Patent Publication Number: US-2012029512-A1

Title: Balloon with surface electrodes and integral cooling for renal nerve ablation

Description:
RELATED APPLICATIONS 
     This application claims the benefit of Provisional Patent Application Ser. No. 61/369,453 filed Jul. 30, 2010, to which priority is claimed pursuant to 35 U.S.C. § 119(e) and which is hereby incorporated herein by reference. 
    
    
     SUMMARY 
     Embodiments of the disclosure are directed to ablating target tissue of the body, such as innervated renal tissue, using an intravascular ablation device with integral cooling. Embodiments of the disclosure are directed to systems, apparatuses, and methods for ablating target tissue of the body, such as innervated renal tissue, using balloon supported ablation electrodes and an integral cooling arrangement for cooling the ablation electrodes. 
     According to various embodiments, an ablation apparatus includes a catheter arrangement having a flexible shaft and a balloon disposed at a distal end of the shaft. The balloon is configured for deployment within a target vessel of the body. Ablation electrodes are supported by a wall of the balloon and arranged in a predefined pattern. The ablation electrodes are configured to deliver electrical energy sufficient to ablate target tissue proximate a wall of the target vessel when the balloon is in a deployed configuration. A cooling arrangement is encompassed at least in part by the balloon and configured to provide cooling to at least the electrodes during ablation such that a location at which steady-state ablative heating begins is translated from an electrode-tissue interface at the target vessel wall to a location a predetermined distance away from the electrode-tissue interface. 
     In some embodiments, an ablation apparatus includes a catheter arrangement comprising a flexible shaft having a proximal end, a distal end, a length, and a lumen arrangement extending between the proximal and distal ends. The length of the shaft is sufficient to access a patient&#39;s renal artery relative to a percutaneous access location. A therapy unit is provided at the distal end of the shaft and coupled to the lumen arrangement. The therapy unit is dimensioned for deployment within a patient&#39;s renal artery, and includes a balloon fluidly coupled to the lumen arrangement and transformable between a low-profile introduction configuration and a larger-profile deployed configuration. The balloon comprises a wall configured to contact an inner wall of the renal artery when in the deployed configuration. Ablation electrodes are supported by the balloon wall and arranged in a predefined pattern. The ablation electrodes are configured to deliver electrical energy sufficient to ablate perivascular renal nerves adjacent the renal artery when the balloon is in the deployed configuration. A cooling arrangement is encompassed at least in part by the balloon and configured to provide cooling to at least the electrodes during ablation such that a location at which steady-state ablative heating begins is translated from an electrode-tissue interface at the inner renal artery wall to a location a predetermined distance away from the electrode-tissue interface. 
     In accordance with other embodiments, a method of ablating tissue involves expanding an ablation device within a target vessel, wherein a vessel-contacting surface of the ablation device supports ablation electrodes arranged in a predefined pattern. The method also involves delivering electrical energy through a wall of the target vessel sufficient to ablate target tissue proximate the target vessel wall, and cooling at least the ablation electrodes during ablation such that the target vessel is cooled and steady-state ablative heating begins at a predefined distance away from the electrodes. Methods may further involve compressing portions of the target vessel wall at a tissue-electrode interface associated with each of the electrodes, and delivering electrical energy through the compressed target vessel wall portions. The target vessel may include a renal artery and the target tissue may include perivascular renal nerve tissue, for example. 
     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  shows a therapy device of an ablation catheter which includes a cooling arrangement and balloon supported ablation electrodes in accordance with various embodiments; 
         FIG. 5  shows a therapy device of an ablation catheter which includes a cooling arrangement and balloon supported ablation electrodes in accordance with various embodiments; 
         FIG. 6  is a cross-sectional view of a portion of a therapy device showing an electrode-tissue interface defined between a balloon supported ablation electrode and a wall of a renal artery in accordance with various embodiments; 
         FIG. 7  is a cross-sectional view of a portion of a therapy device showing an electrode-tissue interface defined between a balloon supported ablation electrode and a wall of a renal artery in accordance with various embodiments; 
         FIGS. 8-10  show features of a cooling arrangement for a portion of a therapy device which includes a balloon supported ablation electrode in accordance with various embodiments; and 
         FIG. 11  shows a therapy system configured to perform renal denervation using a therapy device of an ablation catheter which includes a cooling arrangement and balloon supported ablation electrodes in accordance with various embodiments. 
