Patent Application
20250040816
Cardiovascular diseases (CVDs) are the leading cause of mortality, representing 32% of deaths globally. CVDs are a group of disorders of the heart and blood vessels and include hypertension, congestive heart failure, stroke, diseases of the arteries, and others. A common element to many of these diseases is the occurrence of abnormal pressures in cardiovascular structures, either as a cause of or as secondary to the underlying disease. Measurement of these pressures is a cornerstone of treatment regimens.
Blood pressure (BP), for example, is among the most important physiologic parameters in the living body. Hypertension (HTN) or high blood pressure is the leading cause of mortality and morbidity in the world today. Treatment of HTN depends on the accurate and reliable measurement of BP in a simple and reproducible manner and is the cornerstone to reducing the cardiovascular complications of patients with this condition.
Similarly, congestive heart failure (CHF) is a complex clinical syndrome in which the heart cannot pump enough blood to meet the body's requirements. A key hallmark of CHF is that the pressures in affected cardiac chambers are elevated reflecting the heart muscle's inability to pump properly. Measurement of the pressures in the heart chambers indirectly or directly is not only diagnostic of the condition, but also can serve as a guide to effective treatment for the condition.
Measurement of cardiovascular pressures is useful for the diagnosis and subsequent treatment of a large range of cardiovascular diseases. The methodologies range from simple cuff measurement of BP with a sphygmomanometer to implantable pressure sensors placed invasively. Established invasive methodologies include placement of highly sensitive implants in the heart or lungs to measure right ventricular pressure (RVP), left atrial pressure (LAP), pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and central venous pressure (CVP). Additionally, implantable pressure sensors have been used to monitor pressure in aneurysms post-endovascular repair.
The vast majority of these invasive methodologies are designed and used for acute or short-term measurement and use cases. For example, it is the standard of care for patients undergoing open heart surgery to have temporary catheters, such as Swan-Ganz catheters, or inter-arterial lines placed for intra and peri-operative monitoring of specific cardiovascular pressures. However, fully implanted sensors and systems for measurement of pressures long-term in patients with chronic cardiovascular diseases, such as hypertension or congestive heart failure, are less developed and in clinical use because of a number of different challenges in the design and engineering of such systems.
As an example, the CardioMEMS HF system measures PAP for the management of CHF. The CardioMEMS HF system is composed of flexible plates bearing inductor windings within a hermetically sealed cavity. They are fused in a silica matrix while a nitinol basket encompasses the system's electronic components. Pressure-dependent changes in resonant frequencies are directionally proportional to pressure changes within the pulmonary artery and are detected using an external antenna activated by the sensor over a radio-frequency impulse. The CardioMEMS HF system does not have any batteries or leads. It is powered by radio-frequency signals from an external antenna. While pioneering in concept when first introduced to the market, the CardioMEMS HF system cannot make continuous measurements or measurements over time. The CardioMEMS HF system also requires significant patient engagement to generate and report data. In addition, the CardioMEMS HF system is very expensive and has been associated with post-implant adverse events.
Unlike other sensors, the implantable cardiovascular pressure sensing systems disclosed here can measure real-time patient pressure data continuously. Inventive implantable cardiovascular pressure sensing systems can generate a far higher quality assessment of patient disease state and treatment efficacy. Each inventive implantable cardiovascular pressure sensing system incorporates a pressure sensor that is sensitive and accurate over a desired range of pressure readings and electronic components that are hermetically sealed, including a rechargeable power supply and a processor for reading the targeted pressure measurements. The processor can be paired with innovations in wireless technologies, current mobile technologies, and data management, including the use of artificial intelligence to analyze data.
An inventive implantable cardiovascular pressure sensing system offers ease of use, high data quality and utilization, and little to no need for patient engagement or interaction. Reducing or eliminating patient engagement or interaction reduces cost and reduces or eliminates the problem of patient non-compliance. Inventive systems are biocompatible and can be implanted easily, improving patient comfort.
Embodiments of the inventive technology include a system with a pressure sensor, circuitry, hermetic sealing and coating, rechargeable battery, gel and/or liquid, and antenna. This system is designed for frequent, automatically generated, high-quality pressure data measurement that is wirelessly transmitted externally to the cloud and output devices in a way that makes the data is highly actionable remotely and in real-time. The system is designed to maximize ease of use and comfort for both patients and physicians to positively impact the management of patients with a range of cardiovascular diseases.
