochemical measurement sequence as working electrodes, or may continue until a threshold number of electrodes within the electrode array have performed an electrochemical measurement sequence as working electrodes, or may continue for a predetermined period of time.

[0082] The cleaning routine is discussed in more detail below.

[0083] Smart implant systems may be implanted in situ for years, with sensors operating for months and then occasionally. Therefore, working (i.e., sensing) electrodes may need to be replenished or cleaned from time to time. Cleaning may be necessary because biofouling or accumulation of biological material on the electrode's surface causes reduced sensitivity and increased surface impedance. A series of potential and / or current steps or bursts may result in a "cleaning routine" when the electrode is deemed to be contaminated, corroded, or encapsulated. An electrode may be determined to require cleaning based on measurements taken by (or near) the electrode that indicate contamination, corrosion, or encapsulation over time (e.g., through abnormal impedance measurements).

[0084] Stimulation sequences are discussed in more detail below.

[0085] Electrical stimulation can be used as an effective treatment for eradicating bacteria and biofilms. Any of the electrodes in a multimodal electrode array can be designated as an anode or a cathode for purposes of electrical stimulation. Controlling which electrodes function as anodes and cathodes can enable steering of the electric field across adjacent volumes to direct therapeutic energy. Sequential switching of anode and cathode configurations can ensure that all electrode surfaces are adequately treated. This can be important for stimulation programs in which treatment is more effective at the cathode versus the anode, or vice versa.

[0086] With respect to electrical stimulation of the working electrodes, the controller may operate to control electrical stimulation of a particular working electrode, or all of the working electrodes of an electrode array, by supplying a direct current voltage from an energy storage device within the smart implant to a level that at least reduces the formation of a biofilm on at least a portion of the implant component while implanted in a patient. For example, the controller may control the supply of a direct current voltage to one electrode pair in the array and the supply of an alternating current swept over a range of frequencies to another electrode pair in the array.

[0087] In another example, the implant circuitry may provide a voltage difference between the working electrode and the counter electrode to extend an electric field therebetween and control the level of current density therebetween to at least reduce the formation of biofilm and / or at least partially eradicate biofilm on at least a portion of the implant component while implanted in a patient. The counter electrode may be a counter electrode within the same electrode array or a counter electrode of an electrode array different from the electrode array to which the working electrode is stimulated. Alternatively, there may be a counter electrode that is not part of the electrode array that is used while the working electrode is stimulated.

[0088] The stimulation sequence can be used independently of the measurement process. For example, the patient or clinician may wish to utilize only the infection treatment functionality as needed and not use other smart implant functions. In these cases, the clinician has a non-invasive treatment option that can be performed on demand. If the patient reports symptoms of infection, the clinician can perform treatment remotely, or the patient can visit the clinic and receive treatment in-office. In either case, the implant can act as an on-demand, in situ delivery system for species-independent infection treatment.

[0089] Stimulation sequences can also be used in conjunction with measurement processes to enable a detection and treatment control loop. For example, measurements from the first 14 days after surgery may indicate biofilm growth that has not yet manifested as an infection. Clinicians can choose to monitor patients more closely for the development of symptoms before administering treatment, or treatment can be administered using a smart implant as a preventative measure.

[0090] 23 illustrates a flowchart of a stimulation sequence used in conjunction with a measurement sequence, according to some embodiments of the present disclosure. Note that while each step in the process is described as being performed by the implant device (e.g., a controller in communication with other components of the implant device), some steps may be performed by or in conjunction with an external device.

[0091] After the implant is implanted in the patient, or several days later (day N), the implant device may perform an electrochemical measurement process (including at least one measurement mode). For example, the measurement mode may be performed by the controller in response to expiration of a measured period of time from implantation of the implant device within the patient's body.

