Patent Application
20240269473
The present invention relates generally to healthcare, and more particularly to a bioresorbable, leadless, battery-free, and fully implantable cardiovascular instruments for control of cardiac rate and rhythm during a stable operating timeframe that subsequently undergoes complete dissolution and clearance via natural biological processes.
The background description provided herein is for the purpose of generally presenting the context of the invention. The subject matter discussed in the background of the invention section should not be assumed to be prior art merely as a result of its mention in the background of the invention section. Similarly, a problem mentioned in the background of the invention section or associated with the subject matter of the background of the invention section should not be assumed to have been previously recognized in the prior art. The subject matter in the background of the invention section merely represents different approaches, which in and of themselves may also be inventions. Work of the presently named inventors, to the extent it is described in the background of the invention section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the invention.
Implantable permanent cardiac pacemakers are the cornerstone of therapy for bradyarrhythmias and atrioventricular (AV) block. As a complement to traditional pacemakers designed as permanent implants, temporary systems provide essential demand-based atrial and/or ventricular pacing for patients where bradyarrhythmias and AV block are expected to be short-lived, such as on the orders of days or weeks. Such devices act as a bridge to permanent pacing therapy or are implemented temporarily following cardiac surgery when post-surgical bradycardia is frequently encountered. Temporary pacing systems include an external generator with one or two transcutaneous pacing leads that are placed, depending on the clinical context, either epicardially or endocardially via a transvenous approach. This hardware, however, carries significant risks of complications. First, bacteria can form biofilms on the foreign materials/devices such as pacing leads, and the transcutaneous access can serve as a route for infections. Second, because the device is not fully implanted, the externalized power supply and control system can be inadvertently dislodged when caring for or mobilizing the patient. Third, removal of temporary transcutaneous devices following completion of therapy can cause laceration and perforation of the myocardium since the pacing leads can become enveloped in fibrotic tissue at the electrode-myocardium interface. These circumstances create a unique need for an alternative temporary pacemaker technology that can deliver the necessary electrotherapy while addressing the associated physiological complications.
In one aspect, the invention relates to a device implantable on a target of interest of a subject for pacemaker, cardiac neuromodulation, and/or defibrillator therapy. In one embodiment, the device comprises a wireless power harvesting unit comprising an antenna for delivering electrical stimuli to the target of interest; and a pair of electrodes, each electrode having a first end electrically connecting to the wireless power harvesting unit and a second end attachable to the target of interest.
In one embodiment, the antenna comprises a loop antenna having at least one coil.
In one embodiment, the loop antenna is in a bilayer, dual-coil configuration having two coils electrically connected to one another in series and a dielectric interlayer positioned between the two coils.
In one embodiment, the dielectric interlayer comprises one or more of poly(lactide-co-glycolide) (PLGA), polyurethane, polyanhydride, and poly(dimethyl siloxane) (PDMS).
In one embodiment, the dielectric interlayer has a thickness in a range of about 1-800 μm.
In one embodiment, each of the two coils is formed of a metallic conductive material comprising magnesium (Mg), tungsten (W), molybdenum (Mo), iron (Fe), and/or zinc (Zn) in a single-layered structure or a multiple-layered structure, or an alloy thereof.
In one embodiment, each of the two coils comprises a two-layered structure of tungsten-coated magnesium (W/Mg).
In one embodiment, the two coils have a width in a range of about 200 nm-500 μm, and a thickness in a range of about 1-800 μm.
In one embodiment, the wireless power harvesting unit further comprises a radiofrequency (RF) PIN diode electrically coupled between the antenna and one of the pair of electrodes.
In one embodiment, the RF PIN diode comprises a doped polycrystalline or monocrystalline semiconductor material, or a two-dimensional semiconductor material, or a combination of them.
In one embodiment, the two-dimensional semiconductor material comprises transition metal dichalcogenides, and/or hexagonal boron nitride.
In one embodiment, the doped polycrystalline or monocrystalline semiconductor material comprises silicon (Si), gallium (Ga), gallium arsenide (GaAs), and/or zinc oxide (ZnO).
In one embodiment, the RF PIN diode comprises a doped monocrystalline silicon nanomembrane (Si NM) having a thickness in a range of about 20-1000 nm.
In one embodiment, the RF PIN diode is configured such that a layout of RF PIN diode tomography allows for a capacitor-free rectifier with high efficiency to realize improved power transfer to the device.
In one embodiment, the wireless power harvesting unit further comprises interconnections electrically connecting the PIN diode to the antenna and said electrode.
In one embodiment, the interconnections are formed of a composite paste comprising conductive particles including W and/or Mo, or a two-dimensional conductive material such as MXenes, or a combination of them.
In one embodiment, the pair of electrodes is flexible, such that the electrode length and/or the distance between the pair of electrodes are adjustable.
In one embodiment, the second end of each electrode includes a contact pad for attaching said electrode to the target of interest.
In one embodiment, the pair of electrodes is of a metallic conductive material comprising Mg, W, Mo, Fe, and/or Zn in a single-layered structure or a multiple-layered structure, or an alloy thereof.
In one embodiment, the device further comprises an encapsulation structure surrounding the device.
In one embodiment, the encapsulation structure comprises one or more of top and bottom layers formed of PLGA, polyurethane, polyanhydride, and/or PDMS.
In one embodiment, the encapsulation layer has a thickness in a range of about 50-500 μm.
In one embodiment, the contact pad is at least partially exposed from the encapsulation structure, so that when sutured, said electrode is in contact with the target of interest.
In one embodiment, the device is configured to be eliminable completely from the target of interest of the subject through natural chemical/biochemical processes of hydrolysis and/or metabolic actions, over a subsequent timeframe following completion of therapy.
In one embodiment, the device is compatible with computed tomography (CT) for non-invasive monitoring of the bioresorption process.
In one embodiment, the device is configured to be a thin, lightweight, flexible, bioresorbable, implantable, leadless cardiac pacemaker, cardiac neuromodulator, and/or defibrillator operating in a battery-free fashion and being externally controllable and programmable.
In another aspect, the invention relates to a device implantable on a target of interest of a subject for pacemaker and/or defibrillator therapy. The device comprises a wireless power harvesting unit configured to deliver power via resonant inductive coupling to the target of interest for stimulation in a manner that eliminates need for batteries and allows for externalized control without transcutaneous leads.
In one embodiment, the wireless power harvesting unit comprises a wireless receiver including one or more inductive coils, an RF PIN diode, and a dielectric interlayer that acts as a power harvester and control interface.
In one embodiment, in operation, electrical waveform is generated by an external waveform generator and transferred to the wireless receiver of the device, and the received waveform is transformed into a direct current output via the RF PIN diode to stimulate tissue of the target of interest.
In one embodiment, each of the one or more inductive coils is formed of a metallic conductive material comprising Mg, W, Mo, Fe, and/or Zn in a single-layered structure or a multiple-layered structure, or an alloy thereof.
In one embodiment, the RF PIN diode comprises a doped polycrystalline or monocrystalline semiconductor material, or a two-dimensional semiconductor material, or a combination of them.
In one embodiment, the two-dimensional semiconductor material comprises transition metal dichalcogenides, and/or hexagonal boron nitride.
