Implantable smartport for ultrasonic, electrical, and optical monitoring of cardiac functions during chemotherapy

Abstract

This invention in one aspect discloses a smartport system that can continuously monitor cardiovascular function during chemotherapy sessions through ECG and dynamic ejection fraction measurements via ultrasound probes. Ultrasound probes monitor the patency of the catheter shaft through Doppler measurements of the flow. Monitoring heart function and patency of the catheter shaft are unmet needs for chemotherapy patients who receive drugs via portacath systems. This monitoring allows immediate real-time assessment of the cardiotoxicity of cytotoxic chemotherapeutic therapies.

Description

[0001] IMPLANTABLE SMARTPORT FOR ULTRASONIC, ELECTRICAL, AND OPTICAL MONITORING OF CARDIAC FUNCTIONS DURING CHEMOTHERAPY

[0002] CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0003] This application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 63 / 567,498, filed March 20, 2024, which is incorporated herein in its entirety by reference.

[0004] FIELD OF THE INVENTION

[0005] The invention relates generally to healthcare, and more particularly to an implantable smartport for ultrasonic, electrical, and optical monitoring of cardiac functions during chemotherapy.

[0006] BACKGROUND OF THE INVENTION

[0007] A chemotherapy port, an implantable chemotherapy catheter, is frequently used to facilitate venous access and therapeutic drug delivery to cancer patients during chemotherapy. This port is surgically implanted under the skin on the chest and connected to a catheter that is guided into the superior vena cava, allowing entry into the heart's right atrium.

[0008] However, cancer patients undergoing chemotherapy are at an increased risk of developing heart complications, including arrhythmia, heart failure, and myocardial dysfunction. Additionally, the prolonged use of a chemotherapy port may lead to thrombosis and flow blockage inside the catheter. One of the significant adverse effects of chemotherapy is cardiotoxicity, which contributes to considerable morbidity and mortality. Acute chemotherapy toxicity has been linked to an increased risk of heart failure due to compromised heart function. Another primary challenge with older catheter iterations used in chemotherapy delivery is the formation of blood clots.

[0009] Additionally, there is currently no solution to address the issues of arrhythmia and reduced ejection fraction of the heart during chemotherapy. These acute symptoms of chemotherapy -induced cardiotoxicity are indicative of potential future heart failure. No existing devices effectively address or prevent heart failure in cancer patients caused by chemotherapy. Real-time monitoring of a patient’s heart ECG, contraction function, and blood flow velocity and direction during chemotherapy is crucial. This monitoring can serve as a reliable predictor for potential heart failure and thrombotic complications. Thus, the development of advanced monitoring and preventive technologies remains an urgent need in the field of oncology.

[0010] Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.

[0011] SUMMARY OF THE INVENTION

[0012] One of the objectives of this invention is to provide an implantable smartport for ultrasonic, electrical, and optical monitoring of cardiac functions during chemotherapy.

[0013] Particularly, the implantable smartport is a device configured to deliver therapeutic drugs to cancer patients, and monitor multiple cardiovascular parameters, including, but are not limited to, the ejection fraction and flow of the drug during chemotherapy treatment.

[0014] In one aspect, the invention relates to an implantable smartport device for chemotherapy delivery to a target region of interest of a living subject. The device implantable smartport device comprises at least one port containing at least one drug solution; a delivering member coupled to the at least one port for operably delivering the at least one drug solution from the at least one port to the target region of interest; and a sensor member for measuring physiological parameters of the living subject so as to monitor a physiological status of the living subject. In one embodiment, the physiological parameters comprises at least one of a blood oxygenation, a heart rate, a respiratory rate, a temperature, an ECG, an EMG, a blood flow, a blood pressure, and a blood chemistry.

[0015] In one embodiment, the implantable smartport device is configured to monitor real-time changes in heart ejection fraction and blood flow velocity, and use the metrics as a predictor for major cardiovascular complications.

[0016] In one embodiment, the at least one port is refillable.

[0017] In one embodiment, a dose and a rate of the drug delivery from the at least one port to the target region of interest are controllable, based on the physiological status determined by the measured physiological parameters.

[0018] In one embodiment, the delivering member comprises a drug delivery device configured to deliver one or more drug solutions at one or more locations simultaneously or sequentially.

[0019] In one embodiment, an amount of each of the one or more drug solutions to be delivered at a respective one of the one or more locations is determined based on the physiological status of the living subject. In one embodiment, the delivering member comprises a first chamber in fluidic communications with the least one port for drug delivery, and a second chamber for electronics housing.

[0020] In one embodiment, the delivering member comprises a catheter in fluidic communications with the least one port, having a tip attached to the target region of interest.

[0021] In one embodiment, the sensor member comprises a plurality of ultrasonic transducers disposed around the tip of the catheter for acquisition of associated information.

