Patent Application
20110263921
The present invention is related to systems and methods for improving cardiac and/or renal function through neuromodulation, including disruption and termination of renal nerve activity.
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.
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.
Devices, systems, and methods of the present invention are directed to modifying renal sympathetic nerve activity using various forms of denervation therapy. Embodiments of the present invention are directed to a renal denervation apparatus that includes a treatment element dimensioned for deployment on or within a renal artery of a patient. The treatment element comprises a predefined pattern arranged to complete at least one revolution of the treatment element. The apparatus includes a treatment source. The treatment source and treatment element are configured to cooperatively facilitate communication of an agent from the treatment source to the pattern arrangement of the treatment element. The treatment element is configured to deliver denervation therapy using the agent via the pattern arrangement to one or more regions of the renal artery adjacent the pattern arrangement, such that at least one complete revolution of the renal artery is subjected to the denervation therapy.
In some embodiments, the treatment element is dimensioned for intravascular deployment within the renal artery. In other embodiments, the treatment element is dimensioned for extravascular deployment at the renal artery.
In various embodiments, the treatment source includes a cryogen source and the agent comprises a cryogen. In some embodiments, the treatment source includes a thermal transfer fluid source and the agent comprises a thermal transfer fluid heated to a predefined temperature above body temperature. In further embodiments, the treatment source includes an electromagnetic energy source and the agent comprises electromagnetic energy that is coupled to the treatment element. In other embodiments, the treatment source includes a microwave source and the agent comprises microwave energy that is coupled to the treatment element. In some embodiments, the treatment source includes an ultrasound source and the agent comprises ultrasound generated by an ultrasonic transducer provided at least in part at the treatment element.
According to further embodiments, the treatment source includes a laser source and the agent comprises a laser emission emitted by a laser apparatus provided at least in part at the treatment element. In other embodiments, the treatment source includes a pharmacological agent source and the agent comprises a neurotoxin or venom. In some embodiments, the treatment source includes a source of radioactivity and the agent comprises a radioactive material suitable for delivering brachytherapy to the renal artery.
In accordance with various embodiments, a catheter system of the present invention includes a catheter 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's renal artery from a location external of the patient. A treatment element is provided at the distal end of the shaft and fluidly coupled to the lumen arrangement. The treatment element is dimensioned for deployment on or within the renal artery and comprises a predefined pattern arranged to complete at least one revolution of the treatment element. The treatment element is configured to receive a thermal transfer fluid from the lumen arrangement and deliver thermal denervation therapy using the thermal transfer fluid via the pattern arrangement to one or more regions of the renal artery adjacent the pattern arrangement, such that at least one complete revolution of the renal artery is subjected to the thermal denervation therapy.
In some embodiments, the catheter includes a hinge mechanism provided on the shaft proximal of the treatment element. The hinge mechanism may include a slotted tube arrangement, for example. The hinge mechanism is configured to facilitate preferential bending at the distal end of the shaft to aid in directing the treatment element into the renal artery from the abdominal aorta. A biasing mechanism may be included and configured to generate a biasing force sufficient to effect engagement between the treatment element and the inner wall of the renal artery.
The pattern arrangement of the treatment element may be formed as an integral part of the distal end of the shaft or as a pre-fabricated sleeve mounted at the distal end of the shaft. In some embodiments, a cryoballoon is fluidly coupled to the lumen arrangement of the shaft and the lumen arrangement is configured to receive the cryoballoon. Pressurizing the cryoballoon expands the pattern arrangement at the distal end of the shaft and causes the pattern arrangement to contact or come into close proximity of an inner wall of the renal artery. The distal end of the shaft is preferably formed from a resilient material that facilitates expansion and contraction of the shaft responsive to expansion and contraction of the cryoballoon. In this configuration, the cryoballoon may define a non-compliant balloon.
According to other embodiments, the distal end of the catheter's shaft is formed from a material having a stiffness greater than a stiffness of the cryoballoon, and the relative stiffness of the shaft's distal end and the cryoballoon material allows portions of the cryoballoon's exterior surface exposed by apertures of the pattern arrangement to expand into the apertures and contact the inner wall of the renal artery. In this configuration, the cryoballoon may define a compliant balloon.
In further embodiments, the treatment element includes a cryoballoon fluidly coupled to the lumen arrangement of the shaft, and the pattern arrangement is formed as an integral part of the cryoballoon or is formed as a separate sleeve that is affixed to an outer surface of the cryoballoon.