The present technology includes an implantable cardiovascular pressure sensing system (“sensing system”) that is configured to be implanted into a patient to measure a specified cardiovascular pressure continually and autonomously over a long period. The sensing system may be implanted against the outer wall of a blood vessel, inside of a blood vessel (e.g., inside of an artery or vein), or inside of the heart. As an example, the sensing system that resides on against the outer wall of a blood vessel or inside of a blood vessel may be used to monitor BP in the care of patients with HTN. As another example, a sensing system that resides in the heart or one of the great vessels of the heart may be used to monitor heart failure or primary pulmonary artery hypertension. The sensing system may collect pressure measurements, store those measurements locally, and transmit those measurements wirelessly to an external device where they can be viewed by the patient or a healthcare provider. The measurement data may be analyzed to determine current disease states and/or guide for optimal patient therapies. In this way, patient therapies can be highly personalized with the goal of improving clinical outcomes, reducing costs, increasing patient quality of life, and simplifying the physicians care of these patients with these challenging diseases.
An inventive device may include a pressure sensor, circuitry, rechargeable battery, gel (e.g., silicone gel) and/or liquid, antenna, and coating. The pressure sensor has at least one sensing surface and is configured to measure a range of desired pressures (e.g., for BP measurement, a range of pressure of about 40 mm Hg to about 250 mm Hg; for LA or PAP a range of 0 mm Hg to 40 or 50 mm Hg). The circuitry is in electrical communication with the pressure sensor. The rechargeable battery is configured to provide power to the pressure sensor and the circuitry. The gel and/or liquid is disposed on the sensing surface comprises water in a weight percent of about 0.001% by weight to about 5% by weight. The antenna is in electrical communication with the rechargeable battery and the circuitry. And a biocompatible, multilayer coating, which comprises parylene and SiOx, is disposed on at least the gel and/or liquid and forms an outer layer of the device and hermetically seals the device.
An inventive method of measuring cardiovascular pressure may include collecting cardiovascular pressure measurements inside of a subject's cardiovascular system with a device for sensing cardiovascular pressure; averaging cardiovascular pressure measurements with the device; wirelessly transferring averaged cardiovascular pressure measurements from the device to an external device; and wirelessly recharging a power source in the device.
An implantable cardiovascular pressure sensing system can be implanted using a variety of approaches. For instance, an inventive sensing system can be inserted into a human per percutaneous insertion or open approaches; placed in contact with or close vicinity to a blood vessel (e.g., any artery or vein in the body, including a natural or synthetic blood vessel); and fixed in place with a direct suture technique or bio-adhesive. The sensing system can also be incorporated in a device, such as a stent or Amplatz device, that is implanted using known techniques.
All combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are part of the inventive subject matter disclosed herein. In particular, all combinations of claimed subject matter appearing at the end of this disclosure are part of the inventive subject matter disclosed herein. The terminology used herein that also may appear in any disclosure incorporated by reference should be accorded a meaning most consistent with the particular concepts disclosed herein.
The skilled artisan will understand that the drawings primarily are for illustrative purposes and are not intended to limit the scope of the inventive subject matter described herein. The drawings are not necessarily to scale; in some instances, various aspects of the inventive subject matter disclosed herein may be shown exaggerated or enlarged in the drawings to facilitate an understanding of different features. In the drawings, like reference characters generally refer to like features (e.g., functionally and/or structurally similar elements).
The sensing system 100 may include an antenna 130, which can be implemented as a circular coil of conductive metal (e.g., gold or copper) that approximately traces the edges of the PCB 120 and is held in place with epoxy 146. In this way, the coiled antenna 130 forms a wall that defines a perimeter of the sensing system 100. An underfill 144 is disposed on at least part of a surface of the PCB 120 and at least some of the electronic components. The underfill 144 may be contained within the perimeter formed by the coiled antenna. A separate sensor filling material 114 is disposed on the pressure sensor's sensing surface 112.
Unlike other implantable devices, the sensing system 100 may not have a rigid housing or casing. Instead of a rigid housing or casing, the sensor system 100 has a multilayer coating 140 disposed on the filling material 144 and exposed surfaces of the antenna 130, PCB 120, and/or electronic components on the PCB 120. This multilayer coating 140 is formed of alternating layers of ceramic (e.g., silicon dioxide) and polymer (e.g., Parylene-C, which is a chlorinated poly(para-xylylene) polymer) and forms the outer surface of the sensing system 100. As explained in greater detail below, the multilayer coating 140 is flexible and hermetically seals the sensing system 100, preventing the sensing system's contents (e.g., the filling material) from leaking out and water from diffusing in. The multilayer coating 140 gives the sensing system 100 several advantages over other implantable sensing systems, including (1) improved sensor sensitivity; (2) improved wireless transmission of power and data; (3) extreme miniaturization (smaller volume); and (4) lower production costs.