     
    
    
     DESCRIPTION 
     Embodiments of the disclosure are directed to apparatuses and methods for ablating target tissue using electrical energy delivered by a multiplicity of cooled ablation electrodes supported by an expandable therapy device. Embodiments of the disclosure are directed to apparatuses and methods for ablating target tissue located adjacent to a body vessel using a multiplicity of cooled ablation electrodes supported by an expandable therapy device deployed in the body vessel. Embodiments are directed to ablating target tissue of the body using cooled ablation electrodes situated at a wall of the target vessel proximate the target tissue, such that the cooled ablation electrodes translate a location at which steady-state ablative heating begins from an electrode-tissue interface at the target vessel wall to a desired location a predetermined distance away from the electrode-tissue interface. Particular embodiments of the disclosure are directed to apparatuses and methods for ablating perivascular renal nerves for the treatment of hypertension. 
     Radiofrequency (RF) ablation of renal nerves, which lie proximate to the adventitia of the renal artery, may be an effective treatment for chronic hypertension. It has been difficult to effectively ablate perivascular renal sympathetic nerves by access from the renal artery, without injury to the renal artery wall. To reduce concern for potential stenotic narrowing of the artery after the ablation procedure, minimizing arterial injury during such an ablation procedure is important. 
     Embodiments of the disclosure incorporate a housing mounted at a distal end of a therapy catheter for supporting ablation electrodes and cooling components of the therapy device. The housing encompasses at least a portion of a cooling arrangement and supports a number of ablation electrodes on an outer surface of the housing. The housing is preferably transformable between a low-profile introduction configuration and a larger-profile deployment configuration. The low-profile introduction configuration allows the therapy catheter to be readily advanced through the venous or arterial system to a desired body location, for example. The larger-profile deployed configuration allows the therapy catheter to be stabilized at the desired body location, such as within the renal artery. In various embodiments, the expandable structure comprises a balloon, such as a cooling balloon or a cryoballoon. 
     Various embodiments of the disclosure include a balloon catheter with electrodes on the balloon to perform ablation of target tissue while cooling the luminal surface of a renal artery prevents undesirable heating of non-targeted tissue of the renal artery, particularly the endothelium of the artery. Apparatuses of the disclosure can provide a number of benefits, including one or more of reduced injury to the artery, ablation with a single treatment rather than multiple treatments which reduces treatment time, and ablation in a manner that is more controllable and repeatable. 
     An RF electrode can be cooled to limit temperature increase at the electrode surface while allowing increased temperature at a distance from the electrode. When the electrode is in contact with tissue, the distance where steady-state heating starts is on the order of about 0.5 mm to about 1 mm into the tissue. Heat is conducted out from that point. In a blood vessel, limiting heat at the electrode-vessel surface (also referred to herein as an electrode-tissue interface) can limit injury at the vessel surface, which can reduce thermal injury to, and yield improved healing of, the vessel surface. One or more temperature sensors, such as thermocouples, can be provided at the site of the electrodes to measure the temperature at or proximate the electrodes. In some embodiments, a temperature sensor is positioned near or at the site of each electrode on the balloon, allowing for precision temperature measurements at individual electrode locations of the ablation electrode arrangement. 