[0092] Based on the measurements, the implant device (e.g., a controller within the implant device) may determine whether an infection is detected. If an infection is not detected, the implant device may start the process again. If an infection is detected, the implant device may alert the patient (e.g., by sending a message to the patient's device) or the clinician (e.g., by sending a message directly to the clinician device, via the patient device, or via an external device used to send / receive messages to / from the clinician). The implant device may then decide to administer a therapy (i.e., electrical stimulation). Alternatively, the clinician may decide to administer a therapy and send instructions to the implant device (through the clinician device) to administer the therapy.

[0093] Optionally, the implant device may determine the level (ie, voltage / current) at which to generate the electrical stimulation.

[0094] If it is determined that a treatment should be administered, the implant device executes a stimulation sequence (e.g., generating an electric field with a low current for a duration, generating multiple potentials and / or current bursts, etc.). After the stimulation sequence is executed, the process can be started over to verify the effectiveness of the treatment or if further treatment is desired. If it is determined that a treatment should not be administered, the process is started over.

[0095] Osteogenic applications are discussed in more detail below.

[0096] Osteogenic (i.e., bone growth) complications are a factor in most musculoskeletal surgeries. Bone growth problems are a significant concern in spinal fusion, long bone trauma, and cementless arthroplasty, especially when patients are considered high risk (e.g., smoking history, obesity, osteoporosis, previous surgery, diabetes, etc.).

[0097] Implant devices can provide therapeutic benefits through direct current electrical stimulation (DCES) in an acceptable form factor and workflow. The addition of DCES technology to static and expandable interbody spacers, including next-generation 3D-printed consumables, can further enhance the clinical effectiveness of these implants. Smart implants can be provided in an open-loop configuration, where a constant dose is delivered for approximately six months after surgery. With the addition of the aforementioned electrodes, the implant can also monitor the effect of stimulation on fusion progression and increase the dose as needed. This feedback loop can also be autonomously controlled by the implant, allowing the implant to adapt therapy to each individual patient's needs.

[0098] Some smart implants may include conductive implant scaffolds. These smart implants may use the conductive implant scaffolds to accelerate bone formation across the intervertebral disc space. The conductive implant scaffolds may act as three-dimensional (3D) electrodes to deliver and distribute electrical bone growth stimuli through the implant window. Conductive implant scaffolds may be advantageous over electrodes integrated into the interbody implant surface because the electric field generated by the conductive implant scaffolds is more uniform across the implant material and can be targeted to the implant material. Elastomeric structures may collapse into a compact shape during insertion and provide the ability to expand along the interbody space during implant expansion. Generally, elastomeric materials are non-conductive, so graphene coatings can make the elastomeric structures conductive.

[0099] A portion of the smart implant can include an anode housing configured to create an anodic charge, and the implant scaffold can be configured to create a cathodic charge. At certain voltages and / or frequencies, the electric field formed between the anode housing and the implant scaffold can accelerate bone formation across the disc space.

[0100] Similar to the infection applications previously described in this disclosure, there may be a need for a multimodal electrode array that can be utilized for both electrochemical sensing and electrical stimulation of bone growth. Note that the embodiments described in the context of infection applications may also be applied to the bone growth applications herein. Further details regarding sensing and stimulation systems for bone formation applications are presented below.

[0101] Electrochemical monitoring of bone healing is described in further detail below.

[0102] Monitoring of healing can be facilitated by measuring changes in the impedance of the tissue surrounding the implant over time. The impedance measurement system utilizes a set of electrodes and a potentiostat subsystem (which can be included in the measurement circuitry). Each distinct type of tissue has unique dielectric properties that can be measured and correlated with EIS technology. By measuring the impedance of adjacent implant material over time, the system allows the clinician to assess changes in tissue type from the integrated implant material to cortical bone. In addition, impedance values ​​can also be correlated with bone mineral density measurements to report not only bone formation but more specifically the bone mineral density of the bone tissue. By adding electrical impedance tomography (EIT) post-processing algorithms, the system can also construct a three-dimensional (3D) visualization of the location and composition of the tissue surrounding the implant. In some embodiments, a controller performs EIS measurements, and the controller is configured to perform electrical impedance tomography (EIT) using measurements acquired during EIS measurements to construct a three-dimensional (3D) model of the location and properties of the tissue adjacent to the set of electrodes. In some of these embodiments, the implant device may generate or otherwise construct a 3D model, while in other embodiments, the implant device may report measurements to a device external to the patient for construction of the 3D model in the external device.