[0022] In one embodiment, the sensor member comprises an ultrasonic imaging probe configured to measure drug flow velocity, direction and volume, an ejection fraction, and monitor the patency of the catheter shaft.

[0023] In one embodiment, the ultrasonic probes dynamically assess the volume of the ventricle and the approximation of the ventricular free wall in order to project the percentage of the ejection fraction.

[0024] In one embodiment, the sensor member comprises at least one electrocardiography (ECG) electrodes configured to monitor ECG signal.

[0025] In one embodiment, the at least one ECG electrode is disposed around the tip of the catheter.

[0026] In one embodiment, the sensor member comprises at least one optical sensor.

[0027] In one embodiment, the sensor member comprises at least one photoplethysmography (PPG) sensor configured to monitor blood oxygen levels.

[0028] In one embodiment, the sensor member comprises at least one thermal sensor.

[0029] In one embodiment, the at least one thermal sensor is configured to measure heat dissipation near the heart during the chemotherapy session.

[0030] In one embodiment, the at least one thermal sensor is configured to measure a patency status of the catheter.

[0031] In one embodiment, the sensor member comprises an impedance spectroscopy technology interface configured to measure heart muscle contractility and cell-cell coupling.

[0032] In one embodiment, the sensor member comprises at least one metabolism sensor configured to monitor nicotinamide adenine dinucleotide (NADH) and flavin adenine di nucleotide (FAD).

[0033] In one embodiment, the sensor member comprises one or more accelerometers configured for motion and / or body orientation measurements. In one embodiment, the sensor member comprises one or more molecular sensors configured to monitor biomarkers of cardiac toxicity, including markers of inflammation.

[0034] In one embodiment, the sensor member comprises at least one haircell flow sensor measuring a surrounding fluid velocity.

[0035] In one embodiment, the at least one haircell flow sensor is disposed on an outer surface of the catheter.

[0036] In one embodiment, the sensor member comprises an ultrasound piezo element configured to emit ultrasound waves.

[0037] In one embodiment, the device further comprises a controller operably in wireless and / or wired communications with the sensor member and the delivering member for obtaining the physiological status of the living subject from the sensor member, and controlling operations of the delivering member based on the physiological status of the living subject.

[0038] In one embodiment, the device operably receives configuration commands and operation commands, wherein the configuration commands instruct the controller to deploy configuration parameters to the sensor member, or timing configuration for the delivering member, and wherein the operation commands trigger activation / deactivation of the sensor member or the delivering member at a time.

[0039] In one embodiment, the configuration commands and the operation commands are initialized from an external device in two-way wireless communications with the controller.

[0040] In one embodiment, the controller is configured to initialize measurement of the sensor member, and collect the measured data therefrom.

[0041] In one embodiment, a customized application with a graphic user interface (GUI) in the external device including a smartphone or tablet is adapted to control the device via its configuration and operation commands.

[0042] In one embodiment, the device comprises a power system to power operations of the device.

[0043] In one embodiment, the power system comprises a battery which is in communication with a battery charging module.

[0044] In one embodiment, the battery charging module comprises a wearable module which is configured to wirelessly provide power to the battery.

[0045] In one embodiment, the wearable module comprises a wireless communication unit which is configured to collect information from the implantable smartport device. In one embodiment, the device comprises a battery-less system to operate the device through a wireless power transfer.

[0046] In one embodiment, the physiological parameters comprise at least one of a blood oxygenation, a heart rate, a respiratory rate, a temperature, an ECG, an EMG, a blood flow, a blood pressure, and a blood chemistry.

[0047] In one embodiment, the device further comprises a valve unit, wherein the value unit is in communication with and controlled by the controller.

[0048] In one embodiment, the controller controls the value unit based on any measurements obtained by the sensor member.

[0049] These and other aspects of the present invention will become apparent from the following description of the preferred embodiment taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure.

[0050] BRIEF DESCRIPTION OF THE DRAWINGS

[0051] The accompanying drawings illustrate one or more embodiments of the invention and together with the written description, serve to explain the principles of the invention. Wherever possible, the same reference numbers are used throughout the drawings to refer to the same or like elements of an embodiment.

[0052] FIG. 1 is a schematic block diagram of an implantable smartport device / system according to embodiments of the invention.

[0053] FIG. 2 shows schematically an implantable smartport device / system according to one embodiment of the invention.

[0054] FIG. 3 shows schematically a catheter as a delivery member of an implantable smartport device / system according to one embodiment of the invention.

[0055] FIG. 4 is a schematic diagram of an implantable smartport device / system according to embodiments of the invention.

[0056] FIG. 5 shows schematically a piezoresistive sensor for vascular flow rate monitoring.