In some embodiments, the pattern arrangement comprises a predetermined pattern of apertures. In other embodiments, the pattern arrangement comprises a predetermined pattern of thermally conductive elements or regions. The pattern arrangement may be contiguous or non-contiguous, and may form a generally spiral or helical pattern.
According to some embodiments, the thermal transfer fluid comprises a cryogen having a boiling temperature at ambient pressure of about 0° C. or lower. In other embodiments, the thermal transfer fluid comprises a cryogen having a boiling temperature at ambient pressure of about −60° C. or lower. In further embodiments, the thermal transfer fluid comprises a cryogen having a boiling temperature at ambient pressure of about −140° C. or lower. In other embodiments, the thermal transfer fluid comprises a cryogen having a boiling temperature at ambient pressure of about −180° C. or lower.
The above summary of the present invention is not intended to describe each embodiment or every implementation of the present invention. Advantages and attainments, together with a more complete understanding of the invention, will become apparent and appreciated by referring to the following detailed description and claims taken in conjunction with the accompanying drawings.
While the invention is amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the drawings and will be described in detail. It is to be understood, however, that the intention is not to limit the invention to the particular embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the scope of the invention as defined by the appended claims.
In the following description, references are made to the accompanying drawings which illustrate various embodiments of the invention. It is to be understood that other embodiments may be utilized, and structural and functional changes may be made to these embodiments without departing from the scope of the present invention.
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 calcitriol. 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
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
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
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.
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 renal nerve 14 is shown proximate the adventitia 36 and extending longitudinally along the renal artery 12. The main trunk of the renal nerves 14 generally lies in or on the adventitia of the renal artery, with certain branches coursing into the media to enervate the renal artery smooth muscle.
Turning now to
System embodiments according to
The treatment surface 52 of the treatment element 50 includes a patterned arrangement 54 that has a longitudinal aspect and a circumferential aspect. Preferably, the patterned arrangement 54 is configured to complete at least one revolution of the treatment element 50. The patterned arrangement 54 may be contiguous or non-contiguous. For example, a contiguous patterned arrangement 54 preferably has a spiral or other shape that completes at least one revolution of the treatment element 50 (e.g., at least one turn of the spiral or helix). A non-contiguous or segmented patterned arrangement 54 preferably comprises a multiplicity of spaced-apart patterned segments that collectively complete at least one revolution of the treatment element 50. A contiguous or segmented patterned arrangement 54 can take on a variety of configurations, and need not be limited to spiral or helical shapes.
The patterned arrangement 54 may be integral to the treatment element 50 or may be a separate structure. The patterned arrangement 54 may comprise one or more surface structures or treatment features, surface discontinuities, voids or apertures, or combinations of these and other features. The patterned arrangement 54 may comprise disparate regions that vary in terms of one or more of material, thermal, electrical, optical, chemical, mechanical, pharmacological, and dimensional properties or characteristics. For example, the patterned arrangement 54 may comprise regions differing in terms of thickness, permeability, porosity, density, elasticity, thermal conductivity, and electrical conductance, among others.
In some embodiments, the patterned arrangement 54 may be disposed or expressed on the surface of the treatment element 50, such that the agent 46 is communicated directly to or through the inner wall 15a of the renal artery 12. In other embodiments, the patterned arrangement 54 may be disposed or expressed over the treatment element 50, such that the agent 46 is communicated through the patterned arrangement 54 and to or through the inner wall 15a of the renal artery 12. In further embodiments, the agent manifests as a form of energy (e.g., ultrasonic, RF, microwave, laser emission, cryogenic) that is coupled to the patterned arrangement 54, such as by a body-external source. Details of these and other embodiments that employ an energy agent that can cooperate with a patterned treatment element 50 of the present invention are disclosed in commonly owned U.S. Published Patent Application No. ______, filed as U.S. Provisional Patent Application Ser. No. 61/324,164 on Apr. 14, 2010, under Attorney Docket No. BCV.005.P1; U.S. Published Patent Application No. ______, filed as U.S. Provisional Patent Application Ser. No. 61/353,853 on Jun. 11, 2010, under Attorney Docket No. BCV.007.P1; and U.S. Published Patent Application No. ______, filed as U.S. Provisional Patent Application Ser. No. 61/324,163 on Apr. 14, 2010, under Attorney Docket No. BCV.009.P1; each of which is incorporated herein by reference in their respective entireties.