     Cooling of the electrodes, and other portions of the balloon wall if desired, can be effected using several different cooling mechanisms. In some embodiments, a therapy catheter incorporates a phase-change cryothermal capability such as by spraying a cryogen to cool at least the electrode supporting portions of an inflated balloon. Temperature and/or pressure sensors or other sensor elements (e.g., impedance sensors) can be incorporated near or at the electrode locations or other locations to facilitate monitoring and control of the ablation procedure. In other embodiments, the therapy catheter incorporates a heat exchange apparatus configured to receive a liquid coolant capable of causing freezing of tissue proximate of the target tissue, such as the wall of the renal artery. In some embodiments, the therapy catheter incorporates one or more solid-state thermoelectric cooling devices, such as Peltier devices. The cooling and ablation electrode components of the therapy catheter can interface with external control units to control device functioning and monitor or display temperatures, power used, impedance, blood pressure, or other parameters. 
     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&#39;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&#39;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&#39;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&#39;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&#39;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  2 A- 2 B 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 T 10 -T 12  and L 1 . Parasympathetic signals originate primarily at spinal segments S 2 -S 4  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  14   a  of nerve fibers  14   b  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  14   c  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  14   b  and bundles  14   a.  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  14   b  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  14   b.  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  14   b,  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  14   b,  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  14   b,  which can prevent regeneration and re-innervation processes. 
     By way of example, and in accordance with Seddon&#39;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  14   b  by imparting damage to the renal nerve fibers  14   b  consistent with neruapraxia. Neurapraxia describes nerve damage in which there is no disruption of the nerve fiber  14   b  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&#39;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  14   b  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  14   b  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  14   c  of the nerve fiber  14   b  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  14   b  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  14   b  by imparting damage to the renal nerve fibers  14   b  consistent with neurotmesis. Neurotmesis, according to Seddon&#39;s classification, is the most serious nerve injury in the scheme. In this type of injury, both the nerve fiber  14   b  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  14   c,  resulting in a complete loss of autonomic function, in the case of renal nerve fibers  14   b.  If the nerve fiber  14   b  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&#39;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&#39;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  14   b  with loss of continuity. 
       FIG. 4  shows an embodiment of the disclosure which includes a therapy catheter  100  configured for placement within a lumen of a target vessel of the body, such as patient&#39;s renal artery. The therapy catheter  100  shown in  FIG. 4  includes a therapy device  104  provided at a distal end of a shaft  102  of the therapy catheter  100 . The therapy device  104  includes a multiplicity of electrodes  108  supported by an expandable housing  121  and configured to deliver ablative electrical energy (e.g., RF energy or other form of high frequency AC energy) to target tissue located adjacent the target vessel. The therapy device  104  further includes a cooling arrangement  106  configured to cool each of the electrodes  108  and, if desired, other portions of a wall of the housing  121 . 
     During ablation, the electrodes  108  are cooled by the cooling arrangement  106  such that a location at which steady-state ablative heating begins is translated from an electrode-tissue interface to a location a predetermined distance away from the electrode-tissue interface. Translating the location at which study-state ablative heating begins away from the electrode-tissue interface provides for effective ablating of target tissue while intervening target vessel wall tissue is thermally protected. 
     As is further shown in  FIG. 4 , the therapy device  104  is fluidly and electrically coupled to a lumen arrangement  103  which runs along the length of the shaft  102 . The lumen arrangement  103  includes an electrical conductor arrangement, a pressurizable lumen arrangement, and a guidewire lumen  101  dimension to receive a guidewire  110 . The guidewire  110  can be used by the clinician to access a patient&#39;s venous or arterial system, locate a target vessel, such as the patient&#39;s renal artery, and advanced the therapy device  104  into the lumen of the target vessel. The proximal end of the shaft  102  is fluidly and electrically coupled to an external control system via the lumen arrangement  103 , an embodiment of which is described hereinbelow with reference to  FIG. 11 . 
     In the embodiment shown in  FIG. 4 , the lumen arrangement  103  includes a supply lumen  118  through which a thermal transfer fluid is supplied to the therapy device  104  from an external source coupled to a proximal end of the shaft  102 . The lumen arrangement  103  also includes a return lumen  119 , through which spent thermal transfer fluid is returned to the proximal end of the shaft  102 . According to some embodiments, the cooling arrangement  106  can include a phase-change cryothermal mechanism, a simpler heat exchanger system with liquid coolant, or a solid-state thermoelectric cooling device, for example. Depending on the particular cooling arrangement employed, one or both of the supply and return lumen&#39;s  118 ,  119  may or may not be required. Various cooling elements and support, connection, and control arrangements and methodologies that can be adapted for use in embodiments of the present disclosure are disclosed in commonly owned U.S. Pat. No. 7,238,184 and U.S. patent application Ser. No. 13/157,844 filed Jun. 10, 2011, which are incorporated herein by reference. 
