# Patent

## Title
Minimally invasive access for renal nerve ablation

## Abstract

An elongated flexible medical device is inserted into a patient's body via a natural orifice, and advanced through the natural orifice to a location proximate innervated tissue that influences renal sympathetic nerve activity. The medical device can be advanced into a body organ and to a location within the organ proximate the innervated tissue. The organ may comprise an organ of the gastrointestinal tract or urinary tract. The medical device may be advanced through and beyond an access hole in a wall of the organ, and situated at a location proximate the innervated tissue. One or both of imaging and ablation energy is delivered from a distal end of the medical device to the innervated tissue. Innervated renal tissue can be ablated using various forms of energy, including RF energy, ultrasound energy, optical energy, and thermal energy.

## Background
RELATED PATENT DOCUMENTS
This application claims the benefit of Provisional Patent Application Ser. Nos. 61/414,299 filed Nov. 16, 2010 and 61/491,731 filed May 31, 2011, to which priority is claimed pursuant to 35 U.S.C. §119(e) and which are hereby incorporated herein by reference.


SUMMARY
Devices, systems, and methods of the disclosure are directed to ablating target tissue of the body, imaging target tissue of the body, and both imaging and ablating target tissue of the body. Devices, systems, and methods of the disclosure are directed to ablating and/or imaging target tissue of the body using a medical device introduced into the body via a natural orifice or a minimally invasive access path. Embodiments are directed to modifying renal sympathetic nerve activity using one or a combination of ablation apparatuses and methodologies. Embodiments are directed to imaging innervated tissue that influences renal sympathetic nerve activity using an imaging arrangement, and ablating the innervated tissue using an ablation apparatus, wherein at least one of the imaging and ablation apparatuses is configured for introduction into the body via a natural orifice or a minimally invasive access path.
Various embodiments of the disclosure are directed to methods involving inserting an elongated flexible medical device into a patient's body via a natural orifice, advancing the medical device through the natural orifice and to a location proximate innervated tissue that influences renal sympathetic nerve activity, and delivering energy from a distal end of the medical device to the innervated tissue. Inserting the medical device into the patient's body may involve inserting the medical device into an organ of the patient's body and to a location within the organ proximate the innervated tissue. The organ may comprise an organ of the patient's gastrointestinal tract or urinary tract. Inserting the medical device into the patient's body may involve advancing the medical device through an access hole in a wall of the organ, and advancing the medical device beyond the access hole and to a location proximate the innervated tissue.
According to some embodiments, the medical device is advanced through at least a portion of the patient's digestive system via an upper gastrointestinal access path. In other embodiments, the medical device is advanced through at least a portion of the patient's digestive system via a lower gastrointestinal access path. In further embodiments, the medical device is advanced through at least a portion of a ureter of the patient accessed via the patient's bladder. The innervated tissue can be ablated using various forms of energy, including RF energy, ultrasound energy, optical energy, and thermal energy.
In accordance with various embodiments, apparatuses of the disclosure include an elongated flexible medical device configured for insertion into a patient's body via a natural orifice. The medical device preferably has a length sufficient for advancement between the natural orifice and a location at or proximate innervated tissue that influences renal sympathetic nerve activity via an internal body pathway, such as the gastrointestinal tract or urinary tract of the patient. An energy delivery device is provided at a distal end of the medical device and configured to communicate energy to the location at or proximate the innervated tissue. The energy delivery device may include a radiofrequency ablation device, an ultrasound ablation device, an optical ablation device, or a thermal ablation device.
The medical device may be configured for insertion into an organ of the patient's body via the natural orifice. The medical device may be configured for extra-organ deployment via an access hole in the organ. The medical device may be configured for advancement through at least a portion of the patient's digestive system via an upper gastrointestinal access path or a lower gastrointestinal access path. In some embodiments, the medical device may be configured for advancement through at least a portion of a ureter of the patient accessed via the patient's bladder.
These and other features can be understood in view of the following detailed discussion and the accompanying drawings.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an illustration of a right kidney and renal vasculature including a renal artery branching laterally from the abdominal aorta;
FIGS. 2A and 2B illustrate sympathetic innervation of the renal artery;
FIG. 3A illustrates various tissue layers of the wall of the renal artery;
FIGS. 3B and 3C illustrate a portion of a renal nerve;
FIG. 4 illustrates a medical system including a medical device positioned within an organ, body of tissue, or cavity of the patient's body near the renal artery accessed via a natural orifice in accordance with various embodiments;
FIG. 5 illustrates a medical device positioned within a gastrointestinal organ of the patient's body near the renal artery accessed via a natural orifice and an upper gastrointestinal pathway in accordance with various embodiments;
FIG. 6 illustrates a medical device positioned within a gastrointestinal organ of the patient's body near the renal artery accessed via a natural orifice and a lower gastrointestinal pathway in accordance with various embodiments;
FIG. 7 illustrates a medical device positioned outside of a gastrointestinal organ of the patient's body near the renal artery accessed via a natural orifice and a lower gastrointestinal pathway in accordance with various embodiments;
FIGS. 8 and 9 illustrate a medical device positioned within an organ, body of tissue, or cavity of the patient's body near the renal artery accessed via a natural orifice and a second medical device positioned within the renal artery in accordance with various embodiments;
FIG. 10 illustrates a medical device positioned within an organ of the patient's body near the renal artery accessed via a natural orifice and a urinary tract pathway, and further illustrates an optional second medical device positioned within the renal artery in accordance with various embodiments;
FIG. 11 illustrates a medical system including a medical device positioned within a blood vessel of the patient's body near the renal artery accessed via a minimally invasive access pathway in accordance with various embodiments;
FIGS. 12 and 13 illustrate ultrasound energy delivery devices provided at a distal end of a medical device in accordance with various embodiments;
FIGS. 14 and 15 illustrate optical energy delivery devices provided at a distal end of a medical device in accordance with various embodiments;
FIG. 16 illustrates a thermal energy delivery device provided at a distal end of a medical device in accordance with various embodiments; and
FIG. 17 illustrates a medical system for ablating innervated renal tissue using radiofrequency energy in accordance with various embodiments.



