Patent Application
20240424263
The present technology is related to chemical neuromodulation.
The sympathetic nervous system (SNS) is a primarily involuntary bodily control system typically associated with stress responses. Fibers of the SNS extend through tissue in almost every organ system of the human body and can affect characteristics such as pupil diameter, gut motility, and urinary output. Such regulation can have adaptive utility in maintaining homeostasis or in preparing the body for rapid response to environmental factors. Chronic over-activation of the SNS, however, is a common maladaptive response that can drive the progression of many disease states. Excessive activation of the renal SNS in particular has been identified experimentally and in humans as a likely contributor to the complex pathophysiology of arrhythmias, hypertension, states of volume overload (e.g., heart failure), and progressive renal disease.
The present technology is directed to devices, systems, and techniques for neuromodulation, such as renal neuromodulation, using needles. More specifically, the present disclosure describes a medical system and associated techniques for delivering a chemical agent (e.g., an ablation fluid), into perivasculature tissue of a patient, such as renal perivasculature tissue. Although renal neuromodulation is primarily described herein, devices, systems, and techniques described herein may be applied to other types of neuromodulation, such as neuromodulation performed on nerves other than the renal nerves, at sites other than within a renal vessel, or both. In general, the devices, systems, and techniques described herein may be used to perform neuromodulation from within any suitable anatomical lumen that has nerves adjacent to the anatomical lumen.
In some examples, the medical system includes a neuromodulation catheter, a distal portion of which includes a neuromodulation assembly having a plurality of therapeutic elements, e.g., fluid-delivery needles, and a radially expandable support frame positioned both proximal and distal to the therapeutic elements. The support frame may include an expandable basket-like, cage-like, and/or stent-like structure.
In an expanded or deployed configuration, the expandable support frame is configured to contact a vessel wall of the vessel both proximal and distal to the locations at which the plurality of therapeutic elements are configured to extend at least partially through the renal vessel wall to deliver the chemical agent. By contacting the vessel wall at these locations, the expandable support frame helps approximately center the distal portion of the catheter within the vessel and helps retain the distal catheter portion in position relative to the vessel wall during a neuromodulation treatment. In some examples, the neuromodulation catheter further includes a corresponding guide tube surrounding or housing each needle, e.g., extending radially outward from the catheter. In some such examples, the expandable support frame is configured to help protect the vessel wall by distributing, over a larger area, a pressure applied by contact between the neuromodulation assembly and the vessel wall.
Also disclosed herein is a medical system for delivering a chemical agent into a perivasculature of a patient includes a catheter defining a central longitudinal axis; and a neuromodulation assembly at a distal portion of the catheter, wherein the neuromodulation assembly includes one or more fluid-delivery needles configured to extend radially outward from the central longitudinal axis at a distal portion of the catheter; and a radially expandable support frame positioned both proximal and distal to the one or more fluid-delivery needles, the radially expandable support frame configured to contact a vessel wall of a vessel of a patient to approximately radially center the distal portion of the catheter within the vessel and to distribute an applied pressure between the neuromodulation assembly and the vessel wall.
The details of one or more aspects of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the techniques described in this disclosure will be apparent from the description and drawings, and from the claims.
Reference is made to the attached drawings, wherein elements having the same reference numeral designations represent similar elements throughout.
The present technology is directed to devices, systems, and methods for neuromodulation, such as renal neuromodulation, using chemical agents. Although the following examples will be described primarily with respect to renal neuromodulation, a person having ordinary skill in the art will understand that the devices, systems, and methods described herein may be used for neuromodulation at any suitable intravascular location within a body of a patient. As used herein, the terms “proximal” and “distal” define relative positions or directions with respect to a treating clinician or clinician's control device (e.g., a handle assembly). For instance, “proximal” and “proximally” can refer to a position near or in a direction toward the clinician or clinician's control device, whereas “distal” or “distally” can refer to a position distant from or in a direction away from the clinician or clinician's control device.
Renal neuromodulation, such as renal denervation, may be accomplished using one or more of a variety of treatment modalities, including radio frequency (RF) energy, microwave energy, ultrasound energy, a chemical agent, or the like. When using a chemical agent, a neuromodulation catheter may be delivered to a renal vessel, such as a renal artery or renal vein, of a patient. The neuromodulation catheter may include at least one port or needle through which the chemical agent is delivered. The chemical agent may be selected to modulate activity of one or more renal nerves adjacent to the renal vessel in which the neuromodulation catheter is positioned. For example, the chemical agent may be a neurotoxic chemical selected to chemically ablate the one or more renal nerves near the renal vessel.