[0057] FIG. 6 shows schematically thermal sensors in association with the catheter according to one embodiment of the invention.

[0058] FIG. 7 shows schematically a flow rate sensor for flow rate monitoring according to one embodiment of the invention. FIG. 8 shows schematically an implantable EGG device in association with an implantable smartport device / system according to embodiments of the invention.

[0059] FIG. 9 shows schematically an ultrasonic probe.

[0060] FIG. 10 shows schematically an implantable smartport device / system in association with a wireless charging and communication system according to another embodiment of the invention.

[0061] FIG. 11 shows schematically a catheter of an implantable smartport device / system in association with a haircell flow sensor attached to an inside surface of the superior vena cava.

[0062] FIG. 12 shows a chart reflecting data of flow measurement data from a haircell sensor having a sensor thickness of 25 pm.

[0063] FIG. 13 shows charts reflecting a comparison of flow measurement data by two different types of sensors having a sensor thickness of 25 pm.

[0064] FIG. 14 shows a chart reflecting example data from a haircell sensor having a sensor thickness of 12.5 pm.

[0065] FIG. 15 shows charts reflecting a comparison of flow measurement data by two different types of sensors having a sensor thickness of 12.5 pm.

[0066] FIG. 16 shows charts reflecting flow measurement in a bench-top pulsatile pump using customized blood mimicking fluid (BMF) under different pump settings.

[0067] FIG. 17 shows charts reflecting comparison of flow measurement in a bench-top pulsatile pump (120 bpm at 0.17 gain) between BMF and water.

[0068] FIG. 18 shows chart reflecting long-term continuous measurement of the flow in a bench- top cardiac pulsatile pump using customized BMF over 15 hours.

[0069] DETAILED DESCRIPTION OF THE INVENTION

[0070] The invention will now be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this invention will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like reference numerals refer to like elements throughout. The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and / or quotation marks. The use of highlighting has no influence on the scope and meaning of a term; the scope and meaning of a term is the same, in the same context, whether or not it is highlighted. It will be appreciated that same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.

[0071] One of ordinary skill in the art will appreciate that starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such materials and methods are intended to be included in this invention. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

[0072] Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the invention. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the claims herein.

[0073] It will be understood that, as used in the description herein and throughout the claims that follow, the meaning of “a”, “an”, and “the” includes plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and equivalents thereof known to those skilled in the art. As well, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably.

[0074] It will be understood that when an element is referred to as being “on”, “attached” to, “connected” to, “coupled” with, “contacting”, etc., another element, it can be directly on, attached to, connected to, coupled with or contacting the other element or intervening elements may also be present. In contrast, when an element is referred to as being, for example, “directly on”, “directly attached” to, “directly connected” to, “directly coupled” with or “directly contacting” another element, there are no intervening elements present. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature.

[0075] It will be understood that, although the terms first, second, third etc. may be used herein to describe various elements, components, regions, layers and / or sections, these elements, components, regions, layers and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the invention.

[0076] Furthermore, relative terms, such as “lower” or “bottom” and “upper” or “top,” may be used herein to describe one element’s relationship to another element as illustrated in the figures. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation depicted in the figures. For example, if the device in one of the figures is turned over, elements described as being on the “lower” side of other elements would then be oriented on “upper” sides of the other elements. The exemplary term “lower”, can therefore, encompasses both an orientation of “lower” and “upper,” depending of the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as “below” or “beneath” other elements would then be oriented “above” the other elements. The exemplary terms “below” or “beneath” can, therefore, encompass both an orientation of above and below.

[0077] It will be further understood that the terms “comprises” and / or “comprising”, or “includes” and / or “including”, or “has” and / or “having”, or “carry” and / or “carrying”, or “contain” and / or “containing”, or “involve” and / or “involving”, “characterized by”, and the like are to be open-ended, i.e., to mean including but not limited to. When used in this disclosure, they specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0078] 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 this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the invention, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0079] As used in the disclosure, “around”, “about”, “approximately” or “substantially” shall generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term “around”, “about”, “approximately” or “substantially” can be inferred if not expressly stated.

[0080] As used in the disclosure, the phrase “at least one of A, B, and C” should be construed to mean a logical (A or B or C), using a non-exclusive logical OR. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items.

[0081] Embodiments of the invention are illustrated in detail hereinafter with reference to accompanying drawings. The description below is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. The broad teachings of the invention can be implemented in a variety of forms. Therefore, while this invention includes particular examples, the true scope of the invention should not be so limited since other modifications will become apparent upon a study of the drawings, the specification, and the following claims. For purposes of clarity, the same reference numbers will be used in the drawings to identify similar elements. It should be understood that one or more steps within a method may be executed in different order (or concurrently) without altering the principles of the invention.