     According to various embodiments, the electrodes  108  are cooled using a thermal transfer fluid supplied by an external coolant source and transported through the lumen arrangement  103  of the shaft  102 . A variety of thermal transfer fluids 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 cooling arrangement  106  of the therapy unit  104  may include a tube (e.g., a cryoprobe), lumen, manifold, and/or a balloon arrangement through which the thermal transfer fluid passes. The cooling arrangement  106  may be integral or separate from the expandable housing  121 . In some configurations, the cooling arrangement  106  may be configured to cool a substantial portion of the housing wall, including locations where the electrodes  108  are mounted. In other configurations, the cooling arrangement  106  may be configured to cool only those portions of the housing wall where the electrodes  108  are mounted. 
     In accordance with various embodiments, the electrodes  108  are energized by a conductive thermal transfer fluid within the housing  121 . An electrical conductor extends along the lumen arrangement of the shaft  102  and is in electrical communication with the conductive fluid. In some configurations, the electrical conductor is electrically coupled to an electrode  112  positioned on the shaft  102  within the housing  121 . High frequency AC power is communicated to the electrodes  108  supported by the housing  121  via the electrical conductor, electrode  112 , and electrically conductive fluid within the housing  121 . Various embodiments may incorporate selected structural, electrical, thermal, and control features of the devices disclosed in the commonly owned U.S. Publication No. ______, filed as Ser. No. 13/188,677 on Jul. 22, 2011, which claims priority to U.S. Provisional Application Nos. 61/411,795, filed on Nov. 9, 2010, and 61/369,442, filed on Jul. 30, 2010, each of which is incorporated herein by reference. In other embodiments, the electrodes  108  are energized by electrical conductors that couple each electrode  108  to a conductor arrangement of the shaft  102 . The electrodes  108  can be connected to an external control system individually or in series. 
     In some embodiments, the thermal transfer fluid, when released inside the cooling arrangement  106  (e.g., a cryoballoon) via the supply lumen  118 , undergoes a phase change that cools some or all of the housing  121  and each of the electrodes  108  by absorbing the latent heat of vaporization from the tissue surrounding the therapy unit  104 , and by cooling of the vaporized gas as it enters a region of lower pressure inside the cooling arrangement  106  (the Joule-Thomson effect). As a result of the phase change and the Joule-Thompson effect, heat is extracted from the surroundings of the housing  121 , thereby cooling at least the electrodes  108  (and other portions of the housing wall if desired) which are in contact with vessel wall tissue. In configurations where cooling is limited to the electrodes  108 , a manifold can be implemented within the housing  121  or housing wall to transport thermal transfer fluid to and from the electrodes  108 . The gas released inside the cooling arrangement  106  may be exhausted through the return lumen  119  of the shaft  102 . The pressure inside the cooling arrangement  106  may be controlled by regulating one or both of a rate at which thermal transfer fluid is delivered and a rate at which the exhaust gas is extracted. The lumen  118 ,  119  of the lumen arrangement  103  which transport thermal transfer fluid are preferably lined with or otherwise incorporate insulation material(s) having appropriate thermal and mechanical characteristics suitable for a selected thermal transfer fluid. 