In accordance with techniques of this disclosure, a distal portion of a neuromodulation catheter includes a plurality of therapeutic elements and a radially expandable support frame positioned both proximal and distal to a plurality of therapeutic elements. The plurality of therapeutic elements may be arranged around an outer perimeter (e.g., referred to herein as a circumference, though the catheter may have a cross-section other than a circle in other examples) of the distal portion of the catheter. For example, the neuromodulation catheter may include three or more therapeutic elements arranged around a circumference of the distal portion of the catheter. In some implementations, the therapeutic elements may each include a needle (also referred to herein as a “microneedle”). The needle(s) are configured to deploy or extend radially outward, relative to a longitudinal axis of the neuromodulation catheter, to pierce a wall of the renal vessel and deliver a chemical agent.
In an expanded or deployed configuration, the expandable support frame is configured to contact the renal vessel wall both proximal and distal to the locations at which the plurality of therapeutic elements are configured to extend through the vessel wall. By contacting the vessel wall at these locations, the expandable support frame increases a contact area between the catheter and the vessel wall, e.g., compared to examples in which the needles or guide tubes for the needles are the only structures that contact the vessel wall. This may help approximately center the distal portion of the catheter within the renal vessel, help retain the distal catheter portion in position relative to the renal vessel wall during the neuromodulation treatment, and/or help protect the vessel wall by redistributing an applied pressure between the therapeutic elements and the vessel wall.
As shown in
Distal portion 108B of elongated shaft 108, including neuromodulation assembly 112, is configured to be moved within an anatomical lumen of a human patient to locate therapeutic elements 110 at a target site within or otherwise proximate to the anatomical lumen. For example, elongated shaft 108 may be configured to position therapeutic elements 110 within a blood vessel, a ureter, a duct, an airway, or another naturally occurring lumen within the human body. The examples described herein focus on the anatomical lumen being a blood vessel, such as a renal vessel, but it will be understood that similar techniques may be used with other anatomical lumens. In certain examples, intravascular delivery of the therapeutic elements 110 includes percutaneously inserting a guidewire (not shown) into a vessel of a patient and moving elongated shaft 108 and/or therapeutic elements 110 along the guidewire until therapeutic elements 110 reach a target treatment site (e.g., within a renal artery). For example, distal portion 108B of elongated shaft 108 may define a passageway for engaging the guidewire for delivery of therapeutic elements 110 using over-the-wire (OTW) or rapid-exchange (RX) techniques. In other examples, neuromodulation catheter 102 can be a steerable or non-steerable device configured for use without a guidewire. In still other examples, neuromodulation catheter 102 can be configured for delivery within an inner lumen of a guide catheter or sheath (not shown), or other guide device.
Once at the target site, therapeutic elements 110 can be configured to deliver therapy, such as RF energy, microwave energy, ultrasound energy, a chemical agent, or the like, to provide or facilitate neuromodulation therapy at the target site. For ease of description, the techniques of this disclosure are described with respect to examples in which the therapy includes a chemical agent, such as a neurotoxic chemical, and in which therapeutic elements 110 include needles (e.g., microneedles). It is to be understood, however, that therapeutic elements 110 may include elements or structures configured to deliver other types of therapy. For example, therapeutic elements 110 may include needle-electrodes configured to deliver RF energy for RF ablation of nerves near the blood vessel in which neuromodulation catheter 102 is positioned.
In examples in which neuromodulation catheter 102 is configured to deliver a chemical agent, therapeutic elements 110 may include deployable needles, configured to extend radially outward from distal shaft portion 108B and at least partially pierce a wall of the blood vessel (e.g., artery, vein, etc.) in which distal shaft portion 108B is positioned. Needles 110 may extend to and/or through the intima, media, and/or adventitia of the vessel wall and deliver the chemical agent to the adventitia and/or peri-adventitia, in which renal nerves are located. By having therapeutic elements 110 distributed around a circumference of distal shaft portion 108B, neuromodulation catheter 102 may be used to deliver the chemical agent around a circumference of the blood vessel in which distal shaft portion 108B is positioned. Again, while a “circumference” of the blood vessel is generally referred to herein, the blood vessel may not necessarily be perfectly circular in cross-section, and instead, may define any suitable cross-sectional geometry.
In accordance with techniques of this disclosure, neuromodulation assembly 112 includes a radially expandable support frame 124 that positioned both proximal and distal to therapeutic elements 110. Support frame 112 may include one or more expandable cage-like or stent-like elements that provide a number of benefits over neuromodulation assemblies that do not include a support frame of this nature. For instance, support frame 124 is configured to expand radially outward in the vicinity of therapeutic elements 110 so as to approximately center distal shaft portion 108B within a target vessel. In this way, therapeutic elements 110 may be more accurately deployed and positioned around the circumference of the interior surface of the vessel, and/or more accurately deployed a desired depth into and/or through the vessel wall.