The treatment surface 52 of the treatment element 50 includes a patterned arrangement 54 of a type discussed hereinabove. As discussed above, the patterned arrangement 54 has a longitudinal aspect and a circumferential aspect, may be contiguous or non-contiguous, and preferably completes at least one revolution of the treatment element 50.
In some embodiments, the patterned arrangement 54 may be disposed or expressed on the surface of the treatment element 50, such that the agent 46 is communicated directly to or at least partially through the outer wall 15a of the renal artery 12 (e.g., direct thermal or drug treatment). In other embodiments, the patterned arrangement 54 may be disposed or expressed over or within the treatment element 50, such that the agent 46 is communicated through the patterned arrangement 54 and to or at least partially through the outer wall 15b of the renal artery 12 (e.g., thermal or drug treatment delivered through apertures or a permeable layer). The agent 26 may take the form of energy (e.g., ultrasonic, RF, microwave, laser emission, cryogenic) that is coupled to the patterned arrangement 54, such as by an energy source located outside the body.
A patterned treatment element 50 of the present invention advantageously facilitates a “one-shot” denervation therapy of the renal artery or other vessel in accordance with embodiments of the present invention. The term “one-shot” treatment refers to treating the entirety of a desired portion of a vessel without having to move the treatment implement or arrangement to other vessel locations in order to complete the treatment procedure (as is the case for a step-and-repeat denervation therapy approach). A one-shot treatment approach of the present invention advantageously facilitates delivery of denervation therapy that treats at least one location of each nerve fiber extending along a target vessel, such as the renal artery, without having to reposition the treatment element 50 during denervation therapy delivery. Embodiments of the present invention allow a physician to position a treatment element 50 at a desired vessel location, and completely treat the vessel without having to move the treatment element 50 to a new vessel location. It is to be understood that devices and methods that utilize a patterned treatment element 50 provide advantages and benefits other than facilitating one-shot treatment of a vessel, and that treatment element patterning that enables one-shot vessel treatment is not a required feature in all embodiments of the present invention.
It can be appreciated that the type of agent 46 will vary in accordance with the particulars of the treatment source 42 and treatment element 50. The agent 46 may take the form of a thermal transfer fluid (hot or cold), a pharmacological agent or mixture of agents (e.g., a neurotoxin or venom), radioactive material or seeds (e.g., iodine-125 or palladium-103 for low dosage rate brachytherapy, iridium-192 for high dose rate brachytherapy), or electromagnetic energy (e.g., RF, microwave, laser/light, X-rays, gamma rays). X-rays, for example, may be delivered from an external source as in the case of radiation beam therapy or use of a gamma knife, or via a catheter based miniature X-ray tube. The agent 46 may take the form of mechanical energy, such as a mechanical compression arrangement or ultrasound, for example.
The treatment source 42 may be external to the body, implantable (temporarily or chronically), or comprise external and implantable elements. In some embodiments, the treatment source 42 is physically connected to the treatment element 50, and the agent 46 is communicated to the treatment element 52 via the connection. In other embodiments, the treatment source 42 is physically separate from the treatment element 50, and the agent 46 is communicated or coupled to the treatment element 50 by means other than a physical connection with the treatment element 50. In further embodiments, different agents 46 and means for communicating or coupling the agent 46 to the treatment element 50 may be employed.
A biasing mechanism may be employed to maintain engagement between the treatment element 50 and the inner wall 15a (for intravascular embodiments) or the outer wall 15b (for extravascular embodiments) of the renal artery 12. Various biasing mechanisms may be employed, including single and multiple balloon arrangements, multi-lumen catheters, combinations of balloons and catheters, spring arrangements, elastic arrangements, clamp or cuff arrangements, stent or cage structures, mechanical inter-linking arrangements, and shape-memory elements, among others. The biasing mechanism and/or the treatment element 50 may include a radio-opaque material or include radio-opaque markers to facilitate fluoroscopic visualization.
The medical system 40 shown in
The cryogen source 42 is coupled to a cryothermal catheter apparatus 44, which may be a unitary or multi-component apparatus.
In some embodiments, the cryogen 46, when released inside the cryoablation element 50 (e.g., a cryoballoon), undergoes a phase change that cools the treatment portion of the cryoablation element 50 by absorbing the latent heat of vaporization from the tissue surrounding the cryoablation element 50, and by cooling of the vaporized gas as it enters a region of lower pressure inside the cryoablation element 50 (the Joule-Thomson effect).
