Patent Application
20240138768
The present disclosure generally relates to non-invasive methods and systems for measuring mechanical properties of tissues within the chambers of the heart or other body organs, e.g., via an electronic implantable device comprising an integrated sensor and implant, e.g., to evaluate the progression of, and/or treat, coronary arterial disease and other cardiovascular diseases.
Atherosclerosis is a common cause of coronary artery disease and a significant factor in broader cardiovascular diseases, which is a leading cause of premature death in the United States. While implantation of a stent is a common treatment of coronary artery disease, a frequent complication is restenosis which can cause the narrowing and stiffening of the stented artery over the stent.
Restenosis is generally defined as a lumen reduction of the artery or vein with a varying degree of severity. Restenosis can progress gradually and often may not exhibit symptoms until one or more of the blockages become severe. Current methods of monitoring for restenosis include periodic imaging or catheterization procedure such as angiography, intravascular ultrasound, optical coherence tomography, and catheter-based measurements.
There is a benefit to improving the detection of restenosis and providing alternative methods to non-invasively measure metrics within the heart or body.
An exemplary method and system are disclosed for a fully implantable soft-membrane electronic system that can provide the continuous monitoring of real-time or semi real-time measurements of strain and/or other mechanical properties, via electrical measurements such as capacitance, of the heart or organ of the body that are acquired over an inductive coupling between the measurement system and the implanted device. In the example of an electronic stent, the implanted device includes a mechanical-sensing sensor that is integrated with an implanted device body (e.g., stent body) that, collectively, is configured to expand and contract with a motion of the body organ to provide a mechanical measure of the body organ within which the implanted device is placed. The implanted device body (e.g., stent body) can be configured as an inductive device that serves as an antenna to provide inductive coupling with the measurement system. The inductive device can form, e.g., a resonant circuit, in some embodiments, to which changes in the mechanical measure of the implanted device in the body organ correlate to a change in the electrical measurements of that implanted device.
In some embodiments, the implantable soft-membrane electronic system is employed to measure restenosis.
In some embodiments, the implantable soft-membrane electronic system includes a set of one or more nanomembrane strain sensors that couple to a stent body to form an electronic stent. The implantable soft-membrane electronic system may be configured as a low-profile system that requires minimal invasive implantation to deploy into a blood vessel in a catheterization procedure.
In some embodiments, the implantable soft-membrane electronic system is printable, in whole or in part, from the nanomaterial-based set of soft, membrane strain sensors. The implantable soft-membrane electronic system is configured to utilize a sliding mechanism that can enhance the sensitivity and detection of low strain measurements.
The implantable soft-membrane electronic system may be integrated with a stent body comprising an inductive stent that serves as an antenna or antenna array for wireless sensing operation (e.g., passive wireless sensing operation). The stent body may be fabricated with microscale features to form the antenna or antenna elements.
A study was conducted and evaluated the sensor platform in wireless monitoring restenosis in an artery model and an ex-vivo study in a coronary artery of ovine hearts. The capacitive sensor-based artery implantation system offers unique benefits in wireless, real-time monitoring of stent treatments and arterial health for cardiovascular disease. It was observed that the printed nanomaterials (e.g., aerosol jet printed) could provide improvements for capacitive strain sensing. The wireless electronic stent can also provide unobtrusive monitoring of restenosis in a biomimetic artery model and in an ex-vivo study with ovine hearts. The electronic stent can be configured to operate via inductive coupling operation in a battery-free operation.
In another aspect, a stent is disclosed comprising a mechanical-sensing sensor comprising a plurality of flexible membrane members, including a first membrane member and a second membrane member, wherein the first membrane member is separated from the second membrane member across a dielectric member (e.g., dielectric layer) to form a capacitive structure, wherein the first membrane member is configured to move in a first direction in relation to the second membrane and the second membrane is configured to move in a second direction in relation to the first membrane member different from the first direction to change capacitance defined between the first membrane member and the second membrane member, and wherein the capacitance, or change of capacitance, corresponds to a measure of strain or mechanical properties; and a stent body comprising a plurality of annular struts positioned at intervals in a circumferential direction of the stent body, wherein the mechanical-sensing sensor is coupled, via one or more stretchable interconnects, to the stent body to measure strain of the stent.
In some embodiments, the plurality of annular struts include a first annular strut and a second annular strut, wherein the first annular strut is configured as an electromagnetic radiating body to serve as an antenna for the stent.
In some embodiments, the second annular strut is configured as a second electromagnetic radiating body to serve as an antenna array for the stent with the first annular member.
In some embodiments, the first annular strut is connected to a second annular strut via a plurality of non-conductive interconnects.
In some embodiments, the first annular strut is configured as a wave-shaped strut (e.g., triangular wave, sinusoidal wave, triangular wave offset, sinusoidal wave with offset, asymmetric triangular wave, asymmetric sinusoidal wave, etc.).
In some embodiments, the mechanical-sensing sensor is laminated (e.g., on an inner or outer surface) on the stent body.
In some embodiments, the mechanical-sensing sensor is integrated into the mechanical-sensing sensor.
In some embodiments, each of the plurality of annular struts comprises a laminated structure comprising: a metal core (e.g., strain-less steel); a conductive layer that surrounds the metal core (e.g., Au, Ag, Cu, Al, Zi, Ni, or combination thereof (alloys); and a coating (e.g., an elastomer, e.g., parylene, or an active agent, such as a therapeutic agent).
