EXPLANTABLE VAGUS NERVE STIMULATION LEAD
CLAIM OF PRIORITY
[0001] This application is related to and claims priority to United States Provisional Application No. 63/467,725, filed on May 19, 2023, and entitled “Explantable Vagus Nerve Stimulation Lead,” the entirety of which is incorporated herein by reference.
BACKGROUND
[0002] Implantable medical devices can be provided to electrically stimulate the central and peripheral nervous systems (e.g., including the autonomic system), cardiac muscle tissue, and other muscle tissues. Electrical signals delivered to neural tissue or muscle tissue can be used to treat various bodily dysfunctions and disorders by blocking, masking, stimulating, or replacing electrical signals within the body. In a particular example, electrical signals delivered to the vagus nerve can be used to treat epilepsy, seizures, depression, anxiety, obesity, and other disorders.
[0003] Vagus Nerve Stimulation (VNS) for treatment of epilepsy can involve stimulating the left cervical vagus nerve using one or more electrodes on an implanted lead. A neurostimulation lead can include one or more electrodes implanted or installed at or adjacent to the target tissue (e.g., the vagus nerve) such that electrical energy from the electrodes can be delivered to the target tissue. In an example, an epilepsy therapy can comprise a bipolar, biphasic electrical stimulation pulse, or series of such pulses, delivered to a nerve target using the implanted lead and electrodes.
[0004] In an example, an implantable electrode can comprise a cuff type electrode or a helical electrode, among others. A cuff type electrode comprises a substantially or partially cylindrical structure that can be open at one side and can be placed around the nerve target and closed with a suture or other device. A helical electrode can comprise a flexible structure that can, in some examples, expand or contract to help size the electrode around the nerve target. [0005] In some cases, the body recognizes the implanted lead as foreign, which in turn can trigger a response such as an inflammatory response. The inflammatory response can include encapsulation of the implant with glial tissue, and scarring (i.e., fibrosis or gliosis) can result. Scar tissue can compromise the efficiency of energy delivery to the target tissue and therefore can compromise the efficacy of a neurostimulation therapy. Scarring and in-growth of tissue over time can hinder surgical removal or adjustment of leads and electrodes.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0006] To easily identify the discussion of any particular element or act, the most significant digit or digits in a reference number refer to the figure number in which that element is first introduced. The drawings are not drawn to scale.
[0007] FIG. 1 illustrates an example of a system for providing neurostimulation to a nerve.
[0008] FIG. 2 illustrates generally an example of a first lead assembly with a first retention member.
[0009] FIG. 3 illustrates generally an example of a second lead assembly. [0010] FIG. 4 illustrates generally an example of a third lead assembly.
[0011] FIG. 5 illustrates generally an example of a fourth lead assembly.
[0012] FIG. 6 illustrates generally an example of a fifth lead assembly.
[0013] FIG. 7 illustrates generally an example of a helical electrode structure.
[0014] FIG. 8 illustrates an example method for implanting a neurostimulation lead.
DETAILED DESCRIPTION
[0015] The present inventor has recognized, among other things, the difficulty of safely removing a neurostimulation lead, such as a vagus nerve stimulation lead, after it is implanted for an extended period of time, such as months or years. The difficulty can be due in part to scar tissue, other tissue ingrowth, affixation features of the lead (e.g., tines), or other reasons. [0016] In an example, a helical lead or helical electrode structure can include a conductive or non-conductive support member with one or more conductive electrode members coupled thereto. The helical structure can be wrapped around a nerve target, such as comprising a portion of a cervical vagus nerve. The cervical vagus nerve is in a sensitive body area, adjacent to the carotid artery, the internal jugular vein, and the laryngeal nerve, and it can be difficult to extract such a lead without adversely affecting these structures and other nearby arteries, veins, and nerves. Furthermore, there can be scar tissue around or within the helical structure, further compromising access and dissection.
[0017] In some examples, a neurostimulation lead can require maintenance or replacement. Such maintenance or replacement can include removing or explanting the lead and then installing a new lead. Removing helical electrode structures prior to implanting a new lead can damage the vagus nerve, for example, if the nerve is accidentally cut, scratched, or stretched, during an explant or implant procedure. In an example, an older implanted lead can be dissected or cut apart to facilitate removal in multiple pieces. However, this can be undesirable because cutting the lead could lead to fragmentation of the lead and pieces of the lead could be inadvertently left inside of the patient. In some examples, a helical structure can be cut apart from a lead body and left inside the patient body because it can be too difficult to remove the structure, in whole or in part. Leaving conductive structures inside the patient body is undesirable for a variety of reasons, including that the patient may be ineligible for future full-body MRI scanning. In other examples, a helical electrode structure is left on the cervical vagus nerve and a new lead is placed in a different location on the vagus nerve. The different location may or may not be optimized for therapy delivery and efficacy.
[0018] The present inventor has recognized that a solution to these and other problems can include an electrostimulation lead that comprises a coating on some or all of its surfaces that can be in contact with body tissue. For example, the coating can be provided on an inner surface of a circular or helical structure adjacent to or proximate to the target tissue (e.g., a nerve or muscle tissue). In an example, the coating can be provided on an outer surface of lead or structure adjacent to other tissue at or near the target tissue. The lead surfaces can include suture tabs or other features or accessories that are configured to hold or anchor the lead to tissue. In an example, the coating can comprise one or more of a hydrophobic, high density material such as polytetrafluoroethylene (PTFE) or expanded PTFE (ePTFE) (e.g., Gore-Tex), or a sterile, bioresorbable, hydrophilic adhesion barrier (e.g., Seprafilm(R)), or an absorbable gelatin film (e.g., Gelfilm), or a microporous textile made from polyesterurethane (e.g., Neuro-Patch), or a hydrogel, or a combination of such materials, among others.
[0019] In an example, an anti-scarring agent or anti-ingrowth agent, such as a cell cycle inhibitor, can be provided on an electrode or lead at the time of implantation. In an example, the agent can be embedded in a polymer that comprises the sheath of a lead or that comprises the support of an electrode (e.g., a helical support or cuff). Stated differently, the polymer can be impregnated, coated, or the like with the anti-ingrowth agent. The agent can be provided, additionally or alternatively, on the interior or exterior surface of the electrode or lead.