As a result of the phase change and the Joule-Thompson effect, heat is extracted from the surroundings of the cryoablation element 50, thereby cooling the treatment portion of the cryoablation element 50 and renal tissue that is in contact with the treatment portion of the cryoablation element 50. The gas released inside the cryoablation element 50 may be exhausted through a separate exhaust lumen provided in the catheter 44. The pressure inside the cryoablation element 50 may be controlled by regulating one or both of a rate at which cryogen 46 is delivered and a rate at which the exhaust gas is extracted.
It has been shown experimentally that at sufficiently low temperatures, the blood in contact with the cryoablation element's treatment portion will freeze, thereby acting as a thermally conducting medium to conduct heat away from adjacent blood and tissue of the renal artery 12. The diameters and insulating properties of the cryoablation element 50 can be designed such that the middle region of the renal artery 12 is a primary target for treatment. Cryogenically treating the middle region of the renal artery 12 reduces the adverse impact on the distal and proximal portions of the renal artery 12. For example, the cryoablation element 50 can be designed such that only partial contact with the renal artery wall is permitted and insulating material is placed elsewhere in order to reduce and control the region(s) that are subject to cryotherapy.
The catheter apparatus 44 is preferably lined with or otherwise incorporates insulation material(s) 60 having appropriate thermal and mechanical characteristics suitable for a selected cryogen. A lumen arrangement is shown in
In some embodiments, the lumen arrangement includes a first lumen 66, for supplying a cryogen to the distal end of the catheter apparatus 44, and a second lumen 68, for returning the cryogen to the proximal end of the catheter apparatus 44. The supply and return lumens 66, 68 may be coupled to a cryotube or cryoballoon disposed at the distal end of the catheter apparatus 44. The cryogen may be circulated through the cryotube or cryoballoon via a hydraulic circuit that includes the cryogen source 42, supply and return lumens 66, 68, and the cryotube or cryoballoon disposed at the distal end of the catheter apparatus 44.
In configurations that incorporate a cryoballoon, the supply lumen 66 may be supplied with a pressurized cryogen by the cryogen source 42 that both pressurizes the cryoballoon and provides the cryogen to the cryoablation element 50. In configurations that incorporate a cryotube, the catheter apparatus 44 may include one or more inflation lumens (e.g., lumens 67 and/or 69) that fluidly communicate with one or more balloons disposed at the distal end of the catheter apparatus 44. In further embodiments, one or more cryoballoons and one or more biasing balloons may be incorporated at the distal end of the catheter apparatus 44, with appropriate supply, return, and pressurization lumens provided to fluidly communicate with the cryogen source 42 and an optional inflation fluid source 63.
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, 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.
According to the embodiment shown in
The cryoablation element 50 may incorporate a cuff mechanism that can be manipulated so that opposing edges of the cuff contact each other. The cuff coupling mechanism shown in
With further reference to
In other configurations, the catheter apparatus 44 includes a guide lumen 64 through which a guide wire may be advanced. The guide wire may be advanced through a vascular access port into the femoral artery to the aorta 20 and into the renal artery 12. The catheter apparatus 44 may then be advanced over the guide wire using an over-the-wire navigation technique. The control mechanism 51 may include a steerable portion that facilitates physician control of orientation and longitudinal displacement of the guide wire and/or the catheter apparatus 44 during navigation to, and cannulation of, the renal artery 12. A marker band may be attached or applied to the guide wire and/or the catheter apparatus 44 so that the position of the guide wire and/or the catheter apparatus 44 in the patient's body may be visualized using known imaging techniques.
The control mechanism 51 may accommodate a number of physician tools that are external of a patient's body when in use, and allow the physician to perform various functions at the distal section of the catheter apparatus 44. Each of the tools may be coupled to one or more associated lumens in the catheter apparatus 44 using one or more manifolds at the proximal section, for example.
As will be discussed in greater detail hereinbelow, some embodiments incorporate a biasing or anchoring mechanism disposed at the distal end of the catheter apparatus 44, such as at the cryoablation element 50. The type and configuration of the biasing or anchoring mechanism varies depending on whether the cryoablation element 50 is configured for intravascular or extravascular positioning. As previously discussed, suitable biasing mechanisms include single and multiple balloon arrangements, multi-lumen catheters, combinations of balloons and catheters, spring arrangements, elastic arrangements, clamp or cuff arrangements, stent or cage structures, mechanical inter-linking arrangements, shape-memory elements, and other mechanisms or structures that are capable of creating a biasing force sufficient to facilitate engagement between the cryoablation element 50 and the inner or outer vessel wall 15a, 15b. For example, a saline solution or a cryogen may be forced into a balloon or inflatable catheter structure that mechanically cooperates with the cryoablation element 50 to cause expansion of the balloon or catheter structure. Other inflation fluids may also be used, including liquids and gases.