In some embodiments, the change of capacitance, strain, or mechanical property is employed to measure a state of restenosis of a patient.
In some embodiments, the mechanical-sensing sensor is configured to measure strain or a change in strain.
In some embodiments, the first membrane member has a first protruding structure, wherein the second membrane member has a second protruding structure, and wherein the first protruding structure is parallel to the second protruding structure.
In some embodiments, the first membrane member has a plurality of conductive non-parallel members (e.g., mesh).
In another aspect, a method is disclosed of fabricating a stent of any one of the above embodiments, the method comprising providing a substrate metal core; cutting, via a laser operation, a plurality of bridges in the substrate metal core; filling each of the plurality of bridges with a printed polymer (e.g., polyimide) to form a stretchable interconnect; cutting, the substrate metal core to form the plurality of annular struts positioned at intervals in a circumferential direction of the stent body; electroplating the plurality of annular struts; and coating the plurality of electroplated annular struts.
In some embodiments, the method includes fabricating a first membrane for a strain sensor; fabricating a second membrane for the strain sensor; assembling the first membrane over a first side of a dielectric layer; and assembling the second membrane over a second side of the dielectric layer.
In another aspect, a stent is disclosed comprising a strain sensor comprising a plurality of flexible membrane members, including a first membrane member and a second membrane member, wherein the first membrane member has first protruding structure and the second membrane member has a second protruding structure separated from the first membrane member to form a laminated structure, wherein the first membrane member is configured to move in a first direction in relation to the second membrane and the second membrane is configured to move in a second direction in relation to the first membrane member different from the first direction to change electrical properties defined between the first protruding structure and the second protruding structure, and wherein the electrical properties, or change of electrical properties, corresponds to a measure of strain; and a stent body comprising a plurality of annular struts positioned at intervals in a circumferential direction of the stent body, including a first annular strut and a second annular strut, wherein the strain sensor is coupled, via one or more stretchable interconnects, to the stent body to measure strain of the stent, and wherein the first annular strut is configured as an electromagnetic radiating body to serve as an antenna for the stent.
In some embodiments, the second annular strut is configured as a second electromagnetic radiating body to serve as an antenna array for the stent with the first annular member.
In some embodiments, the stent further includes features of any one of the above embodiments.
In another aspect, a system is disclosed comprising a measurement system comprising an antenna, an acquisition electronics, and a processing unit, wherein the processing unit comprises a processor a memory having instructions stored thereon, wherein execution of the instructions by the processor cause the processor to direct the acquisition electronics to measure and/or interrogate (i) a change in the resonant frequency of an electronic stent implanted in a patient and/or (ii) a change in arterial wall strain properties.
In some embodiments, the electronic stent comprises the stent of any one of above embodiments.
In another aspect, a method is disclosed of monitoring restenosis or progression of restenosis, the method comprising wirelessly interrogating an electronic stent implanted in a subject to determine a first resonant frequency (e.g., during implantation) associated with a strain or mechanical measurement, wherein the electronic stent comprises an inductive and a capacitive component; wirelessly interrogating the electronic stent implanted in the subject to determine a second resonant frequency (e.g., months or years after implantation) associated with the strain or mechanical measurement; determining a change the strain or mechanical measurement as a change between the first resonant frequency and the second resonant frequency to determine a presence of restenosis or the progression of restenosis.
In some embodiments, the wirelessly interrogation is continuously performed.
In some embodiments, the electronic stent includes the stent of any one of the above-discussed embodiments.
The skilled person in the art will understand that the drawings described below are for illustration purposes only.
Some references, which may include various patents, patent applications, and publications, are cited in a reference list and discussed in the disclosure provided herein. The citation and/or discussion of such references is provided merely to clarify the description of the disclosed technology and is not an admission that any such reference is “prior art” to any aspects of the disclosed technology described herein. In terms of notation, “[n]” corresponds to the nth reference in the list. For example, [4] refers to the fourth reference in the list. 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.
The electronic implantable device 102 includes an integrated sensor 104 (also referred to herein as a “mechanical-sensing sensor”) and an implant device body 106 (e.g., a stent body) that is coupled to the integrated sensor 104 through stretchable or flexible interconnects 108. In the example shown in
The inductive device can form, e.g., a resonant circuit 122 (shown in
The implantable device body may be configured as a stent such as a balloon-expandable coronary stent, a vascular stent, a ureteral stent, a prostatic stent, a pancreatic or biliary stent, and the like.
The measurement system 112 includes the transceiver 110 and acquisition electronics 118. The acquisition electronics 118 is configured to drive the transceiver 110 and to receive and convert the sensed signal to a data set. The measurement system 112 may operate with a monitoring/control device 120. In some embodiments, the monitoring device 120 includes a data store to store the data set. In other embodiments, the monitoring device 120 is configured to display the acquired data set or to generate an alert.
The monitoring device 120 may be configured as a portable device to provide continuous monitoring of the sensed signal. In other embodiments, the monitoring device 120 may be configured as a medical instrument, e.g., to be employed in a clinician's office, hospital, or medical center, to measure the sensed signal and to direct treatment based on the sensed signal.
In the example shown in
The first membrane member (e.g., 124a, 124a′) of the integrated sensor (e.g., 104a, 104b) is configured, in some embodiments, to move in a first direction in relation to the second membrane (e.g., 124b, 124b′), and the second membrane (e.g., 124b, 124b′) is configured to move in a second direction in relation to the first membrane member (e.g., 124a, 124a′) different from the first direction to change electrical properties (e.g., capacitance) defined between the first protruding structure and the second protruding structure, e.g., in which the capacitance, or change of capacitance, corresponds to a measure of strain.