[0020] By embedding an anti-scarring agent or anti-ingrowth agent directly into the polymers that make up the sheath or support structures of a lead, such as helical supports or cuffs, the ingrowth of surrounding tissues can be controlled. This control is achieved by creating a localized barrier or inhibitory environment that prevents the encroachment of fibrotic tissues into the areas where precise electrical stimulation can be important. As a result, the electrical performance of the lead remains more consistent over time, and the therapeutic efficacy is maintained. Controlled ingrowth helps ensure that removal or replacement procedures are less invasive and less likely to cause damage to the surrounding nerve tissues. This not only facilitates a safer explantation procedure but also potentially enhances patient outcomes by preserving nerve function and reducing post-surgical recovery times.
[0021] In an example, a lead or electrode can include or use a suture, such as for securing the lead or electrode at or near or around a neural target. In an example, a suture can be embedded in, or comprise a portion of, a helical structure polymer, and can be used to cinch or secure the helical structure at the time of implant. The suture can be bioabsorbable. Such a bioabsorbable suture can dissolve in, or can be absorbed by, the tissue in which it is installed such that the suture does not inhibit subsequent removal of the lead. [0022] In an example, a lead (e.g., comprising one or more electrodes) can comprise a retention member or affixation feature. The affixation feature can be provided at a proximal or distal end of the lead or can be provided at an intermediate location along the length of the lead. The affixation feature can be electrically functional and can include, for example, one or more electrodes for sensing or delivery of electrical neurostimulation. In an example, the affixation feature can be electrically non-functional, for example, without conductive materials or without electrodes.
[0023] FIG. 1 illustrates an example of a system for providing neurostimulation to a nerve. An illustrative (but non-restrictive) example, as shown in FIG. 1, includes a system for providing neurostimulation to a vagus nerve 102, or for providing vagus nerve stimulation (VNS). In an example, the system can be configured to sense nerve activity or other electrical activity or motion. In an example, the system includes an implantable device 116 such as can comprise a processor circuit 118 and a pulse generator 120. The implantable device can include or can be coupled to an electrostimulation or neurostimulation lead, such as one or more of those discussed below. The processor circuit 118 can control operation of the pulse generator 120 according to various therapy delivery algorithms. In an example, the implantable device 116 comprises or is coupled to one or more physiologic status sensors that are configured to sense information about a patient. For example, the system can include an accelerometer 122. The accelerometer 122 can comprise a portion of the implantable device 116 or can be coupled to a lead that is coupled to the implantable device 116.
[0024] In an example, seizure detection and VNS can include or use one or two vagus nerve sensing electrodes (e.g., “recording cuff’ or helical electrodes), such as located in different longitudinal positions along the cervical vagus region, relative to a stimulation site. Separate stimulating electrodes (e.g., an anode and a cathode) can be positioned to provide VNS. In the example of FIG. 1, the system includes a first electrode 108, a separate second electrode 110, a separate third electrode 112, and a separate nth electrode 114 positioned at or near the vagus nerve 102.
[0025] The count and position of electrodes in the example of FIG. 1 is merely illustrative. For example, an implantable device can include circuitry for sensing (e.g., recording) neural activity (e.g., an action potential or compound action potential), along with circuitry for generating VNS. In such an example, a machine-learning or trained-learning approach, such as an instance of a machine-learning-based model (e.g., such as can be referred to as an artificial intelligence or “Al” -based technique) can be instantiated by the implant circuitry or the processor circuit 118. Such a machinelearning-based model can be used for detection of a seizure, or for therapy control in response thereto, or both.
[0026] In an example, the sensing electrodes and related circuitry can be separate from the stimulating electrodes and the sensing electrodes can be monitored by a separate unit (e.g., an external assembly) that can be used in an acute or temporary manner, such as supporting the implant procedure or implantable device configuration. For example, in the case that the sensing and stimulating electrodes are separate, the sensing electrode may be explanted acutely as a portion of a first procedure or soon after the first procedure. In yet another example, there could be three or more electrodes that could be configurable as either a stimulating electrode or a sensing electrode at any time. For example, two electrodes closest to a brain of a patient could be assigned as an anode and a cathode, respectively, and another electrode that is located more distally could be assigned as a sensing electrode to detect efferent nerve activation. As another illustration, two electrodes most distal to the brain could be assigned as an anode and a cathode, respectively, and an electrode more or most proximal to the brain could be assigned as a sensing electrode to detect afferent activity.
[0027] FIG. 2 illustrates generally an example of a first lead assembly 200 with a first retention member 216. The first lead assembly 200 can be configured for implantation at a neural target, such as at the vagus nerve 202. The first lead assembly 200 can comprise a lead body 204 and one or more distal electrodes, anchors, or affixation features. The first lead assembly 200 includes a first helical anchor 206, support member, or nerve tether, such as can comprise a helical structure without electrodes. The first helical anchor 206 can be configured to receive the vagus nerve 202 (or other nerve) and can be adjustable to accommodate variations in size of the vagus nerve 202.
[0028] The first lead assembly 200 includes a second helical anchor 208 configured to receive the vagus nerve 202. In an example, the second helical anchor 208 is coupled to the lead body 204 using a first tether 220. The first tether 220 can comprise a portion of, or can be coupled to one or more components of, the lead body 204. In an example, the first tether 220 comprises one or more conductors. The second helical anchor 208 can comprise a first electrode 210, such as can comprise a single electrode or an array of separately addressable electrodes.
[0029] The first lead assembly 200 includes a third helical anchor 212 configured to receive the vagus nerve 202. The third helical anchor 212 is coupled to the lead body 204 using a second tether 222. In another example, the third helical anchor 212 can be coupled to the second helical anchor 208 or the first tether 220. The third helical anchor 212 can comprise a second electrode 214, such as can comprise a single electrode or an array of separately addressable electrodes. In the example of FIG. 2, the electrodes are illustrated schematically as having discrete locations, however, other locations in, on, or around the respective helical anchors can be used. In an example, one or more of the electrodes can comprise a ring electrode or conductive ribbon that extends partially or entirely around a revolution of its respective helical anchor, such as to encircle the target tissue (e.g., the vagus nerve 202). Examples of ring electrodes are illustrated schematically in the example of FIG. 3.
[0030] In an example, the first retention member 216 is coupled to the first lead assembly 200 using a retention member tether 218. The retention member tether 218 can be coupled to the third helical anchor 212, to the second tether 222, to the second helical anchor 208, to the first helical anchor 206, to the lead body 204, or to another component of the lead assembly. The example of the first retention member 216 comprises a mesh structure.