Accessing each of the right and left renal arteries from the abdominal aorta 20 is often a challenge, since each of the renal arteries form nearly a right angle with respect to the abdominal aorta 20. Embodiments of the invention are directed to intravascular delivery apparatuses that enhance access to, and cannulation of, the renal arteries via the superior or inferior abdominal aorta 12.
The catheter shaft 151 may be formed to include an elongate core member 157 and a tubular member 153 disposed about a portion of the core member 157. The tubular member 153 may have a plurality of slots 161 formed therein. The slotted hinge region of the catheter shaft 151 may be configured to have a preferential bending direction.
For example, and as shown in
A hinge arrangement 156 constructed to provide for a preferential bending direction allows a physician to more easily and safely navigate the treatment element 50 to make the near 90 degree turn into the renal artery from the abdominal aorta 20. One or more marker bands may be incorporated at the hinge region 156 to provide visualization of this region of the catheter shaft 151 during deployment. Details of useful hinge arrangements that can be incorporated into embodiments of a treatment catheter 150 of the present invention are disclosed in U.S. Patent Publication Nos. 2008/0021408 and 2009/0043372, which are incorporated herein by reference. It is noted that the treatment catheter 150 may incorporate a steering mechanism in addition to, or exclusion of, a hinge arrangement 156. Known steering mechanisms incorporated into steerable guide catheters may be incorporated in various embodiments of a treatment catheter 150 of the present invention.
With the guide catheter 171 positioned near the ostium 19 of the renal artery 12, the treatment element 50, typically in a collapsed configuration, is advanced through the lumen of the guide catheter 171. Marker bands may be provided on or near the treatment element 50 to facilitate visualization of the treatment element 50 when being advanced through the guide catheter 171. As is shown in
Turning now to
Embodiments of the treatment element 50 include those configured for intravascular placement (e.g., endoluminal), extravascular placement (e.g., on or proximate the outer wall of a vessel), or both intra- and extravascular placement. A treatment agent may be delivered to the patterned surface 54 via an intravascular source (e.g., via a catheter or balloon), an extravascular source (e.g., via a catheter), or a body-external source (e.g., via an energy source external to the body). In some embodiments, the patterned surface 54 of the treatment element 50 is disposed on, or expressed at, the outer surface of the treatment element 50. In other embodiments, the patterned surface 54 of the treatment element 50 is fashioned to incorporate voids, apertures, or thin wall portions (e.g., permeable or non-permeable) that take on a desired pattern. Portions of the treatment surface 52 adjacent to, or otherwise devoid of, the treatment pattern 54 may include material or features that provide enhanced thermal insulation to protect tissue surrounding the target tissue to be treated. A treatment agent may be delivered through the voids, apertures, or thin wall portions of the treatment element 50.
Useful treatment elements 50 include those that impart nerve injury to the renal vasculature in accordance with a desired shape that at least disrupts, and preferably irreversibly terminates, renal sympathetic nerve activity. Particularly useful treatment elements 50 include those that can impart such nerve injury to the renal artery using a one-shot denervation therapy approach. In other words, a particularly useful treatment element 50 is one that facilitates delivery of denervation therapy that treats at least one location of each renal nerve fiber 14 extending along the renal artery 12 without having to reposition the treatment element 50 during denervation therapy delivery. It is noted that renal nerve fibers 14 are depicted in
Referring now to
According to some embodiments, one or both of the treatment element 50 and the distal end 44a of the catheter may incorporate a biasing or anchoring mechanism, such as an expandable structure, stent, cage, elastic arrangement, or interlinking mesh arrangement, for example, which is capable of expanding or otherwise creating a biasing force sufficient to facilitate engagement between the treatment element 50 and the inner wall of a vessel.