     Embodiments of the present invention may incorporate selected balloon, catheter, lumen, control, and other features of the devices disclosed in the following commonly owned U.S. patents and published patent applications: U.S. Patent Publication Nos. 2009/0299356, 2009/0299355, 2009/0287202, 2009/0281533, 2009/0209951, 2009/0209949, 2009/0171333, 2008/0312644, 2008/0208182, 2008/0058791 and 2005/0197668, and U.S. Pat. Nos. 5,868,735, 6,290,696, 6,648,878, 6,666,858, 6,709,431, 6,929,639, 6,989,009, 7,022,120, 7,101,368, 7,172,589, 7,189,227, and 7,220,257, which are incorporated herein by reference. Embodiments of the present invention may incorporate selected balloon, catheter, and other features of the devices disclosed in U.S. Pat. Nos. 6,355,029, 6,428,534, 6,432,102, 6,468,297, 6,514,245, 6,602,246, 6,648,879, 6,786,900, 6,786,901, 6,811,550, 6,908,462, 6,972,015, and 7,081,112, which are incorporated herein by reference. In various embodiments, the cooling arrangement  106  can include one or more thermoelectric elements configured to thermally couple to the wall of the housing  121  at or near the electrodes  108  and operate in a hypothermic mode. The thermoelectric elements preferably comprise solid-state thermoelectric elements, such as Peltier elements. Various Peltier-effect elements and support, connection, and control arrangements and methodologies that can be adapted for use in embodiments of the present invention are disclosed in commonly owned U.S. Pat. No. 7,238,184, which is incorporated herein by reference. 
     In some embodiments, for example, the expandable housing  121  includes or is constructed as a balloon which is fluidly coupled to the lumen arrangement  103  and transformable between a low-profile introduction configuration and a larger-profile deployed configuration. The housing  121  is typically constructed from polymeric material, and preferably has a diameter dimensioned to fit within a target vessel, such as a renal artery of an average patient. It is understood that different models of ablation catheters  100  can be constructed each having specific housing configurations and dimensions appropriate for a given population of patients. In some embodiments, the housing  121  may comprise an expandable element, such as a pressurizable balloon or a mechanically expandable arrangement (e.g., an expandable-collapsible mesh structure). Use of such an expandable element in the construction of the housing  121  allows for use of a common housing design for a population of patients having varying anatomy. In accordance with various embodiments in which a pressurizable balloon is used in the construction of the housing  121 , a thermal transfer fluid may be used for pressurizing the balloon and cooling of vessel tissue and the electrodes  108 . 
     The balloon  121  includes a wall configured to contact an inner wall of a target vessel when in its deployed configuration. A multiplicity of ablation electrodes  108  are supported by the balloon wall and are preferably arranged in a predefined pattern. The electrodes  108  may, for example, be arranged to form one or more circumferential patterns. By way of further example, the electrodes  108  may be arranged to form a helical or spiral pattern. The ablation electrodes  108  are configured to deliver electrical energy sufficient to ablate target tissue located adjacent to the target vessel when the balloon  121  is in its deployed configuration. All or at least part of the cooling arrangement  106  is encompassed by the balloon  121 . 
     As discussed previously, the cooling arrangement  106  is configured to cool at least the electrodes  108  during ablation, such that a location at which steady-state ablative heating begins is translated from an electrode-tissue interface at the inner vessel wall to a location a predetermined distance away from electrode-tissue interface. In some embodiments, the cooling arrangement is configured to cool the electrodes  108  such that the steady-state ablative heating begins at a distance of about 0.5 mm to about 1 mm from the electrodes  108  (away from the electrode-tissue interface and towards target tissue). In other embodiments, the location at which steady-state ablative heating begins is translated from the electrode-tissue interface to a distance of about 1 mm. 
     As is shown in  FIG. 5 , one or more temperature sensors  115  can be situated on the therapy device  104  to provide for temperature sensing at or near the electrodes  108  and/or the target vessel wall. In the embodiment shown in  FIG. 5 , each of the electrodes  108  is mounted to the wall of the housing  121  along with a corresponding temperature sensor  115 . In some configurations, the electrodes  108  can be mounted so as to directly contact the corresponding temperature sensor  115 . In such a configuration, the temperature of each electrode  108  can be individually monitored and energy delivered from each electrode  108  can be individually controlled. Although in some embodiments it may be desirable to connect the electrodes  108  in series to a common conductor, it may be more desirable to provide individual connectivity with at least some of the electrodes  108 , allowing for selective energizing of the electrodes  108 . 