DESCRIPTION
Embodiments of the disclosure are directed to apparatuses and methods for ablating target tissue of the body using at least one of various forms of energy. Embodiments of the disclosure are directed to apparatuses and methods for imaging target tissue of the body using at least one of various forms of energy. Embodiments of the disclosure are directed to apparatuses and methods for both imaging and ablating target tissue of the body using at least one of various forms of energy. One or both of imaging and ablating target tissue of the body is preferably performed by accessing an organ, body of tissue, or a cavity or space of the body situated near the target tissue via a natural orifice of the body. Embodiments of the disclosure are directed to one or both of imaging and ablating innervated tissue that influences sympathetic renal nerve activity performed by accessing an organ, body of tissue, cavity or space of the body situated near the innervated renal tissue via a natural orifice of the body, such as for control of hypertension.
Various embodiments are directed to apparatuses and methods for utilizing one or more body pathways for accessing target tissue within a patient's body. Suitable body pathways include those that utilize a natural orifice of the body. In some embodiments, a minimally invasive percutaneous access location of the patient's body is used to gain access to a body pathway within the patient. In this context, a percutaneous access location is not considered part of the body pathway, but instead provides access to the body pathway.
Representative non-limiting body pathways include internal pathways that pass at least partially into, through, or around one or a combination of organs, tissue bodies, cavities, vessels, ducts, chambers, spaces between organs (sometimes filled with fluid), virtual spaces defined by loosely connected interfaces between organs or tissues usually directly apposed but capable of being separated when deformed or displaced (such as when fluid is injected or a catheter introduced), space between an abdominal wall and adjacent fascia, intraperitoneal space, and retroperitoneal space, for example. Representative non-limiting organs in the context of various body pathway embodiments include the brain, kidney, heart, liver, nerves, small intestine, colon, lungs, bladder and ureter, and psoas muscle, among many others. Preferred body pathways are those that originate from a natural orifice of the body.
According to various embodiments, an endoscope or other medical device is placed in the gastrointestinal tract, such as through the mouth or nose, through the esophagus, stomach, and into the small intestine. At the duodenum or the jejunum, an imaging device can be placed to aid in treatment of perivascular renal nerves and/or an ablation device can be placed to ablate the renal nerves. A medical device can be used inside the intestines, or the intestinal wall can be pierced to gain access to the nearby renal nerves.
In other embodiments, an endoscopic access through the anus is used to place an imaging or treatment device in the colon, which passes near the renal nerves. In further embodiments, the hepatic or portal venous circulation is accessed, such as in a manner similar to a TIPS (transjugular intrahepatic portosystemic shunt) procedure, and used to gain access to nearby renal nerves. In some embodiments, renal nerve access can be achieved using a trans-hepatic route via the inferior vena cava and hepatic vein, similar to a TIPS procedure. In various embodiments, renal nerve access can be achieved using a body pathway that includes the inferior vena cava, hepatic vein, liver, and intraperitoneum. According to other embodiments, the ureter(s) are accessed by a ureteroscope or other catheter system in a manner similar to ureteral stenting or kidney stone removal, and used to gain access to nearby renal nerves.
Combinations of various access approaches and/or conventional approaches can be used to provide improved location, imaging, and focusing of energy sources to provide improved renal nerve ablation with less injury to the renal artery. For example, a large or distributed electrode in the small intestine or colon, and a smaller electrode in the renal artery or renal vein, can be used for a bipolar RF ablation procedure with improved treatment area localization. Other body cavities, vessels, chambers, organs, or potential spaces can be used to access the renal nerves. Other forms of energy can be delivered for one or both of imaging and ablating innervated renal tissue.
Various embodiments of the disclosure are directed to apparatuses and methods for renal denervation for treating hypertension. Hypertension is a chronic medical condition in which the blood pressure is elevated. Persistent hypertension is a significant risk factor associated with a variety of adverse medical conditions, including heart attacks, heart failure, arterial aneurysms, and strokes. Persistent hypertension is a leading cause of chronic renal failure. Hyperactivity of the sympathetic nervous system serving the kidneys is associated with hypertension and its progression. Deactivation of nerves in the kidneys via renal denervation can reduce blood pressure, and may be a viable treatment option for many patients with hypertension who do not respond to conventional drugs.
The kidneys are instrumental in a number of body processes, including blood filtration, regulation of fluid balance, blood pressure control, electrolyte balance, and hormone production. One primary function of the kidneys is to remove toxins, mineral salts, and water from the blood to form urine. The kidneys receive about 20-25% of cardiac output through the renal arteries that branch left and right from the abdominal aorta, entering each kidney at the concave surface of the kidneys, the renal hilum.
Blood flows into the kidneys through the renal artery and the afferent arteriole, entering the filtration portion of the kidney, the renal corpuscle. The renal corpuscle is composed of the glomerulus, a thicket of capillaries, surrounded by a fluid-filled, cup-like sac called Bowman's capsule. Solutes in the blood are filtered through the very thin capillary walls of the glomerulus due to the pressure gradient that exists between the blood in the capillaries and the fluid in the Bowman's capsule. The pressure gradient is controlled by the contraction or dilation of the arterioles. After filtration occurs, the filtered blood moves through the efferent arteriole and the peritubular capillaries, converging in the interlobular veins, and finally exiting the kidney through the renal vein.
Particles and fluid filtered from the blood move from the Bowman's capsule through a number of tubules to a collecting duct. Urine is formed in the collecting duct and then exits through the ureter and bladder. The tubules are surrounded by the peritubular capillaries (containing the filtered blood). As the filtrate moves through the tubules and toward the collecting duct, nutrients, water, and electrolytes, such as sodium and chloride, are reabsorbed into the blood.
The kidneys are innervated by the renal plexus which emanates primarily from the aorticorenal ganglion. Renal ganglia are formed by the nerves of the renal plexus as the nerves follow along the course of the renal artery and into the kidney. The renal nerves are part of the autonomic nervous system which includes sympathetic and parasympathetic components. The sympathetic nervous system is known to be the system that provides the bodies “fight or flight” response, whereas the parasympathetic nervous system provides the “rest and digest” response. Stimulation of sympathetic nerve activity triggers the sympathetic response which causes the kidneys to increase production of hormones that increase vasoconstriction and fluid retention. This process is referred to as the renin-angiotensin-aldosterone-system (RAAS) response to increased renal sympathetic nerve activity.
In response to a reduction in blood volume, the kidneys secrete renin, which stimulates the production of angiotensin. Angiotensin causes blood vessels to constrict, resulting in increased blood pressure, and also stimulates the secretion of the hormone aldosterone from the adrenal cortex. Aldosterone causes the tubules of the kidneys to increase the reabsorption of sodium and water, which increases the volume of fluid in the body and blood pressure.
Congestive heart failure (CHF) is a condition that has been linked to kidney function. CHF occurs when the heart is unable to pump blood effectively throughout the body. When blood flow drops, renal function degrades because of insufficient perfusion of the blood within the renal corpuscles. The decreased blood flow to the kidneys triggers an increase in sympathetic nervous system activity (i.e., the RAAS becomes too active) that causes the kidneys to secrete hormones that increase fluid retention and vasorestriction. Fluid retention and vasorestriction in turn increases the peripheral resistance of the circulatory system, placing an even greater load on the heart, which diminishes blood flow further. If the deterioration in cardiac and renal functioning continues, eventually the body becomes overwhelmed, and an episode of heart failure decompensation occurs, often leading to hospitalization of the patient.
FIG. 1 is an illustration of a right kidney 10 and renal vasculature including a renal artery 12 branching laterally from the abdominal aorta 20. In FIG. 1, only the right kidney 10 is shown for purposes of simplicity of explanation, but reference will be made herein to both right and left kidneys and associated renal vasculature and nervous system structures, all of which are contemplated within the context of embodiments of the disclosure. The renal artery 12 is purposefully shown to be disproportionately larger than the right kidney 10 and abdominal aorta 20 in order to facilitate discussion of various features and embodiments of the present disclosure.
The right and left kidneys are supplied with blood from the right and left renal arteries that branch from respective right and left lateral surfaces of the abdominal aorta 20. Each of the right and left renal arteries is directed across the crus of the diaphragm, so as to form nearly a right angle with the abdominal aorta 20. The right and left renal arteries extend generally from the abdominal aorta 20 to respective renal sinuses proximate the hilum 17 of the kidneys, and branch into segmental arteries and then interlobular arteries within the kidney 10. The interlobular arteries radiate outward, penetrating the renal capsule and extending through the renal columns between the renal pyramids. Typically, the kidneys receive about 20% of total cardiac output which, for normal persons, represents about 1200 mL of blood flow through the kidneys per minute.