As another example, and as detailed further below, in examples in which therapeutic elements 110 include a plurality of micro-needles, the therapeutic elements may often further include a corresponding plurality of guide tubes to surround and house the respective micro-needles. In some such examples, a radially outward portion of each guide tube may be operatively coupled to, or integrated with, a radially inward portion of the expandable support frame. In such configurations, expandable support frame 124 is configured to redistribute an applied pressure that might otherwise result from contact between the outward portions of the guide tubes and the vessel wall, thereby reducing a pressure exerted on the vessel wall and protecting the vessel wall. In some examples, the increased surface area of expandable support frame 124 is further configured to increase friction between neuromodulation assembly 112 and the vessel wall, thereby helping to retain neuromodulation assembly 112 in place relative to the vessel wall during the procedure.
In the example illustrated in
An imaging device may enable image guidance, e.g., computed tomography (CT). fluoroscopy, intravascular ultrasound (IVUS), optical coherence tomography (OCT), intracardiac echocardiography (ICE), or another suitable guidance modality, or combinations thereof, to be used to aid the clinician's positioning and manipulation of distal shaft portion 108B and therapeutic elements 110. For example, a fluoroscopy system (e.g., including a flat-panel detector, x-ray, or C-arm) can be rotated to accurately visualize and identify the target treatment site. In other examples, the target treatment site can be determined using IVUS, OCT, and/or other suitable image mapping modalities that can correlate the target treatment site with an identifiable anatomical structure (e.g., a spinal feature) and/or a radiopaque ruler (e.g., positioned under or on the patient) before delivering therapeutic elements 110. Further, in some examples, image guidance components (e.g., IVUS, OCT) may be integrated with neuromodulation catheter 102 and/or run in parallel with neuromodulation catheter 102 to provide image guidance during positioning of therapeutic elements 110. For example, image guidance components (e.g., IVUS or OCT) can be coupled to therapeutic elements 110 to provide three-dimensional images of the vasculature proximate the target site to facilitate positioning or deploying therapeutic elements 110 within the target renal blood vessel.
Renal neuromodulation is the partial or complete incapacitation or other effective disruption of nerves of the kidneys (e.g., nerves terminating in the kidneys or in structures closely associated with the kidneys). In particular, renal neuromodulation can include inhibiting, reducing, and/or blocking neural communication along neural fibers (e.g., efferent and/or afferent neural fibers) of the kidneys. Such incapacitation can be long-term (e.g., permanent or for periods of months, years, or decades) or short-term (e.g., for periods of minutes, hours, days, or weeks). Renal neuromodulation is expected to contribute to the systemic reduction of sympathetic tone or drive and/or to benefit at least some specific organs and/or other bodily structures innervated by sympathetic nerves. Accordingly, renal neuromodulation is expected to be useful in treating clinical conditions associated with systemic sympathetic overactivity or hyperactivity, particularly conditions associated with central sympathetic overstimulation. For example, renal neuromodulation is expected to efficaciously treat hypertension, heart failure, acute myocardial infarction, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic and end stage renal disease, inappropriate fluid retention in heart failure, cardio-renal syndrome, polycystic kidney disease, polycystic ovary syndrome, osteoporosis, erectile dysfunction, and sudden death, among other conditions.
Renal neuromodulation can be electrically induced, thermally induced, chemically induced, or induced in another suitable manner or combination of manners at one or more suitable target sites during a treatment procedure. The target site can be within or otherwise proximate to a renal lumen (e.g., a renal artery, a ureter, a renal pelvis, a major renal calyx, a minor renal calyx, or another suitable structure), and the treated tissue can include tissue at least proximate to a wall of the renal lumen. For example, with regard to a renal artery, a treatment procedure can include modulating nerves in the renal plexus, which lay intimately within or adjacent to the adventitia of the renal artery.
The following discussion provides further details regarding patient anatomy and physiology as it may relate to renal denervation therapy. This section is intended to supplement and expand upon the previous discussion regarding the relevant anatomy and physiology, and to provide additional context regarding the disclosed technology and the therapeutic benefits associated with renal denervation. For example, several properties of the renal vasculature may inform the design of treatment devices and associated methods for achieving renal neuromodulation via intravascular access and impose specific design requirements for such devices. Specific design requirements may include accessing the renal artery, positioning therapeutic elements 110 within the renal artery and relative to other physiological structures (such as an accessory renal artery), delivering the chemical agent to targeted tissue, and/or effectively modulating the renal nerves with the therapy delivery device.
As noted previously, the sympathetic nervous system (SNS) is a branch of the autonomic nervous system along with the enteric nervous system and parasympathetic nervous system. It is always active at a basal level (called sympathetic tone) and becomes more active during times of stress. Like other parts of the nervous system, the sympathetic nervous system operates through a series of interconnected neurons. Sympathetic neurons are frequently considered part of the peripheral nervous system (PNS), although many lie within the central nervous system (CNS). Sympathetic neurons of the spinal cord (which is part of the CNS) communicate with peripheral sympathetic neurons via a series of sympathetic ganglia. Within the ganglia, spinal cord sympathetic neurons join peripheral sympathetic neurons through synapses. Spinal cord sympathetic neurons are therefore called presynaptic (or preganglionic) neurons, while peripheral sympathetic neurons are called postsynaptic (or postganglionic) neurons.