[0082] The present invention is directed to an implantable smartport device / system used to deliver chemotherapeutic drugs to patients and monitoring conditions in association with blood and cardiological system.

[0083] Chemotherapy often relies on using an implantable chemotherapy catheter to ease the process of gaining venous access. The port is surgically implanted under the skin on the chest and attached to a catheter guided into the superior vena cava to allow entry into the heart's right atrium. However, one of the major adverse effects of chemotherapy is cardiotoxicity, contributing to significant morbidity and mortality. Acute chemotherapy toxicity was found to contribute to a higher chance of heart failure due to compromised heart functions. Therefore, cancer patients undergoing chemotherapy are at an increased risk of developing heart complications, including arrhythmia, heart failure, and myocardial dysfunction. Additionally, the prolonged use of chemotherapy port may also cause subsequent thrombosis and flow blockage inside the catheter. Therefore, real-time monitoring of cardiac function and blood flow velocity can be used as a reliable predictor for potential heart failure and thrombotic complications during chemotherapy.

[0084] The present invention develops an implantable smartport bioelectronic system / device for chemotherapy delivery that contains ultrasonic, electrical, and optical sensing features. The device is configured to monitor real-time changes in heart ejection fraction and blood flow velocity, and use these metrics as a predictor for major cardiovascular complications.

[0085] Several sensing modalities are integrated into the implantable smartport bioelectronic system to enable real-time monitoring of cardiovascular functions.

[0086] In certain embodiments, the implantable smartport system continuously monitors cardiovascular function during chemotherapy sessions through electrocardiography (ECG) and dynamic ejection fraction measurements via ultrasound probes. Ultrasound probes monitor the patency of the catheter shaft through Doppler measurements of the flow. Monitoring heart function and patency of the catheter shaft are unmet needs for chemotherapy patients who receive drugs via portacath systems. This monitoring allows immediate real-time assessment of the cardiotoxicity of cytotoxic chemotherapeutic therapies.

[0087] In certain embodiments, the implantable smartport system includes ECG and ultrasonic imaging technology as two sensing methods. Specifically, in some embodiments, an adequate number of ultrasonic transducers is disposed around the tip of the catheter to achieve the acquisition of associated information. Further, in certain embodiments, Doppler ultrasonic technology is used to measure drug flow velocity, direction, and volume and monitor the patency of the catheter shaft.

[0088] In certain embodiments, cardiac mechanical function, specifically cardiac output, is also monitored using sensors integrated with the catheter of the implantable smartport system. In certain embodiments, one approach for assessing cardiac output involves measuring the total blood flow returning to the right heart using bi-directional "haircell" flow rate sensors developed as shown in FIG. 5. These sensors are fabricated from thin piezoresistive materials, approximately 200 nm thick, which change resistance due to strain induced by bending motion. Both forward and backward blood flows cause mechanical deformation of the sensor structure, leading to tensile and compressive strains that alter the material's resistance. As shown in FIG. 11, by continuously measuring the flow rate with these piezoresistive sensors positioned inside the superior vena cava, the total amount of blood flowing into the right heart can be calculated. Consequently, cardiac output can be estimated in real-time, providing continuous monitoring of cardiac mechanical function.

[0089] In certain embodiments, the patency of the catheter of the implantable smartport system are monitored using an integrated thermal actuator and temperature sensor, as shown in FIG. 6 upper panel. During monitoring, higher fluid flow rates will dissipate more heat from the thermal actuator. Changes in the actuator's temperature are captured by the temperature sensor and converted into voltage readings. By integrating these thermal sensors within the catheter, flow patency can be monitored continuously, allowing for real-time detection of flow blockages in chemotherapy agent delivery.

[0090] Additionally, other sensing modalities are also included to form a multimodal implantable smartport system for comprehensive cardiovascular function monitoring and assessment.

[0091] In one embodiment, ECG is conducted via built-in electrodes to monitor arrhythmia events and abnormal morphology of ECG during therapy.

[0092] In one embodiment, photoplethysmography (PPG) sensing technology is implemented to monitor blood oxygen levels.

[0093] In one embodiment, a thermal conductivity sensor is included to measure heat dissipation near the heart during the chemotherapy session.

[0094] In one embodiment, an impedance spectroscopy technology interface is added to measure heart muscle contractility and cell-cell coupling.

[0095] In one embodiment, metabolism sensing technology is included to monitor Nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD).

[0096] In certain embodiments, the implantable smartport system is capable of continuous monitoring of heart function during chemotherapy sessions through dynamic ejection fraction measurements via ultrasound probes, in addition to ECG, PPG, and other parameters. In some embodiments, an array of ultrasound probes is disposed at the tip of the catheter. These ultrasound (echo) probes dynamically assess the volume of the ventricle and the approximation of the ventricular free wall to project the percentage of the ejection fraction. The ultrasound probes perform several tasks: they monitor the patency of the catheter shaft through Doppler measurements of flow and dynamically measure the ejection fraction.