In the example shown in
The implant device body 106a can be laminated, e.g., in a mid-region, or other regions, e.g., via adhesives or via a conductive polymer (e.g., polyimide) with a mechanical-sensing sensor 104a (e.g., a capacitive sensor), e.g., that can measure strain or a change in strain. In some embodiments, the mechanical-sensing sensor 104a can be integrated into the implant device body.
The term “polymer” as used herein refers to a relatively high molecular weight organic compound, natural or synthetic, whose structure can be represented by a repeated small unit, the monomer. Synthetic polymers are typically formed by the addition or condensation polymerization of monomers. The polymers used or produced in the present invention are biodegradable. The polymer is suitable for use in the body of a subject, i.e., is biologically inert and physiologically acceptable, non-toxic, and is biodegradable in the environment of use, i.e., can be resorbed by the body. The term “polymer” encompasses all forms of polymers, including, but not limited to, natural polymers, synthetic polymers, homopolymers, heteropolymers or copolymers, addition polymers, etc.
As discussed herein, a “subject” may be any applicable human, animal, or other organisms, living or dead, or other biological or molecular structure or chemical environment, and may relate to particular components of the subject, for instance, specific tissues or fluids of a subject (e.g., human tissue in a particular area of the body of a living subject), which may be in a particular location of the subject, referred to herein as an “area of interest” or a “region of interest.” It should be appreciated that, as discussed herein, a subject may be a human or any animal. It should be appreciated that an animal may be a variety of any applicable type, including, but not limited thereto, mammal, veterinarian animal, livestock animal or pet type animal, etc. As an example, the animal may be a laboratory animal specifically selected to have certain characteristics similar to humans (e.g., rat, dog, pig, monkey), etc. It should be appreciated that the subject may be any applicable human patient, for example.
In
In some embodiments, the two membrane members (e.g., 124a, 124b) are exactly aligned and overlapping with one another to form a capacitive structure. In some embodiments, the two membrane members (e.g., 124a, 124b) can be identical and has a small offset to one another. In yet other embodiments, the two membrane members (e.g., 124a, 124b) can be non-identical to one another.
In
Example #1. In the example shown in
In some embodiments, the presence of restenosis can be determined as having a low or lower resonance frequency in relation to a reference resonant frequency associated with a healthy or non-restenosis heart.
In some embodiments, the presence of restenosis can be determined as a decrease in resonance frequency, e.g., associated with wall thickening of the vessel walls. In some embodiments, the presence of restenosis can be determined as a decrease in resonance frequency, e.g., associated with increased pressure within a lumen that the electronic implantable device is implanted or deployed.
In some embodiments, the method may assess for an increase in the resonance frequency of the electronic implantable device in the increase in resonance frequency may correspond to a change in strain or mechanical property of a lumen that the electronic implantable device is implanted or deployed, e.g., as a result of a thinning of the lumen or a reduction in pressure in said lumen.
The terms “treat,” “treating,” “treatment,” and grammatical variations thereof, as used herein, include partially or completely delaying, alleviating, mitigating, or reducing the intensity of one or more attendant symptoms of a disorder or condition and/or alleviating, mitigating or impeding one or more causes of a disorder or condition. Treatments according to the invention may be applied preventively, prophylactically, palliatively, or remedially. Prophylactic treatments are administered to a subject prior to onset (e.g., before obvious signs of a lung disorder), during early onset (e.g., upon initial signs and symptoms of a lung disorder), or after an established development of a disease (e.g., a coronary arterial disease, atherosclerosis, restenosis). Prophylactic administration can occur for several days to years prior to the manifestation of symptoms of a disease (e.g., coronary arterial disease, atherosclerosis, restenosis, etc.).
Example #2. In the example shown in
The method 500a includes wirelessly interrogating (506) the electronic implantable device (e.g., 102, 102a, 102b, etc.) to determine a resonant frequency associated with a strain or mechanical measurement at a first-time instance. Method 500b includes wirelessly interrogating (508) the electronic implantable device (e.g., 102, 102a, 102b, etc.) to determine a resonant frequency associated with the strain or mechanical measurement at a second-time instance.
Method 500b includes determining (504) a change in the strain or mechanical measurement based on the determined change in the resonant frequency between the first-time instance and the second-time instance to determine a presence of disease or condition or the progression of a disease or condition (e.g., coronary arterial disease, atherosclerosis, restenosis, etc.), e.g., to treat said disease or condition.
In some embodiments, the first-time instance refers to a scan performed during a visit to a clinician to evaluate for restenosis (or coronary arterial disease, atherosclerosis, or other disease or conditions described herein). The second-time instance refers to a scan performed during another visit to a clinician to evaluate for restenosis (or coronary arterial disease, atherosclerosis, or other disease or conditions described herein). The time period between the first and the second time instance may be days, weeks, months, or years apart.
Example #3. In the example shown in
Method 500c includes wirelessly interrogating (506) the electronic implantable device (e.g., 102, 102a, 102b, etc.) to determine a resonant frequency associated with a strain or mechanical measurement at a first-time instance. The method 500c includes wirelessly interrogating (508) the electronic implantable device (e.g., 102, 102a, 102b, etc.) in a continuous manner in which each interrogation determines a resonant frequency associated with the strain or mechanical measurement at a second-time instance.