Optionally, a silastic coating 142 may be disposed on the sensing system 100 on an inner or outer surface of the multilayer coating 140. In
The filling material 114 and multilayer coating 140 are deformable materials that allow pressure to be communicated from the environment outside of the sensing system 100 to the pressure sensor 110 in the sensing system 100. The multilayer coating 140 is thin and flexible enough that it transmits pressure P exerted by in environment outside of the sensing system 100 to the sensor filling material 114, which transmits the pressure to the pressure sensor's sensing surface 112.
Amplatzer Septal Occluder with Integrated Cardiovascular Pressure Sensing System
The sensing system 300 includes a pressure sensor 310 on one side of a PCB 320 and a processor 322, accelerometer 324, temperature sensor 326, oxygen sensor 328, and power supply 332 on the other side of the PCB 320. The processor 322 is integrated with a transceiver and coupled to an antenna (not visible in these views) for exchanging data and other signals with an external device. The electronic components are contained within an enclosure 340 that is coated with a multi-layer ceramic/polymer coating as described above and filled with epoxy 344, which can have a thickness of a few microns to about 1 mm, and covered with a silicon cover 342, which can also have a thickness of a few microns to about 1 mm. Filling material 314 is disposed on the surface of the pressure sensor 310 where the sensing elements are disposed. The filling material is not disposed on the PCB 320 or other electronic components.
Each of the implantable cardiovascular pressure sensing systems 100, 200, 300, and 400 described above includes several electronic components, including a pressure sensor, a microcontroller or processor (e.g., an application-specific integrated circuit (ASIC)), a transceiver, an accelerometer, an optional oxygen sensor, an optional temperature sensor, an antenna, and a rechargeable battery or other rechargeable power supply. The electronic components are electrically coupled to each other via the PCB upon which they are disposed and configured to operate autonomously and continually while implanted into a subject. Unless explicitly noted otherwise, each of these sensing systems 100, 200, 300, and 400 may include electronic components and operate as described below.
Together, the processor and sensors, including the pressure sensor, accelerometer, optional temperature sensor, and optional oxygen sensor, make automatic measurements at regular intervals, providing a nearly constant, continuous data flow without patient compliance or intervention. In operation, the pressure sensor measures BP in an artery or other blood vessel or vascular chamber. At the same time, the accelerometer measures the subject's motion. The processor can either store and report both the BP and motion measurements or use the motion measurements to identify, quantify, and remove motion artefacts from the BP measurements and to reported the processed BP data. The process for identification, quantification, and removal of motion artefacts is based on a combination of digital signal processing techniques and artificial intelligence.
The multilayer coating allows the entire sensing system to be small and reduces sensor drift. For instance, the sensing system's small size and shape enables the sensing system to be placed on an artery or to be shaped specifically to fit a particular structure. For instance, the sensing system 300 is roughly longitudinal in shape to fit on top of long tubular structure (artery) or to fit in the left atrium on an Amplatz device. Sensing systems of other shapes and sizes are also possible, for example, to fit within the heart.
The pressure sensor measures a fluid pressure, for example, BP in an artery. The pressure sensor may have a length of about 0.3 mm to about 1 mm (e.g., about 0.6 mm), a width of about 0.1 mm to about 1.5 mm (e.g., about 0.3 mm), and a height of 0.05 mm to about 0.4 mm (e.g., about 0.2 mm). The pressure sensor may have an accuracy of about 0.075 mm Hg to about 0.75 mm Hg. Preferably, the pressure sensor's drift over a three-month period is smaller than the pressure sensor's accuracy. Preferably, the power consumption of the pressure sensor is less than about 200 μW (100 μA) at its peak current consumption during measurement acquisition.
The pressure sensor in the sensing system may be a microelectromechanical sensor that is capacitive or piezoelectric. The pressure sensor can measure pressure in the range of 0 to about 40 or 50 mm Hg or in the range of about 40 mm Hg to about 250 mm Hg, depending on whether the sensing system is to be implanted in the heart (e.g., in the left atrium) or in or on a blood vessel, respectively. Measured blood pressures can range as high as 220 mm Hg for someone with high blood pressure or hypertension.