The primary function of the kidneys is to maintain water and electrolyte balance for the body by controlling the production and concentration of urine. In producing urine, the kidneys excrete wastes such as urea and ammonium. The kidneys also control reabsorption of glucose and amino acids, and are important in the production of hormones including vitamin D, renin and erythropoietin.
An important secondary function of the kidneys is to control metabolic homeostasis of the body. Controlling hemostatic functions include regulating electrolytes, acid-base balance, and blood pressure. For example, the kidneys are responsible for regulating blood volume and pressure by adjusting volume of water lost in the urine and releasing erythropoietin and renin, for example. The kidneys also regulate plasma ion concentrations (e.g., sodium, potassium, chloride ions, and calcium ion levels) by controlling the quantities lost in the urine and the synthesis of calcitrol. Other hemostatic functions controlled by the kidneys include stabilizing blood pH by controlling loss of hydrogen and bicarbonate ions in the urine, conserving valuable nutrients by preventing their excretion, and assisting the liver with detoxification.
Also shown in FIG. 1 is the right suprarenal gland 11, commonly referred to as the right adrenal gland. The suprarenal gland 11 is a star-shaped endocrine gland that rests on top of the kidney 10. The primary function of the suprarenal glands (left and right) is to regulate the stress response of the body through the synthesis of corticosteroids and catecholamines, including cortisol and adrenaline (epinephrine), respectively. Encompassing the kidneys 10, suprarenal glands 11, renal vessels 12, and adjacent perirenal fat is the renal fascia, e.g., Gerota's fascia, (not shown), which is a fascial pouch derived from extraperitoneal connective tissue.
The autonomic nervous system of the body controls involuntary actions of the smooth muscles in blood vessels, the digestive system, heart, and glands. The autonomic nervous system is divided into the sympathetic nervous system and the parasympathetic nervous system. In general terms, the parasympathetic nervous system prepares the body for rest by lowering heart rate, lowering blood pressure, and stimulating digestion. The sympathetic nervous system effectuates the body's fight-or-flight response by increasing heart rate, increasing blood pressure, and increasing metabolism.
In the autonomic nervous system, fibers originating from the central nervous system and extending to the various ganglia are referred to as preganglionic fibers, while those extending from the ganglia to the effector organ are referred to as postganglionic fibers. Activation of the sympathetic nervous system is effected through the release of adrenaline (epinephrine) and to a lesser extent norepinephrine from the suprarenal glands 11. This release of adrenaline is triggered by the neurotransmitter acetylcholine released from preganglionic sympathetic nerves.
The kidneys and ureters (not shown) are innervated by the renal nerves 14. FIGS. 1 and 2A-2B illustrate sympathetic innervation of the renal vasculature, primarily innervation of the renal artery 12. The primary functions of sympathetic innervation of the renal vasculature include regulation of renal blood flow and pressure, stimulation of renin release, and direct stimulation of water and sodium ion reabsorption.
Most of the nerves innervating the renal vasculature are sympathetic postganglionic fibers arising from the superior mesenteric ganglion 26. The renal nerves 14 extend generally axially along the renal arteries 12, enter the kidneys 10 at the hilum 17, follow the branches of the renal arteries 12 within the kidney 10, and extend to individual nephrons. Other renal ganglia, such as the renal ganglia 24, superior mesenteric ganglion 26, the left and right aorticorenal ganglia 22, and celiac ganglia 28 also innervate the renal vasculature. The celiac ganglion 28 is joined by the greater thoracic splanchnic nerve (greater TSN). The aorticorenal ganglia 26 is joined by the lesser thoracic splanchnic nerve (lesser TSN) and innervates the greater part of the renal plexus.
Sympathetic signals to the kidney 10 are communicated via innervated renal vasculature that originates primarily at spinal segments T10-T12 and L1. Parasympathetic signals originate primarily at spinal segments S2-S4 and from the medulla oblongata of the lower brain. Sympathetic nerve traffic travels through the sympathetic trunk ganglia, where some may synapse, while others synapse at the aorticorenal ganglion 22 (via the lesser thoracic splanchnic nerve, i.e., lesser TSN) and the renal ganglion 24 (via the least thoracic splanchnic nerve, i.e., least TSN). The postsynaptic sympathetic signals then travel along nerves 14 of the renal artery 12 to the kidney 10. Presynaptic parasympathetic signals travel to sites near the kidney 10 before they synapse on or near the kidney 10.
With particular reference to FIG. 2A, the renal artery 12, as with most arteries and arterioles, is lined with smooth muscle 34 that controls the diameter of the renal artery lumen 13. Smooth muscle, in general, is an involuntary non-striated muscle found within the media layer of large and small arteries and veins, as well as various organs. The glomeruli of the kidneys, for example, contain a smooth muscle-like cell called the mesangial cell. Smooth muscle is fundamentally different from skeletal muscle and cardiac muscle in terms of structure, function, excitation-contraction coupling, and mechanism of contraction.
Smooth muscle cells can be stimulated to contract or relax by the autonomic nervous system, but can also react on stimuli from neighboring cells and in response to hormones and blood borne electrolytes and agents (e.g., vasodilators or vasoconstrictors). Specialized smooth muscle cells within the afferent arteriole of the juxtaglomerular apparatus of kidney 10, for example, produces renin which activates the angiotension II system.
The renal nerves 14 innervate the smooth muscle 34 of the renal artery wall 15 and extend lengthwise in a generally axial or longitudinal manner along the renal artery wall 15. The smooth muscle 34 surrounds the renal artery circumferentially, and extends lengthwise in a direction generally transverse to the longitudinal orientation of the renal nerves 14, as is depicted in FIG. 2B.
The smooth muscle 34 of the renal artery 12 is under involuntary control of the autonomic nervous system. An increase in sympathetic activity, for example, tends to contract the smooth muscle 34, which reduces the diameter of the renal artery lumen 13 and decreases blood perfusion. A decrease in sympathetic activity tends to cause the smooth muscle 34 to relax, resulting in vessel dilation and an increase in the renal artery lumen diameter and blood perfusion. Conversely, increased parasympathetic activity tends to relax the smooth muscle 34, while decreased parasympathetic activity tends to cause smooth muscle contraction.
FIG. 3A shows a segment of a longitudinal cross-section through a renal artery, and illustrates various tissue layers of the wall 15 of the renal artery 12. The innermost layer of the renal artery 12 is the endothelium 30, which is the innermost layer of the intima 32 and is supported by an internal elastic membrane. The endothelium 30 is a single layer of cells that contacts the blood flowing though the vessel lumen 13. Endothelium cells are typically polygonal, oval, or fusiform, and have very distinct round or oval nuclei. Cells of the endothelium 30 are involved in several vascular functions, including control of blood pressure by way of vasoconstriction and vasodilation, blood clotting, and acting as a barrier layer between contents within the lumen 13 and surrounding tissue, such as the membrane of the intima 32 separating the intima 32 from the media 34, and the adventitia 36. The membrane or maceration of the intima 32 is a fine, transparent, colorless structure which is highly elastic, and commonly has a longitudinal corrugated pattern.
Adjacent the intima 32 is the media 33, which is the middle layer of the renal artery 12. The media is made up of smooth muscle 34 and elastic tissue. The media 33 can be readily identified by its color and by the transverse arrangement of its fibers. More particularly, the media 33 consists principally of bundles of smooth muscle fibers 34 arranged in a thin plate-like manner or lamellae and disposed circularly around the arterial wall 15. The outermost layer of the renal artery wall 15 is the adventitia 36, which is made up of connective tissue. The adventitia 36 includes fibroblast cells 38 that play an important role in wound healing.
A perivascular region 37 is shown adjacent and peripheral to the adventitia 36 of the renal artery wall 15. A renal nerve 14 is shown proximate the adventitia 36 and passing through a portion of the perivascular region 37. The renal nerve 14 is shown extending substantially longitudinally along the outer wall 15 of the renal artery 12. The main trunk of the renal nerves 14 generally lies in or on the adventitia 36 of the renal artery 12, often passing through the perivascular region 37, with certain branches coursing into the media 33 to enervate the renal artery smooth muscle 34.
Embodiments of the disclosure may be implemented to provide varying degrees of denervation therapy to innervated renal vasculature. For example, embodiments of the disclosure may provide for control of the extent and relative permanency of renal nerve impulse transmission interruption achieved by denervation therapy delivered using a treatment apparatus of the disclosure. The extent and relative permanency of renal nerve injury may be tailored to achieve a desired reduction in sympathetic nerve activity (including a partial or complete block) and to achieve a desired degree of permanency (including temporary or irreversible injury).
Returning to FIGS. 3B and 3C, the portion of the renal nerve 14 shown in FIGS. 3B and 3C includes bundles 14a of nerve fibers 14b each comprising axons or dendrites that originate or terminate on cell bodies or neurons located in ganglia or on the spinal cord, or in the brain. Supporting tissue structures 14c of the nerve 14 include the endoneurium (surrounding nerve axon fibers), perineurium (surrounds fiber groups to form a fascicle), and epineurium (binds fascicles into nerves), which serve to separate and support nerve fibers 14b and bundles 14a. In particular, the endoneurium, also referred to as the endoneurium tube or tubule, is a layer of delicate connective tissue that encloses the myelin sheath of a nerve fiber 14b within a fasciculus.