Method 500c includes determining (514) a change in the strain or mechanical measurement based on the determined change in the resonant frequency to determine a presence of disease or condition or the progression of a disease or condition (e.g., coronary arterial disease, atherosclerosis, restenosis, etc.), e.g., to treat said disease or condition.
The method 500c may be performed, e.g., by a remote portable device that may be wearable by the subject or patient, e.g., to monitor for restenosis or other disease or condition as described herein. The remote portable device may be configured to interrogate for a change in resonant frequency responses from the electronic implantable device (e.g., 102, 102a, 102b, etc.) every second, few seconds (e.g., every 10 seconds, 15 seconds, 20 seconds, etc.), minutes (e.g., every minute, 2 minutes, 3 minutes, 4, minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes), hours (e.g., every hour or two hours, etc.), or day. Each scan can then be compared to prior scans to determine a decrease in resonant frequency, for example.
Method of Fabrication
The aerosol jet printer 618 then prints 620 (shown as “Print PI” 620) a first polyimide layer 622 (e.g., bottom layer) on the coated substrate 616 using a polyimide-ink. The polyimide layer 622 can then be cured and plasma-treated (not shown).
The aerosol jet printer 618 then prints 624 (shown as “Print AgNP” 624) a conductive layer 626, e.g., comprising silver nanoparticles, over the polyimide layer 622. The assembly comprising the printed conductive layer 626 and fabricated layers (e.g., 622) can then be sintered, welded, adhered, or otherwise joined via laser, acoustic, etc.
The aerosol jet printer 618 then prints 628 (shown as “Print PI” 628) a second polyimide layer 630 over the conductive layer 626 shown comprising layers 622, 626. The polyimide layer 630 can then be cured and plasma-treated (not shown).
After printing, the PMMA layer (or sacrificial layer) can be removed or dissolved (632), e.g., via a solution bath. The printed sensor plate 634 can then be transferred 608 (e.g., manually transferred) onto an elastomer layer (e.g., thin elastomer film) and aligned on said layer.
The second plate 604 can be fabricated (636) using similar fabrication processes 638 to fabricate the first plate 602. In some embodiments, the process is performed twice, e.g., where the first and second plates (602, 604) are identical. In other embodiments, the process is performed in parallel and serial for each respective design.
During the assembly operation 610, the first plate 604 can be placed on a thin elastomer layer (e.g., elastomer film, not shown), and then the first plate 602 can be placed over the second plate 604 while aligning the overlapping fingers (e.g., protruding structures 128a, 128b) of the two plates. A second thin elastomer layer (e.g., elastomer film, not shown) can then be joined to, e.g., placed on top of, the sensor, e.g., comprising the top and bottom plates 602, 604) to sandwich the two plates (602, 604) between two elastomer films (not shown) in the coating operation 612. The elastomer layers (e.g., a resin comprising polydimethylsiloxane (PDMS; Sylgard 184, Dow Corning) and poly(styrene-isoprene-styrene) (SIS)) can then be sealed at the edges (e.g., via uncured elastomer or adhesive).
The fabricated sensor 640 can then be connected (e.g., laminated) or integrated into the implant device body 106 (e.g., a stent body 106a). The contacts of the fabricated sensor 640 can be connected to contacts of the implant device body 106 via a conductive paint (e.g., silver paint). The conductive paint may be further coated with a sealing layer (e.g., another elastomer layer). Other conductive means may be employed, e.g., soldering.
In the example shown in
The operation 650 may then include coating 660 (shown as “Fill bridges with PI” 660) polyimide or other connector material onto the tubing, including at least at the locations 658. The coating can then be cured (not shown). The coating process can be repeated multiple times to get the desired connector thickness. The tubing surface can then be sanded and/or polished to remove excess coated material to have only the polyimide or connector material in the precut connector locations 658 (see 658a for an example embodiment of an S-shaped connector).
The operation 650 may then include laser machining 662 (shown as “Laser cut stent structure” 662), e.g., via the femtosecond laser 652 to form the stent structure via a series of patterned cutting operations. The machined surface can then be electropolished to provide the core substrate 664 (e.g., 208 of
The operation 650 may then include forming 664 (shown as “Electroplate AU” 664) a conductive layer (e.g., 210) over the core substrate 664, e.g., via an electroplating or electrodeposition operation. The layer (e.g., 210) may be 1 and 50 μm thick, e.g., 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39 μm, 40 μm, 41 μm, 42 μm, 43 μm, 44 μm, 45 μm, 46 μm, 47 μm, 48 μm, 49 μm, 50 μm. In some embodiments, the layer (e.g., 210) may be thicker than 50 μm.
The operation 650 may then include forming 668 a coating layer (e.g., 212) over the conductive layer (e.g., 210). In some embodiments, the coating layer (e.g., 212) is formed of an elastomer, e.g., parylene. In some embodiments, additional processing may be performed to treat the coating layer to embed an active agent such as a therapeutic agent in the elastomer. In other embodiments, the active agent is the coating layer. The term “active agent” as used herein can refer to a chemical compound, composition, or organism that has a biological effect. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of active agents specifically mentioned herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, isomers, fragments, analogs, organisms, and the like. When the term “active agent” is used, then, or when a particular agent is specifically identified, it is to be understood that the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, conjugates, active metabolites, isomers, fragments, analogs, etc.