In one embodiment, the doped polycrystalline or monocrystalline semiconductor material comprises Si, Ga, GaAs, and/or ZnO.
In one embodiment, the RF PIN diode comprises a doped monocrystalline silicon nanomembrane (Si NM).
In one embodiment, the device further comprises interconnections electrically connecting the one or more inductive coils to the RF PIN diode.
In one embodiment, the interconnections are formed of a composite paste comprising conductive particles including W and/or Mo, or a two-dimensional conductive material such as MXenes, or a combination of them.
In one embodiment, the device further comprises In one embodiment, each of the pair of flexible extension electrodes is formed of a metallic conductive material comprising Mg, W, Mo, Fe, and/or Zn in a single-layered structure or a multiple-layered structure, or an alloy thereof.
In one embodiment, each of the pair of flexible extension electrodes is provided with a contact pad at its distal end to the one or more inductive coils or the RF PIN diode for interfacing with tissue of the target of interest.
In one embodiment, the device further comprises an encapsulation structure surrounding the device, excluding the contact pad.
In one embodiment, the encapsulation structure comprises one or more of top and bottom layers formed of PLGA, polyurethane, polyanhydride, and/or PDMS.
In one embodiment, the device is flexible such that device dimensions are alterable by adjusting a length of the extension electrodes to meet requirements for a target application.
In one embodiment, the device has a miniaturized geometry that facilitates full implantation into the target of interest of the subject to eliminate the need for percutaneous hardware, thereby minimizing the risk of device-associated infections and dislodgement.
In one embodiment, the device is capable of effectively capturing and sustaining cardiac rhythms across different species and platforms.
In one embodiment, the device is eliminable completely from the target of interest of the subject through natural chemical/biochemical processes of hydrolysis and/or metabolic actions, over a subsequent timeframe following completion of therapy.
In one embodiment, the device is fully bioresorbable, implantable, leadless cardiac pacemaker operating in a battery-free fashion and being externally controllable and programmable.
In yet another aspect, the invention relates to a method of making a leadless and battery-free cardiac pacemaker and/or defibrillator. The method in one embodiment comprises forming a wireless receiver; forming an RF PIN diode electrically coupled to the wireless receiver; forming a pair of flexible electrodes electrically connecting the wireless receiver and the RF PIN diode, respectively; and assembling the wireless receiver, the RF PIN diode and the flexible electrodes on a bioresorbable encapsulation structure comprising one or more of top and bottom layers formed of PLGA, polyurethane, polyanhydride, and PDMS.
In one embodiment, the wireless receiver comprises a loop antenna in a bilayer, dual-coil configuration having two inductive coils electrically connected to one another in series and a dielectric interlayer positioned between the two coils.
In one embodiment, each of the two inductive coils is formed of a metallic conductive material comprising Mg, W, Mo, Fe, and/or Zn in a single-layered structure or a multiple-layered structure, or an alloy thereof.
In one embodiment, the dielectric interlayer comprises one or more of PLGA, polyurethane, polyanhydride, and PDMS.
In one embodiment, said forming the wireless receiver comprises: defining Mg coil structures on a temporary substrate; depositing W on the Mg coil structures to form double-layered W/Mg coils; and transferring the double-layered W/Mg coils onto the dielectric interlayer to serve as the loop antenna for power harvesting
In one embodiment, said defining the Mg RF coil structure is performed by laser-cutting, and said depositing W on the Mg coil structures is performed by sputter coating.
In one embodiment, the RF PIN diode is formed of a doped polycrystalline or monocrystalline semiconductor material, or a two-dimensional semiconductor material, or a combination of them.
In one embodiment, the two-dimensional semiconductor material comprises transition metal dichalcogenides, and/or hexagonal boron nitride.
In one embodiment, the doped polycrystalline or monocrystalline semiconductor material comprises Si, Ga, GaAs, and/or ZnO.
In one embodiment, said forming the RF PIN diode comprises solid-state diffusion of boron and phosphorus through a photolithographically defined mask of SiO2 to yield the PIN RF diode with monocrystalline Si nanomembranes (Si NMs) derived from a Si-on-insulator wafer.
In one embodiment, said forming the RF PIN diode further comprises: removing buried oxide by immersion in hydrofluoric acid to release and transfer printing of the Si NMs onto a sacrificial layer of diluted poly(pyromellitic dianhydride co-4,4′-oxydianiline) (DPI) on a film of poly(methyl methacrylate) on the silicon wafer; photolithographic patterning and reactive ion etching to determine the lateral dimensions of the doped Si NMs for integration into the PIN diode; lift-off procedures applied with Mg deposited by electron beam evaporation to define electrical contacts; and spin casting an overcoat of DPI and dry etching through the underlying DPI and poly(methyl methacrylate) to define an open mesh layout, followed by immersion in acetone, to release the PIN diode for its transfer on the PLGA substrate.
In one embodiment, said forming the RF PIN diode further comprises oxygen reactive ion etching to remove the DPI layer during/after the transfer printing.
In one embodiment, said forming electrodes comprises laser-cutting a piece of Mg foil into the electrodes.
In one aspect, the invention relates to a method of transcutaneous pacing a target of interest of a subject for pacemaker and/or defibrillator therapy. The method comprises implanting a device in the target of interest, wherein the device comprises a wireless power harvesting unit comprising a receiver antenna for receiving electrical stimuli, and a pair of electrodes electrically coupled to the wireless power harvesting unit for delivering the electrical stimuli from the receiver antenna to the target of interest; and wirelessly transmitting the electrical stimuli to the receiver antenna. The electrical stimuli are delivered by the implanted device to pace the target of interest at frequency, rate, stimulation strength, and/or time period that are adjustable based on the need of the pacemaker, neuromodulator, and/or defibrillator therapy.
In one embodiment, the electrical stimuli are adapted such that the implanted device operates at a minimum power that can pace the target of interest in order to minimize voltage-induced electroporation damage to the target of interest and to limit electrochemical degradation of the electrodes.
In one embodiment, said transmitting the electrical stimuli is performed by an external transmitter antenna that is placed at a distance from the receiver antenna of the implanted device.
In one embodiment, the distance between the external transmitter antenna and the receiver antenna of the implanted device is up to about 50 cm.
In one embodiment, the external transmitter antenna and the receiver antenna are optimized for operation at a fixed input frequency in a range of about 10-15 Mhz, preferably about 13.56 MHz.
In one embodiment, the wireless power harvesting unit further comprises a radiofrequency (RF) PIN diode electrically coupled to the receiver antenna for rectifying the received electrical stimuli to DC-like pulses that are delivered by the pair of electrodes to the target of interest.
In one embodiment, the device is eliminable completely from the target of interest of the subject through natural chemical/biochemical processes of hydrolysis and/or metabolic actions, over a subsequent timeframe following completion of therapy.
In one embodiment, the device is fully bioresorbable, implantable, leadless cardiac pacemaker operating in a battery-free fashion and being externally controllable and programmable.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Temporary cardiac pacemakers provide critical functions in pacing through periods of need during post-surgical recovery. The percutaneous leads and externalized hardware associated with these systems present, however, risks of infection and constraints on patient mobility. Furthermore, the pacing leads can become enveloped in fibrotic tissue at the electrode-myocardium interface, which thereby increases the potential for myocardial damage and perforation during lead removal.