At synapses within the sympathetic ganglia, preganglionic sympathetic neurons release acetylcholine, a chemical messenger that binds and activates nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulus, postganglionic neurons principally release noradrenaline (norepinephrine). Prolonged activation may elicit the release of adrenaline from the adrenal medulla.
Once released, norepinephrine and epinephrine bind adrenergic receptors on peripheral tissues. Binding to adrenergic receptors causes a neuronal and hormonal response. The physiologic manifestations include pupil dilation, increased heart rate, occasional vomiting, and increased blood pressure. Increased sweating is also seen due to binding of cholinergic receptors of the sweat glands.
The sympathetic nervous system is responsible for up-and down-regulating many homeostatic mechanisms in living organisms. Fibers from the SNS innervate tissues in almost every organ system, providing at least some regulatory function to physiological features as diverse as pupil diameter, gut motility, and urinary output. This response is also known as sympatho-adrenal response of the body, as the preganglionic sympathetic fibers that end in the adrenal medulla (but also all other sympathetic fibers) secrete acetylcholine, which activates the secretion of adrenaline (epinephrine) and to a lesser extent noradrenaline (norepinephrine). Therefore, this response that acts primarily on the cardiovascular system is mediated directly via impulses transmitted through the sympathetic nervous system and indirectly via catecholamines secreted from the adrenal medulla.
Science typically looks at the SNS as an automatic regulation system, that is, one that operates without the intervention of conscious thought. Some evolutionary theorists suggest that the sympathetic nervous system operated in early organisms to maintain survival as the sympathetic nervous system is responsible for priming the body for action. One example of this priming is in the moments before waking, in which sympathetic outflow spontaneously increases in preparation for action.
As shown in
In order to reach the target organs and glands, the axons should travel long distances in the body, and, to accomplish this, many axons relay their message to a second cell through synaptic transmission. The ends of the axons link across a space, the synapse, to the dendrites of the second cell. The first cell (the presynaptic cell) sends a neurotransmitter across the synaptic cleft where it activates the second cell (the postsynaptic cell). The message is then carried to the final destination.
In the SNS and other components of the peripheral nervous system, these synapses are made at sites called ganglia, discussed above. The cell that sends its fiber to the ganglion is called a preganglionic cell, while the cell whose fiber leaves the ganglion is called a postganglionic cell. As mentioned previously, the preganglionic cells of the SNS are located between the first thoracic (T1) segment and third lumbar (L3) segments of the spinal cord. Postganglionic cells have their cell bodies in the ganglia and send their axons to target organs or glands.
The ganglia include not just the sympathetic trunks but also the cervical ganglia (superior, middle and inferior), which sends sympathetic nerve fibers to the head and thorax organs, and the celiac and mesenteric ganglia (which send sympathetic fibers to the gut).
As
Preganglionic neuronal cell bodies are located in the intermediolateral cell column of the spinal cord. Preganglionic axons pass through the paravertebral ganglia (they do not synapse) to become the lesser splanchnic nerve, the least splanchnic nerve, the first lumbar splanchnic nerve, the second lumbar splanchnic nerve, and travel to the celiac ganglion, the superior mesenteric ganglion, and the aorticorenal ganglion. Postganglionic neuronal cell bodies exit the celiac ganglion, the superior mesenteric ganglion, and the aorticorenal ganglion to the renal plexus (RP) and are distributed to the renal vasculature.
Messages travel through the SNS in a bidirectional flow. Efferent messages may trigger changes in different parts of the body simultaneously. For example, the sympathetic nervous system may accelerate heart rate; widen bronchial passages; decrease motility (movement) of the large intestine; constrict blood vessels; increase peristalsis in the esophagus; cause pupil dilation, piloerection (goose bumps) and perspiration (sweating); or raise blood pressure. Afferent messages carry signals from various organs and sensory receptors in the body to other organs and, particularly, the brain.
Hypertension, heart failure, and chronic kidney disease are a few of many disease states that result from chronic activation of the SNS, especially the renal sympathetic nervous system. Chronic activation of the SNS is a maladaptive response that drives the progression of these disease states. Pharmaceutical management of the renin-angiotensin-aldosterone system (RAAS) has been a longstanding, but somewhat ineffective, approach for reducing over-activity of the SNS.
As mentioned above, the renal sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload (such as heart failure), and progressive renal disease, both experimentally and in humans. Studies employing radiotracer dilution methodology to measure overflow of norepinephrine from the kidneys to plasma revealed increased renal norepinephrine (NE) spillover rates in patients with essential hypertension, particularly so in young hypertensive subjects, which in concert with increased NE spillover from the heart, is consistent with the hemodynamic profile typically seen in early hypertension and characterized by an increased heart rate, cardiac output, and renovascular resistance. It is now known that essential hypertension is commonly neurogenic, often accompanied by pronounced sympathetic nervous system overactivity.