[0097] In certain embodiments, the ability of the implantable smartport system to sense in different modalities offers the advantage with each modality:

[0098] Ultrasonic Imaging modality - allowing both Doppler measurements and ejection fraction assessment.

[0099] ECG measurements modality - allowing early arrhythmia detection and monitoring PPG modality - the ability to record a pulse wave and saturation.

[0100] Thermal conductivity modality - measuring the dissipation of heat - cardiac output measurement to backup ejection fraction assessment through ultrasound.

[0101] Impedance spectroscopy modality - the ability to measure contractility and cell-cell coupling

[0102] Without intent to limit the scope of the invention, exemplary embodiments of the invention are given below.

[0103] Referring to FIG. 1, in one embodiment, the implantable smartport device for chemotherapy delivery to a target region of interest of a living subject comprises at least one port containing at least one drug solution; a delivering member coupled to the at least one port for operably delivering the at least one drug solution from the at least one port to the target region of interest; and a sensor member for measuring physiological parameters of the living subject so as to monitor a physiological status of the living subject. In one embodiment, the physiological parameters comprise at least one of a blood oxygenation, a heart rate, a respiratory rate, a temperature, an ECG, an EMG, a blood flow velocity, a blood flow amount, a blood pressure, and a blood chemistry.

[0104] In certain embodiments, the implantable smartport device is configured to monitor realtime changes in heart ejection fraction and blood flow velocity, and use the metrics as a predictor for major cardiovascular complications.

[0105] In certain embodiments, the at least one port is refillable.

[0106] In certain embodiments, a dose and a rate of the drug delivery from the at least one port to the target region of interest are controllable, based on the physiological status determined by the measured physiological parameters.

[0107] In certain embodiments, the delivering member comprises a drug delivery device configured to deliver one or more drug solutions at one or more locations simultaneously or sequentially.

[0108] In certain embodiments, an amount of each of the one or more drug solutions to be delivered at a respective one of the one or more locations is determined based on the physiological status of the living subject.

[0109] In certain embodiments, as shown in FIG. 3, the delivering member comprises a first chamber in fluidic communications with the least one port for drug delivery, and a second chamber for electronics housing.

[0110] In certain embodiments, the delivering member comprises a catheter in fluidic communications with the least one port, having a tip attached to the target region of interest, as shown in FIGS. 2-4, and 11.

[0111] In certain embodiments, the sensor member comprises a plurality of ultrasonic transducers disposed around the tip of the catheter for acquisition of associated information, as shown in FIGS. 2-4.

[0112] In certain embodiments, the sensor member comprises an ultrasonic probe configured to measure drug flow velocity, direction, and volume and monitor the patency of the catheter shaft.

[0113] In certain embodiments, the sensor member comprises ECG electrodes configured to monitor arrhythmia events and abnormal morphology of ECG during therapy, as shown in FIGS. 2-4.

[0114] In certain embodiments, the at least one ECG electrode is disposed around the tip of the catheter, as shown in FIGS. 2-3.

[0115] In certain embodiments, the sensor member comprises at least one optical sensor.

[0116] In certain embodiments, the sensor member comprises at least one photoplethysmography (PPG) sensor configured to monitor blood oxygen levels, as shown in FIG. 4.

[0117] In certain embodiments, the sensor member comprises a thermal conductivity sensor configured to measure heat dissipation near the heart during the chemotherapy session, as shown in FIG. 4.

[0118] In certain embodiments, the sensor member comprises an impedance spectroscopy technology interface configured to measure heart muscle contractility and cell-cell coupling, as shown in FIG. 4.

[0119] In certain embodiments, the sensor member comprises a metabolism sensor configured to monitor nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD), as shown in FIG. 4.

[0120] In certain embodiments, the sensor member comprises one or more accelerometers configured for motion and / or body orientation measurements.

[0121] In certain embodiments, the sensor member comprises one or more molecular sensors configured to monitor biomarkers of cardiac toxicity, including markers of inflammation.

[0122] In certain embodiments, as shown in FIG. 1 and 10, the device further comprises a controller operably in wireless or wired communications with the sensor member, and the delivering member for obtaining the physiological status of the living subject from the sensor member, and controlling operations of the delivering member based on the physiological status of the living subject.

[0123] In certain embodiments, the device operably receives configuration commands and operation commands, wherein the configuration commands instruct the controller to deploy configuration parameters to the sensor member, or timing configuration for the delivering member, and wherein the operation commands trigger activation / deactivation of the sensor member or the delivering member at a time.