The balloon arrangement 59 shown in
According to some embodiments, the outer surface of the balloon arrangement 59 incorporates material with a relatively low thermal conductivity (e.g., thermally insulating material) that forms the main body of the balloon arrangement 59. The treatment pattern 54 or pattern segments 54 are formed from relatively high thermally conductive material. In other embodiments, an inner layer of the balloon arrangement 59 may incorporate a polymeric composite material with a low thermal conductivity, and the outer portion of the balloon arrangement 59 may incorporate a patterned or apertured layer comprising a polymeric composite material with a low thermal conductivity. In such embodiments, regions of the inner layer with high thermal conductivity are exposed for thermally treating the inner wall of a target vessel through apertures of the outer layer with low thermal conductivity.
In some embodiments, the outer balloon 59a may have a generally cylindrical outer profile. In other embodiments, the profile of the outer balloon 59a may have a fluted, wave, or other complex shape that is configured to contact a vessel's inner wall at longitudinally and circumferentially spaced-apart locations. Each of these contact locations of the outer balloon 59a preferably incorporates a treatment pattern segment or segments, and the effective coverage area (e.g., area of pattern structure or void) of the treatment pattern segments preferably completes at least one revolution or turn of the outer balloon 59a.
According to other embodiments, as shown in
According to one denervation therapy delivery approach, the dual balloon treatment element 50 illustrated in
A cryogen may be used to pressurize the inner balloon 59b which causes thermal cooling/freezing of renal artery tissue in contact with or located proximate to the bulged portions of the inner balloon 59b. The outer balloon structure surrounding the apertures 54a provides a desired degree of thermal insulation so that tissue surrounding the treatment sites experience reduced or negligible injury.
In another configuration, the outer balloon 59a may include a single slot or multiple slots that alone (in the case of a single slot) or collectively (in the case of multiple slots) completes at least one revolution or turn of the outer balloon 59a. When inflated, portions of the inner balloon 59b bulge at least partially into the slot or slots.
The embodiment illustrated in
As is best seen in
It is understood that other types of treatment agents may be delivered using a single or multiple balloon and/or catheter implementation for denervating the renal artery in accordance with embodiments of the invention. For example, a thermal transfer fluid that is heated to a sufficiently high temperature (e.g., greater and 50° C.) to disrupt or terminate renal sympathetic nerve activity may be used. A drug eluting or perfusion balloon, such as a weeping balloon or a drug coated balloon, may be used to facilitate delivery of a neurotoxin or venom to the renal artery to disrupt or terminate renal sympathetic nerve activity. In some configurations, the outer balloon 59a (or sleeve/sheath) may include permeable or porous wall portions through which a pharmacological agent or venom may be communicated. The pharmacological agent or venom may be communicated through the permeable wall portions by a pressurized source, such as an inner balloon 59b or inner catheter or lumen of the balloon structure.
Another view of the treatment element 50 illustrated in
The treatment element configurations shown in
The treatment element embodiment shown in
In other embodiments, the membrane 67 is formed from a permeable material through which a pharmacological agent or venom may pass. In such embodiments, the inner balloon 59b need not be a cryoballoon, but may instead be configured as a drug eluting balloon.
Pressurization of the biasing balloon 59a forces the treatment balloon or lumen 59b to move in a radially outward direction and toward the inner wall of a target vessel. In a configuration that employs a treatment balloon 59b, inflation of the treatment balloon 59b enhances direct or indirect contact between the treatment balloon 59b and the inner wall of the target vessel.
The treatment element 50 of the catheter shown in
Embodiments of the present invention may be implemented to provide varying degrees of denervation therapy to innervated renal vasculature. For example, embodiments of the present invention 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 present invention. 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
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 present invention 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 present invention 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 present invention 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 present invention 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 present invention.
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.
As discussed above in accordance with various embodiments, denervation therapy may be delivered to innervated renal vasculature using a treatment arrangement that incorporates a cryoballoon 50. Renal denervation therapy may be controlled to achieve a desired degree of attenuation in renal nerve activity in accordance with embodiments of the present invention. Selecting or controlling cryotherapy delivered by a cryoballoon catheter of the present invention advantageously facilitates experimentation and titration of a desired degree and permanency of renal sympathetic nerve activity cessation.
For example, renal nerve fiber regeneration and re-innervation may be permanently compromised by applying cryogenic therapy to innervated renal vasculature, including the ostium of the renal artery and renal ganglia, at a sufficiently low temperature to allow ice crystals to form inside nerve fibers 14b. Formation of ice crystals inside nerve fibers 14b of innervated renal arterial tissue and renal ganglia tears the nerve cells apart, and physically disrupts or separates the endoneurium tube, which can prevent regeneration and re-innervation processes. Delivery of cryogenic therapy to renal nerves 14 at a sufficiently low temperature in accordance with embodiments of the present invention can cause necrosis of renal nerve fibers 14b, resulting in a permanent and irreversible loss of the conductive function of renal nerve fibers 14b.