[0031] In the example of FIG. 2, the mesh structure of the first retention member 216 can be coupled to a distal portion of the lead body 204 and configured to grow into tissue at, near, adjacent to, or around the vagus nerve 202 or other nerve tissue. In an example, additionally or alternatively to providing the first retention member 216 at the distal portion of the lead body 204, one or more other instances of the first retention member 216 can be coupled to a proximal or intermediate portion of the lead body 204. For example, an instance of the first retention member 216 can be provided proximally relative to the first helical anchor 206 or can be provided between the first helical anchor 206 and the second helical anchor 208, or between the second helical anchor 208 and the third helical anchor 212, or elsewhere. Although the example of FIG. 2 illustrates the first retention member 216 adjacent to a portion of the vagus nerve 202, the first retention member 216 can be provided at or can be coupled to other tissue (e.g., muscle tissue, ligaments or other connective tissue, etc.). The particular location of the first retention member 216 can be selected by the implanting clinician at the time of implantation.
[0032] The first retention member 216 can be configured to help retain a portion of the lead (e.g., a distal, proximal, or intermediate portion of the lead), such as to help prevent movement or migration of the lead or the other helical anchors or electrodes that are coupled to the lead. The first retention member 216 can be a sacrificial structure. That is, at the time of explantation of the lead body 204, the first retention member 216 can be configured to be separated from one or more other portions of the lead and can remain inside the body. For example, in the example of FIG. 2, the first retention member 216 can be separated from the lead by cutting or otherwise disconnecting a coupling member that couples the first retention member 216 to the third helical anchor 212, or to the lead body 204, or to another portion of the lead assembly.
[0033] In an example, the particular size or shape of the retention member 216 can be determined by an implanting clinician. For example, the retention member 216 can be cut or sized during implantation. This flexible design of the retention member 216 allows for a tailored approach to each patient’s anatomical and physiological conditions. For example, by adjusting the placement and extent of the mesh structure during the implantation procedure, clinicians can optimize the contact between the lead and the nerve tissue, potentially enhancing the overall effectiveness of the neurostimulation therapy. The customization can be particularly beneficial in cases where anatomical variations might otherwise compromise standard positioning of the lead.
[0034] FIG. 3 illustrates generally an example of a second lead assembly 300. The second lead assembly 300 can comprise one or more tethers, anchors, or other structures, such as including the first helical anchor 206. In an example, the second lead assembly 300 can include the second helical anchor 208, the third helical anchor 212, or other structures from the example of the first lead assembly 200. The second lead assembly 300 can include a second retention member 302. The example of FIG. 3 includes a first ring electrode 310 and a second ring electrode 314. The ring electrodes each comprise a conductive material that is configured to encircle, partially or entirely, the vagus nerve 202 or other tissue target. In the example of FIG. 3, each of the first and second ring electrodes 310 and 314 comprises a portion of a respective helical anchor. Other support members for the electrodes, or other electrode configurations, can similarly be used.
[0035] In an example, the second retention member 302 comprises a helical structure. The second retention member 302 can be coupled to a portion of the lead body 204 and can be configured to couple with tissue at, near, adjacent to, or around the vagus nerve 202 or other nerve tissue. In an example, the second retention member 302 can be provided at a distal end of the lead and can be configured to help retain a distal end portion of the lead, such as to help prevent movement or migration of the lead or the other helical anchors or electrodes that are coupled to the lead. The second retention member 302 can be provided elsewhere along the lead, or one or more instances of the second retention member 302 can be provided at various locations along the lead, such as proximally (e.g., proximal to the first helical anchor 206), intermediately (e.g., between one or more of the helical anchors), or distally.
[0036] In an example, the second retention member 302 can be a sacrificial structure. That is, at the time of explantation of the lead body 204, the second retention member 302 can be configured to be separated, disconnected, or the like from another portion of the lead and can remain inside the body. For example, the second retention member 302 can be separated from the lead by cutting or disconnecting a coupling member that couples the second retention member 302 to an adjacent anchor or tether of the lead assembly.
[0037] In an example, the second retention member 302 can be joined or tethered to the lead body 204 or to one or more of the helical anchors using various attachment methods, such as using a suture. A length of the tether that joins the second retention member 302 with another portion of the lead can be adjustable and, optionally, can be coupled to one or more of the helical anchors or to another portion of the lead body 204, for example, by the implanting clinician at the time of implantation. In an example, the second retention member 302 can be coupled to multiple lead features, such as to each of two or more of the helical anchors, to further enhance the stability of the electrodes.
[0038] FIG. 4 illustrates generally an example of a third lead assembly 400. The third lead assembly 400 can comprise one or more tethers, anchors, or other structures, such as including the first helical anchor 206. In an example, the third lead assembly 400 can include the second helical anchor 208 (e.g., comprising the first electrode 210, the third helical anchor 212 (e.g., comprising the second electrode 214), or other structures from the example of the first lead assembly 200. The third lead assembly 400 can include a third retention member 402. In an example, the third retention member 402 comprises one or more tines.
[0039] In the example of FIG. 4, electrodes 404 and 406 are provided on respective helical anchors. The electrodes are illustrated schematically as having discrete locations, however, other locations in, on, or around the respective helical anchors can be used. In an example, one or more of the electrodes can comprise a ring electrode or conductive ribbon that extends partially or entirely around a revolution of its respective helical anchor, such as to encircle the target tissue (e.g., the vagus nerve 202). Examples of ring electrodes are illustrated schematically in the example of FIG. 3.
[0040] The third retention member 402 can be coupled to a portion of the lead body 204 and can be configured to be inserted into tissue that is at or near the vagus nerve 202 or other nerve tissue. The third retention member 402 can be configured to help retain a portion of the lead, such as to help prevent movement or migration of the lead or the other helical anchors or electrodes 404 and 406 that are coupled to the lead. In the example of FIG. 4, the third retention member 402 can be coupled to a distal portion of the lead, however, other proximal or intermediate positions along the lead can similarly be used. In an example, multiple instances of the third retention member 402 can be used, and each instance can be located at a different location along the lead. For example, one or more instances of the retention member can be coupled to each of the helical anchors using a respective tether. The length of the tethers can be determined by the implanting clinician. Providing retention members at or in association with the helical anchors can help prevent migration of the helical anchors along the nerve.
[0041] In an example, the third retention member 402 includes one or more tines. Tines are small, spike-like projections that are typically made from a biocompatible material such as titanium or a medical-grade polymer. The tines are designed to penetrate slightly into the surrounding tissue, providing a mechanical anchor that helps to prevent the lead (or other feature coupled to the lead) from migrating or shifting after implantation. The tines can be straight, curved, or barbed structures. The particular tines used can be selected based on the specific requirements of the implant site and the type of tissue interaction desired.