Activation of cardiorenal sympathetic nerve activity is even more pronounced in heart failure, as demonstrated by an exaggerated increase of NE overflow from the heart and the kidneys to plasma in this patient group. In line with this notion is the recent demonstration of a strong negative predictive value of renal sympathetic activation on all-cause mortality and heart transplantation in patients with congestive heart failure, which is independent of overall sympathetic activity, glomerular filtration rate, and left ventricular ejection fraction. These findings support the notion that treatment regimens that are designed to reduce renal sympathetic stimulation have the potential to improve survival in patients with heart failure.
Both chronic and end stage renal disease in some patients are characterized by heightened sympathetic nervous activation. In patients with end stage renal disease, plasma levels of norepinephrine above the median have been demonstrated to be predictive for both all-cause death and death from cardiovascular disease. This can also be true for patients suffering from diabetic or contrast nephropathy. There is compelling evidence suggesting that sensory afferent signals originating from the diseased kidneys are major contributors to initiating and sustaining elevated central sympathetic outflow in this patient group; this facilitates the occurrence of the well-known adverse consequences of chronic sympathetic over activity, such as hypertension, left ventricular hypertrophy, ventricular arrhythmias, sudden cardiac death, insulin resistance, diabetes, and metabolic syndrome.
Sympathetic nerves to the kidneys terminate in the blood vessels, the juxtaglomerular apparatus and the renal tubules. Stimulation of the renal sympathetic nerves causes increased renin release, increased sodium (Na+) reabsorption, and a reduction of renal blood flow. These components of the neural regulation of renal function are considerably stimulated in disease states characterized by heightened sympathetic tone and clearly contribute to the rise in blood pressure in hypertensive patients. The reduction of renal blood flow and glomerular filtration rate as a result of renal sympathetic efferent stimulation may be a cornerstone of the loss of renal function in cardio-renal syndrome, which is renal dysfunction as a progressive complication of chronic heart failure, with a clinical course that typically fluctuates with the patient's clinical status and treatment. Pharmacologic strategies to thwart the consequences of renal efferent sympathetic stimulation include centrally acting sympatholytic drugs, beta blockers (intended to reduce renin release), angiotensin converting enzyme inhibitors and receptor blockers (intended to block the action of angiotensin II and aldosterone activation consequent to renin release), and diuretics (intended to counter the renal sympathetic mediated sodium and water retention). However, the current pharmacologic strategies can have significant limitations including limited efficacy, compliance issues, side effects and others.
The kidneys communicate with integral structures in the central nervous system via renal sensory afferent nerves. Several forms of “renal injury” may induce activation of sensory afferent signals. For example, renal ischemia, reduction in stroke volume or renal blood flow, or an abundance of adenosine enzyme may trigger activation of afferent neural communication. As shown in
The physiology therefore suggests that (i) modulation of tissue with efferent sympathetic nerves will reduce inappropriate renin release, salt retention, and reduction of renal blood flow, and that (ii) modulation of tissue with afferent sensory nerves will reduce the systemic contribution to hypertension and other disease states associated with increased central sympathetic tone through its direct effect on the posterior hypothalamus as well as the contralateral kidney. In addition to the central hypotensive effects of afferent renal denervation, a desirable reduction of central sympathetic outflow to various other sympathetically innervated organs such as the heart and the vasculature is anticipated.
As provided above, renal denervation is likely to be valuable in the treatment of several clinical conditions characterized by increased overall and particularly renal sympathetic activity such as hypertension, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic end stage renal disease, inappropriate fluid retention in heart failure, cardio-renal syndrome, and sudden death. Since the reduction of afferent neural signals contributes to the systemic reduction of sympathetic tone/drive, renal denervation might also be useful in treating other conditions associated with systemic sympathetic hyperactivity. Accordingly, renal denervation may also benefit other organs and bodily structures innervated by sympathetic nerves, including those identified in
In accordance with the present technology, neuromodulation of a left and/or right renal plexus (RP), which is intimately associated with a left and/or right renal artery, may be achieved through intravascular access. As
As
In some examples, the femoral artery may be accessed and cannulated at the base of the femoral triangle just inferior to the midpoint of the inguinal ligament. A catheter may be inserted percutaneously into the femoral artery through this access site, passed through the iliac artery and aorta, and placed into either the left or right renal artery. This comprises an intravascular path that offers minimally invasive access to a respective renal artery and/or other renal blood vessels.
The wrist, upper arm, and shoulder regions provide other locations for introduction of catheters into the arterial system. For example, catheterization of either the radial, brachial, or axillary artery may be utilized in select cases. Catheters introduced via these access points may be passed through the subclavian artery on the left side (or via the subclavian and brachiocephalic arteries on the right side), through the aortic arch, down the descending aorta and into the renal arteries using standard angiographic technique. Other access sites can also be used to access the arterial system.