[0103] The proposed smart implant system can provide clinicians with a robust tool for clinical decision-making, including healing assessment, follow-up protocols, and treatment planning. Additionally, data collected by this system can be used to train diagnostic algorithms that are accurate and reliable enough to provide clinical diagnoses of delayed union, nonunion, and mechanical failure. These diagnostic algorithms can be coupled with a bone growth stimulation system (discussed further below) to form a closed-loop union enhancement system that automatically steers stimulation and adjusts dosage without intervention from the clinician or patient.

[0104] Electrical stimulation of bone growth is discussed in more detail below.

[0105] Bone growth promotion is enabled by electrical stimulation, which takes advantage of natural bone modeling processes and enhances osteogenic activity. Cathodically biased current pulses are delivered to the adjacent bone graft tissue using the same set of electrodes described for sensing / measurement. Current-controlled pulses are generated by a controller via measurement circuitry (e.g., via a signal generator, which may include a pulse generator or potentiostat IC). The stimulation current may be cathodically biased because cathodic current has been shown to be more effective at inducing osteogenic activity, such as alkaline phosphatase, compared to anodic current. For example, the implant device may perform EIS measurements, and based on the measurements, the implant device may control cathodically biased electrical stimulation of different electrode pairs in the array in response to measurements obtained during the EIS measurements, which indicate the amount of bone growth.

[0106] Biphasic pulses may be used to balance the charge between designated anodic and cathodic electrodes. In one example, the maximum voltage may be set to 1.5 V or less to avoid electrolysis, and the pulse frequency may be in the range of 0.5 Hz to 100 Hz, with a pulse duration of less than 1 millisecond and an amplitude of less than 1 mA. The implant device and accompanying software may allow the clinician to program the stimulation therapy, much like programming a spinal cord stimulator. Programming may allow the clinician to set which electrodes are to be administered, along with the treatment current amplitude, frequency, pulse profile, pulse duration, and total treatment duration (or the implant device controller may provide instructions on how to select which electrodes to administer). An example program may include a biphasic square wave with a 10 Hz frequency, 0.5 millisecond pulse duration, and 100 μA amplitude. This program may then be prescribed within a treatment protocol, which may consist of one hour of treatment per week for 24 weeks. Over time, clinician-prescribed treatment programs can be correlated with measured fusion outcomes (as measured by the implant device) to assess which programs and protocols are most effective for a particular patient population.

[0107] Bone union detection and treatment via smart implant systems is discussed in more detail below.

[0108] Some embodiments of the present disclosure are discussed with reference to minimally invasive transforaminal lumbar interbody fusion (MIS TLIF), however, the disclosed embodiments may also be applied to any type of musculoskeletal implant.

[0109] 24A-24I illustrate a smart interbody spacer according to some embodiments of the present disclosure.

[0110] The smart interbody spacer of Figures 24A-24I is an expandable posterior lumbar interbody spacer with porous 3D-printed titanium endplates and an integrated intelligent healing system that enables in situ bone growth stimulation and fusion monitoring. The interbody can be inserted with a low retracted height of as little as 6 mm to reduce disruption during insertion and can provide up to 8 mm of expansion and 22° of lordosis. The integrated intelligent healing system (also referred to herein as a smart interbody spacer) can include several subsystems, including electrochemical sensing, electrical stimulation, strain sensing, temperature sensing, and motion sensing. These subsystems can be separate subsystems or can be integrated into the same subsystem configured to perform different functions.