One of the objectives of the invention is to provide a bioresorbable, leadless, and fully implantable cardiac pacemaker for post-operative control of cardiac rate and rhythm during a stable operating timeframe that subsequently undergoes complete dissolution and clearance via natural biological processes. A combined set of in vitro, ex vivo, and in vivo studies across mouse, rat, rabbit, canine, and human cardiac models demonstrates that these devices provide an effective, battery-free means for pacing hearts of various sizes with tailored geometries and timescales for operation and bioresorption. These features enable programmable cardiac pacing in a manner that overcomes all of the key disadvantages of traditional temporary pacing devices. As such, this novel cardiac pacemaker may serve as the basis for the next generation of post-operative temporary pacing technology.
In one aspect, the invention relates to a device implantable on a target of interest of a subject for pacemaker neuromodulator, and/or defibrillator therapy. Neuromodulation targets autonomic nervous system aiming to prevent heart diseases such as heart failure and arrhythmias. In some embodiments, the device comprises a wireless power harvesting unit comprising an antenna for delivering electrical stimuli to the target of interest; and a pair of electrodes, each electrode having a first end electrically connecting to the wireless power harvesting unit and a second end attachable to the target of interest.
In some embodiments, the antenna comprises a loop antenna having at least one coil. In some embodiments, the loop antenna is in a bilayer, dual-coil configuration having two inductive coils electrically connected to one another in series and a dielectric interlayer positioned between the two coils.
In some embodiments, each of the two inductive coils is formed of a metallic conductive material comprising magnesium (Mg), tungsten (W), molybdenum (Mo), iron (Fe), and/or zinc (Zn) in a single-layered structure or a multiple-layered structure, or an alloy thereof. In some embodiments, each of the two coils comprises a two-layered structure of tungsten-coated magnesium (W/Mg). In some embodiments, the two coils have a width in a range of about 200 nm-500 μm, and a thickness in a range of about 1-800 μm.
In some embodiments, the dielectric interlayer comprises one or more of poly(lactide-co-glycolide) (PLGA), polyurethane, polyanhydride, and poly(dimethyl siloxane) (PDMS). In some embodiments, the dielectric interlayer has a thickness in a range of about 1-800 μm.
In some embodiments, the wireless power harvesting unit further comprises a radiofrequency (RF) PIN diode electrically coupled between the antenna and one of the pair of electrodes.
In some embodiments, the RF PIN diode comprises a doped polycrystalline or monocrystalline semiconductor material, or a two-dimensional semiconductor material, or a combination of them. In some embodiments, the two-dimensional semiconductor material comprises transition metal dichalcogenides, and/or hexagonal boron nitride. Transition-metal dichalcogenides are atomically thin semiconductors of the type MX2, with M a transition-metal atom (Mo, W, etc.) and X a chalcogen atom (S, Se, or Te), e.g., MoS2, WS2, MoSe2, WSe2, MoTe2, where one layer of M atoms is sandwiched between two layers of X atoms.
In some embodiments, the doped polycrystalline or monocrystalline semiconductor material comprises silicon (Si), gallium (Ga), gallium arsenide (GaAs), and/or zinc oxide (ZnO). In some embodiments, the RF PIN diode comprises a doped monocrystalline silicon nanomembrane (Si NM) having a thickness in a range of about 20-1000 nm.
In some embodiments, the RF PIN diode is configured such that a layout of RF PIN diode tomography allows for a capacitor-free rectifier with high efficiency to realize improved power transfer to the device.
In some embodiments, the wireless power harvesting unit further comprises interconnections electrically connecting the PIN diode to the antenna and said electrode. In some embodiments, the interconnections are formed of a composite paste comprising conductive particles including W and/or Mo, or a two-dimensional conductive material such as MXenes, or a combination of them. MXenes are a class of two-dimensional inorganic compounds. These materials include a-few-atoms-thick layers of transition metal carbides, nitrides, or carbonitrides.
In some embodiments, the pair of electrodes is flexible, such that the electrode length and/or the distance between the pair of electrodes are adjustable, whereby the device is flexible such that device dimensions are alterable by adjusting a length of the extension electrodes to meet requirements for a target application.
In some embodiments, the second end of each electrode includes a contact pad for attaching said electrode to the target of interest. In some embodiments, the pair of electrodes is of a metallic conductive material comprising Mg, W, Mo, Fe, and/or Zn in a single-layered structure or a multiple-layered structure, or an alloy thereof.
In some embodiments, the device further comprises an encapsulation structure surrounding the device. In some embodiments, the encapsulation structure comprises one or more of top and bottom layers formed of PLGA, polyurethane, polyanhydride, and/or PDMS. In some embodiments, the encapsulation layer has a thickness in a range of about 50-500 μm.
In some embodiments, the contact pad is at least partially exposed from the encapsulation structure, so that when sutured, said electrode is in contact with the target of interest.
In some embodiments, the device has a miniaturized geometry that facilitates full implantation into the target of interest of the subject to eliminate the need for percutaneous hardware, thereby minimizing the risk of device-associated infections and dislodgement.
In some embodiments, the device is capable of effectively capturing and sustaining cardiac rhythms across different species and platforms.
In some embodiments, the device is eliminable completely from the target of interest of the subject through natural chemical/biochemical processes of hydrolysis and/or metabolic actions, over a subsequent timeframe following completion of therapy.
In some embodiments, the device is compatible with computed tomography (CT) for non-invasive monitoring of the bioresorption process.
In some embodiments, the device is configured to be a thin, lightweight, flexible, bioresorbable, implantable, leadless cardiac pacemaker and/or defibrillator operating in a battery-free fashion and being externally controllable and programmable.
In another aspect, the invention relates to a method of making a leadless and battery-free cardiac pacemaker and/or defibrillator. The method in one embodiment comprises forming a wireless receiver; forming an RF PIN diode electrically coupled to the wireless receiver; forming a pair of flexible electrodes electrically connecting the wireless receiver and the RF PIN diode, respectively; and assembling the wireless receiver, the RF PIN diode and the flexible electrodes on a bioresorbable encapsulation structure comprising one or more of top and bottom layers formed of PLGA, polyurethane, polyanhydride, and PDMS.
In some embodiments, the wireless receiver comprises a loop antenna in a bilayer, dual-coil configuration having two inductive coils electrically connected to one another in series and a dielectric interlayer positioned between the two coils. In some embodiments, each of the two inductive coils is formed of a metallic conductive material comprising Mg, W, Mo, Fe, and/or Zn in a single-layered structure or a multiple-layered structure, or an alloy thereof. In some embodiments, the dielectric interlayer comprises one or more of PLGA, polyurethane, polyanhydride, and PDMS.
In some embodiments, said forming the wireless receiver comprises: defining Mg coil structures on a temporary substrate; depositing W on the Mg coil structures to form double-layered W/Mg coils; and transferring the double-layered W/Mg coils onto the dielectric interlayer to serve as the loop antenna for power harvesting
In some embodiments, said defining the Mg RF coil structure is performed by laser-cutting, and said depositing W on the Mg coil structures is performed by sputter coating.