[0124] In certain embodiments, the configuration commands and the operation commands are initialized from an external device in two-way wireless communications with the controller.

[0125] In certain embodiments, the controller is configured to initialize measurement of the sensor member, and collect the measured data therefrom.

[0126] In certain embodiments, a customized application with a graphic user interface (GUI) in the external device including a smartphone or tablet is adapted to control the device via its configuration and operation commands.

[0127] In certain embodiments, the device further comprises a power system to power operations of the device. In certain embodiments, the implantable device comprises a power system for providing power to the implantable device and for receiving power charging either wired or wirelessly. In certain embodiments, the power receiving unit includes a RX coil. In certain embodiments, a wireless charging unit having a TX coil is configured to be disposed outside of the patient’s body for wirelessly charging the implantable device.

[0128] In certain embodiments, the power system comprises a battery and a battery charging module.

[0129] In certain embodiments, the battery is a rechargeable battery.

[0130] In certain embodiments, the device further comprises a battery-less system to operate the device through a wireless power transfer.

[0131] In certain embodiments, the device is biocompatible.

[0132] In certain embodiments, as shown in FIG. 11, the catheter as the delivering member of the implantable smartport system is disposed inside the patient’s superior vena cava for monitoring the cardiac functions. In certain embodiments, the catheter is attached to the inside surface of the superior vena cava via supporting means or attaching means such as biocompatible adhesive. One or more sensors for detecting the blood flow velocity, blood flow amount, blood pressure, or other blood parameters are disposed in association with the catheter. In certain embodiments, the one or more sensors include haircell flow sensor. In certain embodiments, the one or more sensors are disposed on the outer surface of the catheter.

[0133] In certain embodiments, ECG electrodes are embedded to continuously record ECG signals.

[0134] In certain embodiments, an ultrasound piezo-element is capable of emitting ultrasound waves across a wide spectrum, aimed at the heart muscle. The ultrasound frequency is adjustable according to the tissue thickness to measure the dynamic approximation of the free wall of the left ventricle and the septum. This allows for the assessment of cardiac output, ejection fraction, and the end-systolic and end-diastolic sizes of the heart chambers.

[0135] In certain embodiments, ciliary or haircell flow sensors is capable of measuring flow dynamics both outside the shaft of the port. This enables dynamic velocity measurements inside the heart chambers, particularly the right atrium and right ventricle. The placement of haircell sensors inside the shaft of the port will also allow for the assessment of its patency.

[0136] In certain embodiments, a thermistor probe and thermal sensor enable patency measurements inside the shaft of the port by measuring dynamic temperature changes and assessing flow. The thermal sensor / thermistor are used for indirect measurements of cardiac output based on the dynamic measurements of the injected volume and the corresponding temperature changes, allowing for the calculation of cardiac output.

[0137] In certain embodiments, a wearable module is included for the interrogation of the implanted module. This facilitates wireless power transfer, charging the energy storage element, and the storage, collection, or erasure of information.

[0138] In certain embodiments, a thermal sensor and calculation module are included for the dynamic assessment of the volume of fluids flowing per second, as well as the total cumulative volume.

[0139] In certain embodiments, a valve or stop-flow device is included to halt the flow of fluids on demand and as a result of cumulative measurements.

[0140] Example

[0141] The present invention validates the robustness of haircell sensors in a customized bench- top cardiac simulation pulsatile pump using blood mimicking fluid (BMF) that has comparable viscosity to human blood. These haircell sensors are fabricated from polyimide using advanced nanofabrication techniques, resulting in various sensor thicknesses that yield different flow rate measurement performances.

[0142] As disclosed in the present invention, in the bench-top experiment, the haircell sensor was powered by a constant current source, and changes in voltage were measured based on the piezoresistive effect generated by the sensor's motion. The bench-top pump includes two tunable parameters for manipulating the pulsatile flow: gain and simulated heart rate. FIG. 12 illustrates the signal from a haircell sensor with a thickness of 25 pm, measured under a pump setting of 0.17 gain and 120 bpm, using customized BMF.

[0143] The bench-top pump system also incorporates a commercially available flow rate sensor as a gold-standard reference. A demonstration of flow rate measurements from both the haircell sensor and the reference sensor is shown in FIG. 13. Panel (a) shows the BMF flow data measurements by haircell sensor (sensor thickness 25 pm), and panel (b) shows the BMF flow data measurements by the conventional flow rate sensor. As it can be seen in panel (c), identical pulsatile flow patterns are observed from the haircell sensor compared to the reference sensor, with a peak flow rate of 70 mL / s corresponding to a signal amplitude of nearly 0.005 V.