[0111] Referring to FIG. 24I, the intelligent healing system includes an electronic module and a carrier. The electronic module houses the circuitry that enables electrochemical sensing and electrical stimulation functions. The carrier houses the electrodes and distributes electrical signals between these elements and the electronic module. The expandable interbody mechanical structure is hidden in FIGS. 24G-24I to illustrate how the electronic module and carrier are integrated within the interbody structure.

[0112] The measurement process is described in further detail below.

[0113] As previously described in the microbial application, each electrode in the multimodal electrode array can function as a working electrode for electrochemical measurements. By cycling through a sequence of electrochemical measurements at each electrode, a map of the electrochemical environment surrounding the electrode array can be constructed. This can enable a spatial understanding of when cortical bone is present and absent within the interbody space. The map can also show changes in tissue adjacent to a set of electrodes in the array and changes in tissue density over time. For example, an EIS measurement mode can be implemented, and the controller can be configured to generate a map showing changes in tissue properties across an area adjacent to a set of electrodes in the array and changes in tissue density across an area adjacent to a set of electrodes in the array.

[0114] FIG. 25 illustrates a flow chart of a stimulation sequence used in conjunction with a bone growth measurement sequence, according to some embodiments of the present disclosure.

[0115] In FIG. 25 , the measurement process can be designed to determine whether union (i.e., cortical bone) is present on or around the area of ​​the implant. The measurement process can be performed automatically by the smart implant system at regular monitoring intervals, such as once per day or once per week. Shorter intervals may be desirable when bone healing is most likely to occur. For example, the implant may wait until day 14, after postoperative inflammation has subsided, to perform the measurement process, and then continue measuring once per week from week 2 through week 52. After union is confirmed, the clinical value of union monitoring is no longer needed, so automatic measurements can be deactivated to conserve battery life or avoid patient compliance issues related to wirelessly powering the device. In addition to the automatic execution of the measurement process, measurements can also be manually initiated at any time by the patient or clinician using the connected system.

[0116] After the implant is implanted in the patient, or several days later (day N), the implant device can perform an electrochemical measurement process (including at least one measurement mode). Based on the measurements, the implant device (e.g., a controller within the implant device) can determine whether a bone growth problem has been detected. For example, if a predetermined level of bone growth has not occurred by a certain time.

[0117] If no bone growth problems are detected, the implant device may begin the process again. If bone growth problems are detected, the implant device may alert the patient (e.g., by sending a message to the patient's device) or the clinician (e.g., by sending a message directly to the clinician's device, via the patient's device, or via an external device used to send / receive messages to / from the clinician). These alerts may include messages with explicit indications of the bone growth problems and / or measurements.

[0118] The implant device may then decide to administer the therapy (i.e., electrical stimulation). Alternatively, the clinician may decide to administer the therapy and send instructions to the implant device (through the clinician device) to administer the therapy.

[0119] If it is determined that treatment should be performed, the implant device executes a stimulation sequence to promote bone growth in response to measurements obtained during the performed measurement mode that indicate the amount of bone growth, and the process starts over to verify the effectiveness of the treatment. If it is determined that treatment has not been performed, the process can start over.

[0120] The cleaning routine is discussed in more detail below.

[0121] Smart implants may be implanted in situ for several years, with sensors having months of operation and occasional operation thereafter; therefore, it may be necessary to occasionally replenish or clean the working (i.e., sensing) electrodes. Cleaning may be necessary because biofouling or accumulation of biological material on the surface of the electrodes causes a decrease in sensitivity and an increase in surface impedance. The embodiments discussed herein enable the controller to control a “cleaning routine,” which may be updated with a series of potential and / or current steps or bursts, when an electrode is deemed to be fouled, corroded, and / or encapsulated. For example, based on measurements obtained during a measurement mode, the implant device may determine that an electrode is fouled, corroded, and / or encapsulated. Based on this, the controller can control the multiplexer to selectively connect different electrode pairs in the array (including the determined fouled / corroded / encapsulated electrodes) over time and execute a cleaning routine that includes electrically stimulating the different electrode pairs using multiple potentials and / or current bursts.