     With further reference to the embodiment shown in  FIG. 5 , the therapy unit  104  incorporates a cooling arrangement  106  in which cooling of the housing wall and electrodes  108  is provided by blood passing through the target vessel within which the therapy unit  104  is deployed. The embodiment shown in  FIG. 5  includes a cooling channel  150  that extends through a longitudinal portion of the housing  121 . The cooling channel  150  includes an inlet  152  which is configured to divert blood flowing through the target vessel into the cooling channel  150 . The cooling channel  150  further includes an outlet  154  through which heated blood returns to the target vessel. Although the cross-sectional illustration of the embodiment shown in  FIG. 5  shows a single cooling channel  150 , it is understood that two or more cooling channels  150  may be incorporated into the housing  121  (e.g., between 2 and 6). 
       FIG. 6  illustrates a portion of a therapy unit  104  of an ablation catheter  100  positioned within a lumen of a renal artery  12  in its deployed configuration. More particularly,  FIG. 6  shows an ablation electrode  108  supported by the wall  121   a  of a balloon  121 . According to some embodiments, an electrical conductor  117  is connected to the electrode  108  and extends within or along the balloon wall  121   a.  The conductor  117  extends along the length of the shaft  102  and terminates at a coupling at the proximal end of the ablation catheter  100 . The electrical conductor  117  may alternatively be disposed in an interior or exterior lumen provided along the interior or exterior of the balloon  121 . In other embodiments, the electrical conductor  117  terminates at a location within the balloon other than at the electrode(s)  108 . For example, and as previously discussed with reference to the embodiment of  FIG. 4 , an electrode can be situated on the shaft of the balloon structure and coupled to the electrical conductor  117  which extends along the length of the catheter&#39;s shaft. High frequency alternating current is conducted from the shaft electrode to the electrode(s)  108  via an electrically conductive thermal transfer fluid within the balloon  121 . 
     The electrode  108  is shown mounted to the outer surface of the balloon wall  121   a . In the embodiment shown in  FIG. 6 , a thermal conductor  160  is affixed to the balloon wall  121   a  and can serve as a base structure to facilitate mounting of the electrode  108  to the balloon wall  121   a.  The thermal conductor  160  preferably enhances the transfer of thermal energy between the cooling media  107  and the electrode  108 . Although the thermal conductor  160  is shown extending through the thickness of the balloon wall  121   a , the thermal conductor  160  can extend into the balloon interior  123  or only partially within the balloon wall  121   a.  The thermal conductor  160  may be fabricated using a matrix of polymeric and conductive material, which provides for pliancy of the thermal conductor  160 . 
     As is further shown in the embodiment of  FIG. 6 , the electrode  108  includes a protuberance  109  defining a tissue contacting surface which serves to compress a portion of the renal artery wall  15  when the balloon  121  is in its pressurized deployed configuration. The protuberance  109  of the electrode  108  is shown to have a continuous curved shape. The pressurized balloon  121  forces the protuberance  109  of the electrode  108  against the renal artery wall  15 , thereby compressing a portion of the renal artery wall  15  shown as compression region, R C , surrounding the electrode protuberance  109 . 
     Compressing the renal artery wall  15  using the electrode protuberance  109  reduces the width of a renal artery wall portion  15   a  in the area of the electrode  108  and shortens the distance between the electrode  108  and target tissue (e.g., perivascular renal nerves  37 ). The effective reduction in the distance between the electrode  108  and the perivascular renal nerves  37  adjacent the renal artery  12  can facilitate a reduction in the amount of electrical energy needed to ablate the perivascular renal nerve tissue, due to a reduced amount of tissue through which the electrical energy must pass. A reduction in the amount of electrical energy needed to ablate target tissue can result in a reduction in the total amount of heat generated during ablation, resulting in reduced risk of thermal injury to non-targeted tissue. 