In some embodiments, the RF PIN diode is formed of a doped polycrystalline or monocrystalline semiconductor material, or a two-dimensional semiconductor material, or a combination of them. In some embodiments, the two-dimensional semiconductor material comprises transition metal dichalcogenides, and/or hexagonal boron nitride. In some embodiments, the doped polycrystalline or monocrystalline semiconductor material comprises Si, Ga, GaAs, and/or ZnO.
In some embodiments, said forming the RF PIN diode comprises solid-state diffusion of boron and phosphorus through a photolithographically defined mask of SiO2 to yield the PIN RF diode with monocrystalline Si nanomembranes (Si NMs) derived from a Si-on-insulator wafer.
In some embodiments, said forming the RF PIN diode further comprises: removing buried oxide by immersion in hydrofluoric acid to release and transfer printing of the Si NMs onto a sacrificial layer of diluted poly(pyromellitic dianhydride co-4,4′-oxydianiline) (DPI) on a film of poly(methyl methacrylate) on the silicon wafer; photolithographic patterning and reactive ion etching to determine the lateral dimensions of the doped Si NMs for integration into the PIN diode; lift-off procedures applied with Mg deposited by electron beam evaporation to define electrical contacts; and spin casting an overcoat of DPI and dry etching through the underlying DPI and poly(methyl methacrylate) to define an open mesh layout, followed by immersion in acetone, to release the PIN diode for its transfer on the PLGA substrate.
In some embodiments, said forming the RF PIN diode further comprises oxygen reactive ion etching to remove the DPI layer during/after the transfer printing.
In some embodiments, said forming electrodes comprises laser-cutting a piece of Mg foil into the electrodes.
In one aspect, the invention relates to a method of transcutaneous pacing a target of interest of a subject for pacemaker and/or defibrillator therapy. The method comprises implanting a device in the target of interest, wherein the device comprises a wireless power harvesting unit comprising a receiver antenna for receiving electrical stimuli, and a pair of electrodes electrically coupled to the wireless power harvesting unit for delivering the electrical stimuli from the receiver antenna to the target of interest; and wirelessly transmitting the electrical stimuli to the receiver antenna. The electrical stimuli are delivered by the implanted device to pace the target of interest at frequency, rate, stimulation strength, and/or time period that are adjustable based on the need of the pacemaker and/or defibrillator therapy. In some embodiments, the device is eliminable completely from the target of interest of the subject through natural chemical/biochemical processes of hydrolysis and/or metabolic actions, over a subsequent timeframe following completion of therapy. In some embodiments, the device is fully bioresorbable, implantable, leadless cardiac pacemaker operating in a battery-free fashion and being externally controllable and programmable.
In some embodiments, the electrical stimuli are adapted such that the implanted device operates at a minimum power that can pace the target of interest in order to minimize voltage-induced electroporation damage to the target of interest and to limit electrochemical degradation of the electrodes.
In some embodiments, said transmitting the electrical stimuli is performed by an external transmitter antenna that is placed at a distance from the receiver antenna of the implanted device.
In some embodiments, the distance between the external transmitter antenna and the receiver antenna of the implanted device is up to about 50 cm.
In some embodiments, the external transmitter antenna and the receiver antenna are optimized for operation at a fixed input frequency in a range of about 10-15 Mhz, preferably about 13.56 MHz.
In some embodiments, the wireless power harvesting unit further comprises an RF PIN diode electrically coupled to the receiver antenna for rectifying the received electrical stimuli to DC-like pulses that are delivered by the pair of electrodes to the target of interest.
These and other aspects of the present invention are further described below. Without intent to limit the scope of the invention, exemplary instruments, apparatus, methods and their related results according to the embodiments of the present invention are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the invention. Moreover, certain theories are proposed and disclosed herein; however, in no way they, whether they are right or wrong, should limit the scope of the invention so long as the invention is practiced according to the invention without regard for any particular theory or scheme of action.
This exemplary example discloses a bioresorbable, leadless, and fully implantable cardiac pacemaker for post-operative control of cardiac rate and rhythm during a stable operating timeframe that subsequently undergoes complete dissolution and clearance via natural biological processes. A combined set of in vitro, ex vivo, and in vivo studies across mouse, rat, rabbit, canine, and human cardiac models demonstrates that these devices provide an effective, battery-free means for pacing hearts of various sizes with tailored geometries and timescales for operation and bioresorption. These features enable programmable cardiac pacing in a manner that overcomes all of the key disadvantages of traditional temporary pacing devices. As such, this novel cardiac pacemaker may serve as the basis for the next generation of post-operative temporary pacing technology.
The fully bioresorbable, implantable, leadless cardiac pacemaker operates in a battery-free fashion and is externally controlled and programmable. The device relies exclusively on materials that resorb when exposed to biofluids in a time-controlled manner via metabolic action and hydrolysis. The materials and design choices create a thin, flexible, and lightweight form that maintain excellent biocompatibility and stable function throughout a desired period of use. Over a subsequent timeframe following the completion of therapy, the devices disappear completely through natural biological processes. Wireless energy transfer via resonant inductive coupling delivers power to the system in a manner that eliminates the need for batteries and allows for externalized control without transcutaneous leads. These characteristics and a miniaturized geometry facilitate full implantation into the body to eliminate the need for percutaneous hardware, which thereby minimizes the risk of device-associated infections and dislodgement. A set of systematic animal studies reported below highlights aspects in bioresorbability, biocompatibility, and electrical functionality of this type of temporary pacemaker technology. The device can effectively capture and sustain cardiac rhythms across different species and platforms, including human cardiac slices and mouse, rat, rabbit, and canine hearts. Demonstrations in mouse models illustrate capabilities in the treatment of atrioventricular (AV) nodal heart block, a common indication for pacemaker therapy. In vivo tests with canine models suggest the feasibility of this pacemaker system for adult human patients. Device implantation in rats highlights functionality for several days without degradation followed by complete resorption within 3 months. Taken together, these results establish the foundations for a bioresorbable electronics technology designed to address unmet needs in important areas of care for cardiac patients.