[0122] Stimulation sequences are discussed in more detail below.

[0123] Electrical stimulation can be used as an effective treatment for stimulating bone formation activity after musculoskeletal surgery. As previously mentioned, any of the electrodes in a multimodal electrode array can be designated as an anode or a cathode for purposes of electrical stimulation. Controlling (by the implant device controller) which electrodes function as anodes and cathodes can enable steering of the electric field across adjacent volumes to direct therapeutic energy. For example, treatment can be directed more toward areas with implant material compared to areas of soft tissue. Sequential switching of anode and cathode configurations can ensure that all adjacent volumes are adequately treated. This can be important for stimulation programs in which treatment is more effective at the cathode versus the anode, or vice versa.

[0124] The stimulation sequence can be used independently of the union measurement process. For example, a patient or clinician may wish to utilize only the bone growth treatment feature and not use other smart implant features. In these cases, the clinician has a non-invasive, highly controlled treatment option that can be performed on demand as a more effective alternative to wearable bone growth stimulation devices. Depending on the treatment protocol and program, a patient can experience accelerated bone growth with only one treatment session per day.

[0125] The stimulation sequence (i.e., treatment session) can also be used in conjunction with a measurement process to enable a detection and treatment control loop. For example, measurements from the first six weeks after surgery may indicate delayed bone healing. The clinician can choose to monitor the patient more closely before administering treatment, or treatment can be implemented using a smart implant as a therapeutic tool. This clinical monitoring and treatment loop is described and illustrated in FIG. 25.

[0126] Combined applications are discussed in more detail below.

[0127] The previously described systems for microbial and osteogenic applications can be combined into a single system. A single multimodal electrode array can be used for the purposes of electrochemical sensing and electrical stimulation of biofilms and tissues. As described above, each electrode in the multimodal array can act as a working electrode, counter electrode, reference electrode, anode, or cathode, depending on the system's programming. Switching between functions across the electrode array allows for steerable full-range stimulation as well as spatial electrochemical measurements. An example of how these measurement and treatment processes can be combined into a single automated process is illustrated in Figure 26.

[0128] FIG. 26 illustrates a flow chart of a combined osteogenic and microbial application system according to some embodiments of the present disclosure.

[0129] The process may begin and the implant device may perform a measurement process. For example, a controller of the implant device may control a multiplexer of the implant device to selectively connect different electrode pairs in the array over time to perform a measurement mode that includes at least two of: an open circuit potential (OCP) measurement, in which a measurement circuit measures the free potential across a first electrode pair when the controller applies no current between the first electrode pair; an amperometry measurement, in which the controller applies power to one of the electrodes in a second electrode pair and the measurement circuit measures the resulting current at the other electrode in the second electrode pair; and an electrochemical impedance spectroscopy (EIS) measurement, in which the controller applies an alternating current to one of the electrodes in a third electrode pair and the measurement circuit measures the resulting current at the other electrode in the third electrode pair.

[0130] Measurement data obtained by performing the measurement mode may be transmitted to a cloud accessible to the patient in whom the implant device is implanted and / or the clinician.

[0131] The implant device may determine, based on the measurements, whether a biofilm has formed on or near one of the electrodes. If the implant device determines that a biofilm has formed, the implant device may determine that biofilm treatment (i.e., electrical stimulation) is needed. If so, the implant device executes a biofilm stimulation sequence. If not, the implant device determines whether bone stimulation is needed based on the measurements (e.g., whether a level of bone density is measured during the measurement of impedance by the electrode pair). If the implant device determines that bone stimulation is not needed, the process may stop. Optionally, instead of stopping the process, the implant device may start the process over again, either immediately or after a predetermined period of time.