[0144] The present invention therefore demonstrates that haircell sensors can accurately measure flow rates in a simulated cardiac environment, providing reliable data comparable to established commercial sensors. The ability to tune the pulsatile flow parameters and the use of blood mimicking fluid ensure that the experimental setup closely replicates physiological conditions, thereby confirming the efficacy and robustness of the haircell sensors for potential clinical applications.

[0145] FIGs. 14 and 15, similarly, illustrate the flow rate measured in bench-top studies using a haircell sensor with a different thickness of 12.5 pm, under the same pump settings 0.17 gain, 80 bpm. In particular, FIG. 14 shows example data from the haircell sensor having a thickness of 12.5 pm tested in bench-top cardiac pulsatile pump (0.17 gain, 80 bpm) using customized BMF. FIG. 15 shows comparison between flow measurement in a bench-top pulsatile pump (0.17 gain, 80 bpm) using BMF, with panel (a) shows the readings by the haircell sensor (sensor thickness 12.5 pm), panel (b) shows the readings by the conventional flowrate sensor, and panel (c) shows real-time, synchronous measurement between the two. As it can be seen, despite the reduced thickness, the haircell sensor continues to deliver flow measurement results that are comparable to the gold-standard reference sensor. The peak flow rate observed is 70 mL / s, corresponding to a signal amplitude of nearly 0.006 V.

[0146] The consistency in performance across different sensor thicknesses highlights the versatility and reliability of the haircell sensors. The ability to maintain accurate flow measurements even with a thinner sensor dimension demonstrates the robustness of the piezoresistive materials and the effectiveness of the nanofabrication techniques used in their production.

[0147] These findings further validate the haircell sensor's capability to provide precise and reliable flow rate measurements in a simulated cardiac environment. The bench-top studies, utilizing blood mimicking fluid and adjustable pulsatile flow parameters, ensure that the experimental conditions closely replicate physiological scenarios. This robustness across varying sensor dimensions underscores the potential of haircell sensors for diverse clinical applications, particularly in continuous cardiac monitoring and chemotherapy delivery systems.

[0148] The various pump settings are used for validating the haircell sensor’s compatibility. FIG. 16 shows flow measurement in a bench-top pulsatile pump using customized BMF under different pump settings. Panel (a) shows a pump setting of 0.17 gain_80 bpm, with a peak flow ~ 70mL / s. Panel (b) shows a pump setting of 0.2 gain_80 bpm with a peak flow ~ 90mL / s. Panel (c) shows a pump setting of 0.3 gain_80 bpm, with a peak flow ~ 125 mL / s. As it can be seen that the haircell flow sensor is compatible with all different pump flow settings.

[0149] In addition, the necessity of using BMF to approximate real -case blood hemodynamics was validated by comparing the flow rate measurements from the haircell sensor in both BMF and water in FIG. 17. The experimental results indicated significantly different peak flow rate values between the BMF (45 mL / s) and water (80 mL / s) under the same bench-top pump settings. This disparity underscores the importance of using BMF to achieve accurate and realistic simulations of blood flow dynamics, as water does not adequately replicate the viscosity and flow characteristics of blood.

[0150] Furthermore, the stability of the haircell sensor in continuous measurement was demonstrated in FIG. 18. The data showed a consistent baseline voltage within a 20-hour monitoring window, following an initial elevation in the first 2 hours. This stability indicates the sensor's capability for robust long-term operation, making it suitable for continuous cardiac function monitoring in chronic in-vivo settings.

[0151] The foregoing description of the exemplary embodiments of the invention has been presented only for the purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching.

[0152] The embodiments were chosen and described in order to explain the principles of the invention and their practical application so as to enable others skilled in the art to utilize the invention and various embodiments and with various modifications as are suited to the particular use contemplated. Alternative embodiments will become apparent to those skilled in the art to which the present invention pertains without departing from its spirit and scope. Accordingly, the scope of the present invention is defined by the appended claims rather than the foregoing description and the exemplary embodiments described therein.

[0153] Some references, which may include patents, patent applications and various publications, are cited and discussed in the description of this invention. The citation and / or discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any such reference is “prior art” to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entireties and to the same extent as if each reference was individually incorporated by reference.

Claims

CLAIMSWhat is claimed is:

1. An implantable smartport device for chemotherapy delivery to a target region of interest of a living subject, comprising: at least one port containing at least one drug solution; a delivering member coupled to the at least one port for operably delivering the at least one drug solution from the at least one port to the target region of interest; and a sensor member for measuring physiological parameters of the living subject so as to monitor a physiological status of the living subject.

2. The device of claim 1, being configured to monitor real-time changes in heart ejection fraction and blood flow velocity, and use the metrics as a predictor for major cardiovascular complications.

3. The device of claim 1, wherein the at least one port is refillable.

4. The device of any one of claims 1-3, wherein a dose and a rate of the drug delivery from the at least one port to the target region of interest are controllable, in accordance with the physiological status determined by the measured physiological parameters.