Preparation of bioresorbable components and integration into leadless and battery-free cardiac pacemakers. Laser-cutting defined the Mg (50 μm thick; Solution Materials) radio frequency (RF) coil structures on temporary substrates of poly(dimethylsiloxane) (PDMS, 9:1). A sputter coating of W (700 nm thick) deposited on the Mg coil improves the contrast in CT images to allow for non-invasive imaging of the bioresorption process. The double-layered W/Mg RF coil was transferred onto a substrate of PLGA (65:35 (lactide:glycolide); Sigma-Aldrich) to serve as a receiving antenna for the power harvesting unit. Solid-state diffusion of boron (tube furnace at 1,050° C. with N2 flow) and phosphorus (tube furnace at 1,000° C. with N2 flow) through a photolithographically defined mask of SiO2 formed by plasma-enhanced chemical vapor deposition yielded PIN RF diodes with monocrystalline Si nanomembranes (Si NMs) derived from a Si-on-insulator wafer (top silicon ˜320 nm thick, p-type; Soitec). Removing the buried oxide by immersion in hydrofluoric acid allowed release and transfer printing of the Si NMs onto a sacrificial layer of diluted poly(pyromellitic dianhydride co-4,4′-oxydianiline) (DPI; ˜200 nm) on a film of poly(methyl methacrylate) (˜300 nm) on a silicon wafer. Photolithographic patterning and reactive ion etching determined the lateral dimensions of the doped Si NMs for integration into the PIN diodes. Lift-off procedures applied with Mg deposited by electron beam evaporation (˜300 nm thick; Kurt J. Lesker Company) defined the electrical contacts. Spin casting an overcoat of DPI and dry etching through the underlying DPI and poly(methyl methacrylate) to define an open mesh layout, followed by immersion in acetone, released the PIN diodes and allowed their transfer on the PLGA substrate (˜50 μm thick). Oxygen reactive ion etching removed the DPI layers during/after the transfer printing. Finally, these bioresorbable components (RF coil, PIN diode) were collected on a PLGA substrate and electrically interconnected with a biodegradable conductive W paste. Covering the coils with PLGA and stacking the system yielded a compact, double coil structure with openings for interconnections. In addition, laser-cutting a piece of Mg foil (50 μm thick) into 150-μm-wide electrodes and embedding them in PLGA produced electrical extension to the pads for the cardiac tissue interface.
Electric field distribution in heart tissue. Finite element analysis (FEA) was implemented on the commercial software COMSOL 5.2a by using the electrical current module (AC/DC Module User's Guide) to determine the electric field distribution in the heart tissue for voltages applied to magnesium electrodes with thicknesses of 50 μm. The partial differential equation for the current is
where Qj is the current source and J is the current defined as J=σE. The electric field is given by E=−∇V, where σ is the electric conductivity and V is the electric potential in the electrode pads. The effective volume, i.e., volume with an electric field >100 mV/mm shown in panels b-c of
Simulation of mechanical characteristics. Commercial FEA software (ABAQUS, Analysis User's Manual 2016) was used to study the mechanical behaviors of the flexible Mg electrodes after deformations of physiological relevance, i.e., those associated with the surface of the heart. The electrode can experience up to ˜20% compression before the strain in the metal layer reaches the yield strain (0.6%) and initiates plastic deformation (
Electromagnetic simulation. The commercial software package ANSYS HFSS (ANSYS) was used to perform electromagnetic (EM) finite element analysis to 1) determine the inductance, Q factor, and scattering parameters S11, and S21 of the bioresorbable implantable double-layer Rx coils with outer diameters of 8 mm, 12 mm, 18 mm, and 25 mm and its corresponding matching Tx coil of the same diameter and 2) quantify the influence of Rx and Tx coil size on the power transfer efficiency and output voltage. The receiver coils with outer diameters of 8 mm, 12 mm, 18 mm, and 25 mm are tuned to operate at a resonant frequency f of 17.3 MHz, 13.91 MHz, 8.03 MHZ, and 4.24 MHz respectively, where the Q factor is maximum (panel b of
and the output voltage V can be calculated as
where VS and RS are the input voltage and resistance at the source and RL is the resistance of the load in the Rx coil. The relationship between power transfer efficiency and working distance was calculated for a separation of 1-30 mm (panel d of
In vivo studies of rat models. All procedures were performed according to protocols (A364) approved by The George Washington University Institutional Animal Care and Use Committee (IACUC) and conforming with guidance from the Guide for Care and Use of Laboratory Animals published by the National Institutes of Health (NIH). Adult male and female Sprague-Dawley rats (Hilltop Animals, Scottsdale, PA) were used. All procedures were performed under general anesthesia using inhaled isoflurane vapors (1-3%). Throughout the surgery, ventilation was provided by the VentElite small animal ventilator (Harvard Apparatus, Holliston, MA). The heart was exposed via left thoracotomy, and the pacemaker electrodes were implanted on the myocardial surface of the left ventricle using 6-0 non-resorbable monofilament sutures. The pacemaker receiver was placed within the subcutaneous pocket on the ventral surface of the rat. Subsequent layers of thoracic cavity, muscle, and skin were closed. Pacemakers were tested at the end of the procedure to verify their function and confirm adequate placement. Animals were then taken off of general anesthesia and allowed to recover. Appropriate post-operative monitoring and care were provided following surgery. For analgesia, an intraperitoneal dose of buprenorphine (0.5-1.0 mg/kg) was administered before incision and once every 12 hours for 48 hours following surgery.
Optical mapping of whole heart cardiac pacing. All procedures were performed according to protocols (Mouse: A367; Rat: A364; Rabbit: A327) approved by The George Washington University Institutional Animal Care and Use Committee (IACUC). Optical mapping was performed on ex vivo mouse and rabbit hearts. For mice, the adult mice were anesthetized with isoflurane vapors. For rabbits, the adult rabbit was anesthetized using a mixture of 50 mg/kg ketamine and 10 mg/kg xylazine. The following procedure for optical mapping was performed for both mouse and rabbit hearts: Cessation of pain was confirmed by toe pinch, the heart was excised, and the aorta was cannulated in cardioplegic solution. The heart was then placed into a constant-pressure Langendorff system where the perfused solution was a modified Tyrode's solution (128.2 mM NaCl, 4.7 mM KCl, 1.05 mM MgCl2, 1.3 mM CaCl2, 1.19 mM NaH2PO4, 20 mM NaHCO3, 11.1 mM glucose) which was maintained at 37° C. and was bubbled with 95% O2/5% CO2. The pressure of the heart was maintained between 60-80 mmHg throughout the experiment. Far-field ECG signals were acquired with two sensing electrodes and one ground electrode placed into the bath around the heart and recorded using LabChart software (ADInstruments, Sydney, Australia). Mechanical motion of the heart was arrested using blebbistatin (5-10 μM), an electromechanical uncoupler. The tissue was stained with di-4-ANEPPS (125 nM), a voltage-sensitive fluorescent dye, to optically map voltage changes in the membrane potential. Signals were recorded at 1-2 kHz using a high-speed CMOS camera with the MiCAM Ultima acquisition system (SciMedia, Costa Mesa, CA). The electrode of the bioresorbable pacemaker was placed on the anterior myocardial surface of the heart. Using a function generator, the frequency (˜10 MHz) and stimulating duration (1-5 msec) were set to match the settings of the device for wireless inductive power transfer. The heart was paced at a range of increasing frequencies. Capture of the heartbeat was verified by far-field ECG measurements, and the spatiotemporal dynamics of the activation of the transmembrane potential were recorded by optical mapping. To induce atrioventricular (AV) block, ischemic reperfusion was performed until 2nd degree AV block was confirmed by ECG.