The pressure sensor may be a capacitive pressure sensor (also called a transducer). A capacitive pressure sensor measures pressure by detecting changes in electrical capacitance caused by the movement of a diaphragm between capacitor plates. The capacitive pressure sensor offers many advantages. The capacitive pressure sensor has higher accuracy and a lower total error band than some other pressure sensors. Moreover, the capacitive pressure sensor has a low power consumption since there is no DC current flowing through the sensor elements. Thus, the cardiovascular pressure sensing system may operate using very little power with only a small bias to the circuit.
The capacitive pressure sensor may provide very high accuracy and long-term stability. Additionally, the capacitive pressure sensor is tolerant to overpressure so that it may be safely implanted in a subject without fear of the sensor being compromised. The MEMS capacitive pressure sensor may have a lifetime of up to about 20 years.
The pressure sensor may alternatively be a piezoelectric pressure sensor. A piezoelectric pressure sensor includes a piezoelectric element that creates a difference in resistance or electrical charge when a cardiovascular pressure applies mechanical stress to the piezoelectric element. The pressure sensor measures the voltage across the piezoelectric element generated by the applied pressure to determine the amount of applied pressure. The voltage across the piezoelectric element may be measured by a Wheatstone bridge configuration, which is two piezoelectric resistors and two conventional resistors.
The device can take pressure measurements continually or intermittently at a variety of logging intervals, sampling intervals, and sampling frequency. The sensing system may be configured (e.g., using the pressure sensor and ASIC described below) to acquire pressure measurements at defined logging intervals. Logging intervals define the period of time between pressure measurement logging events when the pressure sensor is not acquiring data. The pressure sensor may be configured for logging intervals of about every 5 minutes (mins.) to about every 48 hours (hrs.) (e.g., every 5 mins., 10 mins., 15 mins, 20 mins, 40 mins, 1 hr., 2 hrs., 5 hrs., 10 hrs., 24 hrs., or 48 hrs.). Within each logging interval, the pressure sensor may be configured to acquire multiple pressure measurements at defined sampling intervals and sampling rates.
Sampling intervals are programmable and define the length of time of pressure measurements within a logging event. The sampling interval may be about 1 second (sec.) to about 10 mins. (e.g., 1 sec., 2 secs., 3 secs., 4 secs., 5 secs., 10 secs., 20 secs., 30 secs., 1 min., 2 mins., 5 mins., or 10 mins.). During the sampling interval, the pressure sensor's sampling frequency may be about 1 measurement per second (Hz) to about 500 Hz (e.g., 1 Hz, 2 Hz, 5 Hz, 10 Hz, 20 Hz, 50 Hz, 90 Hz, 100 Hz, 200 Hz, 300 Hz, or 500 Hz).
The sensing system can measure up to 90 data points per second when taking a programmed interval reading. The sensing system's processor or an external processor averages the data points. The ability to get 90 data points per second means that the sensing system can capture and present the pressures over an entire cardiac cycle. This means that unlike conventional measures of blood pressure (e.g., using a blood pressure cuff or wearable sensor), which measure only systolic and diastolic pressure, the sensing system measures waveform pressure data throughout the complete cardiac cycle. Waveform BP data for instance will measure systolic pressure, diastolic pressure, pulse pressure, and dicrotic notch—all richer data that is clinically relevant.
As an example, the pressure sensor may monitor pressure within the cardiovascular system at logging intervals of 10 minutes, with every sampling interval being a period of 10 seconds to 30 seconds of continuous pressure sensing, e.g., at a frequency of 90 Hz. As another example, the capacitive pressure sensor may collect 1 to 90 measurements about every 10 minutes to about every 24 hours. As another example, the pressure sensor may be configured to acquire beat-to-beat measurements, where the time interval between heart beats is measured. In this example, the pressure sensor may be configured to acquire measurements with sampling intervals of about 1 second to 2 seconds at frequencies of about 90 Hz.