     A significant reduction in the total heat generated within the renal artery wall  15  is realized by cooling the electrode  108  during ablation. As previously discussed, it has been found that cooling the electrode  108  using a cooling arrangement of the type discussed herein advantageously translates outwardly the location at which steady-state ablative heating begins a predetermined distance away (i.e., a predetermined distance away from the tissue-electrode interface defined between the electrode protuberance  109  and adjacent renal artery wall tissue and in a direction of the perivascular renal nerve tissue). 
     The magnitude of this translation may be influenced by a number of factors including the amount of power delivered to the electrode  108 , shape, size, and material of the electrode protuberance  109 , temperature of the electrode  108  during cooling, renal artery wall thickness, the amount of renal artery wall compression, and other properties of the renal artery and neighboring tissue, among others. In general, the magnitude of this translation can range between about 0.5 mm to about 1 mm. An appreciable reduction in thermal injury to the artery wall is realizable when the start of steady-state heating is translated about 0.5 mm from the electrode-tissue interface, with further reductions in artery wall injury being realized until a translation of about 1 mm is achieved. Because artery anatomy differs between individual patients, it is understood that the range of about 0.5 mm to about 1 mm is an estimated range in which a beneficial reduction in thermal injury to the artery wall can be achieved for most patients. This range may be greater or smaller by about +/−0.1 mm, +/−0.2 mm, or +/−0.3 mm (for one or both extremes of the range), for example, for some patients. In qualitative terms, the magnitude of this translation is preferably such that target tissue is effectively ablated while non-targeted tissue is subject to an acceptable level of thermal injury (e.g., little or no permanent thermal injury). 
       FIG. 7  shows a portion of the therapy unit  104  of an ablation catheter  100  positioned within a lumen of the renal artery  12  in its deployed configuration. The therapy unit  104  shown in  FIG. 7  is similar in most aspects to that shown in  FIG. 6 , but differs in terms of the shape of the protuberance  109  of ablation electrode  108 . Whereas the protuberance  109  of the electrode  108  in the embodiment of  FIG. 6  has a continuous curved shape, the protuberance  109  of the electrode  108  in the embodiment of  FIG. 7  has a complex curved shape. The profile of the protuberance  109  of the electrode in  FIG. 7  includes a discontinuity such that a lower portion of the electrode  108  has a more gradual slope relative to that of an upper portion of the electrode  108 . The smaller radius of curvature of the upper portion of the electrode  108  serves to concentrate greater compressive force at the tip of the electrode  108  when compared to an electrode  108  having a continuous curved shape. The protuberance  109  of  FIG. 7  provides for increased compression of the renal artery wall portion  15   a  in contact with the electrode  108 , resulting in a further reduction in separation distance between the electrode  108  and the target tissue (perivascular renal nerves  37 ) located adjacent to the renal artery  12 . 
     It is understood that, in some embodiments, the electrodes  108  can be flush or nearly flush with the outer surface of the housing  121  of the therapy unit  104 . Many of the attributes described herein with regard to cooled electrodes  108  having protuberances  109  can be realized when using flush or near-flush mounted ablation electrodes  108 , but with some degree of reduced benefits. 
       FIGS. 8-10  show a portion of a therapy unit  104  of an ablation catheter  100  including different cooling arrangements incorporated into a balloon  121  in accordance with various embodiments of the disclosure.  FIG. 8  shows an embodiment in which blood passing through the vessel is used for cooling within the therapy unit  104  (see, e.g., embodiment of  FIG. 5 ). The sectional view of  FIG. 8  shows an ablation electrode  108  supported by the wall  121   a  of a balloon  121  of the therapy unit  104 . The electrode  108  is mounted on or otherwise coupled to a temperature sensor  115 . In some embodiments, an inner surface of the balloon wall  121   a  is lined with a thermally conductive layer of material  180 , such as a metallic foil layer. The thermally conductive layer  180  serves to enhance the transfer of thermal energy from the blood  170  flowing through the vessel, thereby enhancing cooling of the electrode  108 . It is noted that the configuration and material of the temperature sensor  115  may be selected to also enhance thermal energy transfer between the electrode  108  and the blood  170 . For example, the temperature sensor  115  may be constructed as a heat sink. An electrical insulator  162  may be used to electrically insulate the electrode  108  from the thermally conductive layer  180 . 