[0132] If the implant device determines that bone stimulation is required, the implant device may perform a bone growth stimulation sequence, which may be different from the biofilm stimulation sequence.

[0133] As described herein (either as part of other embodiments and processes or as a stand-alone process / embodiment), the method may be performed by a controller of an implantable device implantable within a patient's body. The method may include controlling a multiplexer to selectively connect different electrode pairs of a set of spaced electrodes on the implant device to a measurement circuit over time to perform measurement modes, including at least two of: an open-circuit potential (OCP) measurement, in which the measurement circuit of the implant device measures a free potential across a first electrode pair while the controller applies no current between the first electrode pair; an amperometry measurement, in which the controller applies power to one of the electrodes in a second electrode pair while the measurement circuit measures the resulting current at the other electrode in the second electrode pair; and an electrochemical impedance spectroscopy (EIS) measurement, in which the controller applies an alternating current to one of the electrodes in a third electrode pair while the measurement circuit measures the resulting current at the other electrode in the third electrode pair. The method may further include a controller controlling electrical stimulation of at least one electrode pair based on the measurements. For example, electrical stimulation may be responsive to measurements indicative of bone growth problems, infection (eg, biofilm development), and the like.

[0134] Further definitions and embodiments: In the above description of various embodiments of the inventive concept, it should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the inventive concept. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the inventive concept belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted to have a meaning consistent with their meaning in the context of this specification and related art, and should not be interpreted in the idealized or overly formal sense explicitly defined herein.

[0135] When an element is referred to as being "connected," "coupled," or "responsive" to another element, or variations thereof, it may be directly connected, coupled, or responsive to the other element, or intervening elements may be present. In contrast, when an element is referred to as being "directly connected," "directly coupled," or "directly responsive" to another element, or variations thereof, there are no intervening elements present. Like numbers refer to like elements throughout. Furthermore, as used herein, "coupled," "connected," "responsive," or variations thereof may include wirelessly coupled, connected, or responsive. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context clearly indicates otherwise. Well-known features or structures may not be described in detail for the sake of brevity and / or clarity. The term "and / or" includes any and all combinations of one or more of the associated listed items.

[0136] In this specification, terms such as first, second, and third may be used to describe various elements / operations, but it is understood that these elements / operations should not be limited by these terms. These terms are used only to distinguish one element / operation from another. Thus, a first element / operation in some embodiments may be referred to as a second element / operation in other embodiments without departing from the teachings of the inventive concept. The same reference numbers or characters refer to the same or similar elements throughout this specification.

[0137] As used herein, the words "comprise," "comprising," "comprises," "include," "including," "includes," "have," "has," "having," or variations thereof, are open-ended and refer to the inclusion of one or more stated features, integers, elements, steps, components, or functions, but do not exclude the presence or addition of one or more other features, integers, elements, steps, components, functions, or groups thereof. Furthermore, as used herein, the common abbreviation "eg," derived from the Latin phrase "exempli gratia," may be used to introduce or designate a general example or examples of a previously mentioned item and is not intended to be limiting of such items. The common abbreviation "ie," derived from the Latin phrase "id est," may be used to designate a particular item from a more general list.

[0138] Exemplary embodiments are described herein with reference to block diagrams and / or flowchart illustrations of computer-implemented methods, apparatus (systems and / or devices), and / or computer program products. It will be understood that blocks of the block diagrams and / or flowchart illustrations, and combinations of blocks in the block diagrams and / or flowchart illustrations, can be implemented by computer program instructions executed by one or more computer circuits. These computer program instructions can be provided to general-purpose computer circuits, special-purpose computer circuits, and / or processor circuits of other programmable data processing devices to produce machines such that the instructions, executed via a processor of a computer and / or other programmable data processing device, transform and control transistors, values ​​stored in memory locations, and other hardware components within such circuits to implement the function(s) / operations specified in the block diagram and / or flowchart block(s), thereby forming means (functions) and / or structure for performing the function(s) / operations specified in the block diagram and / or flowchart block(s).