The sensing system may prevent or substantially reduce drift caused by fibrotic buildup by exposing sense and reference capacitors to the same environment. A conventional MEMS capacitive pressure sensor element includes two sense capacitors and two reference capacitors. In a conventional MEMS capacitive pressure sensor, the reference capacitors are not sensitive to pressure variations. A conventional MEMS capacitive pressure sensor's long-term stability may be determined by the aging of the sensing elements and thereby the drift in its measurement accuracy over time. In contrast, the MEMS capacitive pressure sensor in the cardiovascular pressure sensing system may include at least one sense capacitor and reference capacitor that are exposed to the same environment. The sense and reference capacitors are exposed to the same conditions and stimuli that cause sensor aging and long-term drift. Since the sense and reference capacitors are exposed to the same conditions and are manufactured using the same materials and procedures, they also age with the same rate. Therefore, the MEMS capacitive pressure sensor's long-term drift effect may be reduced so that it may provide accurate measurements with long-term stability.
The sensing system may include other sensors, including a temperature sensor and/or an oxygen sensor. An oxygen sensor may be used to measure blood oxygen levels in the subject. Blood oxygen measurements may be used with absolute relative pressure measurements to calculate fundamental hemodynamic index calculations. The sensing system may also include a temperature sensor.
The sensing system may include an accelerometer. The accelerometer may be used to detect and possibly compensate motion artefacts. In addition to this, the accelerometer may also compensate for pressure variations due to variations of posture (e.g., standing, lying, lifting of arm). Compensation of artefacts and variations can be done by either discarding the pressure data during artefacts and variations, or by correcting for the artefact or variation based on patterns that have been learned from training data. Furthermore, the accelerometer may also be used for saving energy during certain periods of the day, e.g., when the patient is lying down and sleeping.
The sensing system includes an ASIC. The ASIC receives signals from the sensors on the sensing system and acts as the sensing system's controller. The ASIC may include a pressure to data converter function that processes signals from the one or more pressure sensors and data processing functions to process the data (e.g., time-averaging). The ASIC may include one or more forms of memory. For example, the ASIC may include volatile memory (e.g., RAM) that is used for control and processing functions. The ASIC may also perform timer and sequencer functions. In another example, the ASIC may have a flash memory that is used to perform some data processing. For example, the flash memory may be used to perform signal averaging of sensor data received from the pressure sensor. The ASIC may also include a power controller to manage electrical power usage by the sensing system. For example, the ASIC may determine the charge state of a rechargeable battery in the sensing system that provides electrical power to the electrical components in the sensing system and indicate to the patient or healthcare provider when the battery needs to be recharged (e.g., by sending a wireless notification to an external device). The ASIC may also manage wireless communication components in the sensing system. For example, the ASIC may adjust electrical characteristics of an antenna circuit in order to maximize wireless coupling efficiency. As an example, the ASIC may have dimensions of 1.1 mm by 1.1 mm by 0.1 mm. Alternatively, the functions of the ASIC may be implemented with a microcontroller and additional discrete components.
The ASIC may provide autonomous operation of the sensing system. Autonomous operation means that the patient does not need to manual intervene in order for the sensing system to operate. In this way, the sensing system is not plagued by issues related to patient compliance. The ASIC may perform internal calibrations of the various sensors in the sensing system. For example, the ASIC may perform internal calibration of the pressure sensor using data on the amount of fibrous tissue buildup measured by the mass sensor. The ASIC may also receive calibration signals from an external device via the antenna and trans-receiver described below. As another example, the ASIC may be programmed to activate the pressure sensor and/or other sensors in the sensing system according to desired logging intervals, sampling intervals, and sampling frequencies. Alternatively, the functions of the ASIC may be implemented with a microcontroller and additional discrete components.
The sensing system may include a trans-receiver coupled to the ASIC and to the antenna. The trans-receiver may transmit and receive data to and from an external device. The trans-receiver may also receive power from the external device to charge the sensing system's power source. The trans-receiver may transmit and receive data and power over a range of about 2 meters to 20 mm (e.g., 2 meters, 1.5 meters, 1 meter, 50 cm, 10 cm, 1 cm, 50 mm, or 20 mm). The trans-receiver uses an RF frequency of about 100 kHz to 6 GHz.
The sensing system may also include another form of non-volatile memory to store sensor data. For example, the non-volatile memory may be an electrically erasable programmable read-only memory (EEPROM) disposed on the PCB. The EEPROM may receive pressure sensor data from the ASIC and store that data. The data received by the EEPROM may be signal-averaged data that was signal averaged by the ASIC. The data stored in the EEPROM may be transferred to an external device using the wireless communication components in the sensing system.