[0042] In an example, the third retention member 402 can be customized by the implanting clinician. Depending on the patient anatomy and the specific characteristics of the implantation site, a clinician may choose to modify the tines at the time of surgery. The customization can involve cutting the tines to a specific length or shaping them to better fit the implant site. Such modifications are facilitated by the material properties of the tines, which allow for onsite adjustments without compromising their structural integrity or biocompatibility.
[0043] This ability to customize the tines is particularly beneficial in complex anatomical regions where standard tine configurations may not provide optimal engagement with the tissue. By adjusting the tines, the clinician can ensure a more secure and stable placement of the lead, tailored to the unique characteristics of the patient's body. This customization not only enhances the stability of the implant but also contributes to the overall safety and efficacy of the neurostimulation therapy, ensuring that the lead remains precisely positioned for optimal therapeutic outcomes.
[0044] Lead migration in each of multiple directions can be inhibited using tines that extend in multiple directions. In the example of FIG. 4, the tines of the third retention member 402 form an “X”-shaped structure or a pair of oppositely-oriented “V” structures. The tines in this example are configured to inhibit motion of the lead along the axial direction of the vagus nerve 202. [0045] In an example, each instance of the third retention member 402 can be a sacrificial structure. That is, at the time of explantation of the lead body 204, the third retention member 402 can be configured to be separated or otherwise disconnected from a more proximal portion of the lead and can remain inside the body. For example, the third retention member 402 can be separated from the lead by cutting, separating, or disconnecting a tether or other coupling member that couples the third retention member 402 to an adjacent anchor or tether of the lead assembly. Alternatively, the tines can be individually cut and separated from the lead.
[0046] FIG. 5 illustrates generally an example of a fourth lead assembly 500. The fourth lead assembly 500 can comprise one or more tethers, anchors, or other structures, such as including the first helical anchor 206. In an example, the fourth lead assembly 500 can include the second helical anchor 208 (e.g., comprising the first electrode 210), the third helical anchor 212 (e.g., comprising the second electrode 214), or other structures from the example of the first lead assembly 200. The fourth lead assembly 500 can include a fourth retention member 502. In an example, the fourth retention member 502 comprises a bulbous structure.
[0047] In the example of FIG. 5, electrodes 504 and 506 are provided on respective helical anchors. The electrodes are illustrated schematically as having discrete locations, however, other locations in, on, or around the respective helical anchors can be used. In an example, one or more of the electrodes can comprise a ring electrode or conductive ribbon that extends partially or entirely around a revolution of its respective helical anchor, such as to encircle the target tissue (e.g., the vagus nerve 202). Examples of ring electrodes are illustrated schematically in the example of FIG. 3.
[0048] The fourth retention member 502 can be coupled to a portion of the lead body 204 and can be configured to be disposed in tissue at, near, or adjacent to the vagus nerve 202 or other nerve tissue. The fourth retention member 502 can be configured to help retain a portion of the lead, such as to help prevent movement or migration of the lead or the other helical anchors or electrodes 504 and 506 that are coupled to the lead. In the example of FIG. 5, the fourth retention member 502 can be coupled to a distal portion of the lead, however, other proximal or intermediate positions along the lead can similarly be used. In an example, multiple instances of the fourth retention member 502 can be used, and each instance can be located at a different location along the lead. For example, one or more instances of the retention member can be coupled to each of the helical anchors using a respective tether. The length of the tethers can be determined by the implanting clinician. Providing retention members at or in association with the helical anchors can help prevent migration of the helical anchors along the nerve.
[0049] In an example, each instance of the fourth retention member 502 can be a sacrificial structure. That is, at the time of explantation of the lead body 204, the fourth retention member 502 can be configured to be separated or otherwise disconnected from a more proximal portion of the lead and can remain inside the body. For example, the fourth retention member 502 can be separated from the lead by cutting, separating, or disconnecting a tether or other coupling member that couples the fourth retention member 502 to an adjacent anchor or tether of the lead assembly.
[0050] The bulbous fourth retention member 502 is configured to provide a secure anchor while minimizing tissue damage and irritation. In an example, the bulbous feature can be solid, rigid, malleable, or expandable and contractible. A solid bulbous retention member can be made from biocompatible materials such as silicone or polyurethane. The feature can have a smooth, rounded surface or can have a porous or roughened surface. The solid nature of the bulbous retention member provides a stable anchor that resists migration within the body.
[0051] In an example, a bulbous retention member can be a filled or fillable structure made from flexible materials. This design allows for a softer interaction with the tissue, which can be beneficial in sensitive or densely innervated areas. In an example, the bulbous feature can be inflated or expanded after it is placed inside the body, allowing for a customizable fit that adapts to the specific anatomical site. In an example, an implanting clinician can create a tissue pocket, and the bulbous feature can be placed inside the tissue pocket and then expanded.
[0052] FIG. 6 illustrates generally an example of a fifth lead assembly 600. In an example, the fifth lead assembly 600 comprises the first lead assembly 200 from the example of FIG. 2. The example of FIG. 6 includes an ingrowth inhibitor 602. The ingrowth inhibitor 602 can comprise a flexible material that can be cut to size at the time of implantation. In an example, the ingrowth inhibitor 602 can comprise a material that prevents tissue from growing into it, for example Gore-Tex or Seprafilm or Gelfilm or Neuropatch. Other materials can similarly be used.
[0053] In an example, the ingrowth inhibitor 602 can comprise a molded sheet, a woven or non-woven textile or mesh, or a film, any of which can comprise a polymer or other biocompatible material that helps prevent tissue ingrowth in or around the ingrowth inhibitor 602. The ingrowth inhibitor 602 can optionally comprise a pharmaceutical agent (e.g., a solid, liquid, or gel material) that prevents tissue ingrowth. In an example, the agent can comprise a portion of a ingrowth inhibitor 602 component itself or the agent can be applied to another implantable component. The ingrowth inhibitor 602 can be applied in a manner or pattern that promotes selective tissue integration while preventing unwanted tissue ingrowth.
[0054] In an example, the ingrowth inhibitor 602 comprises a substantially planar, flexible material that can be wrapped, in whole or in part, around one or more of an implantable lead, an implantable electrode, or one or more helical structures coupled to the lead. In an example, by virtue of wrapping around a helical anchor, the ingrowth inhibitor 602 can be wrapped around a nerve that is enclosed by the helical anchor. The ingrowth inhibitor 602 can thus include a sheath (e.g., a cylindrical member) that encases or encircles all or a portion of the lead or a helical anchor that is coupled to the lead.