Major components of a neuron include the soma, which is the central part of the neuron that includes the nucleus, cellular extensions called dendrites, and axons, which are cable-like projections that carry nerve signals. The axon terminal contains synapses, which are specialized structures where neurotransmitter chemicals are released in order to communicate with target tissues. The axons of many neurons of the peripheral nervous system are sheathed in myelin, which is formed by a type of glial cell known as Schwann cells. The myelinating Schwann cells are wrapped around the axon, leaving the axolemma relatively uncovered at regularly spaced nodes, called nodes of Ranvier. Myelination of axons enables an especially rapid mode of electrical impulse propagation called saltation.
In some embodiments, a treatment apparatus of the disclosure may be implemented to deliver denervation therapy that causes transient and reversible injury to renal nerve fibers 14b. In other embodiments, a treatment apparatus of the disclosure may be implemented to deliver denervation therapy that causes more severe injury to renal nerve fibers 14b, which may be reversible if the therapy is terminated in a timely manner. In preferred embodiments, a treatment apparatus of the disclosure may be implemented to deliver denervation therapy that causes severe and irreversible injury to renal nerve fibers 14b, resulting in permanent cessation of renal sympathetic nerve activity. For example, a treatment apparatus may be implemented to deliver a denervation therapy that disrupts nerve fiber morphology to a degree sufficient to physically separate the endoneurium tube of the nerve fiber 14b, which can prevent regeneration and re-innervation processes.
By way of example, and in accordance with Seddon's classification as is known in the art, a treatment apparatus of the disclosure may be implemented to deliver a denervation therapy that interrupts conduction of nerve impulses along the renal nerve fibers 14b by imparting damage to the renal nerve fibers 14b consistent with neruapraxia. Neurapraxia describes nerve damage in which there is no disruption of the nerve fiber 14b or its sheath. In this case, there is an interruption in conduction of the nerve impulse down the nerve fiber, with recovery taking place within hours to months without true regeneration, as Wallerian degeneration does not occur. Wallerian degeneration refers to a process in which the part of the axon separated from the neuron's cell nucleus degenerates. This process is also known as anterograde degeneration. Neurapraxia is the mildest form of nerve injury that may be imparted to renal nerve fibers 14b by use of a treatment apparatus according to embodiments of the disclosure.
A treatment apparatus may be implemented to interrupt conduction of nerve impulses along the renal nerve fibers 14b by imparting damage to the renal nerve fibers consistent with axonotmesis. Axonotmesis involves loss of the relative continuity of the axon of a nerve fiber and its covering of myelin, but preservation of the connective tissue framework of the nerve fiber. In this case, the encapsulating support tissue 14c of the nerve fiber 14b are preserved. Because axonal continuity is lost, Wallerian degeneration occurs. Recovery from axonotmesis occurs only through regeneration of the axons, a process requiring time on the order of several weeks or months. Electrically, the nerve fiber 14b shows rapid and complete degeneration. Regeneration and re-innervation may occur as long as the endoneural tubes are intact.
A treatment apparatus may be implemented to interrupt conduction of nerve impulses along the renal nerve fibers 14b by imparting damage to the renal nerve fibers 14b consistent with neurotmesis. Neurotmesis, according to Seddon's classification, is the most serious nerve injury in the scheme. In this type of injury, both the nerve fiber 14b and the nerve sheath are disrupted. While partial recovery may occur, complete recovery is not possible. Neurotmesis involves loss of continuity of the axon and the encapsulating connective tissue 14c, resulting in a complete loss of autonomic function, in the case of renal nerve fibers 14b. If the nerve fiber 14b has been completely divided, axonal regeneration causes a neuroma to form in the proximal stump.
A more stratified classification of neurotmesis nerve damage may be found by reference to the Sunderland System as is known in the art. The Sunderland System defines five degrees of nerve damage, the first two of which correspond closely with neurapraxia and axonotmesis of Seddon's classification. The latter three Sunderland System classifications describe different levels of neurotmesis nerve damage.
The first and second degrees of nerve injury in the Sunderland system are analogous to Seddon's neurapraxia and axonotmesis, respectively. Third degree nerve injury, according to the Sunderland System, involves disruption of the endoneurium, with the epineurium and perineurium remaining intact. Recovery may range from poor to complete depending on the degree of intrafascicular fibrosis. A fourth degree nerve injury involves interruption of all neural and supporting elements, with the epineurium remaining intact. The nerve is usually enlarged. Fifth degree nerve injury involves complete transection of the nerve fiber 14b with loss of continuity.
Referring now to FIG. 4, there is shown a medical system 100 configured to provide minimally invasive access to innervated tissue that influences renal sympathetic nerve activity, such as renal nerves and ganglia. In some embodiments, the medical system 100 can be configured to provide minimally invasive access to innervated renal tissue via a natural orifice of the body. In various embodiments, for example, the medical system 100 can be configured to provide minimally invasive access to innervated renal tissue via the patient's gastrointestinal tract or urinary tract. In further embodiments, the medical system 100 can be configured to provide minimally invasive access to innervated renal tissue via an organ or body pathway in proximity to the innervated renal tissue.
The medical system 100, according to various embodiments, includes a therapy system 102 coupled to an elongated flexible medical device 130. The medical device 130 is configured to be inserted into the patient's body via a natural orifice 106. The medical device 130 preferably has a length sufficient for advancement between the natural orifice 106 and a location at or proximate innervated tissue that influences renal sympathetic nerve activity via a gastrointestinal tract or a urinary tract of the patient. An energy delivery device 131 is provided at a distal end of the medical device 130.
The energy delivery device 131 is configured to communicate energy to the location at or proximate the innervated renal tissue. In some embodiments, the energy delivery device 131 is configured to communicate energy generated by the therapy system 102 sufficient in power or intensity to ablate the innervated renal tissue. In other embodiments, the energy delivery device 131 is configured to communicate energy generated by an imaging system 120 sufficient to image tissue of the body, including the innervated renal tissue. In further embodiments, the energy delivery device 131 is configured to communicate energy sufficient to image tissue of the body, including the innervated renal tissue, and energy sufficient to ablate the innervated renal tissue respectively generated by the therapy system 102 and the imaging system 120.
The energy delivery device 131 can be configured to deliver various forms of energy or a combination of energy forms. In some embodiments, the energy delivery device 131 is configured to deliver radiofrequency energy in a bipolar mode using an ablation electrode arrangement at or near the innervated renal tissue and a return electrode arrangement positioned within the patient's body. In other embodiments, the energy delivery device 131 is configured to deliver radiofrequency energy in a unipolar mode using an ablation electrode arrangement at or near the innervated renal tissue and an external return electrode arrangement. In other embodiments, the energy delivery device 131 is configured to deliver ultrasound energy in one or both of an imaging mode and an ablation mode. In further embodiments, the energy delivery device 131 is configured to deliver optical energy (e.g., laser) in one or both of an imaging mode and an ablation mode. Other forms of energy deliverable by the energy delivery device 131 are contemplated, such as electrical current, electromagnetic energy of various forms, thermal energy (heat or cold), and acoustic energy of various forms for example. In some embodiments, a venom or a neurotoxin can be delivered to ablate innervated renal tissue.
According to various embodiments, two or more medical devices can be used cooperatively for one or both of ablating and imaging innervated renal tissue. For example, and as shown in FIG. 4, medical device 130 may be implemented to operate cooperatively with medical device 150, which includes an energy delivery device 151. The energy delivery devices 131 and 151 may be configured to deliver or respond to the same or different form of energy. In some embodiments, one of the two medical devices 131, 151 may be configured for imaging innervated renal tissue while the other of the two medical devices 131, 151 is configured for ablating the innervated renal tissue. In other embodiments, each of the two medical devices 131, 151 are configured for ablating the innervated renal tissue, in which case a third medical device 160 (or an external imaging system) can be used for imaging the innervated renal tissue, such as by use of an ultrasound energy device 161.
In some embodiments, each of the medical devices 130, 150, and 160 is positioned within or in proximity to a patient's renal artery 12 via a separate access path through the body. In other embodiments, two or more of the medical devices 130, 150, and 160 can be positioned within or in proximity to the patient's renal artery 12 via a body pathway 110 (e.g., a gastrointestinal organ or urinary vessel) accessed by way of a natural orifice 106.