Since neuromodulation of a left and/or right renal plexus (RP) may be achieved in accordance with the present technology through intravascular access, properties and characteristics of the renal vasculature may impose constraints upon and/or inform the design of apparatus, systems, and methods for achieving such renal neuromodulation. Some of these properties and characteristics may vary across the patient population and/or within a specific patient across time, as well as in response to disease states, such as hypertension, chronic kidney disease, vascular disease, end-stage renal disease, insulin resistance, diabetes, metabolic syndrome, and the like. These properties and characteristics, as explained herein, may have bearing on the efficacy of the procedure and the specific design of the intravascular device. Properties of interest may include, for example, material/mechanical, spatial, fluid dynamic/hemodynamic and/or thermodynamic properties.
As discussed previously, a catheter may be advanced percutaneously into either the left or right renal artery via a minimally invasive intravascular path. However, minimally invasive renal arterial access may be challenging, for example, because as compared to some other arteries that are routinely accessed using catheters, the renal arteries are often extremely tortuous, may be of relatively small diameter, and/or may be of relatively short length. Furthermore, renal arterial atherosclerosis is common in many patients, particularly those with cardiovascular disease. Renal arterial anatomy also may vary significantly from patient to patient, which further complicates minimally invasive access. Significant inter-patient variation may be seen, for example, in relative tortuosity, diameter, length, and/or atherosclerotic plaque burden, as well as in the take-off angle at which a renal artery branches from the aorta. Further, some patients include multiple left renal arteries and/or right renal arteries. Apparatus, systems and methods for achieving renal neuromodulation via intravascular access should account for these and other aspects of renal arterial anatomy and its variation across the patient population when minimally invasively accessing a renal artery.
In addition to complicating renal arterial access, specifics of the renal anatomy also complicate establishment of stable contact between neuromodulatory apparatus and a luminal surface or wall of a renal artery. For example, navigation can be impeded by the tight space within a renal artery, as well as tortuosity of the artery. Furthermore, establishing consistent contact is complicated by patient movement, respiration, and/or the cardiac cycle because these factors may cause significant movement of the renal artery relative to the aorta, and the cardiac cycle may transiently distend the renal artery (i.e., cause the wall of the artery to pulse).
Even after accessing a renal artery and facilitating stable contact between neuromodulatory apparatus and a luminal surface of the artery, nerves in and around the adventitia of the artery should be safely modulated via the neuromodulatory apparatus. As discussed in greater detail below, the intima-media thickness separating the vessel lumen from its adventitia means that target renal nerves may be multiple millimeters distant from the luminal surface of the artery. The chemical agent should be delivered to the target renal nerves to modulate the target renal nerves without excessively adversely affecting the vessel wall.
The neuromodulatory apparatus 112 may also be configured to allow for adjustable positioning and repositioning of the therapeutic elements 110 (
As noted above, an apparatus positioned within a renal artery should be configured so that therapeutic elements 110 may intimately contact the vessel wall and/or extend at least partially through the vessel wall. A renal artery vessel diameter DRA is typically in a range of about 2-10 millimeters (mm), with most of the patient population having a DRA of about 4 mm to about 8 mm and an average of about 6 mm. A renal artery vessel length LRA, between its ostium at the aorta/renal artery juncture and its distal branchings, is generally in a range of about 5-70 mm, and a significant portion of the patient population is in a range of about 20-50 mm. Since the target renal plexus is embedded within the adventitia of the renal artery, the composite Intima-Media Thickness, IMT, (i.e., the radial outward distance from the artery's luminal surface to the adventitia containing target neural structures) also is notable and generally is in a range of about 0.5-2.5 mm, with an average of about 1.5 mm. Although a certain depth of treatment is important to reach the target neural fibers, the treatment should not be too deep (e.g., >10 mm from inner wall of the renal artery) to avoid non-target tissue and anatomical structures such as anatomical structures of the digestive system or psoas muscle.
An additional property of the renal artery that may be of interest is the degree of renal motion relative to the aorta induced by respiration and/or blood flow pulsatility. A patient's kidney, which is located at the distal end of the renal artery, may move as much as 10 centimeters cranially with respiratory excursion. This may impart significant motion to the renal artery connecting the aorta and the kidney, thereby requiring from the neuromodulatory apparatus 112 a unique balance of stiffness and flexibility to maintain contact between the therapy-delivery element 110 and the vessel wall during cycles of respiration. Furthermore, the take-off angle between the renal artery and the aorta may vary significantly between patients, and also may vary dynamically within a patient, e.g., due to kidney motion. The take-off angle generally may be in a range of about 30°-135°.