[0055] In the example of FIG. 6, the ingrowth inhibitor 602 comprises a mesh structure that is wrapped around the second helical anchor 208. In other examples, the ingrowth inhibitor 602 can be wrapped around one or more of the first helical anchor 206, the second helical anchor 208, the third helical anchor 212, or can be wrapped around all of the helical anchors. Respective instances of the ingrowth inhibitor 602 can optionally be used to wrap the one or more anchors. The ingrowth inhibitor 602 can help prevent or slow tissue ingrowth in or around the helical structures, and therefore explantation of the structures, and the lead comprising the structures, can be expedited.
[0056] In an example, the ingrowth inhibitor 602 can be sized at the time of implantation. For example, the ingrowth inhibitor 602 can comprise a large sheet of material that can be cut to size by the implanting clinician. In an example, the ingrowth inhibitor 602 can extend proximally beyond the most proximal helical anchor (e.g., the first helical anchor 206) or can extend distally beyond the most distal helical electrode structure (e.g., the third helical anchor 212), such as by 0.5-1.0 cm, or by an amount selected by the implanting clinician. Specific length or width characteristics of the ingrowth inhibitor 602 to be used can depend on the patient anatomy. In an example, the ingrowth inhibitor 602 can be provided along a portion of a length of the lead body, such as excluding one or more of the helical anchors and electrodes. [0057] Although the example of the ingrowth inhibitor 602 shows the first lead assembly 200 from FIG. 2, the ingrowth inhibitor 602 can be similarly used with other lead assemblies.
[0058] In an example, suture tabs or suture sleeves can be used together with any of the lead assemblies discussed herein. A suture tab or sleeve can include a member that is coupled or affixed to an implantable lead, and the tab or sleeve can be coupled to patient tissue using a suture. In an example, one or more suture tabs or sleeves can be provided proximally or distally to any one or more of the helical anchors discussed herein or depicted in the illustrated examples.
[0059] FIG. 7 illustrates generally an example of a helical electrode structure 702. The example of the helical electrode structure 702 is shown decoupled from a lead but wrapped around the vagus nerve 202. The helical electrode structure 702 comprises a flexible structure or anchor that is configured to extend or wrap about one and a half times (e.g., 640 degrees) around a nerve, such as the vagus nerve 202. The helical electrode structure 702 can be reduced in rotational length relative to conventional helical structures that wrap around a nerve three or more times (e.g., 1080 degrees).
[0060] The illustrated example of the helical electrode structure 702 comprises multiple addressable electrodes 706, such as can be distributed around the helical electrode structure 702. By distributing the addressable electrodes 706 around the helical electrode structure 702, a stimulation pulse can be delivered to the vagus nerve 202 in substantially any radial direction. In other examples, the helical electrode structure 702 can comprise a single, unitary conductive structure that wraps partially or entirely around the target tissue.
[0061] Leads and various structures coupled to leads (herein, components) are often made from transparent polymers. The present inventor has recognized that it can be difficult to visually locate such components when implanted or installed in a patient, particularly after tissue ingrowth or other absorption or encapsulation has occurred. If the components are difficult to see, then an explant procedure can be more difficult and can take more time than would be used if the components could be visually distinguished from the surrounding body tissue. Furthermore, it may be more likely that one or more of the components is left inside the body and not explanted due to the difficulty in visually locating all of the components.
[0062] The present inventor has recognized that a solution to these and other problems can include an implantable neurostimulation lead comprising a lead body or a helical structure that comprises a material having a color that contrasts with body tissue. For example, the lead body or helical structure can be made of a white or black biocompatible polymer.
[0063] In an example, a neurostimulation lead can comprise a cable inside the lead and/or the helical structures coupled to the lead. The example of the helical electrode structure 702 includes a first cable 704. The first cable 704 can extend partially or entirely along the length of the helical structure. The cable can have a high tensile strength such that the cable, and any structure(s) coupled to the cable, can be pulled out of the patient and will stay together during explantation. It may be particularly advantageous to provide a lead assembly (e.g., comprising one or multiple electrodes) with the cable and with an anti-ingrowth agent (e.g., as described elsewhere herein) that is applied to, or integrated with, one or more components of the lead assembly, to help facilitate later removal of the lead assembly. The cable can comprise one or more materials selected for their high tensile strength and biocompatibility. Suitable materials may include stainless steel, platinum-iridium alloys, Nitinol (Nickel-Titanium Alloy), tungsten, or biocompatible polymers or fibers.
[0064] In the example of FIG. 7, the helical electrode structure 702 extends from a first end 708 of the structure to a second end 710 of the structure. The first cable 704 can be embedded in a polymer that comprises the helical electrode structure 702. In an example, the first cable 704 can extends beyond the extents of the polymer. For example, a portion of the first cable 704 can extend beyond the first end 708 of the helical electrode structure 702 and a second portion of the first cable 704 can extend beyond the second end 710 of the helical electrode structure 702. The extension portions of the first cable 704 can be used to position the helical electrode structure 702 during implantation or can be used to retrieve the helical electrode structure 702 during explantation.
[0065] FIG. 8 illustrates generally an example of a method 800 for implanting a neurostimulation lead. The example of the method 800 can include or comprise a number of operations. The operations described herein are examples only; other examples of the method 800 can omit one or more of the listed operations, can repeat operations, can include other operations, or can execute the operations concurrently, substantially simultaneously, or in another order, as appropriate or desired.
[0066] At operation 802, the method 800 can include providing an implantable neurostimulation lead assembly. In an example, the lead assembly comprises a lead body, a proximal helical anchor, a distal helical anchor, and a retention member. The distal helical anchor can include one or more therapy delivery electrodes.
[0067] At operation 804, the method 800 can include positioning the proximal helical anchor around a first portion of a first nerve. For example, operation 804 can include positioning the helical anchor around a first portion of a vagus nerve.
[0068] At operation 806, the method 800 can include positioning the distal helical anchor around a second portion of the first nerve. For example, operation 806 can include positioning the distal helical anchor around a second portion of the vagus nerve that is axially spaced apart from the first portion of the first nerve.