Optical mapping was also performed on ex vivo human hearts. All tissue procurement, preparation, and experiments are performed according to protocols approved by the Institutional Review Board (IRB) of The George Washington University and international guidelines for human welfare. Donor human hearts rejected for organ transplant were acquired from the Washington Regional Transplant Community (WRTC) as de-identified discarded tissue with approval from IRB of The George Washington University. Human ventricular heart slices were created according to methods previously described. The heart slice was then transferred and placed into a system perfused with a modified Tyrode's solution (NaCl 140 nN; KCl 4.5 mM; glucose 10 mM; HEPES 10 mM; MgCl2 1 mM; CaCl2 1.8 mM; pH 7.4) which was maintained at 37° C. and was bubbled with O2. Optical mapping of the human ventricular heart slice was performed as previously detailed. In brief, the optical mapping methods involve the following: Mechanical motion of the slice was arrested using blebbistatin (5-10 μM), an electromechanical uncoupler. The tissue was stained with di-4-ANEPPS (125 nM), a voltage-sensitive fluorescent dye, to optically map voltage changes in the membrane potential. Signals were recorded at 1 kHz using a high-speed CMOS camera with a MICAM Ultima acquisition system (SciMedia, Costa Mesa, CA). The electrode of the bioresorbable pacemaker was placed on top of the slice in the central area. Using a function generator, the frequency (˜10 MHz) and stimulating duration (1-5 msec) were set to match the settings of the device for wireless inductive power transfer. The heart slice was paced at a range of frequencies. Capture of the heartbeat was verified by evoked optical action potentials, and the spatiotemporal dynamics of the activation of the transmembrane potential were recorded by optical mapping.
Processing of data from optical mapping. Optical signals were processed using a custom MATLAB software (RHYTHM) that is openly available at https://github.com/optocardiography. Each pixel was spatially filtered with a 3×3 uniform average bin. A Finite Impulse Response filter was used to filter each temporal sequence with a cutoff frequency of 100 Hz. Baseline drift was removed using a polynomial subtraction, and the magnitude of the signals was normalized. Activation times across the membrane were determined by the time of dV/dtmax of the recorded optical action potentials.
Chronic in vivo pacing. Pacemakers in all animals were tested daily post-procedure. Each day, animals were anesthetized with inhaled isoflurane vapors (2-3%) per protocols approved by the Institutional Animal Care and Use Committee (IACUC) at The George Washington University. The Tx antenna was placed parallel to the receiver of the implanted device to power the pacemaker and pace the heart. The frequencies of the pacing stimulation were adjusted such that the stimulation frequency was greater than that of the intrinsic rhythm of the heart. Three-lead ECG was monitored by subdermal needle electrodes in the Lead I configuration (positive electrode on the right arm, negative electrode on the left arm, ground electrode on the leg) using a PowerLab data acquisition system with the LabChart software (ADInstruments, Sydney, Australia). The heart rate was calculated from the R-R interval associated with the ECG. Daily testing in the same manner continued until the pacemaker failed to capture the heart.
Wireless operation of the bioresorbable pacemaker. A commercial RF system (Neurolux, Inc., Evanston, IL) was used to wirelessly deliver power to the bioresorbable cardiac pacemaker for whole heart stimulation. The system included the following: (1) a laptop with custom software (Neurolux, Inc., Evanston, IL) to control and command the data center, (2) a Power Distribution Control box to supply wireless power and communicate with the devices through interactive TTL inputs, (3) an antenna tuner box to maximize power transfer and match the impedance of the source and the antenna, and (4) an enclosed cage with customizable loop antenna designs for in vivo operation of the devices.
Weight monitoring, Masson's trichrome staining, and immunohistochemistry. Devices were implanted into both male and female Sprague Dawley adult rats. Animals were weighed every 3 days to monitor their weight post-surgery. n=3-6 independent animals. The hearts of animals without implanted devices (control) and those with implanted device for 3 weeks and 6 weeks were analyzed. n=3 biologically independent animals per group. Animals were euthanized using 5% isoflurane vapors at 2 mL/min oxygen flow with an EZ anesthesia machine (EZ Systems Inc.) until loss of consciousness. Once the cessation of pain was confirmed by toe pinch, the heart was excised for euthanasia by exsanguination. The excised hearts were immediately cannulated and retrograde-perfused first with cardioplegic solution and then with neutral-buffered formalin. After 24 hours, the hearts were transferred to a 70% ethanol solution and embedded in paraffin. Cross-sections underwent either Masson's trichrome staining for assessment of fibrosis or immunohistochemical staining to visualize localization of CD45 in the myocardium.
For Masson's trichrome-stained samples, cross-sections of the anterior left ventricle were imaged at 4× magnification using an EVOS XL light microscope (Thermo Fisher Scientific). A custom MATLAB code was used to quantify the percent volume of myocytes, collagen, and interstitial space in these images. The region of interest was selected along the left ventricular free wall near the site of device implantation. Color deconvolution was performed to identify pink, blue, and white pixels which represent myocytes, collagen, and interstitial space, respectively. The percent volume encompassed by each of these structures was quantified by calculating the relative number of pixels per color in the selected region of interest.
For immunohistochemistry, sections were stained using the peroxidase/avidin-biotin-complex method. Briefly, the procedure was performed as follows: Sections were deparaffinized using xylene and dehydrated using a gradient of concentration of ethanol. Antigen retrieval was performed using citrate buffer (pH=6.0) in a pressure cooker for 10 minutes. Slides were washed 3 times with ultra-pure de-ionized H2O (3 min/wash). Endogenous peroxidase activity was blocked with BLOXALL solution (SP-6000, Vector Laboratories) for 10 minutes. Slides were again washed 3 times with ultra-pure de-ionized H2O (3 min/wash). Samples were blocked for another 30 minutes with normal goat blocking buffer (PBS, 0.15% Triton X-100, 1% BSA, 3% goat serum (005000121, Jackson ImmunoResearch)) and incubated with the CD45 primary antibody overnight at 4° C. (1:50; ab 10558, Abcam). Next, the samples were washed in PBS with 0.5% Triton X-100 and 2 times in PBS (3 min/wash). Slides were incubated at room temperature with a biotinylated goat anti-rabbit IgG secondary antibody (1:500; 65-6140, Invitrogen) for 60 minutes and with an avidin biotin complex (ABC) reagent (PK-6100, Vector Laboratories) for 30 minutes. Samples were rinsed 3 times in PBS (3 min/wash) before and after application of the ABC reagent. Chromogenic development was achieved using the DAB Peroxidase Substrate Kit (SK-4100, Vector Laboratories). Samples were counterstained with hematoxylin (6765007, Thermo Scientific) for 10 minutes, rinsed with tap water until colorless, and dehydrated in an increasing gradient of ethanol followed by xylene. Slides were mounted with DPX mountant (13512, Electron Microscopy Sciences), and the images near the site of pacemaker implantation were taken using brightfield microscope (DMi8, Leica Microsystems) in a tiled manner at 20× and 40× magnification using the Leica Application Suite (LAX) X software (Leica Microsystems). CD45+ cells were manually quantified in a blinded manner using ImageJ (v2.1.0, National Institutes of Health). Each counted cell was marked so that no cell was counted twice. A custom MATLAB code quantified the myocardial volume in each image using color deconvolution and calculated the frequency of CD45+ cells per mm2. To determine statistical differences, a non-parametric Kruskal-Wallis one-way analysis of variance with Dunn's test for pairwise comparison was performed across each condition between the 0-week (control), 3-week, and 6-week endpoints at a significance level of p<0.05.