As shown in
Therapeutic elements 110 are configured to deliver a chemical agent, such as a neurotoxic chemical, through the plurality of therapeutic elements 110. The chemical agent may be selected to neuromodulate (e.g., chemically ablate) nerve tissue of the renal plexus adjacent to renal artery 116. The chemical agent may include, for example, an alcohol, such as ethanol; distilled water; hypertonic saline; hypotonic saline; phenol; glycerol; lidocaine; bupivacaine; tetracaine; benzocaine; guanethidine; botulinum toxin; another appropriate neurotoxic fluid; or combinations thereof. In some examples, the chemical agent may be heated or cooled to additionally or alternatively thermally ablate nerve tissue of the renal plexus adjacent to renal artery 116. In other examples, the chemical agent may include a fluid configured for another purpose, such as a protective fluid, a fluid configured to increase conductivity, or fluids for other applications.
As shown in
Therapeutic elements 110 are configured to be carried by neuromodulation catheter 102 in a “delivery” configuration as distal shaft portion 108B of neuromodulation catheter 102 is advanced through vasculature of the patient to renal artery 116. Therapeutic elements 110 are also configured to transform to a “deployed” configuration, which is shown in
As another example, in the delivery configuration, needles 120 may be withdrawn into guide tubes 122 and guide tubes 122 may be urged (e.g., collapsed radially inward) against an outer surface of neuromodulation catheter 102 using a guide sheath (not shown in
As shown in
Expandable support frame 124 may be located adjacent to therapeutic elements 110, e.g., both proximally and distally. As detailed further below with respect to
Expandable support frame 124 may be configured to expand via any suitable mechanism. For instance, expandable support frame 124 may be operatively coupled to an elongated pullwire that extends the length of catheter body 108 to an appropriate actuator mechanism, e.g., on handle 106 (
As described above with respect to
While
As shown in
In some examples, a radially outer tube portion 228 (e.g., outer tube portions 128 of
Proximal and distal rings 234A, 234B are positioned on longitudinally opposite sides of the guide tubes 222, respectively. Collectively, rings 234 define a longitudinally central portion of support frame 224 that is approximately radially consistent (e.g., along an exterior surface of rings 234). Similar to the example described above with respect to
Rings 234 may be configured to expand and collapse via any suitable mechanism. For example, rings 234 may define a plurality of circumferential folds or pleats that guide or enable rings 234 to collapse circumferentially inward toward catheter 102. Additionally or alternatively, rings 234 may each include a planar coil structure, configured to self-expand circumferentially outward, e.g., when no longer retained within a lumen of a delivery sheath. In other examples, rings 234 may each include a planar coil structure configured (e.g., biased) to self-collapse circumferentially inward. For instance, rings 234 may be in a default state when in the low-profile delivery configuration. A clinician may actuate a proximal actuator (e.g., pullwire, pushwire, etc.) to cause struts 230 to expand radially outward away from catheter 102, thereby forcing rings 234 circumferentially outward and retaining rings 234 in the deployed configuration shown in
In some examples, proximal and/or distal rings 234A, 234B may include an expandable-stent-like expansion mechanism. For instance,
In some examples, elongated arms 230 and/or rings 234 may include or may be formed from one or more elongated filaments or filars formed from a shape-memory material, such as Nitinol. For instance, an elongated shape-memory filar may be advanced outward from a sidewall of catheter 102, or alternatively, from a distal opening to a lumen defined by a more-rigid tubular structure of one of support arms 230. The elongated filar may then be actuated to assume its predefined (e.g., heat-set) shape. For example, a distal portion of the elongated filar may be configured to convert from a substantially linear shape into a substantially circular or coiled shape, forming a structure similar to rings 234.
In other examples, such as the example illustrated in
Similar to neuromodulation assembly 212, neuromodulation assembly 312 includes an expandable support frame 324 that includes proximal and distal rings 234A, 234B, positioned on either longitudinal side of coiled guide tubes 222. However, in place of more-rigid support struts 230, support frame 324 includes a plurality of more-flexible support struts 330 (e.g., longitudinal legs 130 of
As shown in
In some examples, such as the example illustrated in
Outer tube portions 428 (e.g., outer tube portions 128 of
In some examples, such as the example illustrated in
As shown in
For instance, in a first example “umbrella-like” expansion mechanism of support frame 524, the proximal ends of longitudinal struts 530 are rigidly coupled to outer shaft 548A, such that a distal motion of outer shaft 548A relative to inner shaft 548B is configured to cause the plurality of longitudinal struts 530 to expand radially outward into the deployed configuration of expandable support frame 524 shown in
Similarly, in a second example expansion mechanism of support frame 524, distal element 554 may be rigidly coupled to a central elongated member 538 (e.g., central elongated member 338 of
In a third example “retractable-sheath-like” expansion mechanism of support frame 524, the proximal ends of longitudinal struts 530 are received within outer shaft lumen 552, e.g., positioned in the annular space between the interior surface of outer shaft 548A and the exterior surface of inner shaft 548B. In such examples, a proximal “retraction” motion of outer shaft 548A relative to inner shaft 548B enables the plurality of longitudinal struts 530 to self-expand radially outward into the expanded configuration of support frame 524. Conversely, outer shaft 548A may be moved distally overtop of inner shaft 548B to collapse longitudinal struts 530 back into the delivery configuration of support frame 524.