In general, embodiments of a cryoballoon catheter of the present invention may be implemented to deliver cryogenic therapy to cause renal denervation at therapeutic temperatures ranging between approximately 0° C. and approximately −180° C. For example, embodiments of a cryoballoon catheter may be implemented to deliver cryogenic therapy to cause renal denervation with temperatures at the renal nerves ranging from approximately 0° C. to approximately −30° C. at the higher end, and to about −140° C. to −180° C. at the lower end. Less robust renal nerve damage is likely for temperatures approaching and greater than 0° C., and more robust acute renal denervation is likely for temperatures approaching and less than −30° C., for example, down to −120 C to −180 C. These therapeutic temperature ranges may be determined empirically for a patient, a patient population, or by use of human or other mammalian studies.
It has been found that delivering cryotherapy to the renal artery and the renal ganglia at a sufficiently low temperature with freeze/thaw cycling allows ice crystals to form inside nerve fibers 14b and disrupt renal nerve function and morphology. For example, achieving therapeutic temperatures that range from −30° C. to +10° C. at a renal nerve for treatment times of 30 seconds to 4 minutes and thaw times of about 1 to 2 minutes has been found to cause acute renal denervation in at least some of the renal nerves in a porcine model.
The representative embodiments described below are directed to cryocatheter apparatuses that can be configured for delivering cryogenic therapy to renal vasculature at specified therapeutic temperatures or temperature ranges, causing varying degrees of nerve fiber degradation. As was discussed above, therapeutic temperature ranges achieved by cryocatheters (e.g., cryoballoon catheters) of the present invention may be determined using non-human mammalian studies. The therapeutic temperatures and degrees of induced renal nerve damage described in the context of the following embodiments are based largely on cryoanalgesia studies performed on rabbits (see, e.g., L. Zhou et al., Mechanism Research of Cryoanalgesia, Neurological Research, Vol. 17, pp. 307-311 (1995)), but may generally be applicable for human renal vasculature. As is discussed below, the therapeutic temperatures and degrees of induced renal nerve damage may vary somewhat or significantly from those described in the context of the following embodiments based on a number of factors, including the design of the cryotherapy apparatus, duration of cryotherapy, and the magnitude of mechanical disruption of nerve fiber structure that can be achieved by subjecting renal nerves to freeze/thaw cycling, among others.
In accordance with various embodiments, a cryoballoon catheter of the present invention may be implemented to deliver cryogenic therapy to cause a minimum level of renal nerve damage. Cooling renal nerve fibers to a therapeutic temperature ranging between about 0° C. and about −20° C. is believed sufficient to temporarily block some or all renal sympathetic nerve activity and cause a minimum degree of renal nerve damage, consistent with neurapraxia for example. Freezing renal nerves to a therapeutic temperature of −20° C. or higher may not cause a permanent change in renal nerve function or morphology. At therapeutic temperatures of −20° C. or higher, slight edema and myelin swelling may occur in some of the renal nerve fibers, but these conditions may be resolved after thawing.
In other embodiments, cooling renal nerve fibers to a therapeutic temperature ranging between about −20° C. and about −60° C. is believed sufficient to block all renal sympathetic nerve activity and cause an intermediate degree of renal nerve damage, consistent with axonotmesis (and possibly some degree of neurotmesis for lower temperatures of the −20° C. and −60° C. range), for example. Cooling renal nerves to a therapeutic temperature of −60° C. may cause freezing degeneration and loss of renal nerve conductive function, but may not result in a permanent change in renal nerve function or morphology. However, renal nerve regeneration is substantially slowed (e.g., on the order of 90 days). At a therapeutic temperature of −60° C., the frozen renal nerve is likely to demonstrate edema with thickening and loosening of the myelin sheaths and irregular swelling of axons, with Schwann cells likely remaining intact.
In further embodiments, cooling renal nerve fibers to a therapeutic temperature ranging between about −60° C. and about −100° C. is believed sufficient to block all renal sympathetic nerve activity and cause an intermediate to a high degree of renal nerve damage, consistent with neurotmesis, for example. Cooling renal nerves to a therapeutic temperature of −100° C., for example, causes swelling, thickening, and distortion in a large percentage of axons. Exposing renal nerves to a therapeutic temperature of −100° C. likely causes splitting or focal necrosis of myelin sheaths, and microfilament, microtubular, and mitochondrial edema. However, at a therapeutic temperature of −100° C., degenerated renal nerves may retain their basal membranes, allowing for complete recovery over time. Although substantially slowed (e.g., on the order of 180 days), renal nerve regeneration may occur and be complete.