The layer (e.g., 212) may be 1 and 100 μm thick, e.g., 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39 μm, 40 μm, 41 μm, 42 μm, 43 μm, 44 μm, 45 μm, 46 μm, 47 μm, 48 μm, 49 μm, 50 μm, 51 μm, 52 μm, 53 μm, 54 μm, 55 μm, 56 μm, 57 μm, 58 μm, 59 μm, 60 μm, 61 μm, 62 μm, 63 μm, 64 μm, 65 μm, 66 μm, 67 μm, 68 μm, 69 μm, 70 μm, 71 μm, 72 μm, 73 μm, 74 μm, 75 μm, 76 μm, 77 μm, 78 μm, 79 μm, 80 μm, 81 μm, 82 μm, 83 μm, 84 μm, 85 μm, 86 μm, 87 μm, 88 μm, 89 μm, 90 μm, 91 μm, 92 μm, 93 μm, 94 μm, 95 μm, 96 μm, 97 μm, 98 μm, 99 μm, 100 μm. In some embodiments, the layer (e.g., 210) may be thicker than 100 μm.
By the term “effective amount” of a therapeutic agent is meant a nontoxic but sufficient amount of a beneficial agent to provide the desired effect. The amount of beneficial agent that is “effective” will vary from subject to subject, depending on the age and general condition of the subject, the particular beneficial agent or agents, and the like. Thus, it is not always possible to specify an exact “effective amount.” However, an appropriate “effective” amount in any subject case may be determined by one of ordinary skill in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an “effective amount” of a beneficial can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts.
An “increase” can refer to any change that results in a greater amount of a symptom, disease, composition, condition, or activity. An increase can be any individual, median, or average increase in a condition, symptom, activity, composition in a statistically significant amount. Thus, the increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% increase so long as the increase is statistically significant.
“Inhibit,” “inhibiting,” and “inhibition” mean to decrease an activity, response, condition, disease, or another biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels.
The study was conducted to develop and evaluate a wireless implantable sensor system, previously referred to as an electronic stent device, to monitor the change in arterial stiffness stemming from restenosis, which measures arterial wall strain. The wireless implantable sensor system can be configured as an implantable, battery-less platform configured with one or more arterial stiffness sensors, e.g., for wireless restenosis monitoring.
The study implanted the stent-based device 702 within an artery 716 via a balloon catheter (not shown). The procedure employed in the study was identical to the current treatment of atherosclerosis of angioplasty and stenting.
The soft arterial strain sensor was manufactured using aerosol jet printing of silver nanoparticles (AgNP) and polyimide (PI).
The sensor 704a was integrated onto a wireless stent platform to enable wireless communication from an artery.
Characterization and Optimization of Membrane Strain Sensors that Use a Sliding Mechanism
The study evaluated and reconfigured the strain sensor design to provide for high sensitivity and low strain detection that can detect minute changes in arterial stiffness. To facilitate passive sensing, the study evaluated both a capacitive strain sensor and an inductive strain sensor. Numerous studies of soft capacitive strain sensors employ a sensing mechanism based on the Poisson effect, where the dielectric layer changes dimensions under strain [42-52]. However, this mechanism can theoretically limit the sensitivity to around a gauge factor of 1 [53]. To enhance sensitivity and detection of low strains, the exemplary system used in the study was configured to employ a sliding mechanism having overlapping plates located in different membrane layers that can slide relative to each other. The membrane layers (also referred to as plates) included a set of fingers that were fabricated with AgNPs and were aligned to one another to form a soft strain sensor. The exemplary system has been characterized to have high sensitivity, as discussed below.
Example sensors and additional descriptions of said sensor that can be employed are provided in C. M. Boutry, Y. Kaizawa, B. C. Schroeder, A. Chortos, A. Legrand, Z. Wang, J. Chang, P. Fox, Z. Bao, Nature Electronics, 1 (2018) 314-321, which is incorporated by reference herein in its entirety.
The two identical plates (802, 804) were aligned on top of each other, with the extended bottom PI layer (804) orientated in opposite directions along the length of the sensor (702a). This orientation allowed the two polyimide base layers (802, 804) to be pulled in opposite directions as the elastomer was stretched.
To evaluate and increase the sensitivity of the strain sensor (e.g., 702, 702b), the study investigated the optimization of the strain sensor design (812) with respect to different sensor finger dimensions and configurations.
It was observed that the spacing of fingers (y) did not impact the sensitivity but could dictate the maximum strain that can be detected, which may occur when the fingers begin to re-overlap. It was also observed that the middle electrode width (d), as the width of the conductor connecting all the fingers, can be eliminated by offsetting the connection to prevent overlap between two plates. Using these parameters, the study developed an analytical model to predict the capacitance change (ΔC/C) for a given strain per Equation 1.
The study evaluated the effects of the finger dimensions using this analytical model. In Equation 1, the model includes the total sensor length (Ltotal) and strain (ε). The study identified the finger length, finger width, and the number of fingers as impacting the sensitivity and the size of the sensor. To validate the analytical model, the study printed and assembled strain sensors of different finger dimensions.