[0069] The helical anchors can each be configured to wrap around a portion of a neural target, such as a portion of a vagus nerve. The helical anchors can be coupled, directly or indirectly, to the lead body. In an example, one or more of the helical anchors can include one or more electrodes that can be coupled to electrical signal generator circuitry using conductors in the lead body. The conductors can transmit respective signals from a neurostimulation pulse generator to the electrodes. In an example, the proximal and/or distal helical anchors can be adjustable so as to accommodate varying sizes (e.g., circumference) of the neural target. [0070] At operation 808, the method 800 can include positioning the retention member at or near the first nerve. In an example, operation 808 can include positioning one or more of a biocompatible mesh, a tine structure, a bulbous structure, or another anchoring or retention structure at or near the first nerve. In an example, operation 808 can include coupling the retention member to one or more other structures of the neurostimulation lead. For example, operation 808 can include coupling the retention member to the proximal helical anchor or the distal helical anchor (or both) using a tether. [0071] The retention member may include a biocompatible mesh, one or more tine structures, a bulbous member, or any similar feature or member capable of securing or anchoring the lead or the helical anchors to tissue that surrounds, is adjacent to, or is otherwise proximate to the neural target. The retention member can facilitate or aid stable positioning of the lead body and/or the electrodes near the neural target.
[0072] At operation 810, the method 800 can include providing a tissue ingrowth inhibitor at least partially around one or both of the proximal and distal helical anchors. Operation 810 can include or use a chemical or pharmaceutical ingrowth inhibitor agent, an anti-scarring agent, an antiingrowth agent, or the like around at least one of the lead body, the proximal helical anchor, and the distal helical anchor, or any other tethers, anchors, support members, or the like, attached to or connected to the lead body. In an example, the ingrowth inhibitor can be a coating provided on an outer surface of a lead. In an example, the coating can comprise one or more of a hydrophobic, high density material such as polytetrafluoroethylene (PTFE) or expanded PTFE (ePTFE) (e.g., Gore-Tex), or a sterile, bioresorbable, hydrophilic adhesion barrier (e.g., Seprafilm(R)), or an absorbable gelatin film (e.g., Gelfilm), or a microporous textile made from polyesterurethane (e.g., Neuro-Patch), or a combination of such materials, among others.
[0073] At operation 812, the method 800 can optionally include decoupling the retention member from one or more other components of the neurostimulation lead assembly provided at operation 802. In an example, the retention member can be a sacrificial feature or component configured to remain within the body of a patient upon explantation or removal of the lead. The retention member can be cut, separated, disconnected, or the like, (such as at a connection point or coupling member) from the lead body, the tethers, anchors, support members, or the like and can remain inside the body of the patient while one or more other components are removed. At operation 814, the method 800 can optionally include explanting at least one of the lead body, the proximal helical anchor, and the distal helical anchor.
[0074] In an example, an anti-scarring agent or anti-ingrowth agent, such as a cell cycle inhibitor, can be provided on an electrode, an electrode support (e.g., a helical structure), or lead at the time of implantation. In an example, the agent can be embedded in a polymer that comprises the sheath of a lead or the support of an electrode. Stated differently, the polymer can be impregnated, coated, or the like with the anti-ingrowth agent. The agent can be provided, additionally or alternatively, on the interior or exterior surface of the electrode support or lead. The agent can help prevent tissue ingrowth around lead structures and thus can help facilitate subsequent removal of the lead.
[0075] To better illustrate the systems, devices, and methods described herein, such as can include or use an explantable lead or a lead with one or more explantable features, a non-limiting set of Example embodiments are set forth below as numerically identified Examples.
[0076] Example 1 is an implantable electrostimulation system comprising: an implantable lead body comprising one or more conductors configured to transmit a neurostimulation signal from an implantable pulse generator to one or more implantable electrodes; a proximal helical anchor coupled to the lead body and configured to encircle a first portion of a first nerve; and a distal helical anchor coupled to one or more of the lead body and the proximal helical anchor using a first tether, wherein the distal helical anchor comprises the one or more implantable electrodes, wherein the distal helical anchor is configured to encircle a second portion of the first nerve, and wherein the distal helical anchor is spaced apart from the proximal helical anchor along an axial direction of the first nerve; wherein at least one of the proximal and distal helical anchors comprises a tissue ingrowth inhibitor agent configured to inhibit body tissue ingrowth around the at least one of the anchors.
[0077] In Example 2, the subject matter of Example 1 optionally includes the at least one of the proximal and distal helical anchors comprises a flexible polymer support, and the polymer support is impregnated with the ingrowth inhibitor agent.
[0078] In Example 3, the subject matter of any one or more of Examples 1-
2 optionally includes the ingrowth inhibitor agent comprises a hydrophobic material comprising one or more of polytetrafluoroethylene (PTFE) and expanded PTFE (ePTFE).
[0079] In Example 4, the subject matter of any one or more of Examples 1-
3 optionally includes the ingrowth inhibitor agent comprises a hydrophilic adhesion barrier.
[0080] In Example 5, the subject matter of any one or more of Examples 1-
4 optionally includes the ingrowth inhibitor agent comprises a coating provided on an outer surface of the proximal or distal helical anchor.
[0081] In Example 6, the subject matter of any one or more of Examples 1-
5 optionally includes the ingrowth inhibitor agent comprises a coating provided on an inner surface of the proximal or distal helical anchor.
[0082] In Example 7, the subject matter of any one or more of Examples 1-
6 optionally includes the ingrowth inhibitor agent comprises a microporous textile.
[0083] In Example 8, the subject matter of any one or more of Examples 1-
7 optionally includes a neurostimulation pulse generator coupled to first and second electrodes using respective conductors of the lead body, and the distal helical anchor comprises the first and second electrodes.
[0084] In Example 9, the subject matter of any one or more of Examples 1-
8 optionally includes a neurostimulation pulse generator coupled to first and second electrodes using respective conductors of the lead body, the proximal helical anchor comprises the first electrode, and the distal helical anchor comprises the second electrode.
[0085] In Example 10, the subject matter of any one or more of Examples 1-9 optionally includes a further distal helical anchor coupled to one or more of the lead body and the distal helical anchor using a second tether; a neurostimulation pulse generator coupled to first and second electrodes using respective conductors of the lead body; the distal helical anchor comprises the first electrode, and the further distal helical anchor comprises the second electrode.
[0086] In Example 11, the subject matter of any one or more of Examples 1-10 optionally includes a tissue ingrowth inhibitor member that is configured to wrap around at least one of the proximal and distal helical anchors.
[0087] In Example 12, the subject matter of Example 11 optionally includes the tissue ingrowth inhibitor member is configured to wrap around and encase both of the proximal and distal helical anchors.