[0139] These computer program instructions may also be stored on a tangible computer-readable medium that can instruct a computer or other programmable data processing apparatus to function in a particular manner to produce an article of manufacture that includes instructions that cause the instructions to implement the function / act specified in the flowchart and / or block diagram block or blocks. Thus, embodiments of the inventive concepts may be embodied in hardware and / or software (including firmware, resident software, microcode, etc.) running on a processor, such as a digital signal processor, which may collectively be referred to as a "circuit," "module," or variations thereof.

[0140] It should also be noted that in some alternative implementations, the functions / acts noted in the blocks may also occur in an order different from that noted in the flowcharts. For example, two blocks shown in succession may in fact be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending on the functions / acts involved. Furthermore, the functionality of a given block in the flowcharts and / or block diagrams may be separated into multiple blocks, or the functionality of two or more blocks in the flowcharts and / or block diagrams may be at least partially integrated. Finally, other blocks may be added / inserted between the illustrated blocks and / or blocks / acts may be omitted without departing from the scope of the inventive concept. Furthermore, while some diagrams include arrows on communication paths to indicate a primary direction of communication, it should be understood that communication may occur in the opposite direction to the depicted arrows.

[0141] Numerous variations and modifications can be made to the embodiments without substantially departing from the principles of the inventive concept. All such variations and modifications are intended to be included herein within the scope of the inventive concept. Accordingly, the above disclosed subject matter should be considered illustrative, and not limiting, and the accompanying examples of embodiments are intended to cover all such modifications, enhancements, and other embodiments that fall within the spirit and scope of the inventive concept. Thus, to the maximum extent permitted by law, the scope of the inventive concept should be determined by the broadest permissible interpretation of this disclosure, including the following examples of embodiments and their equivalents, and is not limited or constrained by the foregoing detailed description.

Claims

1. 1. An implant device implantable within a patient's body, comprising: a set of electrodes in a spaced array on the implant device; a measurement circuit configured to perform a measurement mode on signals from the electrodes; a multiplexer interconnecting different electrode pairs in the array to the measurement circuitry; a controller that controls the multiplexer to selectively connect different electrode pairs in the array over time to perform the measurement mode, the measurement mode comprising: an open circuit potential (OCP) measurement, wherein the measurement circuit measures a free potential across a first pair of electrodes, while the controller applies no current between the first pair of electrodes; an amperometric measurement, in which the controller applies power to one of the electrodes in a second electrode pair while the measurement circuit measures the resulting current at the other electrode in the second electrode pair; and an implant device including at least two electrochemical impedance spectroscopy (EIS) measurements, wherein the controller applies an alternating current to one of the electrodes in a third electrode pair while the measurement circuit measures the resulting current at the other electrode in the third electrode pair.

2. The implant device of claim 1 , wherein at least two of the measurement modes are performed sequentially during separate time windows, and the first, second, and third electrode pairs are the same electrode pairs.

3. 3. The implant device of claim 2, wherein between two sequences of the measurement modes, the controller is configured to delay a period during which the controller applies either no current or a reverse bias current that is a reverse bias of the current applied during a previously completed measurement mode to the electrode pair used during the previously completed measurement mode.

4. 2. The implant device of claim 1, wherein a first of the at least two measurement modes is performed during at least partially overlapping time windows while a second of the at least two measurement modes is performed simultaneously, and the electrode pairs used in the first measurement mode are different from the electrode pairs used in the second measurement mode.

5. 10. The implant device of claim 1, wherein the controller further controls the supply of a DC voltage to one of the electrode pairs in the array and controls the supply of an AC current swept over a range of frequencies to another of the electrode pairs in the array.