In the study, a baseline sensor (
Example Microfabrication of Strain Sensor. The study employed an aerosol jet printer (Optomec, Aerosol Jet 200) to print strain sensors. A glass slide was coated with a layer of polymethyl-methacrylate (PMMA; MicroChem) by a spin-coating operation (at 3,000 r.p.m. for 30 s and cured for 3 minutes at 180° C.). The bottom polyimide layer was printed using ink consisting of polyimide (via HD MicroSystems, PI-2545) and 1-methyl-2-pyrrolidinone (NMP, Sigma Aldrich) mixed at a 3.5:1 ratio. The bottom polyimide layer was cured for 1 hour at 240° C. The cured PI was plasma treated prior to the printing via AgNP ink (UTDOTS, AgNP40X). The printed AgNP layer was sintered for 1 hour at 240° C. A top PI layer was printed and cured, similar to the bottom PI layer. The bottom and top plates were printed separately on the same glass slide using identical printing parameters. After printing, the PMMA layer was removed by covering the glass slide and placing it in acetone for over 1 hour. The printed sensor plates were then manually transferred and aligned on elastomer with tweezers. The bottom plate was placed on a thin elastomer film, and the top plate was placed over the top while aligning the overlapping fingers of the two plates. A thin elastomer film was then placed on top of the sensor, sandwiching the two plates between elastomer films. Uncured elastomer was added around the sensor edges to seal the sensor. Both polydimethylsiloxane (PDMS; Sylgard 184, Dow Corning) and poly(styrene-isoprene-styrene) (SIS) were used as elastomer films. PDMS was used to attach the elastomer layers together and to seal the sensor. PDMS was mixed in a 10:1 ratio of base to curing agent. SIS solution was formed based on prior work, where 15 g of poly(styrene-isoprene-styrene) (14% styrene; Sigma-Aldrich) was mixed with 100 ml of propyl acetate (Alfa Aesar). For wired sensing of capacitive sensors, copper (Cu) wire was attached using silver paint. For wireless sensing with a stent, silver paint was used to connect the sensor to the stent, and PDMS was coated over the connections for insulation.
Microfabrication of Wireless Stent. A femtosecond laser (Optec) was used to fabricate the wireless stent from stainless steel tubing (Vita Needle, 304SS 14XX). First, the steel tubing is laser machined to remove material from the connector locations. The machined surfaces were electropolished and rinsed with DI water. PI was then coated onto the tubing and cured at 240° C. for 1 hour. The coating process was repeated twice before sanding the tubing surfaces to remove PI. This allowed PI to only remain in the precut connector locations. Laser machining was performed to cut the remaining stent structure and followed by electropolishing and rinsing. An electroless gold plating solution (Sigma Aldrich) was used to surface plate the stent with approximately a 15 μm thick layer of Au. Electrodeposition was performed with a three-electrode system while the temperature and pH of the solution were maintained at 55° C. and 8. The plated stent was rinsed before insulating the stent with a 30 μm thick layer of parylene.
Table 1 shows a comparison of different capacitive sensor designs [42-52, 54] and the exemplary integrated sensor 702.
It can be observed that in addition to high sensitivity, the strain sensor of the exemplary system facilitates the detection of small strain changes. It should be appreciated that any of the different capacitive sensor designs can be integrated in an alternative embodiment with implantable device body as described herein.
Indeed, in some embodiments, the exemplary electronic implantable device 102 may employ Poisson effect-based sensors.
Mechanics and Functions Characterization of Strain Sensors for Arterial Stiffness Monitoring
In the study, criteria based on the sensor optimization results were applied to develop a miniaturized strain sensor for integration with a stent and sensing of arterial stiffness.
Characterization of Strain Sensor. Linear strain was applied to the sensors with a motorized test stand (Mark-10 ESM303), while capacitance was measured with an LCR meter (B&K Precision 891). The circumferential strain was applied by embedding sensors in silicone tubing and applying pressure within the tubing. The pressure was measured with a commercial sensor (Honeywell 26PCBFB6G). For strain sensor optimization tests, a linear strain of 4.8% was applied to all sensors. Cyclic stretching and cyclic bending were evaluated using the motorized test stand. Wireless signals from integrated stents and sensors were acquired using a loop antenna connected to a vector network analyzer (VNA; Tektronix TTR506A) to continuously monitor resonant frequency. The resonant frequency was recorded by locating the minimum in the S11 parameter. It was observed that the resistance of the strain sensor remained unchanged during cyclic bending.
Various characteristics of the sensor were evaluated, including response rate, stability, flexibility.
Capacitance Change Dynamics.
Response time.
Stability.
Flexibility.
The resonant frequency of the wireless stent and sensor system was measured with a vector network analyzer (VNA) monitoring the S11 parameter. The resonant frequency was identified as the frequency where the S11 parameter is at a minimum.
Wireless signal.
The study also evaluated the effects of the walls. It was observed that a thicker wall tubing could show less strain at a given pressure as compared to a thinner wall tubing.
Restenosis Sensing in Artery Model with Sensors Integrated in a Stent
To implant the sensor (1000) into arteries, the study evaluated the implantation of the integrated stent and sensor (1000) using compatible conventional catheterization procedures.
Artery Model. A coronary artery model (1108) was formed by molding silicone (Ecoflex 00-30, Smooth-On). The mold formed an artery with a 3 mm inner diameter, 2 mm thickness, and 100 mm length. Restenosis models included restenosis of 60%, 75%, or 90% at the center of the artery model. To simulate blood viscosity and flow, a 58.5 to 41.5 mixture of water to glycerin was flowed through the artery model (1108) with a pulsatile pump (Harvard Apparatus). A flow rate of 60 mL min−1 at 60 b.p.m. was used to compare sensor signals at different levels of restenosis. The sensor and stent were embedded in the silicone artery model, which is consistent with typical tissue growth over implanted stents. Wired and wireless signals from the sensor were acquired with the LCR meter and VNA, respectively. For restenosis detection, the amplitude of capacitance or resonance changes were compared at each restenosis case and normalized to the amplitude recorded in the normal artery.