[0088] In Example 13, the subject matter of Example 12 optionally includes the tissue ingrowth inhibitor is a unitary structure that extends around outer radial surfaces of the proximal and distal helical anchors. [0089] Example 14 is an implantable electrostimulation system comprising: an implantable lead body comprising one or more conductors configured to transmit a neurostimulation signal from an implantable pulse generator to one or more implantable electrodes; a proximal helical anchor coupled to the lead body and configured to encircle a first portion of a first nerve; a distal helical anchor coupled to one or more of the lead body and the proximal helical anchor using a first tether, wherein the distal helical anchor comprises the one or more implantable electrodes, wherein the distal helical anchor is configured to encircle a second portion of the first nerve, and wherein the distal helical anchor is spaced apart from the proximal helical anchor along an axial direction of the first nerve; and a tissue ingrowth inhibitor member configured to wrap at least partially around the proximal and/or distal helical anchors.
[0090] In Example 15, the subject matter of Example 14 optionally includes the tissue ingrowth inhibitor member is a unitary structure configured to wrap around the proximal and distal helical anchors. [0091] In Example 16, the subject matter of any one or more of Examples 14-15 optionally includes the tissue ingrowth inhibitor member comprises a biocompatible polymer impregnated with an anti-ingrowth agent.
[0092] In Example 17, the subject matter of any one or more of Examples 14-16 optionally includes the tissue ingrowth inhibitor member includes a hydrogel agent.
[0093] In Example 18, the subject matter of any one or more of Examples 14-17 optionally includes the tissue ingrowth inhibitor member comprises a microporous textile.
[0094] In Example 19, the subject matter of any one or more of Examples 14-18 optionally includes the tissue ingrowth inhibitor member comprises a mesh structure.
[0095] In Example 20, the subject matter of any one or more of Examples 14-19 optionally includes the tissue ingrowth inhibitor member comprises a removable sheath.
[0096] In Example 21, the subject matter of any one or more of Examples 14-20 optionally includes at least one of the proximal and distal helical anchors comprises a polymer impregnated with a tissue ingrowth inhibitor agent configured to inhibit body tissue ingrowth around the at least one of the anchors.
[0097] In Example 22, the subject matter of any one or more of Examples 14-21 optionally includes a neurostimulation pulse generator coupled to first and second electrodes using respective conductors of the lead body, and the distal helical anchor comprises the first and second electrodes.
[0098] In Example 23, the subject matter of any one or more of Examples 14-22 optionally includes a neurostimulation pulse generator coupled to first and second electrodes using respective conductors of the lead body, the proximal helical anchor comprises the first electrode, and the distal helical anchor comprises the second electrode; and the tissue ingrowth inhibitor member is configured to wrap around the proximal and distal helical anchors.
[0099] In Example 24, the subject matter of Example 23 optionally includes the tissue ingrowth inhibitor member comprises a first member configured to wrap around the proximal helical anchor and a second member configured to wrap around the distal helical anchor, and the first and second members are spaced apart along an axial direction of the first nerve.
[0100] Example 25 is an electrostimulation lead assembly comprising: an implantable lead body comprising one or more conductors configured to transmit a neurostimulation signal from an implantable pulse generator to one or more implantable electrodes; a proximal helical anchor coupled to the lead body and configured to encircle a first portion of a first nerve; a distal helical anchor coupled to one or more of the lead body and the proximal helical anchor using a first tether, wherein the distal helical anchor comprises the one or more implantable electrodes, wherein the distal helical anchor is configured to encircle a second portion of the first nerve, and wherein the distal helical anchor is spaced apart from the proximal helical anchor along an axial direction of the first nerve; and an implantable distal retention member configured to inhibit migration of the distal helical anchor when the electrostimulation lead assembly is implanted in a patient body.
[0101] In Example 26, the subject matter of Example 25 optionally includes the distal retention member is coupled to the distal helical anchor using a retention member tether.
[0102] In Example 27, the subject matter of any one or more of Examples 25-26 optionally includes the distal retention member is coupled to the implantable lead body using a retention member tether.
[0103] In Example 28, the subject matter of any one or more of Examples 25-27 optionally includes the first tether comprises a portion of the lead body.
[0104] In Example 29, the subject matter of any one or more of Examples 25-28 optionally includes the distal retention member comprises a biocompatible mesh.
[0105] In Example 30, the subject matter of Example 29 optionally includes the distal retention member is configured to wrap at least partially around a third portion of the first nerve, wherein the third portion of the first nerve is spaced apart from the second portion of the first nerve along an axial direction of the first nerve. [0106] In Example 31, the subject matter of any one or more of Examples 29-30 optionally includes the distal retention member is configured to wrap at least partially around the distal helical anchor.
[0107] In Example 32, the subject matter of any one or more of Examples 25-31 optionally includes the first nerve comprises a portion of a vagus nerve in a cervical region of the patient body.
[0108] In Example 33, the subject matter of any one or more of Examples 25-32 optionally includes the distal retention member comprises one or more tine structures configured to be embedded in tissue of the patient body at or adjacent to the first nerve.
[0109] In Example 34, the subject matter of any one or more of Examples 25-33 optionally includes the distal retention member comprises a rigid bulbous structure.
[0110] In Example 35, the subject matter of any one or more of Examples 25-34 optionally includes the distal retention member comprises a flexible bulbous structure.
[OHl] In Example 36, the subject matter of any one or more of Examples 25-35 optionally includes the distal retention member comprises an expandable and contractible bulbous structure.
[0112] In Example 37, the subject matter of any one or more of Examples 25-36 optionally includes the distal retention member is a sacrificial member configured to be separated from other components of the electrostimulation lead upon explantation of the other components.
[0113] In Example 38, the subject matter of any one or more of Examples 25-37 optionally includes one or more of the lead body, the proximal helical anchor, the distal helical anchor, and the distal retention member comprises a polymer impregnated with a tissue ingrowth inhibitor.
[0114] In Example 39, the subject matter of any one or more of Examples 25-38 optionally includes a tissue ingrowth inhibitor covering at least a portion of an outer surface of the lead body.
[0115] In Example 40, the subject matter of any one or more of Examples 25-39 optionally includes a tissue ingrowth inhibitor covering at least a portion of an inner surface of one or both of the proximal and distal helical anchors.
[0116] In Example 41, the subject matter of any one or more of Examples 25-40 optionally includes a tissue ingrowth inhibitor covering at least a portion of an outer surface of one or both of the proximal and distal helical anchors.
[0117] In Example 42, the subject matter of any one or more of Examples 25-41 optionally includes at least one of the proximal and distal helical anchors comprises a cable embedded in a polymer support, and wherein the cable extends beyond the extents of the polymer support.