       FIG. 9  shows an embodiment in which a cooling media  107  is supplied to the balloon  121  via a manifold  111 . The embodiment shown in  FIG. 9  is essentially the same as that shown in  FIG. 8 , but differs in terms of the cooling arrangement configuration. In  FIG. 9 , the manifold  111  disperses the cooling media  107  within the balloon  121  as either a gas or a liquid depending on the configuration of the cooling arrangement (e.g., a phase-change or heat exchange cooling arrangement). As previously discussed, the manifold  111  can be configured to disperse the cooling media  107  to all or most of the balloon wall  121   a  or only to those portions where electrodes  108  are mounted, in which case the conductive metallic layer  180  can either be excluded or limited to balloon wall regions adjacent the electrodes  180 . 
       FIG. 10  shows an embodiment in which thermoelectric cooling devices  190  are incorporated in the cooling arrangement. As shown in  FIG. 10 , one or more thermoelectric cooling devices  190  are coupled to an inner surface of the balloon wall  121   a.  The thermoelectric cooling devices  190 , for example, can be mounted to the thermally conductive layer  180 , which provides for lateral conduction of thermal energy along the balloon wall  121   a.  In some configurations, a patch  180  of conductive metallic material can be affixed to the inner surface of the balloon wall  121  a under individual electrodes  180  or under a subset of the electrodes  180 . A thermoelectric cooling device  190  can be affixed to each of the conductive metallic material patches  180 . The thermoelectric cooling devices  190  are preferably individually controlled during ablation, allowing for enhanced control of the temperature at each electrode  108 . It is understood that a therapy unit  104  can incorporate more than one cooling arrangement of a type described herein, and that the cooling arrangements may be modified based on the application of a given therapy unit  104 . 
     Referring now to  FIG. 11 , there is shown a system  300  for ablating tissue that influences sympathetic renal nerve activity in accordance with various embodiments. The system  300  shown in  FIG. 11  includes a therapy device  104  provided at the distal end of a therapy catheter  100  deployed within a patient&#39;s renal artery  12 . The therapy catheter  100  includes a flexible shaft  102  within which a lumen arrangement  103  is provided. The shaft  102  is preferably sufficient in length to reach a patient&#39;s renal artery  12  from a percutaneous access location  129 . It may be desirable to use an external sheath  105  to facilitate delivery of the therapy device  104  into the renal artery  12 . The catheter shaft  102  may include a distal hinge  356  that facilitates navigation of a near 90° turn into the renal artery  12  from the aorta  20 . 
     The therapy device  104  includes an electrode arrangement and a cooling arrangement of a type previously described. The electrode arrangement is electrically coupled to an external radiofrequency (RF) generator  320 . A power control  322  and timing control  324  provide for automatic or semi-automatic control of electrical energy delivery from the therapy unit  104 . The cooling arrangement of the therapy device  104  is shown fluidly coupled to a coolant source  340 . A temperature control  324  is preferably coupled to one or more temperature sensors provided at the therapy device  104 . The temperature control  324  generates temperature signals which are used by the RF generator  320  and coolant source  340  to adjust (automatically via a processor of the system  300  or semi-automatically) power delivered to the ablation electrodes  108  and thermal transfer fluid delivered and/or removed to/from the cooling arrangement of the therapy device  104 . 
     A pump system  341  is shown coupled to the coolant source  340 . The pump system  341  is coupled to a fluid reservoir system which may be configured to store a variety of cryogens, such as cold saline or cold saline and ethanol mixture, Freon or other fluorocarbon refrigerants, nitrous oxide, liquid nitrogen, and liquid carbon dioxide, for example. 
     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 (e.g., the prostate for BPH ablation). 
     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.