Results.
Overall, the artery model validated the use of arterial stiffness sensing and wireless electronics to quantify clinically relevant stages of restenosis. This aspect of the study demonstrated a stent-based arterial stiffness sensor and wireless arterial stiffness sensing [28, 32, 34-36]. By integrating a wireless stent platform with the enhanced soft, capacitive strain sensor, wireless arterial stiffness sensing was achieved while enabling minimally invasive implantation via a catheter. The sensor of the exemplary system can quantify restenosis and offers broader potential for cardiovascular health monitoring.
Table 2. Comparison of implantable sensors for restenosis, occlusion, and arterial stiffness monitoring.
1 Sensitivity is determined from a scaled sensor signal related to photodetector output voltage.
2 Measured stiffness changes from the administration of dopamine.
3 Strain sensor is characterized by comparing capacitance changes with arterial pressure.
4 Device implanted in a graft and then implanted using a bypass procedure.
5 Measured a signal change from a healthy artery to a fully occluded artery.
An ex-vivo study was conducted with ovine hearts that demonstrated the sensing of stiffness changes in soft arteries.
Ex-Vivo Restenosis Monitoring. Ovine hearts were collected for the implantation of stents and sensors into the coronary arteries. A pulsatile pump was connected to the arteries via tubing to enable blood flow. Both a water and glycerin mixture and ovine blood were used for fluid flow in the coronary arteries. Restenosis was simulated by adding silicone (Ecoflex 00-20, Smooth-On) within the artery near the implanted sensor. An LCR meter and VNA were used to measure wired and wireless signals.
Results.
In
Hemocompatibility and Biocompatibility Tests. For the hemocompatibility tests, citrated fresh ovine whole blood was distributed into a vacutainer tube where samples were placed for 2 hours at 37° C. Platelet deposition was quantified by lactate dehydrogenase assay. Biocompatibility was evaluated with rat vascular smooth muscles cells by an indirect contact method for 24 h. Cell viability was analyzed with an MTS assay. Data were normalized to the negative control, which included cells cultured in cell medium only. Cell death was induced in the positive control with 1 M acrylamide dissolved in the cell culture medium.
Discussion
Atherosclerosis, where arteries narrow as artery walls thicken and stiffen, is a leading cause of cardiovascular diseases [1, 2]. In total, cardiovascular diseases are the most common cause of death and account for 31% of deaths [3]. Atherosclerosis can lead to a variety of conditions, including myocardial infarctions, angina, strokes, aneurysms, and gangrene, among others [1]. A common treatment of atherosclerosis is angioplasty and stenting, where the narrowed artery is widened with a balloon catheter and then held open with a stent [4, 5]. Although several million stents are implanted per year, a frequent complication of stenting is restenosis, where the treated artery narrows and stiffens again [6-9]. Restenosis is often defined as a lumen reduction of at least 50% to 70% with varying degrees of severity [10-12]. Restenosis progresses gradually and often causes no symptoms until the blockage becomes severe. While recent advances in drug-eluting stents have reduced restenosis rates to less than 10%, affordability and complication concerns exist for drug-eluting stents [7, 9, 13-15]. Thus, bare metal stents are still often used and have shown restenosis in 17% to 41% of treatments [8, 9]. Notably, restenosis correlates with morbidity and a study has previously indicated restenosis as a predictor of 4 year mortality [12, 16]. Moreover, restenosis may be a risk factor of stent thrombosis, a rarer condition where an acute occlusion occurs of the stented artery [17]. While stent thrombosis occurs in approximately 1% of patients, it shows a mortality rate of up to 45% [18, 19]. Despite the high prevalence of restenosis, monitoring methods are limited to imaging techniques or catheterization, such as angiography, intravascular ultrasound, optical coherence tomography, and catheter-based measurements [12]. Follow-ups occur at varying intervals of time, and, as a result, the progression of restenosis is incompletely monitored. Continuous monitoring would enable early detection and prevention of complications, especially since it has been shown that restenosis rates vary by patient, stent properties, and type of intervention [12, 20].
Continuous, non-invasive monitoring of restenosis enabled by implantable electronics would allow early detection and management of patient health and provide a better understanding of stent designs to minimize restenosis. However, the development of implantable vascular electronics has been restricted due to stringent requirements associated with implantation and operation within soft, narrow arteries. Requirements include a miniaturized, low-profile structure to minimize the impact on blood flow, soft, flexible mechanics to interface with compliant arterial walls, and wireless sensing. Recent advances in soft, wireless electronics offer solutions for the design of implantable vascular sensors [21-29]. Multiple prior works have developed implantable vascular sensors for monitoring blood pressure, and a few have incorporated monitoring of blood flow [26, 28, 30-32]. These works have developed both stent-based sensors and sensors wrapped around the outside of an artery. While some stent-based devices apply a single pressure sensor with a target of monitoring occlusion, it cannot measure the fractional flow reserve (FFR) for restenosis or arterial distensibility [25, 28]. FFR is a widely used measurement to determine the significance of the blockage and is measured by recording pressure both upstream and downstream of restenosis [12, 33]. One work employed two pressure sensors to measure FFR but relies on x-ray imaging to read the sensor [32].