[0118] Example 43 is a method comprising: providing an implantable neurostimulation lead assembly comprising a lead body, a proximal helical anchor, a distal helical anchor, and a retention member, wherein the distal helical anchor comprises one or more therapy delivery electrodes; positioning the proximal helical anchor around a first portion of a first nerve; positioning the distal helical anchor around a second portion of the first nerve, the second portion spaced apart from the first portion of the first nerve in an axial direction of the first nerve; positioning the retention member at or near the first nerve; and providing a tissue ingrowth inhibitor at least partially around one or both of the proximal and distal helical anchors.
[0119] In Example 44, the subject matter of Example 43 optionally includes tethering the retention member to the lead body.
[0120] In Example 45, the subject matter of any one or more of Examples 43-44 optionally includes tethering the retention member to the distal helical anchor.
[0121] In Example 46, the subject matter of any one or more of Examples 43-45 optionally includes tethering the retention member to the proximal helical anchor.
[0122] In Example 47, the subject matter of any one or more of Examples 43-46 optionally includes positioning the retention member at or near the first nerve includes providing a biocompatible mesh adjacent to a portion of the first nerve. [0123] In Example 48, the subject matter of Example 47 optionally includes providing the biocompatible mesh comprises wrapping the biocompatible mesh at least partially around the first nerve.
[0124] In Example 49, the subject matter of any one or more of Examples 43-48 optionally includes positioning the retention member at or near the first nerve includes inserting one or more tines into body tissue at or near the first nerve.
[0125] In Example 50, the subject matter of any one or more of Examples 43-49 optionally includes positioning the retention member at or near the first nerve includes positioning a bulbous retention member at or near the first nerve.
[0126] In Example 51, the subject matter of Example 50 optionally includes expanding the bulbous retention member to secure the retention member within a tissue pocket.
[0127] In Example 52, the subject matter of any one or more of Examples 43-51 optionally includes applying a tissue ingrowth-inhibiting agent to at least one of the proximal helical anchor and the distal helical anchor.
[0128] In Example 53, the subject matter of any one or more of Examples 43-52 optionally includes decoupling the retention member from one or more other components of the implantable neurostimulation lead assembly to facilitate explantation of the one or more other components of the implantable neurostimulation lead assembly.
[0129] In Example 54, the subject matter of Example 53 optionally includes decoupling the retention member includes severing a tether coupling the retention member to the distal helical anchor.
[0130] In Example 55, the subject matter of any one or more of Examples 53-54 optionally includes providing the tissue ingrowth inhibitor includes wrapping an ingrowth inhibitor member substantially around at least one of the helical anchors after the at least one of the anchors is positioned around the first nerve.
[0131] Example 56 is an implantable neurostimulation system comprising: an implantable pulse generator configured to generate neurostimulation therapy signals; an implantable lead body; a first helical anchor coupled to the lead body and configured to wrap around a first portion of a cervical nerve; a second helical anchor coupled to the lead body or the first helical anchor, wherein the second helical anchor is configured to wrap around a different second portion of the cervical nerve; a first electrode affixed to the second helical anchor and electrically coupled to the implantable pulse generator; and a retention member coupled to at least one of the lead body, the first helical anchor, and the second helical anchor, wherein the retention member is configured to couple with tissue adjacent to the cervical nerve to thereby inhibit motion of the lead body, the first helical anchor, and the second helical anchor within a patient body.
[0132] In Example 57, the subject matter of Example 56 optionally includes the retention member comprises a biocompatible mesh configured to accept ingrowth of the tissue adjacent to the cervical nerve.
[0133] In Example 58, the subject matter of any one or more of Examples 56-57 optionally includes the retention member comprises one or more tine structures configured to be embedded with the tissue adjacent to the cervical nerve.
[0134] In Example 59, the subject matter of any one or more of Examples 56-58 optionally includes the retention member comprises a bulbous member configured to be disposed in a pocket of the tissue adjacent to the cervical nerve.
[0135] In Example 60, the subject matter of any one or more of Examples 56-59 optionally includes the retention member is a sacrificial member configured to be decoupled from the at least one of the lead body, the first helical anchor, and the second helical anchor upon explantation of at least one of the lead body, the first helical anchor, and the second helical anchor. [0136] In Example 61, the subject matter of any one or more of Examples 56-60 optionally includes at least one of the lead body, the first helical anchor, and the second helical anchor comprise a polymer impregnated with an anti-ingrowth agent to prevent tissue ingrowth.
[0137] Each of these non-limiting examples can stand on its own, or can be combined in various permutations or combinations with one or more of the other examples. [0138] This detailed description includes references to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments in which the invention can be practiced. These embodiments are also referred to herein as “examples.” Such examples can include elements in addition to those shown or described. However, the present inventors also contemplate examples in which only those elements shown or described are provided. The present inventors contemplate examples using any combination or permutation of those elements shown or described (or one or more aspects thereof), either with respect to a particular example (or one or more aspects thereof), or with respect to other examples (or one or more aspects thereof) shown or described herein.
[0139] In this document, the terms “a” or “an” are used, as is common in patent documents, to include one or more than one, independent of any other instances or usages of “at least one” or “one or more.” In this document, the term “or” is used to refer to a nonexclusive or, such that “A or B” includes “A but not B,” “B but not A,” and “A and B,” unless otherwise indicated. In this document, the terms “including” and “in which” are used as the plain- English equivalents of the respective terms “comprising” and “wherein.” [0140] In the following claims, the terms “including” and “comprising” are open-ended, that is, a system, device, article, composition, formulation, or process that includes elements in addition to those listed after such a term in a claim are still deemed to fall within the scope of that claim. Moreover, in the following claims, the terms “first,” “second,” and “third,” etc. are used merely as labels, and are not intended to impose numerical requirements on their objects.
[0141] The above description is intended to be illustrative, and not restrictive. For example, the above-described examples (or one or more aspects thereof) may be used in combination with each other. Other embodiments can be used, such as by one of ordinary skill in the art upon reviewing the above description. The Abstract is provided to allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also, in the above Detailed Description, various features may be grouped together to streamline the disclosure. This should not be interpreted as intending that an unclaimed disclosed feature is essential to any claim. Rather, inventive subject matter may lie in less than all features of a particular disclosed embodiment. Thus, the following claims are hereby incorporated into the Detailed Description as examples or embodiments, with each claim standing on its own as a separate embodiment, and it is contemplated that such embodiments can be combined with each other in various combinations or permutations. The scope of the invention should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.