In accordance with other embodiments, cooling renal nerve fibers to a therapeutic temperature of between about −140° C. and about −180° C. is believed sufficient to block all renal sympathetic nerve activity and cause a high degree of renal nerve damage, consistent with neurotmesis for example. Application of therapeutic temperatures ranging between about −140° C. and about −180° C. to renal nerve fibers causes immediate necrosis, with destruction of basal membranes (resulting in loss of basal laminea scaffolding needed for complete regeneration). At these low temperatures, axoplasmic splitting, axoplasmic necrosis, and myelin sheath disruption and distortion is likely to occur in most renal nerve fibers. Proliferation of collagen fibers is also likely to occur, which restricts renal nerve regeneration.
It is believed that exposing renal nerves to a therapeutic temperature of about −140° C. or lower causes permanent, irreversible damage to the renal nerve fibers, thereby causing permanent and irreversible termination of renal sympathetic nerve activity. For some patients, exposing renal nerves to a therapeutic temperature ranging between about −120° C. and about −140° C. may be sufficient to provide similar permanent and irreversible damage to the renal nerve fibers, thereby causing permanent and irreversible cessation of renal sympathetic nerve activity. In other patients, it may be sufficient to expose renal nerves to a therapeutic temperature of at least −30° C. in order to provide a desired degree of renal sympathetic nerve activity cessation.
In preferred embodiments, it is desirable that the cryogen used to deliver cryotherapy to renal vasculature be capable of freezing target tissue so that nerve fibers innervating the renal artery 12 are irreversibly injured, such that nerve conduction along the treated renal nerve fibers is permanently terminated. Suitable cryogens include those capable of cooling renal nerve fibers and renal ganglia to temperatures of at least about −120° C. or lower, preferably to temperatures of at least about −130° C. or lower, and more preferably to temperatures of at least about −140° C. or lower. It is understood that use of cryogens that provide for cooling of renal nerve fibers and renal ganglia to temperatures of at least about −30° C. may effect termination of renal sympathetic nerve activity with varying degrees of permanency.
The temperature ranges and associated degrees of induced renal nerve damage described herein are provided for non-limiting illustrative purposes. Actual therapeutic temperatures and magnitudes of resulting nerve injury may vary somewhat or significantly from those described herein, and be impacted by a number of factors, including patient-specific factors (e.g., the patient's unique renal vasculature and sympathetic nervous system characteristics), therapy duration, frequency and duration of freeze/thaw cycling, structural characteristics of the cryotherapy catheter and/or balloon arrangement, type of cryogen used, and method of delivering cryotherapy, among others.
It is believed that higher degrees of renal nerve injury may be achieved by subjecting renal nerves to both cryotherapy and freeze/thaw cycling when compared to delivering cryotherapy without employing freeze/thaw cycling. Implementing freeze/thaw cycling as part of cryotherapy delivery to renal nerves may result in achieving a desired degree of renal sympathetic nerve activity attenuation (e.g., termination) and permanency (e.g., irreversible) at therapeutic temperatures higher than those discussed above. Various thermal cycling parameters may be selected for, or modified during, renal denervation cryotherapy to achieve a desired level of renal nerve damage, such parameters including the number of freeze/thaw cycles, high and low temperature limits for a given freeze/thaw cycle, the rate of temperature change for a given freeze/thaw cycle, and the duration of a given freeze/thaw cycle, for example. As was previously discussed, these therapeutic temperature ranges and associated degrees of induced renal nerve damage may be determined empirically for a particular patient or population of patients, or by use of human or other mammalian studies.
The foregoing description of the various embodiments of the invention has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of the above teaching. For example, the devices and techniques disclosed herein may be employed in vasculature of the body other than renal vasculature, such as coronary and peripheral vessels and structures. It is intended that the scope of the invention be limited not by this detailed description, but rather by the claims appended hereto.
This application claims the benefit of Provisional Patent Application Ser. No. 61/291,480 filed on Dec. 31, 2009, to which priority is claimed under 35 U.S.C. §119(e), and which is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 61291480 | Dec 2009 | US |