Evaluation of hematology and blood chemistry of rats. All procedures followed protocols approved by The George Washington University Institution Animal Care and Use Committee (IACUC). Blood was collected from adult rats with bioresorbable pacemakers implanted using the aforementioned surgical procedures. At 1, 3, 5, and 7-week endpoints, blood was collected from animals via the tail vein into K-EDTA and gel tubes for blood counts and blood chemistry tests, respectively. Charles River Laboratories conducted the assays.
In vivo canine model study. Retired breeder female hound dogs (age 1.2-3.5 years, weight 27-36 kg) used in this study were maintained in accordance to the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85-23, revised 1996) as approved by the IACUC of Northwestern University. Prior to surgery, all animals were premedicated with acepromazine (0.01-0.02 mg/kg) and were induced with propofol (3-7 mg/kg). General anesthesia (inhaled) was achieved with isoflurane (1-3%) after intubation. Adequacy of anesthesia was assessed by toe pinch and palpebral reflex. Surface electrodes were applied to the limbs and continuous 6-lead ECG was recorded at a sampling rate of 977 Hz (Prucka CardioLab). A lateral thoracotomy was performed, and the heart was exposed by pericardiectomy. The electrodes of implanted bioresorbable pacemakers were sutured to the myocardial surface of the right ventricle with 4-0 monofilament non-resorbable sutures. For in vivo long-range tests of wireless operation, the thoracotomy was closed in 4 layers (ribcage, deep fascia and muscles, subcutaneous tissue, and skin). A chest tube was placed prior to closing. The chest was evacuated of air and fluid, and lungs re-expanded. The chest tube was clamped. The antenna was applied at various distances from the receiver, and the selected pacing cycle length was 30-60 ms shorter than the intrinsic ventricular cycle length. Effective ventricular capture was confirmed by surface ECG. Upon finishing the in vivo portion of the study and after confirming a very deep plane of anesthesia, the heart was removed, and euthanasia was achieved by exsanguination.
In vivo bioresorption study. Rats were anesthetized during imaging, with a preclinical microCT imaging system (nanoScan PET/CT, Mediso-USA, Boston, MA). Data was acquired with a 2.2× magnification, <60 μm focal spot, 1×4 binning, with 720 projection views over a full circle, using 70 kVp/240 μA, with a 300 ms exposure time. The projection data was reconstructed with a voxel size of 68 μm (in all directions) and using filtered (Butterworth filter) back projection software from Mediso. Amira 2020.1 (FEI Co, Hilsboro, OR) was used to segment the device and skeleton, followed by 3D rendering.
Statistical analysis. Results are reported as mean±6 SD, unless otherwise noted. Statistical analyses were performed using Statistical software (Version 6.0, Statsoft, Tulsa, Oklahoma) followed by a t-test. *p<0.05, **p<0.01, ***p<0.001. All experiments were performed with at least 3 biological replicates per condition. For quantitative histology and immunohistochemistry analysis, significance in column comparisons was calculated with a non-parametric Kruskal-Wallis test with Dunn's multiple comparison test at a significance level of p<0.05. For echocardiography data, significance in column comparisons was calculated using a Friedman test in conjunction with Dunn's multiple comparison test at a significance level of p<0.05.
Design and Battery-Free Operation of a Bioresorbable Cardiac Pacemaker. The schematic illustration in panel a of
The key defining characteristic of this system is that all of the constituent materials are bioresorbable. The designs support stable function over a relevant time frame with eventual complete disappearance into the surrounding biofluids and eventually from the body itself by natural chemical/biochemical processes of hydrolysis and metabolic action (panel a of
Panels c-d of
Optimized mechanical layouts ensure conformal contact against the curved surface of the heart for effective and reliable pacing. Three-dimensional finite-element modeling (FEM) reveals distributions of principal strain for compression-induced buckling perpendicular to the length of the interconnects, as shown in panel a of
Ex Vivo Electrical Pacing in Various Cardiac Systems: Mouse, Rabbit ad Human. Various ex vivo tests establish the operating features of the device and its efficacy in pacing. Three different cardiac systems with various wall thicknesses (mouse, ˜0.7 mm; rabbit, ˜5.0 mm; human, ˜10 mm) reflect the span of different impedances observed in human hearts depending on size and health status. Finite element analysis (FEA) simulations reveal the electric field distributions near the electrode-myocardium interface upon electrical stimulation (electrode spacing=2 mm; applied voltage=0.75 V) in three-dimensional (3D) and two-dimensional (2D; x, z-axis) space, as shown in panels a-b of
Images shown in panels a and d of
Treating AV Block in an Ex Vivo Mouse Model. High-grade AV block corresponds to an interruption in the transmission of an impulse from the atria to the ventricles due to an anatomical or functional impairment in the conduction system. This intermittent or absent AV conduction can be transient or permanent. For the past 6 decades, electrical pacemakers have been critical for the treatment of patients with AV block. The bioresorbable, leadless cardiac pacemaker introduced here is an attractive potential alternative to conventional pacemakers for such patients, particularly if AV block appears transient. Panel a of
Placing the electrode on the right atrium (RA) near the sinoatrial (SA) node enables electrical stimulation of the atria in a mode that closely matches the physiological conduction system of the heart for native AV conduction. The schematic illustration in panel a of
In Vivo Pacing in a Large Animal Model. In vivo studies with a canine whole heart model at a scale that recapitulates human physiology are of high relevance to the envisioned clinical implementation since the canine cardiovascular system bears high resemblance to that of a human. Here, in vivo testing in a canine model (adult hound dogs, female, 27-36 kg) during open chest surgery demonstrates the feasibility of this bioresorbable, leadless, battery-free pacemaker in a large animal. The illustration in panel a of
The power transfer for device operation depends on the mutual inductance between the Rx and Tx coils. This relationship is represented by M=k√{square root over (LTxLRx)}, where the individual coil inductances are LRx and LTx. The coupling coefficient k defines the linkage of the magnetic flux, and the value mainly depends on the distance and relative angle between the coils. Proper design choices ensure operation for average skin-to-heart distances in adult patients (parasternal 32.1±7.9 mm; apical 31.3±11.3 mm; subcostal 70.8±22.3 mm).