By way of example, and in accordance with one embodiment, the energy delivery device 131 of medical device 130 includes an RF electrode arrangement. The medical device 130 is shown positioned within a body pathway 110, such as within an organ or vessel of the patient's gastrointestinal or urinary tract accessed via a natural orifice 106, so that the RF electrode 131 is in proximity to the renal artery 12. The medical device 150 is shown positioned within the patient's renal artery 12 and includes a distal RF electrode 151. It is noted that the medical device 150 may also be positioned within the patient's renal vein or other blood vessel in proximity to the renal artery 12, such as the hepatic portal vein. In this representative example, the medical device 150 is coupled to the therapy system 102. The RF electrodes 131 and 151 are operated in a bipolar mode for delivering RF energy to tissue of the renal artery 12 sufficient in power to ablate innervated tissue that influences renal sympathetic nerve activity.
FIG. 5 shows delivery of the energy delivery device 131 of medical device 130 through at least a portion of the patient's digestive system to a location proximate a renal artery 12 via an upper gastrointestinal access path in accordance with various embodiments. In the representative embodiment shown in FIG. 5, the medical device 130 is inserted into the patient's upper gastrointestinal tract through the patient's mouth 202. The medical device 130 is advanced through the patient's esophagus 204, stomach 206, duodenum 208, small intestine 209 (jejunum 210 and ileum 212), ascending colon 214 of the large intestine 213, and to a proximal location (relative to the direction of medial device advancement) within the transverse colon 216. The energy delivery device 131 of the medical device 130 is preferably positioned and/or oriented relative to the patient's left renal artery 12a in a manner best suited for imaging and/or ablating innervated tissue of the left renal artery 12a. 
After completion of an imaging and/or ablation procedure for the left renal artery 12a, the medical device 130 is advanced through the transverse colon 216 to a distal location (relative to the direction of medial device advancement) in proximity to the patient's right renal artery 12b. Energy delivery device 131 is preferably positioned and/or oriented relative to the patient's right renal artery 12b in a manner best suited for imaging and/or ablating innervated tissue of the right renal artery 12b. It is noted that anatomical variations between patient's may require positioning of the energy delivery device 131 at locations of the large intestine 213 other than those shown in FIG. 5. For example, the particular anatomy of a given patient may require that the energy delivery device 131 be positioned at or near a distal portion of the ascending colon 214 or proximal portion of the descending colon 218, for example.
FIG. 6 shows delivery of the energy delivery device 131 of medical device 130 through at least a portion of the patient's digestive system to a location proximate a renal artery 12 via a lower gastrointestinal access path in accordance with various embodiments. As is shown in FIG. 6, the medical device 130 is inserted into the patient's lower gastrointestinal tract through the patient's anus 222. The medical device 130 is advanced through the rectum 220 and into the descending colon 218 of the large intestine 213. The energy delivery device 130 can be positioned at a distal location (relative to the direction of medial device advancement) of the descending colon 218 or a proximal location of the transverse colon 216. One or both of imaging and ablating innervated renal tissue of the patient's right renal artery 12b is performed, followed by advancement of the energy delivery device 130 to a location of the large intestine 213 in proximity to the patient's left renal artery 12a. As previously discussed, the particular anatomy of a given patient may require that the energy delivery device 131 be positioned at or near the distal portion of the transverse colon 216 or a proximal portion of the ascending colon 214.
FIG. 7 shows delivery of the energy delivery device 131 of a medical device 132 to a location proximate the patient's renal artery 12 via a lower gastrointestinal access path in accordance with various embodiments. It is understood that, for purposes of the representative example shown in FIG. 7, that the patient's renal artery 12 may alternatively be accessed via an upper gastrointestinal access path in accordance with other embodiments. After positioning the energy delivery device 131 at a location proximate the patient's right renal artery 12b, for example, the distal tip of the medical device 130 is advanced through an access hole 217 created in a wall of a nearby organ or vessel. In the representative example shown in FIG. 7, an access hole 217 is created in a wall of the transverse colon 216, through which the energy delivery device 131 may be advanced to a location on or proximate to the right renal artery 12b. One or both of imaging and ablating innervated renal tissue patient's right renal artery 12b can be preformed from an extra-organ or extra-vessel location, such as externally from the patient's transverse colon 216 is shown in FIG. 7.
The access hole 217 may be created using a variety of techniques. For example, the medical device 130 and energy delivery device 131 can include a lumen through which a wire having a tissue penetrating tip at its distal end may be advanced and retracted. As another example, the energy delivery device 131 can incorporate an activatable tissue piercing feature which can be selectively activated (e.g., extended) and deactivated (e.g., retracted). By way of further example, the energy delivery device 131 can incorporate a device that generates energy sufficient to create the access hole 217, such as a laser device.
FIG. 8 shows an embodiment of a medical system configured for ablating innervated tissue of the patient's renal artery 12 in accordance with various embodiments. In the illustrative embodiment of FIG. 8, a medical device 130 is advanced through a body pathway 110 of the body to a location proximate the renal artery 12 via a natural orifice. In this embodiment, the distal end of the medical device 130 includes an array of RF electrodes 132. The body pathway 110 shown in FIG. 8 may be the transverse colon, the ascending colon, or the descending colon of the patient, for example. A medical device 150 is shown deployed within a lumen 13 of the renal artery 12. The medical device 150 includes an ablation electrode 151 provided at a distal end of the medical device 150. The array of RF electrodes 132 preferably have a combined or distributed surface area greater than that of the ablation electrode 151 so that high current densities are concentrated at the innervated renal tissue while body pathway 110 remains relatively cool during RF ablation.
FIG. 9 shows an embodiment of medical system configured for ablating innervated tissue of the patient's renal artery 12 in accordance with various embodiments. Similar to the illustrative embodiment of FIG. 8, the medical device 130 shown in FIG. 9 is advanced through a pathway 110 of the body to a location proximate the renal artery 12 via natural orifice. The distal end of the medical device 130 is advanced through a wall of the body pathway 110 via an access hole 217. The access hole 217 may be created in a manner previously discussed. The distal end of the medical device 113 includes an RF ablation electrode 132, which is positioned on or proximate the outer wall of the renal artery 12.
FIG. 9 further shows medical device 150 deployed within the lumen 13 of the renal artery 12. In this configuration, the distal end of the medical device 150 includes an array of RF electrodes 151. In this implementation, high current densities are created near the outer wall of the renal artery 12 while the artery's inner wall remains relatively cool. The implementation shown in FIG. 9 advantageously produces high current densities for ablating renal nerves included within the perivascular space adjacent the renal artery's outer wall, with negligible thermal injury to the inner wall of the renal artery 12.
FIG. 10 shows deployment of an energy delivery device 131 of the medical device 132 to a location proximate the patient's left renal artery 12a via a left ureter 160a of the patient's urinary tract. In this illustrative embodiment, the medical device 130 is inserted into the patient's urinary tract via the urethra 164. The medical device 130 is advanced through the urethra 154, the urinary bladder 162, and the left ureter 160a to a position proximal to the left renal artery 12a. At this position, the energy delivery device 131 can be used for one or both of imaging and ablating innervated tissue of the left renal artery 12 depending on the device's configuration.
In some embodiments, a second medical device 150 can be advanced to a blood vessel at or proximate to the left renal artery 12a. Suitable blood vessels include the left renal artery 12a, the left renal vein, or the hepatic portal vein. In some embodiments, each of the energy delivery devices 131 and 151 can include an RF electrode configured for bipolar RF energy delivery for ablating innervated tissue of the left renal artery 12a. In other embodiments, one of the energy delivery devices 131 and 151 can be used for imaging, while the other energy delivery devices used for ablating innervated renal tissue. In further embodiments, various other forms of imaging and ablation energy can be delivered using suitable devices, such as ultrasonic, acoustic, and laser devices.
After imaging and/or innervating tissue of the patient's left renal artery 12a, the distal tip of the medical device 130 can be retracted from the left ureter 160a and positioned within the urinary bladder 162 for insertion into, and advancement through, the patient's right ureter 160b. The procedures and configurations for imaging and/or ablating innervated tissue of the patient's left renal artery 12a are applicable to the patient's right renal artery 12b. 