The sensing system's power source may be a rechargeable battery that is disposed on the PCB and that powers the sensing system. The rechargeable battery may be recharged wirelessly while the sensing system is implanted via the wireless communication components. The ASIC may handle power management functions to manage the rechargeable battery. For example, the battery may be a solid-state rechargeable lithium polymer battery with a cycle life of 2000-3000 cycles. With the battery recharged twice per week, this battery may have a lifetime of greater than 15 years. As an example, the battery may have a size of about 1.7 mm by 2.25 mm by 0.2 mm.
The sensing system in
The EID may include a battery 672 and/or an external power supply 674. The EID may optionally include a second communication chip 668 to upload the data to the other computer 690 and/or a remote database 692. Alternatively, the EID 660 may include a single communication chip that communicates with both the sensing system and other computers.
Communication with the external device may be encoded and each data transfer may be preceded and ended with a handshake. An alert may be included whenever data transfer from the implanted sensing system to the external device is corrupted. The external device can execute user-originated commands to execute data transfer from the implanted sensing system to the external device. The data transferred to the external device may undergo additional data processing at the external device.
The EID or another computer may process the raw data measured by the pressure sensing system, including calibration, compensation, filtering, conversion to pressure units, and/or visualization. The EID may have an absolute pressure sensor (e.g., pressure sensor 676 in
Pressure sensor drift is a common problem with implanted sensors that can lead to inaccurate and unreliable pressure measurements, and eventually sensor failure. Drift is the gradual decrease in accuracy of a sensor's measurements. For example, drift may manifest as a gradual increase or decrease in a baseline pressure measurement. Drift can be caused by several factors, including the natural degradation of the pressure sensor components, fluctuations in environment, and exposure to water and other chemicals. Conventional pressure sensor drift for a conventional pressure sensor is about 2 mm Hg per year.
For implanted pressure sensors, drift can be an especially big problem because the accumulation of the host's tissue (e.g., fibrotic tissue as a result of the foreign body response) on the sensing elements can cause large amounts of drift. Also, implanted pressure sensors are exposed to liquid environments thereby risking liquid (e.g., water or other biological fluid) infiltration into the sensor, which can cause substantial drift, corrosion of sensor elements, and sensor failure.
Conventional pressure sensors should be calibrated regularly to counteract the effects of drift, but implanted pressure sensors are difficult to calibrate. Sensor drift and calibration are two areas generally associated with sensor failure over time and may be the root cause of conventional implanted sensing system failures. Calibration of conventional pressure sensors involves subjecting the pressure sensor to at least two different known pressures, and preferably at least five known pressures, to create a pressure calibration curve. The calibration curve can be used to interpolate to determine experimental pressure measurements.
Conventional calibration is extremely difficult or impossible when the pressure sensor is implanted. Calibration is a complex issue when the pressure sensor is in an environment of fibrous encapsulation. To calibrate an implanted pressure sensor using conventional means, the sensor may need to be explanted, a costly and painful process for the host patient. Even if the calibration of the pressure sensor can be performed in situ, the process still requires a high level of patient involvement and compliance, creating a high risk of sensor failure due to patient non-compliance. Therefore, there is a need for implantable pressure sensors that don't need to be calibrated as often and that have calibration mechanisms that don't require substantial patient involvement.
The inventive sensor system has been designed to minimize the occurrence and effect of sensor drift. The inventive methods for reducing sensor drift are described below.
The sensing systems shown in
The sensing systems shown in
The filling material may be infused with a small amount of water or other liquid (e.g., about 0.001% by weight to about 5% by weight, including 0.002%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, or 5%) that helps stabilize drift. Additionally, the sensing systems shown in
The sensing systems shown in
The multilayer coating shown in
In some embodiments the total thickness of the coating is in the range of 5 μm to 1 mm (e.g., 5 μm, 10 μm, 14 μm, 20 μm, 25 μm, 50 μm, 100 μm, 150 μm, 200 μm, 500 μm or 1 mm). As an example, each layer may be about 1 μm thick, the multilayer coating may alternate between the ceramic layer and polymer layer, and the multilayer coating may have a total thickness of about 14 μm.
Conventionally, when an object is implanted into a host, the object is subjected to a series of well-defined processes characterized as the foreign body reaction that ultimately leads to fibrous encapsulation of the implanted device. The implanted object may be isolated from the body by a dense collagenous capsule as collagenous fibrotic tissue builds up on the surface of the device.