In the example shown in
As illustrated in the end view of
The technique of
Once positioned at the target treatment site, the clinician may deploy (e.g., manually actuate and/or passively enable) radially expandable support frame 124 of a neuromodulation assembly 112 positioned at the distal portion 108B of catheter 102 (704). For instance, the clinician may actuate a pullwire, engage a push mechanism, withdraw a retractable sheath, or perform any other appropriate action to cause or enable support frame 124 to expand radially outward.
The expanded support frame 124 contacts the renal vessel wall 118 at multiple locations to approximately radially center catheter 102 (and neuromodulation assembly 112) within renal vessel 116. Once expandable support frame 124 is positioned within renal artery 116, the clinician may deploy the plurality of therapeutic elements 110 to extend radially outward through expandable support frame 124 and at least partially through renal vessel wall 118 (706). In examples in which therapeutic elements 110 include both fluid-delivery needles 120 and respective guide tubes 122, expandable support frame 124 helps protect vessel wall 118 from excessive pressure applied by outer portions 128 of guide tubes 122, but distributing the applied pressure across the greater outer surface area of the support frame 124.
Once the plurality of therapeutic elements 110 have been deployed to extend at least partially through wall 118 of renal artery 116 (706), the clinician may deliver a chemical agent (e.g., an ablation fluid) through the plurality of therapeutic elements 110 to modulate activity of at least one renal nerve adjacent to renal artery 116 (708). Neuromodulation assembly 112 may then be returned to a collapsed “delivery” configuration, e.g., by retracting needles 120 through guide tubes 122 and by actuating guide tubes 122 and support frame 124 to collapse radially inward toward distal catheter portion 108B (710). The clinician may then proximally withdraw neuromodulation catheter 102 from the patient's vasculature (712).
The above detailed descriptions of examples of the technology are not intended to be exhaustive or to limit the technology to the precise form disclosed above. Although specific examples of the technology are described above for illustrative purposes, various equivalent modifications are possible within the scope of the technology, as those skilled in the relevant art will recognize. For example, while steps are presented in a given order, alternative examples may perform steps in a different order. The various examples described herein may also be combined to provide further examples. All references cited herein are incorporated by reference as if fully set forth herein.
From the foregoing, it will be appreciated that specific examples of the present disclosure have been described herein for purposes of illustration, but that various modifications may be made without deviating from the present disclosure. For example, while particular features of the neuromodulation catheters were described as being part of a single device, in other examples, these features can be included on one or more separate devices that can be positioned adjacent to and/or used in tandem with the neuromodulation catheters to perform similar functions to those described herein. Additionally, while the description of the present technology is focused on delivering chemical agents, the present technology can equally be applied to other methods of neuromodulation therapy, including cooling, heating, electrical stimulation (using needle electrodes), RF energy delivery (using needle electrodes), microwave energy delivery (using microwave needles), ultrasound (using ultrasound transducers), or the like.
Certain aspects of the present disclosure described in the context of particular examples may be combined or eliminated in other embodiments. For example, any sub-components of the expandable support frames 124, 224, 324, 424, 524, and 624 may be combined in any suitable manner. Further, while advantages associated with certain examples have been described in the context of those examples, other examples may also exhibit such advantages, and not all examples need necessarily exhibit such advantages to fall within the scope of the present disclosure. Accordingly, the present disclosure and associated technology can encompass other examples not expressly shown or described herein.
Further, although techniques have been described in which a neuromodulation catheter is positioned at a single location within a single renal artery, in other examples, the neuromodulation catheter may be repositioned to a second treatment site within the single renal artery (e.g., proximal or distal of the first treatment site, may be repositioned in a branch of the single artery, may be repositioned within a different renal vessel on the same side of the patient (e.g., a renal vessel associated with the same kidney of the patient), may be repositioned in a renal vessel on the other side of the patient (e.g., a renal vessel associated with the other kidney of the patient), or any combination thereof. At each location where the neuromodulation catheter is positioned, renal neuromodulation may be performed using any of the techniques described herein or any other suitable renal neuromodulation technique, or any combination thereof.
Moreover, unless the word “or” is expressly limited to mean only a single item exclusive from the other items in reference to a list of two or more items, then the use of “or” in such a list is to be interpreted as including (a) any single item in the list, (b) all of the items in the list, or (c) any combination of the items in the list. Additionally, the terms “about” or “approximately,” when preceding a value, should be interpreted to mean plus or minus 10% of the value, unless otherwise indicated. Additionally, the term “comprising” is used throughout to mean including at least the recited feature(s) such that any greater number of the same feature and/or additional types of other features are not precluded.
Further disclosed herein is the subject-matter of the following clauses:
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/079788 | 10/25/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63273669 | Oct 2021 | US |