FIG. 11 shows delivery of an energy delivery device 131 of a medical device 132 to a location proximate the patient's left renal artery 12a via an access vein in accordance with various embodiments. In this illustrative embodiment, the access vein to the left renal artery 12a is represented by the patient's hepatic portal vein 155. In this illustrative embodiment, the medical device 130 is advanced into the hepatic portal vein 155 via the venous system and a percutaneous access hole 107. The embodiment shown in FIG. 9 differs from those of previous embodiments in that a natural orifice of the patient is not used for delivering the medical device 130 to a body location proximate the patient's left renal artery 12a. However, it is believed that imaging and/or ablating innervated renal tissue from a location within the hepatic portal vein 155 represents a less invasive access approach when compared to inserting a device into the patient's femoral artery or vein (or other major blood vessel) or through laparoscopic or open surgical approaches.
In some embodiments, as discussed previously, renal nerve access can be achieved using a trans-hepatic route via the inferior vena cava and hepatic vein, similar to a TIPS procedure. In various embodiments, renal nerve access can be achieved using a body pathway that includes the inferior vena cava, hepatic vein, liver, and intraperitoneum.
As discussed previously, various types of energy delivery devices may be used for imaging and/or ablating tissue of the body, such as innervated renal tissue that influences renal sympathetic nerve activity. Suitable energy delivery devices include electrical, electromagnetic, optical, acoustic, and thermal (heat or cryogenic) energy devices, among others. The following representative energy delivery devices may be implemented in one or more medical devices in accordance with embodiments of the invention, understanding that this listing is a non-exhaustive, non-limiting recitation of suitable energy delivery devices.
With reference to FIGS. 12 and 13, energy delivery devices 231 may be implemented to include an ultrasound unit 250 configured for denervating renal tissue that contributes to renal sympathetic nerve activity in accordance with various embodiments. In the embodiments shown in FIGS. 12 and 13, an emitter 252 of the ultrasound unit 250 includes an acoustic phased array transducer 252a which comprises a multiplicity of acoustic elements 252b. The phased array transducer 252a shown in FIG. 12 extends over a radial segment of the ultrasound unit's circumference, allowing an acoustic energy beam 262 to pass through an aperture 265 (e.g., focusing lens arrangement) and impinge on target tissue. The emitter 252 of the ultrasound unit 250 may be aimed at target tissue by rotating and translating the catheter 251 (i.e., the body of the medical device) or by moving the ultrasound unit 250 relative to the catheter 251, either manually or robotically. The ultrasound unit 250 shown in FIG. 12 may be deployed within a body pathway (e.g., organ or vessel) near the renal artery, and may be particularly useful when positioned outside of an organ or vessel near the outer wall of the renal artery.
In the embodiment shown in FIG. 13, a phased array transducer 252a extends over all or nearly all of the ultrasound unit's circumference, allowing an acoustic energy beam 262 to pass through an annular aperture 265 (e.g., focusing lens arrangement) and impinge on a circular or cylindrical target tissue region. This embodiment of ultrasound unit 250 is particularly useful when positioned within the renal artery, for example, with renal denervation being conducted without having to translate or rotate the catheter 251 or ultrasound unit 250.
The ultrasound unit 250 preferably has a capability that allows for focusing of acoustic energy at desired distances so that all or most of the perivascular space adjacent the outer wall of the renal artery can be treated. For example, a preferred focusing arrangement allows for the projection of ultrasonic energy through a near wall portion of the renal artery (without thermally injuring the near wall portion) which is focused at perivascular space adjacent a far wall portion of the artery (which is subject to ablation). Such as focusing arrangement reduces or eliminates the need to reposition the ultrasound unit 250 to treat a circumferential section of the renal artery.
A cooling arrangement may be incorporated in the embodiments of FIGS. 12 and 13 to ensure that the temperature of inner arterial wall tissue is limited to prevent thermal injury to this tissue. In embodiments that include focused acoustic transducers or transducer arrays, however, such cooling arrangement may not be required or desired, which can result in intravascular denervation apparatuses of reduced size and complexity. Details of these and other ultrasound denervation therapy apparatuses and methods are described in commonly owned U.S. Patent Publication Ser. No. 20110257523, filed as U.S. patent application Ser. No. 13/086,116 on Apr. 13, 2011, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/324,164 filed Apr. 14, 2010 and entitled “Focused Ultrasound for Renal Denervation,” all of which are incorporated herein by reference.
FIGS. 14 and 15 show different embodiments of a phototherapy energy delivery device for denervating tissue that contributes to renal sympathetic nerve activity in accordance with various embodiments. In the embodiment shown in FIG. 14, an emitter 352 of a phototherapy unit 350 includes an aperture 365 through which an optical energy beam 362 passes. The aperture 365 may be a void or a material that allows for efficient transmission of the optical energy beam 362 from the emitter 352 and out of the phototherapy unit 350. The aperture 365 and emitter 352 are situated at a desired location of the phototherapy unit 350, and can be “aimed” at target tissue by rotating and translating the catheter 351 to which the phototherapy unit 350 is attached. The phototherapy unit 350 shown in FIG. 14 may be deployed within a body pathway (e.g., organ or vessel) near the renal artery, and may be particularly useful when positioned outside of an organ or vessel near the outer wall of the renal artery.
According to some embodiments, the phototherapy unit 350 can be used to ablate perivascular renal nerves tissue using a photodynamic therapy approach. The phototherapy unit 350 can be positioned at an intravascular location within or proximate a renal artery (e.g., renal vein, hepatic portal vein). Alternatively, the phototherapy unit 350 can be advanced through a natural orifice to a location proximate the outer wall of the renal artery via one or a combination of body pathways. A second medical device can be advanced through a natural orifice and body pathway so that its distal end is positioned at or near the outer wall of the renal artery. Alternatively, the second medical device can be advanced along an intravascular pathway and positioned at or near the outer wall of the renal artery by way of a perivascular or intra-to-extra-vascular approach. A photosensitizer may be delivered from the distal end of the second medical device and into perivascular space surrounding the renal artery. The photosensitizer may be excited by light emitted by the phototherapy unit 350. The excited photosensitizer interacts with molecular oxygen within the perivascular space causing a rapid reaction that destroys nearby biomolecules, including renal nerves, through apoptosis or necrosis.
FIG. 15 shows a phototherapy unit 350 comprising a multiplicity of apertures 365 and emitters 352. The apertures 365 and emitters 352 are preferably situated so that their beam patterns 362 collectively impinge on renal artery tissue in a desired pattern, such as a circumferential or spiral pattern, and at desired target depths in the outer renal artery wall and/or perivascular space adjacent the outer renal artery wall. The circumferential or spiral lesion may either be continuous or a sequential and overlapping line of ablated spots. This embodiment of a phototherapy unit 350 is particularly useful when positioned within the renal artery, for example, with renal denervation being conducted without having to translate or rotate the catheter 351 or ultrasound unit 350.
The phototherapy apparatuses depicted in FIGS. 14 and 15 are configured to optically couple to a laser light source that generates laser light having a desired wavelength and intensity. In some embodiments, the laser light source is configured to generate a continuous wave (CW) light beam. In other embodiments, the laser light source is configured to generate pulses of light. For example, the laser light source may be configured as an ultrashort or ultrafast laser that produces tightly focused pulses of light. Embodiments that utilize a high intensity flash lamp are also contemplated. Details of these and other phototherapy denervation therapy apparatuses and methods are described in commonly owned U.S. patent publication Ser. No. 20110257641, filed as U.S. patent application Ser. No. 13/086,121 on Apr. 13, 2011, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/324,163 filed Apr. 14, 2010 and entitled “Phototherapy for Renal Denervation,” all of which are incorporated herein by reference.
FIG. 16 shows a thermal energy delivery device for thermally ablating innervated tissue that contributes to renal sympathetic nerve activity in accordance with various embodiments. In the embodiment shown in FIG. 16, the energy delivery device 410 includes a thermal transfer apparatus 420, which may include a cryotube, cryoballoon, or other cryotherapy element disposed at the distal end of a medical device catheter 430. The energy delivery device 410 shown in FIG. 16 is preferably used cooperatively with one or more other energy delivery devices configured for one or both of imaging and ablating innervated renal tissue. The one or more other energy deliver devices are configured for advancement through a pathway of the body (e.g., organ or vessel) to a location proximate the renal artery 12 via a natural orifice.
In some embodiments, an ultrasound device can be inserted into the patient's body via a natural orifice and advanced through a pathway of the body to a location proximate the renal artery 12 in which the thermal energy delivery device 410 is deployed. The ultrasound device can be used for imaging tissue at or proximate the renal artery 12 and/or for ablating innervated renal tissue from a location at or proximate the outer wall of the renal artery 12. Rather than being used for cryoablation, the thermal energy delivery device 410 can be used to cool the inner renal artery wall and prevent thermal injury thereto. In some embodiments, the energy delivery device 410 can be controlled to freeze target tissue of the renal artery 12, and the ultrasound device can be controlled to heat the target tissue using a freeze/thaw cycling procedure. The ultrasound device (or a laser device) can be used to create cavitation bubbles in the target tissue which generate nerve destroying acoustic shock waves when exploding within the target tissue, for example.