The multilayer coating on the sensing system reduces or prevents adhesion of the host's cells present in the surrounding environment, including macrophages, to the multilayer coating surface in order to reduce or prevent the host's foreign body response. If the host's cells were to adhere to the surface of the implanted sensing system, they may trigger an immune response leading to proliferation of these cells. Even when cells attach to the surface of the coating, this attachment may be reversible, with the cells retaining their round shape. The surface of the multilayer coating may also prevent or substantially reduce attachment of proteins and smaller peptides to the coating surface. Even when attachment does take place, the energy of adhesion is reduced, so that the attached protein does not undergo denaturation that may change the cell's shape. The multilayer coating may be hydrophilic to reduce adhesion of cells and proteins.
The multilayer coating may also be composed of materials that have biocompatible and/or non-toxic molecular structures. The multilayer coating formed from such chemicals may be non-toxic, especially when it is post-processed to remove all reactant chemicals, after it has been formed (e.g., polymerized in place).
The multilayer coating may also modulate the immune response by including chemicals that are slowly released from the multilayer coating over time. For example, the coating may include an inhibitory peptide for the IL-1 receptor. As another example, the multilayer coating may include an inhibitor of the cytokine TGFβ, which is widely implicated as being a central mediator of the fibrotic response. One particular example of a chemical that inhibits expression of critical cytokines is Pirfenidone having the following molecular structure:
Pirfenidone is an inhibitor for TGF-β production and TGF-β stimulated collagen production, and it reduces production of TNF-α and IL-1β, and also has anti-fibrotic and anti-inflammatory properties. Another example chemical that can be incorporated into any of coatings herein to inhibit expression of cytokines is Galunisertib, a potent TGFβ receptor I (TβRI) inhibitor, having the chemical structure:
Another example chemical that can be incorporated into any of coatings herein to inhibit expression of critical cytokines is LY2109761, which is a selective TGF-β receptor type I/II (TβRI/II) dual inhibitor, having the chemical structure:
Other pharmaceuticals can also be incorporated into the multilayer coating, including but not limited to heparin, both low and medium molecular weight to control fibrosis and provide anticlotting functionality; steroids; anti-inflammatories such as dexamethasone, or other corticosteroids; Cox 1- and Cox-2 inhibitors to control inflammation: pressure reducing agents such as beta blockers and carbonic anhydrase inhibitors. The steroid prednisolone may also be incorporated.
Since the total weight of the coatings herein is generally in the range of 4-6×10−4 g, a 10% loading of a corticosteroid (e.g., Prednisolone) provides an average life of 500 hours.
The coatings herein may be hydrophilic coatings, to reduce adhesion of cells and protein. The coatings may incorporate drugs and/or other agents that are released at a sustainable rate ranging from a period of 1 week to 6 months. The coatings may comprise inhibitors of fibrosis, including, for example, TGF-β, other cytokines expressed as mediators of the inflammatory cascade, SMA, and/or integrins.
In some embodiments, the multilayer coating includes pendant hydroxyl groups, with the number density of hydroxyl groups varying between the layers of the coating. Preferably the number density is the lowest in the layer closest to the surface of the implant (i.e., the innermost layer of the coating) and highest at the uppermost layer of the coating.
The multilayer coating may be deposited on the sensing system through a vacuum deposition process (e.g., chemical vapor deposition or physical vapor deposition).
The filling material (e.g., filling material 114 and 214 in
The liquid or gel filling material may fill one or more voids in the sensing system between the multilayer coating and the other components. In one example, the filling material may be a soft silicone gel. The silicone gel may be inert so as to not cause any substantial changes to the sensor elements over a period of ten years or more. The silicone gel may pose less of a safety risk than a liquid because it is less likely to leak out of the sensing system while implanted. The thickness of the silicone gel may vary from about 1 μm to about 25 μm (e.g., 1 μm, 2 μm, 5 μm, 10 μm, 20 μm, or 25 μm). The elastic modulus of the silicone gel may vary from about 0.4 kPa to about 300 kPa. The pressure in the environment of the sensing system is transmitted through this range of gel thicknesses and elastic moduli.
The filling material may be used to keep the multilayer coating in mechanical contact with the pressure sensor's sensing elements so that the pressure sensor is able to measure pressure while encapsulated by the coating. The force exerted by the pressure is transmitted through the coating and the filling material to the sensing elements in the pressure sensor. The pressure sensor can accurately measure pressure through a significant range of gel or liquid thicknesses and levels of rigidity.