6. further comprising another set of electrodes in another array spaced apart on the implant device, the another set of electrodes being physically separate and electrically isolated from the set of electrodes in the array; The implant device of claim 1 , wherein the controller controls the multiplexer to selectively connect different electrode pairs in the separate arrays over time to sequentially execute the measurement modes.

7. 10. The implant device of claim 1, wherein during a first time window, the controller controls the multiplexer to select a first electrode in the electrode pair to operate as a working electrode and a second electrode in the electrode pair to operate as a counter electrode.

8. 8. The implant device of claim 7, wherein the controller controls the multiplexer to select the first electrode to operate as the counter electrode and to select a third electrode, different from the second electrode, to operate as the working electrode during a non-overlapping time window with respect to the first time window.

9. 10. The implant device of claim 1, wherein the controller further generates a measurement report indicating the results of the measurement mode performed and controls transmission of the report to a device external to the patient's body.

10. 2. The implant device of claim 1, wherein the controller controls the multiplexer to sequentially select each electrode in the set of electrodes in the array to operate as a working electrode during different time windows while the controller sequentially executes the at least two of the measurement modes.

11. The implant device of claim 1 , wherein at least two of the measurement modes are repeatedly executed by the controller at time intervals that are electronically configurable in a memory of the implant device.

12. The implant device of claim 1 , wherein at least two of the measurement modes are executed by the controller in response to expiration of a measured period of time from implantation of the implant device within the body of the patient.

13. 10. The implant device of claim 1, wherein the controller further controls the multiplexer to perform a cleaning routine including selectively connecting different electrode pairs in the array over time and electrically stimulating the different electrode pairs using multiple potentials and / or current bursts.

14. 2. The implant device of claim 1, wherein one of the at least two measurement modes performed includes EIS measurement, and the controller is configured to generate a map indicative of tissue properties across an area adjacent to the set of electrodes in the array and variations in density of the tissue across the area adjacent to the set of electrodes in the array.

15. 2. The implant device of claim 1, wherein one of the at least two measurement modes performed includes an EIS measurement, and the controller is configured to perform electrical impedance tomography (EIT) using measurements obtained during the EIS measurement to construct a three-dimensional (3D) model of the location and properties of tissue adjacent the set of electrodes.

16. 10. The implant device of claim 1, wherein one of the at least two measurement modes performed includes EIS measurement, and the controller further controls cathodic biased electrical stimulation of the different electrode pairs in the array in response to measurements obtained during the EIS measurement indicative of an amount of bone growth.

17. the implant device is an interbody spacer, and the controller is housed within the interbody spacer; 10. The implant device of claim 1, wherein the controller further controls electrical stimulation of the different electrode pairs on the surface of the interbody spacer to promote bone growth in response to measurements indicative of an amount of bone growth obtained during at least one of the measurement modes performed.

18. 1. A method performed by a controller of an implant device implantable within a patient's body, comprising: and controlling a multiplexer to selectively connect different pairs of electrodes of a set of spaced electrodes on the implant device to a measurement circuit over time to implement a measurement mode, the measurement mode comprising: an open circuit potential (OPC) measurement, in which a measurement circuit of the implant device measures a free potential through a first pair of electrodes, while the controller applies no current between the first pair of electrodes; an amperometric measurement, in which the controller applies power to one of the electrodes in a second electrode pair while the measurement circuit measures the resulting current at the other electrode in the second electrode pair; and the controller applies an alternating current to one of the electrodes in a third electrode pair while the measurement circuit measures the resulting current at the other electrode in the third electrode pair.

19. 20. The method of claim 18, wherein at least two of the measurement modes are performed sequentially during separate time windows, and the first, second, and third electrode pairs are the same electrode pairs.

20. 20. The implant device of claim 18, wherein a first of the at least two measurement modes is performed during an at least partially overlapping time window during which a second of the at least two measurement modes is performed, and wherein the electrode pairs used in the first measurement mode are different from the electrode pairs used in the second measurement mode.

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