In some embodiments, the thermal transfer apparatus 420 includes a balloon arrangement 420 comprising one or more inflation balloons and a fluid delivery arrangement 421 configured to transport a thermal transfer fluid to and from the distal end the medical device catheter 430. The fluid delivery arrangement 421 is fluidly coupled to a fluid source which may be configured to supply a pressurized thermal transfer fluid to the balloon arrangement 420.
The fluid delivery arrangement 421 shown in FIG. 16 includes at least two lumens 422 and 424 configured as supply and return lumens for supplying a cryogen to the thermal transfer apparatus 420 and returning spent cryogen or gas to the proximal end of the catheter 430, respectively. The cryogen may be circulated through the thermal transfer apparatus 420 via a hydraulic circuit that includes a cryogen source, supply and return lumens 422, 424, and a cryotherapy element of the thermal transfer apparatus 420 disposed at the distal end of the catheter 430. The shaft of the catheter 430 is preferably lined with or otherwise incorporates insulation material(s) having appropriate thermal and mechanical characteristics suitable for a selected cryogen.
The fluid delivery arrangement 421 is preferably fluidly coupled to a cryogen source which includes a reservoir fluidly coupled to a pump. A cryogen is contained within the reservoir. A variety of cryogens may be employed, including cold saline or cold saline and ethanol mixture, Freon or other fluorocarbon refrigerants, nitrous oxide, liquid nitrogen, and liquid carbon dioxide, for example.
The thermal transfer apparatus 420 may be a unitary or multi-component apparatus. In some embodiments, the cryogen, when released inside the thermal transfer apparatus 420, undergoes a phase change that cools the treatment portion of the thermal transfer apparatus 420 by absorbing the latent heat of vaporization from the tissue surrounding the thermal transfer apparatus 420, and by cooling of the vaporized gas as it enters a region of lower pressure inside the thermal transfer apparatus 420 (via the Joule-Thomson effect).
As a result of the phase change and the Joule-Thompson effect, heat is extracted from the surroundings of the thermal transfer apparatus 420, thereby cooling the treatment portion of the thermal transfer apparatus 420 and renal tissue that is in contact with the treatment portion of the thermal transfer apparatus 420. The gas released inside the thermal transfer apparatus 420 may be exhausted through an exhaust lumen 424 provided in the catheter 430. The pressure inside the thermal transfer apparatus 420 may be controlled by regulating one or both of a rate at which cryogen is delivered and a rate at which the exhaust gas is extracted.
Details of these and other denervation therapy apparatuses and methods are described hereinbelow and in commonly owned U.S. patent publication Ser. No. 20110270238, filed as U.S. patent application Ser. No. 12/980,952 on Dec. 29, 2010, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/291,476 filed Dec. 31, 2009; U.S. patent publication Ser. No. 20110263921, filed as U.S. patent application Ser. No. 12/980,972 on Dec. 29, 2010, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/291,480 filed Dec. 31, 2009; and U.S. patent publication Ser. No. 20110307034, filed as U.S. patent application Ser. No. 13/157,844 on Jun. 10, 2011, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/353,853 filed Jun. 11, 2010, all of which are incorporated herein by reference.
In other embodiments, the medical device shown in FIG. 16 is configured to supply a treatment agent to a drug delivery element 420 provided at the distal end of the catheter 430. The drug delivery element 420 may include a weeping balloon or other delivery arrangement configured to deliver a drug to the wall of the renal artery 12. In some embodiments, a drug delivery medical device can be configured for placement at an outer wall of the renal artery via a body pathway accessed through a natural orifice (see, e.g., FIG. 7). A drug or other ablation agent can be expelled from the drug delivery element 420 and introduced into the perivascular space adjacent the outer wall of the renal artery.
According to various embodiments, the drug delivery element 420 may be configured to deliver a pharmacological agent or mixture of agents (e.g., a neurotoxin or venom) to innervated renal tissue. In other embodiments, the drug delivery element 420 may be configured to deliver brachytherapy to innervated renal vasculature, such as by exposing the renal artery 12 to radioactive material or seeds (e.g., iodine-125 or palladium-103 for low dosage rate brachytherapy, iridium-192 for high dose rate brachytherapy).
Details of these and other denervation therapy apparatuses and methods are described hereinbelow and in commonly owned U.S. patent publication Ser. No. 20110264086, filed as U.S. patent application Ser. No. 13/087,163 on Apr. 14, 2011, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/324,165 filed Apr. 14, 2010, each of which is incorporated herein by reference.
It can be appreciated that the type of agent delivered by the medical device 410 shown in FIG. 16 and/or a separate medical device deployed at a location external of the renal artery 12 via a natural orifice pathway will vary in accordance with the particulars of the therapy delivery device 420, examples of which include a thermal transfer fluid (hot or cold), a pharmacological agent(s), radioactive material or seeds, electromagnetic energy (e.g., RF, microwave), optical energy (e.g., laser, white light), or acoustic energy (e.g., ultrasound). In some embodiments, a combination of denervation therapy and/or imaging apparatuses of disparate type or technology can be used together (concurrently or sequentially) to enhance the efficacy of renal denervation therapy. Combinations of disparate denervation therapy apparatuses may provided for improved therapy outcomes with reduced tissue trauma when compared to renal denervation approaches that employ one type of denervation therapy apparatus.
FIG. 17 shows a representative RF renal therapy apparatus 500 in accordance with various embodiments. The apparatus 500 illustrated in FIG. 17 includes external electrode activation circuitry 520 which comprises power control circuitry 522 and timing control circuitry 524. The external electrode activation circuitry 520, which includes an RF generator, is coupled to temperature measuring circuitry 528 and may be coupled to an optional impedance sensor 526. The RF generator of the external electrode activation circuitry 520 can be coupled to one or both of medical devices 130 and 150 in various configurations as indicated by the dashed lines in FIG. 17. As shown, the RF generator of the external electrode activation circuitry 520 is preferably coupled to each of the medical devices 130 and 150 in a bipolar configuration. The electrode arrangement 131 of medical device 130 can be deployed within a body pathway 110 accessed via a natural orifice or external of the body pathway via an access hole. In other embodiments, the RF generator of the external electrode activation circuitry 520 may include a return pad electrode 530 that is configured to comfortably engage the patient's back or other portion of the body near the kidneys for operation in a unipolar mode. Radiofrequency energy produced by the RF generator can be supplied to electrode arrangement 131 of the medical device 130, using the return pad electrode 530 as a return, thereby obviating the need for medical device 150 positioned within the renal artery 12 (or renal vein). The radiofrequency energy preferably flows through innervated renal tissue in accordance with a predetermined activation sequence.
In general, when renal artery tissue temperatures rise above about 113° F. (50° C.), protein is permanently damaged (including those of renal nerve fibers). If heated over about 65° C., collagen denatures and tissue shrinks. If heated over about 65° C. and up to 100° C., cell walls break and oil separates from water. Above about 100° C., tissue desiccates.
According to some embodiments, the electrode activation circuitry 520 is configured to control activation and deactivation of one or more electrodes of the electrode arrangements 131 and/or 151 in accordance with a predetermined energy delivery protocol and in response to signals received from temperature measuring circuitry 528. The electrode activation circuitry 520 controls radiofrequency energy delivered to the electrode arrangements 131 and/or 151 so as to maintain the current densities at a level sufficient to cause heating of the target tissue preferably to a temperature of at least 55° C.
In some embodiments, one or more temperature sensors are situated at the arrangements 131 and/or 151, and provide for continuous monitoring of renal tissue temperatures, and RF generator power is automatically adjusted so that the target temperatures are achieved and maintained. An impedance sensor arrangement 526 may be used to measure and monitor electrical impedance during RF denervation therapy, and the power and timing of the RF generator 520 may be moderated based on the impedance measurements or a combination of impedance and temperature measurements.
Various embodiments disclosed herein are generally described in the context of ablation of perivascular renal nerves for control of hypertension. It is understood, however, that embodiments of the disclosure have applicability in other contexts, such as performing ablation from within other vessels of the body, including other arteries, veins, and vasculature (e.g., cardiac and urinary vasculature and vessels), and other tissues of the body, including various organs. For example, various embodiments may be configured to treat benign prostatic hyperplasia or to diagnose and/or treat a tumor using an appropriate medical device advanced to the treatment site through at least a portion of a body pathway of a type described hereinabove.
It is to be understood that even though numerous characteristics of various embodiments have been set forth in the foregoing description, together with details of the structure and function of various embodiments, this detailed description is illustrative only, and changes may be made in detail, especially in matters of structure and arrangements of parts illustrated by the various embodiments to the full extent indicated by the broad general meaning of the terms in which the appended claims are expressed.