As shown in
In another embodiment, shown in
The filling material may include a small amount of water in a weight percent of about 0.001% by weight to about 5% by weight (e.g., about 0.002%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, or 5%). The addition of water into the filling material may prevent or substantially reduce pressure sensor drift by passivating the sensing elements in the pressure sensor and/or by reducing the chemical potential for diffusion of water from outside of the sensing system to inside of the sensing system. For example, the filling material infused with water may reduce drift to values of less than about 2 mm Hg per year.
The sensing system may be a standalone implant or embedded into other implants (e.g., existing FDA-approved implants). The sensing system is configured to be implanted into a subject (e.g., a human or an animal) to measure cardiovascular parameters such as BP or pressure in a vascular structure or heart chamber. The measured pressure is presented as waveform data that captures the pressures generated throughout the cardiac cycle. The measured may be used to diagnose or manage specific cardiovascular diseases (e.g., chronic hypertension, congestive heart failure, primary pulmonary hypertension, and others. The sensing system may autonomously and continually monitor pressure within the cardiovascular system while implanted.
In one embodiment, the sensing system may be implanted into a subject so that it resides on the surface of a blood vessel in the subject to measure blood pressure in that blood vessel. The blood vessel may be a peripheral vessel or a central vessel. The advantages of placing the sensing system on a peripheral blood vessel include easy access for implantation and explantation. The advantages of placing the sensing system on a central blood vessel include the ability to monitor blood pressure in a central blood vessel.
In another embodiment, the sensing system may be implanted so that it resides inside of a chamber of the heart (e.g., an atrium, or ventricle). For example, the sensing system may be implanted into the left atrium for management of CHF. The sensing system may be mounted to a structure (e.g., a stent, a catheter, a prosthetic valve, or other intracardiac or intravascular device).
In another embodiment, the sensing system may be implanted so that it resides inside of a blood vessel (e.g., an artery or a vein). In this embodiment, the sensing system may directly measure intra-arterial pressure. For example, the sensing system may be implanted into a pulmonary artery and measure pulmonary artery pressure, for the management of CHF.
The sensing system may have a capsule shape, a flat cylindrical shape, like the device in
mm in length, about 2 mm to about 5 mm in width, and about 2 mm to about 3 mm in height. The volume of the sensing system may have a volume of about 10 mm3 to about 300 mm3.
The implantable cardiovascular pressure sensing system can be placed on or in proximity to the vessel wall using straightforward percutaneous approaches. Similarly, the implantable cardiovascular pressure sensing system can be placed on any selected targeted vessel with a direct or open approach.
The implantable cardiovascular pressure sensing system can be fixed in place with the use of adjuncts, such as tissue adhesives like Bio Glue, or direct suture technique.
The pressure sensor in the sensing system may be calibrated on the day of implantation. Once the sensing system is implanted, the pressure sensor in the sensing system may be recalibrated by comparing the sensing system's measurements to those acquired using a conventional method of measuring blood pressure (e.g., auscultation with a sphygmomanometer). As an example, the sensing system may be calibrated on the date of implantation and then re-calibrated approximately 4 weeks to about 6 weeks after implantation. The implanted sensing system can be re-calibrated (e.g., by a physician) at intervals of about 6 months to about 2 years (e.g., 6 months, 1 year, 1.5 years, or 2 years) if there is a concern regarding sensor drift.
In another example, a spacer may be used to fix the distance between the implanted sensing system and the outer surface of the artery when the sensing system is implanted. The spacer may be configured to dissolve or degrade over a set period of time determined by the length of time it takes to secure the sensing system, either via fibrotic tissue buildup or glue, thereby fixing the distance of the sensing system from the surface of the artery.
The rechargeable battery may have a discharge capacity of about 4 to about 500 μAh at currents of 0.04 μA to about 5'000 μA and a lifetime of about 15 years The battery may be safely recharged at a rate of about 0.2 C to about 10 C and may be recharged as many as about 2000 times or about 3000 times before failing.
While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.
Also, various inventive concepts may be embodied as one or more methods, of which an example has been provided. The acts performed as part of the method may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.
All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms.
The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”
The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/of” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.
As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.
This patent application claims the priority benefit, under 35 U.S.C. 119(e), of U.S. Application No. 63/370,053, filed Aug. 1, 2022, which is incorporated herein by reference in its entirety for all purposes.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2023/071396 | 8/1/2023 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63370053 | Aug 2022 | US |