Alternatively to blood pressure monitoring, measuring arterial stiffness or distensibility offers a more direct means to quantify restenosis. As restenosis progresses, artery walls thicken and stiffen, decreasing arterial strain and distensibility. In a similar concept, prior works have investigated sensors to detect the expansion and contraction of arterial walls during blood flow [25, 34-36]. These prior works have developed wireless pressure sensors to be wrapped around the artery to detect arterial occlusion [25, 35]. Additionally, strain sensors, including a capacitive sensor and photonic sensor, have been studied for wrapping around an artery to measure response to blood pressure [34, 36]. While these wrapped sensors demonstrate detection of an occlusion, implantation would be significantly more invasive than conventional catheterization procedures. Moreover, the prior wireless sensors do not demonstrate the ability to quantify restenosis or arterial stiffness and, thus, an implantable device is lacking [25, 35]. Beyond restenosis, an arterial stiffness sensor would offer a broad impact on vascular sensing since arterial stiffness is a significant biomarker of cardiovascular disease and mortality [37-40]. Studies have demonstrated arterial stiffening as a warning sign of cardiovascular morbidity and mortality and is an independent predictor of cardiovascular diseases, including hypertension, atherosclerosis, coronary artery disease, strokes, and heart failures [37-40]. Arterial stiffening is also associated with a heightened risk of organ damage, including to the kidneys and brain, due to the effect on blood flow and pressure [37]. Thus, an arterial stiffness sensor could be readily extended to broader applications, such as continuously monitoring local arterial stiffness to understand the role of arterial stiffness further and as a preventative measure of cardiovascular diseases [41].
In contrast, the instant wireless, soft arterial stiffness sensor electronics may comprise a soft capacitive strain sensor and an electronic stent to monitor arterial stiffness changes stemming from restenosis. The stent-based device is deployable by conventional balloon catheters for minimally invasive implantation and offers unobtrusive sensing of arterial wall strain changes during blood flow. The aerosol jet printed, nanomaterial-based soft strain sensor may employ a sliding mechanism that is investigated and optimized to enhance sensitivity compared to existing soft, capacitive strain sensors. The highly flexible, nanomembrane strain sensor may be integrated onto a multi-material, inductive antenna stent to enable wireless sensing via inductive coupling. The wireless vascular device is demonstrated in a biomimetic coronary artery model to detect restenosis progression. An ex-vivo study with ovine hearts demonstrates restenosis sensing in narrow coronary arteries.
Some references, which may include various patents, patent applications, and publications, are cited in a reference list and discussed in the disclosure provided herein. The citation and/or discussion of such references is provided merely to clarify the description of the disclosed technology and is not an admission that any such reference is “prior art” to any aspects of the disclosed technology described herein. In terms of notation, “[n]” corresponds to the nth reference in the reference list. For example, Ref. [1] refers to the 1st reference in the list. 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.
Moreover, the various components may be in communication via wireless and/or hardwire or other desirable and available communication means, systems, and hardware. Moreover, various components and modules may be substituted with other modules or components that provide similar functions.
Although example embodiments of the present disclosure are explained in some instances in detail herein, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the present disclosure be limited in its scope to the details of construction and arrangement of components set forth in the following description or illustrated in the drawings. The present disclosure is capable of other embodiments and of being practiced or carried out in various ways.
It must also be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” or “5 approximately” one particular value and/or to “about” or “approximately” another particular value. When such a range is expressed, other exemplary embodiments include from the one particular value and/or to the other particular value.
By “comprising” or “containing” or “including” is meant that at least the name compound, element, particle, or method step is present in the composition or article or method, but does not exclude the presence of other compounds, materials, particles, method steps, even if the other such compounds, material, particles, method steps have the same function as what is named.
In describing example embodiments, terminology will be resorted to for the sake of clarity. It is intended that each term contemplates its broadest meaning as understood by those skilled in the art and includes all technical equivalents that operate in a similar manner to accomplish a similar purpose. It is also to be understood that the mention of one or more steps of a method does not preclude the presence of additional method steps or intervening method steps between those steps expressly identified. Steps of a method may be performed in a different order than those described herein without departing from the scope of the present disclosure. Similarly, it is also to be understood that the mention of one or more components in a device or system does not preclude the presence of additional components or intervening components between those components expressly identified.
The term “about,” as used herein, means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10%. In one aspect, the term “about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%. Numerical ranges recited herein by endpoints include all numbers and fractions subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, 4.24, and 5).
Similarly, numerical ranges recited herein by endpoints include subranges subsumed within that range (e.g., 1 to 5 includes 1-1.5, 1.5-2, 2-2.75, 2.75-3, 3-3.90, 3.90-4, 4-4.24, 4.24-5, 2-5, 3-5, 1-4, and 2-4). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term “about.”
The following patents, applications, and publications as listed below and throughout this document are hereby incorporated by reference in their entirety herein.
This PCT International Application claims priority to, and the benefit of, U.S. Provisional Patent Application No. 63/156,466, filed Mar. 4, 2021, entitled “Nano-Sensor-Embedded Stent System and Method,” which is incorporated by reference herein in its entirety.
This invention was made with government support under NIH R03EB028928 awarded by the National Institutes of Health, as well as grant ECCS-2025462 supported by the National Science Foundation (NSF). The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/019009 | 3/4/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63156466 | Mar 2021 | US |