Chronic Pacing Capability. Panel a of
Daily pacing trials occur on all animals while awake or under light sedation using optimized parameters (transmitting power ˜6 W; pulse width=7 ms; heart rate=400-430 bpm). Data acquisition hardware monitors the ECG signal through subdermal needle electrodes positioned in the Lead I configuration (positive electrode on the right arm, negative electrode on the left arm, ground electrode on the leg). As before, pacing induces a transition of ECG signals from a narrow QRS complex, consistent with normal rate sinus rhythm (350-400 bpm), to a widened, amplified QRS complex with shortened R-R intervals, consistent with a paced rhythm (400-450 bpm). This change in ECG signal morphology indicates successful ventricular capture (panel d of
In Vivo Bioresorbability and Biocompatibility of Bioresorbable, Implantable Pacemaker. Here, the processes of bioresorption can be monitored non-invasively and at high resolution using computed tomography (CT). Typically, the bioresorbable Mg features have low visibility in the CT image due to the low radiocontrast of Mg. However, an additional coating of high radiocontrast bioresorbable metal (W; ˜700 nm thick) on the Mg (˜50 μm thick) eliminates this limitation. Since the rate of dissolution of W is much smaller (96 nm/day) than that of Mg (7200 nm/day), this thin coating allows imaging over a timeframe similar to that of in vivo bioresorption of the device. Panel a of
Histological examination of the myocardial tissue near the site of pacemaker attachment up to 6 weeks after implantation supports the biocompatibility of the device, its constituent materials, and the products of their dissolution. At the 0, 3, and 6-week endpoints after implantation, histological analysis using Masson's trichrome staining quantifies the volume of myocardium, fibrotic tissue, and interstitial space in the transmural ventricular tissue near the site of device attachment (panel a of
The exemplary example reported here introduce a bioresorbable, leadless class of temporary cardiac pacemakers and demonstrate its efficacy in a comprehensive series of small and large animal models. The material compositions and design choices of the device support the electrical performance characteristics necessary for temporary cardiac pacing applications in a thin, flexible platform and offer timescales for stable operation and complete bioresorption that can be tailored to specific therapeutic timelines. This miniaturized device receives power and control commands through wireless inductive power transfer. This scheme circumvents the need for batteries and their associated mass, physical bulk, and hazardous constituent materials. These fully implanted devices also minimize complications associated with infections by eliminating any percutaneous hardware and bypass requirements for secondary device removal by self-elimination through bioresorption. Although the application evaluated in this series of experiments primarily addresses the need for temporary leadless epicardial pacing, future versions have the potential for transvenous applications of temporary, leadless pacing in patients with AV block due to myocarditis or anti-tachycardia pacing in patients with AF associated with cardiac surgery. Promising directions for future research also include multisite pacing using different RF frequencies, introducing stimuli-responsive materials for active control of process of degradation, and coupling with sensors for closed-loop operation.
In the exemplary example, a bioresorbable low-frequency PIN diode with high parasitic capacitance yields a capacitor-free bioresorbable electrical stimulator with enhanced output performance. With the PIN structured diode in reverse bias, charge accumulates at the PI and IN junctions, thereby creating a diode capacitance (Ct) where the I region acts as a parasitic capacitor with capacitance proportional to the area (A) and inversely proportional to the distance (d). When forward biased, the PIN diode acts as a variable resistor. Switching between reverse and forward bias at timescales much larger than the carriers' lifetime leads to the typical behavior of a diode. However, the diodes have a reverse-recovery time, corresponding to a time for changing its response to a forward-biased from a reverse-biased state. Such switching results in some current flow in the reverse direction, and the reverse-recovery time is proportional to the size of Ct. Based on this mechanism, the bioresorbable PIN diode can be designed with a reverse-recovery time of the order of microseconds. At high-frequency (>1 MHz), the diode cannot fully recover during switching, thereby yielding DC-like output (with ripples) without the need for a smoothing capacitor. To illustrate the electrical characteristics of capacitor-free device with low-frequency PIN diode, we implemented the circuit shown in panel a of
where f is the frequency of the input signal, N is the number of turns of coil in the loop, S is the area of the loop, Q is the quality factor of circuit, BO is the strength of the input signal, and α is the angle of arrival of the signal. In addition, eliminating the capacitor component, simplifying the fabrication process, and reducing the number of interconnections further improves the yields and mechanical reliability of the device.
The one-dimensional cable theory is a useful mathematical model where a “cable” with specific electrical properties approximates the dynamics of a “strip” of myocardium. Using the cable theory model, we can garner some qualitative insights into the optimal electrode design for electrode-induced myocardial excitation. According to cable theory, we can model the extracellular space around the myocyte as a cylinder of radius of de-m, or the distance between the electrode and the excitable myocardium (
where Gout is the extracellular fluid conductivity. The interelectrode extracellular fluid potential difference (ΔΨout) is also the minimum voltage that must be applied across the electrodes to achieve myocardial capture which can be expressed by
where I0 is the threshold current and L is the interelectrode distance. For the same minimum input voltage for pacing (ΔΨout) where Gout and I0 are relatively constant across scenarios, this equation suggests that the interelectrode distance (L) primarily depends the distance between the electrode and excitable myocardium (de-m). Since animals with larger hearts have a greater de-m as evidenced by a greater tissue impedance, a greater L is required for large animals compared to small animals. Based on this approximation, we tune the electrode spacing between 1 mm to 5 mm depending on the size of the hearts.
The coil-to-coil distance is a critical factor that affects the power transfer efficiency in a wireless induction scheme. For example, for a fixed input voltage (i.e., transmitting voltage) of 10 Vpp at the Tx coil, the output voltage at the Rx coil decreases from 16 V to 0.2 V with respect to distances from 1 mm to 8 mm (panel g of
Although many parameters contribute to stable pacing, including input frequency, input power, pulse width, burst period, and coil-to-coil distance, optimization of the wireless energy transfer system simplifies the operation. The designs of the Rx and Tx coils are optimized for operation at a fixed input frequency of 13.56 MHz. Studies using the canine model provide guidelines for the maximum pacing distance for a given input power. The pulse width and burst period can be predefined or manipulated during pacing using insights from the patient's ECG signals and therapeutic treatment strategy. Since the cardiac pacing follows an all-or-nothing threshold behavior, users can change one parameter, such as input power or coil-to-coil distance, until changes in ECG signal indicate a transition from intrinsic to pacing rhythm.
The encapsulation materials and their thickness define the functional lifetime of the devices. Although bioresorbable wax (Candelilla wax) can be considered, its poor mechanical properties and the relatively high melting temperature (˜70° C.) needed for dip-coating-based encapsulation process limit its feasibility for use with bioresorbable electrical stimulators. A hydrophobic polyanhydride (polybuthanedithiol 1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione pentenoic anhydride, PBTPA) can serve as an attractive alternative for an advanced encapsulation structure to allow for long functional lifetimes. The encapsulation process involves placing the device on a partially cured layer of PBTPA and subsequently UV-curing after applying a liquid mixture of precursors on the top. The result is a conformal encapsulation structure with a thickness of approximately 300 μm. This UV-based photocuring process does not damage the bioresorbable devices because it occurs at room temperature, well below the glass transition temperature of the PLGA.
In sum, the disclosure presents, among other things, a fully bioresorbable, implantable, leadless cardiac pacemaker that operates in a battery-free fashion and is externally controlled and programmable. The device relies exclusively on materials that resorb when exposed to biofluids in a time-controlled manner via metabolic action and hydrolysis. The materials and design choices create a thin, flexible, and lightweight form that maintain excellent biocompatibility and stable function throughout a desired period of use. Over a subsequent timeframe following the completion of therapy, the devices disappear completely through natural biological processes. Wireless energy transfer via resonant inductive coupling delivers power to the system in a manner that eliminates the need for batteries and allows for externalized control without transcutaneous leads. These characteristics and a miniaturized geometry facilitate full implantation into the body to eliminate the need for percutaneous hardware, which thereby minimizes the risk of device-associated infections and dislodgement.
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.
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.
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.
This application claims priority to and the benefit of U.S. Provisional Application No. 63/215,070, filed Jun. 25, 2021, which is incorporated herein in its entirety by reference.
This invention was made with government support under HL141470 awarded by the National Institutes of Health. The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/035089 | 6/27/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63215070 | Jun 2021 | US |