## Claims

1. A method, comprising:
inserting an elongated flexible medical device into a patient's body via a natural orifice;
wherein the natural orifice includes a urethra;
advancing the medical device through the urethra, through the bladder, and through a ureter to a location proximate innervated tissue that influences renal sympathetic nerve activity; and
delivering energy from a distal end of the medical device to one or both of image and ablate the innervated tissue.

2. The method of claim 1, wherein delivering energy from the distal end of the medical device comprises delivering energy of sufficient power or intensity to one or both of ablate the innervated tissue and image the innervated tissue.

3. The method of claim 1, wherein delivering energy from the distal end of the medical device comprises delivering energy of sufficient power or intensity to selectively image the innervated tissue and ablate the innervated tissue.

4. The method of claim 1, wherein delivering energy from the distal end of the medical device comprises delivering energy of sufficient power or intensity to ablate the innervated tissue, the method further comprising imaging tissue of or proximate the innervated tissue using an external imaging device to facilitate ablation of the innervated tissue by the medical device.

5. The method of claim 1, wherein delivering energy from the distal end of the medical device comprises ablating the innervated tissue using at least one of RF energy, ultrasound energy, optical energy, and thermal energy.

6. An apparatus, comprising:
an elongated flexible medical device configured for insertion into a patient's body via a natural orifice, the medical device being configured for and having a length sufficient for advancement through a urethra, through a bladder, and through a ureter to a position adjacent to a renal artery proximate innervated tissue that influences renal sympathetic nerve activity via an internal body pathway of the patient; and
an energy delivery device provided at a distal end of the medical device and configured to communicate energy to the location at or proximate the innervated tissue to one or both of image and ablate the innervated tissue.

7. The apparatus of claim 6, wherein the energy delivery device comprises one or both of an ablation device configured to ablate the innervated tissue and an imaging device configured to image the innervated tissue.

8. The apparatus of claim 6, wherein the energy delivery device comprises a device configured to selectively image the innervated tissue and ablate the innervated tissue.

9. The apparatus of claim 6, wherein the energy delivery device comprises at least one of a radiofrequency ablation device, an ultrasound ablation device, an optical ablation device, and a thermal ablation device.

10. The apparatus of claim 6, further comprising:
a second elongated flexible medical device configured for insertion into the patient's body and having a length sufficient for advancement to a second location at or proximate innervated tissue relative to a body access location of the patient; and
a second energy device provided at a distal end of the second medical device.

11. The apparatus of claim 10, wherein the energy delivery device comprises an ablation device and the second energy delivery device comprises an imaging device.

12. The method of claim 1, wherein advancing the medical device through the natural orifice, through the bladder, and into a ureter to a location proximate innervated tissue that influences renal sympathetic nerve activity includes advancing the medical device to a position adjacent to a renal artery.