5. The device of any one of claims 1-4, wherein the delivering member comprises a drug delivery device configured to deliver the at least one drug solution at one or more locations simultaneously or sequentially.

6. The device of any one of claims 1-5, wherein an amount of each of the at least one drug solution to be delivered at a respective one of the one or more locations is determined based on the physiological status of the living subject.

7. The device of any one of claims 1-6, wherein the delivering member comprises a first chamber in fluidic communications with the least one port for drug delivery, and a second chamber for electronics housing.

8. The device of any one of claims 1-7, wherein the delivering member comprises a catheter in fluidic communications with the least one port, having a tip attached to the target region of interest.

9. The device of any one of claims 1-8, wherein the sensor member comprises a plurality of ultrasonic transducers disposed around the tip of the catheter for acquisition of associated information.

10. The device of any one of claims 1-8, wherein the sensor member comprises an ultrasonic imaging probe configured to measure drug flow velocity, direction and volume, an ejection fraction, and monitor the patency of the catheter shaft.1 1 . The device of any one of claims 1 -9, wherein the sensor member comprises at least one electrocardiography (ECG) electrodes configured to monitor ECG signal.

12. The device of claim 11, wherein the at least one ECG electrode is disposed around the tip of the catheter.

13. The device of any one of claims 1-12, wherein the sensor member comprises at least one optical sensor.

14. The device of claim 13, wherein the sensor member comprises at least one photoplethysmography (PPG) sensor configured to monitor blood oxygen levels.

15. The device of any one of claims 1-14, wherein the sensor member comprises at least onethermal sensor.

16. The device of any one of claims 1-15, wherein the at least one thermal sensor is configured to measure heat dissipation near the heart during the chemotherapy session.

17. The device of any one of claims 1-16, wherein the at least one thermal sensor is configured to measure a patency status of the catheter.

18. The device of any one of claims 1-17, wherein the sensor member comprises an impedance spectroscopy technology interface configured to measure heart muscle contractility and cell-cell coupling.

19. The device of any one of claims 1-18, wherein the sensor member comprises at least one metabolism sensor configured to monitor nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD).

20. The device of any one of claims 1-19, wherein the sensor member comprises one or more accelerometers configured for motion and / or body orientation measurements.

21. The device of any one of claims 1-20, wherein the sensor member comprises one or more molecular sensors configured to monitor biomarkers of cardiac toxicity, including markers of inflammation.

22. The device of any one of claims 1-21, wherein the sensor member comprises at least one haircell flow sensor measuring a surrounding fluid velocity.

23. The device of any one of claims 1-22, wherein the at least one haircell flow sensor is disposed on an outer surface of the catheter.

24. The device of any one of claims 1-23, wherein the sensor member comprises anultrasound piezo element configured to emit ultrasound waves.

25. The device of any one of claims 1-24, further comprising a controller operably in wireless and / or wired communications with the sensor member and the delivering member for obtaining the physiological status of the living subject from the sensor member, and controlling operations of the delivering member based on the physiological status of the living subject.

26. The device of claim 25, wherein the device operably receives configuration commands and operation commands, wherein the configuration commands instruct the controller to deploy configuration parameters to the sensor member, or timing configuration for the delivering member, and wherein the operation commands trigger activation / deactivation of the sensor member or the delivering member at a time.

27. The device of claim 26, wherein the configuration commands and the operation commands are initialized from an external device in two-way wireless communications with the controller.

28. The device of claim 27, wherein the controller is configured to initialize measurement of the sensor member, and collect the measured data therefrom.

29. The device of any one of claims 1-28, wherein a customized application with a graphic user interface (GUI) in the external device including a smartphone or tablet is adapted to control the device via its configuration and operation commands.

30. The device of any one of claims 1-29, further comprising a power system to power operations of the device.

31. The device of claim 30, wherein the power system comprises a battery which is incommunication with a battery charging module.

32. The device of claim 32, wherein the battery charging module comprises a wearable module which is configured to wirelessly provide power to the battery.

33. The device of claim 33, wherein the wearable module comprises a wireless communication unit which is configured to collect information from the implantable smartport device.

34. The device of any of claims 1-29, further comprising a battery-less system to operate the device through a wireless power transfer.

35. The device of any one of claims 1-34, wherein the physiological parameters comprise at least one of a blood oxygenation, a heart rate, a respiratory rate, a temperature, an ECG, an EMG, a blood flow, a blood pressure, and a blood chemistry.

36. The device of any one of claims 1-35 further comprising a valve unit, wherein the value unit is in communication with and controlled by the controller.

37. The device of claim 36, wherein the controller controls the value unit based on any measurements obtained by the sensor member.

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